<?xml version="1.0" encoding="UTF-8"?><rss version="2.0" xmlns:content="http://purl.org/rss/1.0/modules/content/" xmlns:wfw="http://wellformedweb.org/CommentAPI/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:atom="http://www.w3.org/2005/Atom" xmlns:sy="http://purl.org/rss/1.0/modules/syndication/" xmlns:slash="http://purl.org/rss/1.0/modules/slash/" > <channel> <title>Creative Biolabs Complement Therapeutics Blog</title> <atom:link href="https://www.creative-biolabs.com/blog/complement-therapeutics/feed/" rel="self" type="application/rss+xml" /> <link>https://www.creative-biolabs.com/blog/complement-therapeutics</link> <description></description> <lastBuildDate>Wed, 04 Sep 2024 02:24:56 +0000</lastBuildDate> <language>en-US</language> <sy:updatePeriod> hourly </sy:updatePeriod> <sy:updateFrequency> 1 </sy:updateFrequency> <generator>https://wordpress.org/?v=6.3.1</generator> <image> <url>https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2022/02/favicon-150x150.png</url> <title>Creative Biolabs Complement Therapeutics Blog</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics</link> <width>32</width> <height>32</height> </image> <item> <title>Epigenetic and Transcriptional Changes in Complement Genes in Metabolic Dysfunction-Associated Steatosis Liver Disease</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/epigenetic-and-transcriptional-changes-in-complement-genes-in-metabolic-dysfunction-associated-steatosis-liver-disease/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Wed, 04 Sep 2024 02:24:20 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[Complement Gene]]></category> <category><![CDATA[Complement Proteins]]></category> <category><![CDATA[Complement Test]]></category> <category><![CDATA[Diseases]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=378</guid> <description><![CDATA[The complement system is an important component of innate immunity, playing a key role in defending against invading pathogens. It consists of approximately 60 soluble and membrane-bound proteins, including core components, receptors,<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/epigenetic-and-transcriptional-changes-in-complement-genes-in-metabolic-dysfunction-associated-steatosis-liver-disease/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The complement system is an important component of innate immunity, playing a key role in defending against invading pathogens. It consists of approximately 60 soluble and membrane-bound proteins, including core components, receptors, and regulatory factors. Recent comprehensive assessments of <a href="/complement-therapeutics/complement-function-activity-test.htm">complement function</a> have revealed its multifaceted involvement beyond typical immune processes.</span></p> <p><span style="font-size: 15px;">Indeed, the complement system contributes to fundamental physiologic processes. However, age-related changes, defects in <a href="/complement-therapeutics/category-proteins-44.htm">complement proteins</a>, as well as genetic variants, can disrupt complement function, leading to harmful consequences. Additionally, emerging research highlights the significant involvement of the complement system in the progression of metabolic dysfunction-associated steatosis liver disease (MASLD). Despite this pathophysiological link, the interaction between complement and MASLD remains poorly understood.</span></p> <p><span style="font-size: 15px;">Few human MASLD cases have been analyzed, leaving questions unanswered regarding the abundance of complement components in health and disease, and the extent to which they are activated or inhibited in MASLD patients. The debate continues over whether complement activation is enhanced or suppressed in MASLD and whether the level of complement components correlates with the severity of the disease.</span></p> <p><span style="font-size: 15px;"><strong>About MASLD</strong></span></p> <p><span style="font-size: 15px;">MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD), has been redefined to include hepatic steatosis accompanied by cardiometabolic risk factors. This array of histopathologic findings includes what was previously known as nonalcoholic steatohepatitis (NASH), now referred to as metabolic dysfunction-associated steatotic liver disease.</span></p> <p><span style="font-size: 15px;">MASH, the inflammatory subtype of MASLD, poses a significant risk of progression to cirrhosis and hepatocellular carcinoma (HCC). individuals diagnosed with MASH face a higher risk of mortality. The prevalence of MASLD has surged alongside the global obesity epidemic, with approximately 25-30% of the adult population worldwide currently affected. Projections suggest that by 2040, more than half of all adults may be affected by MASLD.</span></p> <p><span style="font-size: 15px;">The progression of MASLD is influenced by a variety of factors, including diet, lifestyle choices, and the composition of the gut microbiome, all of which contribute to aberrant epigenetic modifications that drive disease progression. DNA methylation is a relatively stable epigenetic mechanism that regulates gene expression. Typically, hypermethylation silences gene expression, while hypomethylation activates it.</span></p> <p><span style="font-size: 15px;">Therefore, studying the DNA methylome is crucial for identifying biomarkers associated with disease progression and for screening potential therapeutic targets. Research conducted on human liver specimens has revealed an association between MASLD and abnormal DNA methylation patterns.</span></p> <p><span style="font-size: 15px;"><strong>DNA Methylome Analysis Reveals Epigenetic Alteration of Complement Genes in MASLD</strong></span></p> <p><span style="font-size: 15px;">Researchers from the Korea Institute of Life Sciences and Technology recently published a study demonstrating that epigenetic alterations in complement genes are correlated with the severity of MASLD. This research provides valuable insights into the mechanisms driving the progression of MASLD and suggests that inhibiting the function of certain complement proteins may offer a promising strategy for treating this condition.</span></p> <p><span style="font-size: 15px;">Blocking the complement system shows potential as a strategy to halt the progression of MASLD. However, the exact interaction between complement dysregulation and MASLD remains to be fully elucidated. This integrative approach aims to explore the potential association between complement dysregulation and the histologic severity of MASLD.</span></p> <p><span style="font-size: 15px;">The investigators obtained liver biopsy specimens from a cohort of 106 Koreans, including 31 controls, 17 patients with isolated steatosis, and 58 patients with MASH. An in-depth analysis of methylation changes in 61 complement genes was performed using the Infinium Methylation EPIC array. Quantitative RT-PCR and pyrophosphate sequencing were used to detect the expression and methylation status of 9 complement genes in a mouse MASH model.</span></p> <p style="text-align: center;"><img decoding="async" fetchpriority="high" class="aligncenter wp-image-380" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/09/2024090401.png" alt="" width="390" height="370" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/09/2024090401.png 317w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/09/2024090401-300x285.png 300w" sizes="(max-width: 390px) 100vw, 390px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 Schematic diagram of the experimental design for expression and methylation analysis of complement genes.<sup>1</sup></span></p> <p><span style="font-size: 15px;">Methylome and transcriptome analyses of liver biopsies showed that hypermethylation and down-regulation of <a href="/complement-therapeutics/category-complement-c1r-512.htm">complement C1R</a>, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation and up-regulation of <a href="/complement-therapeutics/category-complement-c5a-receptor-1-c5ar1-565.htm">complement C5AR1</a>, C7, and CD59, were correlated with the histological severity of MASLD. In addition, DNA methylation and the relative expression of these nine complement genes in the MASH diet mouse model were consistent with the findings in human data. This study demonstrates a correlation between epigenetic alterations in complement genes and the severity of MASLD, providing valuable insights into the mechanisms driving the progression of the disease. It also suggests that inhibiting certain complement proteins could be a promising strategy for the treatment of MASLD.</span></p> <p style="text-align: center;"><img decoding="async" class="aligncenter wp-image-381" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/09/2024090402.png" alt="" width="687" height="165" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/09/2024090402.png 520w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/09/2024090402-300x72.png 300w" sizes="(max-width: 687px) 100vw, 687px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 2 Expression patterns of 9 complement genes in cells.<sup>1</sup></span></p> <p><span style="font-size: 15px;">In summary, this study is the first to reveal the epigenetic and transcriptional changes in hepatic complement genes during the progression of MASLD. These findings have significant implications for understanding the core mechanisms of MASLD progression and for developing targeted therapies.</span></p> <p><span style="font-size: 15px;">With state-of-the-art technology and extensive experience, Creative Biolabs is the trusted choice for <a href="/complement-therapeutics/complement-genetic-test.htm">complement genetic tests</a>. We provide the highest standards in genetic testing, utilizing the latest technology, strict quality control, and unparalleled service and reliability.</span></p> <p><span style="font-size: 15px;">Reference:<br /> 1. Magdy, Amal, <em>et al</em>. “DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease.” <em>Clinical and Molecular Hepatology</em> (2024).</span></p> ]]></content:encoded> </item> <item> <title>A New Theory of Immune Complement-Mediated Synaptic Loss in Alzheimer’s Disease</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/a-new-theory-of-immune-complement-mediated-synaptic-loss-in-alzheimers-disease/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Fri, 02 Aug 2024 06:02:47 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[Complement Proteins]]></category> <category><![CDATA[Complement Therapy]]></category> <category><![CDATA[Nervous System Diseases]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=368</guid> <description><![CDATA[The immune complement system is a crucial component of the body’s intrinsic immunity, playing roles such as regulating immune responses and clearing pathogens. A growing body of research suggests that the complement system is aberrantly<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/a-new-theory-of-immune-complement-mediated-synaptic-loss-in-alzheimers-disease/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The immune complement system is a crucial component of the body’s intrinsic immunity, playing roles such as regulating immune responses and clearing pathogens. A growing body of research suggests that the <a href="/complement-therapeutics/complement-system.htm"><u>complement system</u></a> is aberrantly activated in the Alzheimer’s disease (AD) brain and may play a critical role in synaptic loss and cognitive impairment. In various AD mouse models, aberrant activation of complement-dependent synaptic pruning processes causes excessive synaptic clearance, ultimately leading to synaptic loss and impaired learning and memory. This paper summarizes and discusses several key scientific issues in the process of complement-mediated synapse loss in the AD brain.</span></p> <p><span style="font-size: 15px;"><strong><b>Sources of </b></strong><a href="/complement-therapeutics/category-proteins-44.htm"><strong><u><b>C</b></u></strong><strong><u><b>omplement </b></u></strong><strong><u><b>P</b></u></strong><strong><u><b>roteins</b></u></strong></a><strong><b> </b></strong><strong><b>L</b></strong><strong><b>abeled at </b></strong><strong><b>S</b></strong><strong><b>ynapses</b></strong></span></p> <p><span style="font-size: 15px;">The current study shows that the levels of complement proteins C1q and C3 are significantly elevated in the brains of AD model mice and AD patients. Animal experiments have shown that complement proteins are mainly derived from microglia and astrocytes. So how do complement proteins of glial cell origin, localize to synapses? The current study suggests at least two possibilities: first, targeted transport via extracellular vesicles such as exosomes; and second, specific binding by recognizing receptors on the synapse. Furthermore, in addition to transfer from glial cells, complement proteins on synapses may also be synthesized locally, i.e., within neurons or synapses. For example, mRNA expression of almost all classical complement pathway proteins (from complement C1q to <a href="/complement-therapeutics/category-complement-c9-539.htm"><u>c</u><u>omplement</u><u> </u><u>C9</u></a>) is significantly upregulated in neurons of the brains of AD patients compared with non-AD aged individuals.</span></p> <p><span style="font-size: 15px;"><strong><b>Complement </b></strong><strong><b>P</b></strong><strong><b>roteins </b></strong><strong><b>L</b></strong><strong><b>abel </b></strong><strong><b>S</b></strong><strong><b>ynapses to </b></strong><strong><b>T</b></strong><strong><b>rigger </b></strong><strong><b>Excessive P</b></strong><strong><b>runing</b></strong></span></p> <p><span style="font-size: 15px;">Pathological protein components such as Aβ and hyperphosphorylated tau proteins can lead to overactivation of the complement system and consequent deposition at the synapse. Metabotropic glutamate receptors (mGluR1/5), transcription factors, mitochondrial oxidative stress, and apoptotic cascade responses may be involved. For example, it was found that amyloid injection in the CA1 region of the rat hippocampus caused elevated levels of C1q and increased microglia pruning in synaptosomes, ultimately leading to synaptic loss and learning memory impairments; inhibition or knockdown of mGluR1 reversed these phenomena, whereas mGluR1 agonists exacerbated these phenotypes.</span></p> <p><img decoding="async" class="aligncenter wp-image-370" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080101.png" alt="" width="445" height="493" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080101.png 922w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080101-271x300.png 271w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080101-768x850.png 768w" sizes="(max-width: 445px) 100vw, 445px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 Factors causing synapses to be labeled by complement.<sup>1</sup></span></p> <p><span style="font-size: 15px;"><strong><b>How </b></strong><strong><b>S</b></strong><strong><b>ynapses </b></strong><strong><b>L</b></strong><strong><b>abeled by </b></strong><strong><b>C</b></strong><strong><b>omplement </b></strong><strong><b>A</b></strong><strong><b>re </b></strong><strong><b>C</b></strong><strong><b>leared</b></strong></span></p> <p><span style="font-size: 15px;">Complement-labeled synapses in AD are cleared mainly through phagocytosis by glial cells. Phagocytosis of complement-labeled synapses by microglia has been widely reported, while astrocytes can also phagocytose synapses through the MEGF10 and MERTK pathways. In addition, oligodendrocyte precursor cells can also phagocytose synapses, though whether this process is complement-dependent requires further investigation. Molecules secreted by cerebrovascular endothelial cells and pericytes may induce synaptic pruning by microglia. Recent studies have also found that the CD4+ T cell population in the brain is critical for synaptic pruning in microglia. Since blood-brain barrier dysfunction occurs early in AD, peripheral immune cells may infiltrate the brain and modulate complement-dependent synaptic pruning. The effect of these immune cells on complement-dependent synaptic pruning is an important area for future research that could provide new perspectives for understanding the mechanisms of synaptic loss in AD and help develop new therapeutic strategies.</span></p> <p><span style="font-size: 15px;"><strong><b>Involvement of AD </b></strong><strong><b>R</b></strong><strong><b>isk </b></strong><strong><b>F</b></strong><strong><b>actors</b></strong></span></p> <p><span style="font-size: 15px;">Multiple AD risk factors may be involved in complement-mediated synaptic pruning. For example, reports have found that the AD risk gene TREM2, which binds to <a href="/complement-therapeutics/complement-c1q-binding-assays.htm"><u>complement</u><u> </u><u>C1q</u></a>, protects synapses from pruning. Aging, the greatest risk factor for AD, and reduced levels of Progranulin (PGRN) may promote synaptic pruning by increasing the production of C1q in microglia, which in turn exacerbates synaptic loss. Sex differences in AD risk are also evident, with females being more susceptible to AD. This susceptibility is likely related to the dramatic postmenopausal decline in estrogen that leads to increased levels of S-nitrosylated C3 (SNO-C3). The rise in SNO-C3 exacerbates synaptic pruning and synaptic loss in women with AD. In conclusion, there is growing evidence of a possible interaction between the complement system and AD risk factors during synaptic loss. Understanding the role of these risk factors in complement-dependent synaptic pruning will provide new insights into the pathogenesis of AD and potential therapeutic targets.</span></p> <p><img decoding="async" loading="lazy" class="aligncenter wp-image-371" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080102.png" alt="" width="485" height="338" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080102.png 1100w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080102-300x209.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080102-1024x715.png 1024w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/08/2024080102-768x536.png 768w" sizes="(max-width: 485px) 100vw, 485px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 2 Different cell types and AD risk factors are involved in complement-mediated synaptic pruning in AD.<sup>1</sup></span></p> <p><span style="font-size: 15px;">Despite the growing body of evidence from animal experiments supporting complement-mediated synaptic loss in AD, more in-depth studies of specific cellular and molecular mechanisms are needed to develop effective therapeutic treatments. Due to the limitations of animal models in mimicking the complexity of human AD, the use of human cellular models such as induced pluripotent stem cells and brain-like organoids can provide a more comprehensive study of complement-mediated synaptic loss in a context more closely resembling the human brain.</span></p> <p><span style="font-size: 15px;">Reference:</span></p> <ol> <li><span style="font-size: 15px;">Wen, Lang, Danlei Bi, and Yong Shen. “Complement-mediated synapse loss in Alzheimer’s disease: mechanisms and involvement of risk factors.” <em><i>Trends in Neurosciences</i></em>(2024).</span></li> </ol> ]]></content:encoded> </item> <item> <title>Aging Promotes a Functional Shift in C1q Secreted by Microglia</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/aging-promotes-a-functional-shift-in-c1q-secreted-by-microglia/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Mon, 01 Jul 2024 08:19:12 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[C1q]]></category> <category><![CDATA[Complement Test]]></category> <category><![CDATA[Complement Therapy]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=360</guid> <description><![CDATA[Microglia-neuron interactions regulate brain development, maturation, homeostasis, and disease genesis. The innate immune complement component C1q, produced and secreted by microglia, has brain function specificity. C1q acts as an initiating molecule for<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/aging-promotes-a-functional-shift-in-c1q-secreted-by-microglia/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Microglia-neuron interactions regulate brain development, maturation, homeostasis, and disease genesis. The innate immune <a href="/complement-therapeutics/complement-therapeutic-target-c1q.htm">complement component C1q</a>, produced and secreted by microglia, has brain function specificity. C1q acts as an initiating molecule for the classical complement pathway and mediates synaptic pruning related to development and disease. Interestingly, in the aging brains of humans and rodents, <a href="/complement-therapeutics/category-complement-c1q-509.htm">C1q protein</a> levels are significantly upregulated, while other complement proteins remain at lower levels. This suggests that C1q may have an age-dependent function that is independent of the classical complement pathway.</span></p> <p><span style="font-size: 15px;">During aging, C1q accumulates throughout the brain parenchyma, synapses, and GABAergic interneurons. In C1q-deficient mice (C1qKO), synaptic plasticity is enhanced in the hippocampal regions, ameliorating cognitive and memory decline. However, the knockdown of C1q enhances plasticity without resulting in synaptic pruning mediated by the complement pathway. In the cortex of aging animals, C1q is distributed within neuronal synaptic terminals, axons, and dendrites, suggesting that the age-dependent function of C1q may be mediated through neurons.</span></p> <p><span style="font-size: 15px;">On June 27, 2024, Beth Stevens’ team at the Center for Neurobiology at Boston Children’s Hospital published an article in <em><i>Cell</i></em> titled “Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain.” They found that microglia-derived C1q regulates the translation of specific mRNAs in a phase-separated manner by integrating into neuronal ribonucleoprotein (RNP) complexes, impacting protein homeostasis and cognitive function in the aging brain.</span></p> <p><span style="font-size: 15px;"><strong><b>Microglia-</b></strong><strong><b>S</b></strong><strong><b>ecreted C1q Co-localizes with Neuronal RNP Complexes in an Age-Dependent Manner</b></strong></span></p> <p><span style="font-size: 15px;">Scientists isolated synaptosomes from developing (5 days), adult (2-3 months), and aged (1 year) mice and analyzed them by mass spectrometry after immunoprecipitation with a <a href="/complement-therapeutics/category-complement-c1q-509.htm">C1q antibody</a> (C1q-IP). They found that C1q protein interactions changed dramatically during the aging process. Specifically, during development, C1q mainly interacted with extracellular functional proteins, whereas during aging, C1q primarily interacted with intracellular active proteins. Further experiments revealed that C1q was enriched in ribosomes and interacted with the ribosomal protein RPL10a.</span></p> <p><span style="font-size: 15px;">Immunofluorescence revealed distinct punctate C1q signals within the neuronal cytosol, and these signals were more localized to neurons in an age-dependent manner. Using mice with fluorescently labeled neuronal ribosomes to examine the interaction between <a href="/complement-therapeutics/complement-c1q-binding-assays.htm">complement C1q</a> and RNP complexes within neurons, the team found that C1q co-localized with the neuronal RNP complexes.</span></p> <p style="text-align: center;"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-362" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/1.png" alt="" width="910" height="709" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/1.png 910w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/1-300x234.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/1-768x598.png 768w" sizes="(max-width: 910px) 100vw, 910px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 C1q co-localizes with neuronal RNP complexes in an age-dependent manner.<sup>1</sup></span></p> <p><span style="font-size: 15px;"><strong><b>C1q-RNP Complexes Regulate mRNA Translation by Liquid-Liquid Phase Separation</b></strong></span></p> <p><span style="font-size: 15px;">Liquid-liquid phase separation (LLPS) occurs when the collagen-like domain of C1q interacts with the RNP complex. LLPS droplets can form when purified C1q protein binds to RNA isolated from human brain tissue, and these droplets disappear after treatment with RNase, suggesting that droplet formation depends on both C1q and RNA. Further experiments revealed that exogenous C1q protein integrates into the neuronal RNP complex in an endocytosis-dependent manner.</span></p> <p><span style="font-size: 15px;">Using WT and C1qKO littermates, the team examined the effect of knocking out C1q on neuronal mRNA translation <em><i>in vivo</i></em><em><i> </i></em>at different ages. No significant differences in neuronal mRNA translation <em><i>in vivo</i></em> were detected during the developmental stage (5 days) and adulthood (2-3 months). However, in old age (1 year), C1qKO mice showed significant changes in mRNA translation compared to their WT littermate.</span></p> <p style="text-align: center;"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-363" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/2.png" alt="" width="773" height="639" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/2.png 773w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/2-300x248.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/2-768x635.png 768w" sizes="(max-width: 773px) 100vw, 773px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 2 C1q-RNP complexes regulate mRNA translation by liquid-liquid phase separation.<sup>1</sup></span></p> <p><span style="font-size: 15px;"><strong><b>Microglia-Derived C1q Affects Protein Translation and Fear Memory Dissolution in an Age-Dependent Manner</b></strong></span></p> <p><span style="font-size: 15px;">Whole-brain proteomic analysis revealed significant differences in protein content between the brain tissues of WT and C1qKO littermates. The brain tissues of WT mice were enriched in Septin complex-associated proteins, which regulate dendritic spine formation, axon growth, synaptic vesicle release, and ion channel localization. In contrast, C1qKO mouse brain tissue was enriched in mitochondrial proteins. An examination of learning and memory capacity in aged WT and C1qKO littermate mice found that microglia-specific knockdown of C1q did not affect the acquisition and extraction of fear memories but significantly inhibited the dissipation of fear memories.</span></p> <p style="text-align: center;"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-364" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/3.png" alt="" width="960" height="595" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/3.png 960w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/3-300x186.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/07/3-768x476.png 768w" sizes="(max-width: 960px) 100vw, 960px" /></p> <p style="text-align: center;"> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 3 Microglia-derived C1q affects protein translation and fear memory dissipation in an age-dependent manner.<sup>1</sup></span></p> <p><span style="font-size: 15px;">This study found that microglia-derived C1q integrates into neuronal RNP complexes in an age-dependent manner, regulating neuronal protein translation and homeostasis, thereby affecting cognitive function in the aging brain.</span></p> <p><span style="font-size: 15px;">Reference:</span></p> <ol> <li><span style="font-size: 15px;">Scott-Hewitt, Nicole, <em><i>et al</i></em>. “Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain.” <em><i>Cell</i></em>(2024).</span></li> </ol> ]]></content:encoded> </item> <item> <title>Intestinal Complement System Can Coexist with Symbiotic Bacteria and Resist Pathogens</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/intestinal-complement-system-can-coexist-with-symbiotic-bacteria-and-resist-pathogens/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Tue, 04 Jun 2024 05:58:51 +0000</pubDate> <category><![CDATA[C3 Molecules]]></category> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[Complement C3]]></category> <category><![CDATA[Complement Test]]></category> <category><![CDATA[Complement Therapy]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=354</guid> <description><![CDATA[The complement system is a primary barrier of the innate immune defense system formed by a series of proteins working in a highly coordinated manner to defend against microbial invasion of host tissues. In<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/intestinal-complement-system-can-coexist-with-symbiotic-bacteria-and-resist-pathogens/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The complement system is a primary barrier of the innate immune defense system formed by a series of proteins working in a highly coordinated manner to defend against microbial invasion of host tissues. In the late 19th century, Jules Bordet discovered the complement system in the blood, for which he was awarded the Nobel Prize in Physiology and Medicine in 1919. Over the next hundred years, more <a href="https://www.creative-biolabs.com/complement-therapeutics/complement-component-protein.htm"><u>complement</u><u> </u><u>components</u></a> were discovered, with the complement protein C3 being recognized as the core protein where the three activation pathways (the classical pathway, the lectin pathway, and the alternative pathway) converge.</span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/complement-therapeutics/category-complement-c3-519.htm"><u>C3 protein</u></a> has long been thought to be produced primarily by hepatocytes, with the complement system functioning mainly in the blood and interstitial fluids. But does the complement system exist in the human gut, which is densely populated with microorganisms, including bacteria, archaea, fungi, protozoa, and viruses? If it exists, how does the complement system establish a harmonious coexistence with the commensal microbiota, and how does it deal with pathogens?</span></p> <p><span style="font-size: 15px;">Dennis Kasper’s research team at Harvard Medical School published a paper in <em><i>Cell</i></em> entitled “Gut complement induced by the microbiota combats pathogens and spares commensals. “The paper reveals the existence of a separate complement system in the intestine that is distinct from the blood complement system. By selectively expressing specific complement components, the intestinal complement system can work in harmony with intestinal commensal bacteria while acting as a defense against pathogens.</span></p> <p><span style="font-size: 15px;"><strong><b>Study of the Complement System in the Gut</b></strong></span></p> <p><span style="font-size: 15px;">The team explored the intestinal environment to determine whether a complement system exists within it and how it operates in a microbial symbiotic environment.</span></p> <ul> <li><span style="font-size: 15px;">Using a sterile mouse model, the team demonstrated that intestinal C3 levels are regulated by the microbiota through gut microbial transplantation experiments.</span></li> <li><span style="font-size: 15px;">Using single-cell RNA sequencing, the researchers found that intestinal stromal cells are the main C3-expressing cells in the gut, predominantly located in colonic lymphoid follicles.</span></li> <li><span style="font-size: 15px;">By establishing an <em><i>in vitro </i></em>culture system, the researchers demonstrated that primary intestinal stromal cells can sense microbial signals and secrete C3.</span></li> <li><span style="font-size: 15px;">The researchers verified this finding in humans by testing and analyzing human intestinal samples, discovering that intestinal <a href="https://www.creative-biolabs.com/complement-therapeutics/complement-c3-functional-test.htm"><u>C3 </u><u>tests</u></a> in humans vary depending on individual intestinal flora.</span></li> <li><span style="font-size: 15px;">Further studies found that colonization of the gut with <em><i>Prevotella spp. </i></em>increased C3 levels, suggesting that gut C3 levels can be modulated by regulating the composition of the gut microflora.</span></li> </ul> <p><span style="font-size: 15px;">Their subsequent study revealed the mechanism of action of the intestinal complement system. During the infection stage of intestinal pathogens, the intestinal complement system activates C3 mainly through alternative pathways to generate C3b, which binds to pathogens. At the same time, C3b binds to <a href="https://www.creative-biolabs.com/complement-therapeutics/complement-receptors-of-complement-system.htm"><u>complement receptors</u></a> on neutrophils, leading to the phagocytosis of pathogens by neutrophils.</span></p> <p><span style="font-size: 15px;">It has been shown that in the intestinal complement system, the expression levels of C5-C9, which form the <a href="https://www.creative-biolabs.com/complement-therapeutics/membrane-attack-complex.htm"><u>membrane</u><u> </u><u>attack complex</u></a>, are extremely low and almost undetectable even during infection. In contrast, the expression of C3 and Cfb, the main proteins of the alternative pathway, was significantly up-regulated during infection. Thus, the intestinal complement system functions mainly through phagocytosis. However, under normal physiological conditions, the number of neutrophils in the gut is relatively limited, so the complement system does not massively phagocytose the commensal microbiota in the gut.</span></p> <p><span style="font-size: 15px;">Further studies revealed that the level of C3 in the gut was inversely correlated with the severity of host pathogen infection, offering the possibility of influencing the level of C3 by modulating the intestinal flora to prevent and treat intestinal infections.</span></p> <p><span style="font-size: 15px;">In summary, this study is the first systematic in-depth investigation of the complement system in the intestine. It found that not only does an independent complement system exist in the intestine, but also that by selectively expressing specific complement components, the system achieves harmonious coexistence with the commensal microbial system under the regulation of the intestinal commensal microbiota. Nonetheless, the intestinal complement system is still able to act as a first line of defense for the effective clearance of intestinal pathogens, achieving precise regulation of commensal and pathogen responses.</span></p> <p><img decoding="async" loading="lazy" class="aligncenter wp-image-356" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/06/20240604.png" alt="" width="689" height="689" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/06/20240604.png 1057w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/06/20240604-300x300.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/06/20240604-1024x1024.png 1024w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/06/20240604-150x150.png 150w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/06/20240604-768x768.png 768w" sizes="(max-width: 689px) 100vw, 689px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 Gut complement induced by the microbiota combats pathogens and spares commensals.<sup>1</sup></span></p> <p><span style="font-size: 15px;">This study reveals the function of the complement system on the surface of the intestinal mucosa and provides a new avenue for microbe-targeted precision medicine approaches for the prevention and treatment of intestinal diseases.</span></p> <p><span style="font-size: 15px;">Reference:</span></p> <ol> <li><span style="font-size: 15px;">Wu, Meng, <em><i>et al</i></em>.”Gut complement induced by the microbiota combats pathogens and spares commensals.” <em><i>Cell</i></em> 4 (2024): 897-913.</span></li> </ol> ]]></content:encoded> </item> <item> <title>The Battle Between Tumors and Complement</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/the-battle-between-tumors-and-complement/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Mon, 06 May 2024 07:27:24 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[Complement System]]></category> <category><![CDATA[Complement Therapy]]></category> <category><![CDATA[Drug Development]]></category> <category><![CDATA[Tumor Immunotherapy]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=345</guid> <description><![CDATA[The complement system, as an important component of the body’s immune system, plays a key role in tumor development and therapy. Tumor immunomodulation by the complement system has a dual role in<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/the-battle-between-tumors-and-complement/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The complement system, as an important component of the body’s immune system, plays a key role in tumor development and therapy. Tumor immunomodulation by the complement system has a dual role in tumor development: while it may promote tumor growth, metastasis, and immune escape, it also has potential anti-tumor effects. The complex interactions between the complement system and the tumor microenvironment, as well as complement modulators, hold great promise for application in tumor therapy. Future studies will continue to explore the new findings regarding the complement system’s role in tumors and translate these discoveries into clinical practice for more effective strategies for tumor therapy.</span></p> <p><span style="font-size: 15px;"><strong><b>Introduction to the Complement System</b></strong></span></p> <p><span style="font-size: 15px;">The complement system is a vital and intricate network of proteins within the body’s immune system, boasting numerous physiological functions and immunomodulatory effects. Comprising approximately 30 <a href="/complement-therapeutics/category-proteins-44.htm">complement system proteins</a>, it is categorized into three pathways: the complement activation pathway, regulatory pathway, and membrane attack pathway, forming a complete protective network. The complement system contributes to immune response and body regulation in the following ways:</span></p> <ul> <li><span style="font-size: 15px;">Immunoregulation: It promotes inflammatory responses, regulates immune cell activities, and clears bacteria, viruses, and other pathogens, thereby crucially maintaining the body’s internal and external stability and combating infections.</span></li> <li><span style="font-size: 15px;">Inflammatory response: Activation of complement proteins occurs upon encountering invasive pathogens, triggering an inflammatory response This cascade prompts leukocytes to phagocytose and kill the pathogen, while also initiating subsequent immune cell and mediator responses to create the immune reaction.</span></li> <li><span style="font-size: 15px;">Cytolysis: The complement system is also capable of directly disrupting cell membranes, leading to the lysis of pathogens or abnormal cells. This process involves the formation of <a href="/complement-therapeutics/membrane-attack-complex.htm">membrane attack complexes</a> that result in the destructionlysis of the target cell.</span></li> </ul> <p><span style="font-size: 15px;">Overall, the complement system serves not only as an important component of the immune system but also as a crucial regulatory system for fighting infections, maintaining homeostasis, and participating in immune regulation. An in-depth understanding of the complement system’s structure, function, and regulatory mechanisms is imperative for devising therapeutic strategies for related diseases and the diagnosis and treatment of immune diseases.</span></p> <p><span style="font-size: 15px;"><strong><b>The Interaction of Complement with Tumors</b></strong></span></p> <p><span style="font-size: 15px;">In the usual sense, the complement system plays a pivotal role in tumor eradication.</span></p> <ul> <li><span style="font-size: 15px;">Cytolytic effect: The membrane attack complex (MAC) or cytolytic complex formed after complement activation can directly bind to tumor cell surfaces, forming pores to disrupt cell membrane integrity, ultimately leading to tumor cell lysis and death.</span></li> <li><span style="font-size: 15px;">Promote immune cell-mediated anti-tumor effects: An activated complement system can cause the activation and phagocytosis of immune cells such as macrophages and natural killer cells, thus enhancing their ability to eliminate tumor cells.</span></li> <li><span style="font-size: 15px;">Induce apoptosis: Complement system activation can also induce apoptosis, or programmed cell death, through a series of signaling pathways, thereby limiting the proliferation and dissemination of tumor cells.</span></li> </ul> <p><span style="font-size: 15px;">1. Interaction with Immune Cells</span></p> <p><span style="font-size: 15px;">Complement proteins can activate macrophages, recruit them to tumor tissue, and induce macrophage polarization while inhibiting macrophage inflammatory vesicle activation. Additionally, complement system activation induces the accumulation and differentiation of neutrophils within tumors and promotes their neutrophil recruitment by stimulating the release of leukotriene B4 (LTB4) from epithelial and endothelial cells. <a href="/complement-therapeutics/category-complement-c5a-530.htm">Complement C5a</a> acts as a potent chemoattractant for myeloid-derived suppressor cells (MDSCs), fostering their migration to primary tumors. Cancer cell-derived complement C5a recruits MDSCs, thereby creating a favorable immune microenvironment for lung cancer progression. Moreover, tumor-associated fibroblasts expressing C5aR can enhance cancer stem cell (CSC) enrichment and chemoresistance by secreting IL-6 and IL-8 after receiving complement signals.</span></p> <p><span style="font-size: 15px;">Overall, the complement system may be involved in tumor growth promotion by interacting with various immune cells. A comprehensive understanding of these mechanisms will help us to better understand the complexity of tumor development and provide important clues for tumor therapeutic development targeting the complement system.</span></p> <p><img decoding="async" loading="lazy" class=" wp-image-347 aligncenter" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/05/202405061.png" alt="" width="866" height="611" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/05/202405061.png 951w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/05/202405061-300x212.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/05/202405061-768x542.png 768w" sizes="(max-width: 866px) 100vw, 866px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 Complement Activation in the Tumour Microenvironment Promotes Tumorigenesis<sup>1</sup></span></p> <p><span style="font-size: 15px;">2. Neoangiogenesis and Complement</span></p> <p><span style="font-size: 15px;">The effect of complement on tumor angiogenesis is complex and the role of complement components in tumor angiogenesis needs to be further investigated. The following are some possible mechanisms:</span></p> <ul> <li><span style="font-size: 15px;">Promoting inflammatory response: The activated complement system can induce an inflammatory response and trigger a variety of cells to participate in the inflammatory response in the tissues surrounding the tumor. This inflammatory response promotes neoangiogenesis by releasing inflammatory mediators such as VEGF.</span></li> <li><span style="font-size: 15px;">Regulation of cell signaling pathways: The activated complement system regulates angiogenesis by influencing cell signaling pathways in endothelial and other cells, such as PI3K/AKT, MAPK/ERK, and other pathways, thus promoting angiogenesis.</span></li> <li><span style="font-size: 15px;">Enhancement of vascular permeability: Activation of the complement system can change the morphology and function of vascular endothelial cells, increase vascular permeability, provide convenient conditions for new blood vessel formation, and help tumor cells obtain more nutrients and oxygen.</span></li> </ul> <p><span style="font-size: 15px;">3. </span><span style="font-size: 15px;">Thrombosis, Complement, and NETs</span></p> <p><span style="font-size: 15px;">A complex triangular relationship exists between the complement system, thrombosis, and NETosis (neutrophil extranet release), and these interactions have important implications for both tumorigenesis and progression. Activation of the complement system may both promote thrombosis and induce the NETosis process, which in turn are interconnected and jointly involved in shaping the tumor microenvironment.</span></p> <p><span style="font-size: 15px;">First, complement system activation may trigger thrombosis by activating the coagulation cascade, which leads to platelet aggregation and fibrin deposition, forming a thrombus. These thrombi may not only provide structural support within the tumor microenvironment but also shield tumor cells, aiding in immune evasion and resistance to chemotherapy.</span></p> <p><span style="font-size: 15px;">Second, the activation of the complement system also induces NETosis, the release of extracellular networks by neutrophils. These extracellular networks contain DNA, proteins, and cytokines that attract immune cells and mediate inflammatory responses. However, excessive or prolonged NETosis may lead to excessive inflammation and exacerbate the immunosuppressive state of the tumor microenvironment, fostering tumor progression and metastasis.</span></p> <p><span style="font-size: 15px;">Taken together, the interactions between the complement system, thrombosis, and NETosis form a dynamic network with profound effects on the tumor microenvironment.</span></p> <p><img decoding="async" loading="lazy" class="aligncenter wp-image-348" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/05/202405062.png" alt="" width="683" height="389" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/05/202405062.png 633w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/05/202405062-300x171.png 300w" sizes="(max-width: 683px) 100vw, 683px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 2 Summary of the Interplay Between NETosis, Complement Activation, and Coagulation<sup>2</sup></span></p> <p><span style="font-size: 15px;"><strong><b>Complement in Tumor Therapy</b></strong></span></p> <p><span style="font-size: 15px;">1.C1q Complex Inhibitors</span></p> <p><span style="font-size: 15px;">One notable inhibitor is the protease inhibitor <a href="/complement-therapeutics/category-c1-inhibitor-c1-inh-557.htm">C1 inhibitor</a> (C1-INH), FDA-approved for treating hereditary angioedema. C1-INH effectively inhibits the activation of the classical pathway while preserving the functional activation of other initiating pathways. Studies suggest its potential role in the treatment of neuroblastoma.</span></p> <p><span style="font-size: 15px;">2. C5aR1 Antagonists</span></p> <p><span style="font-size: 15px;">The C5aR1 antagonist PMX205, a cyclized hexapeptide, antagonizes the C5a complement receptor. PMX20 treatment significantly reduces the percentage of MDSCs in the colon and blood, while increasing CD8+ T cell percentage in the blood, mucosa-associated lymphoid tissues, and tumors. This results in a significant blockade of colorectal cancer (CRC) growth. Other C5aR antagonists, such as PMX53, effectively reduce tumor size and enhance the efficacy of anticancer chemotherapy in mouse models.</span></p> <p><span style="font-size: 15px;">3. Anti-C5aR1 Antibody</span></p> <p><span style="font-size: 15px;">Avdoralimab (IPH 5401) is a fully human IgGκ monoclonal antibody that targets <a href="/complement-therapeutics/category-complement-c5a-receptor-1-c5ar1-565.htm">complement C5aR1</a>, preventing its interaction with C5a. Used in complement-driven inflammatory diseases and solid tumor studies, avdoralimab is currently investigated in clinical trials in combination with the anti-PD-L1 antibody Durvalumab for the treatment of advanced solid tumors (non-small cell lung cancer and hepatocellular carcinoma).</span></p> <p><span style="font-size: 15px;">Despite advancements, challenges, and limitations remain in understanding the complex network established between complement and tumors. For example, despite our accumulating knowledge about the role of complement in cancer, the activation molecules that trigger the complement cascade in cancer cells are largely unknown. Due to the high heterogeneity of human cancers, different activation pathways and mechanisms may be involved, necessitating tailored strategies for different tumor types. The role of complement at specific stages of tumor progression must also be considered. In summary, complement-related tumor therapeutic strategies remain a promising yet challenging field, offering great hope for a successful fight against cancer.</span></p> <p><span style="font-size: 15px;">References:</span></p> <ol> <li><span style="font-size: 15px;">Reis, Edimara, <em><i>et al</i></em>. “Complement in cancer: untangling an intricate relationship.” <em><i>Nature Reviews Immunology</i></em>18.1 (2018): 5-18.</span></li> <li><span style="font-size: 15px;">de Bont, Cynthia M., Wilbert C. Boelens, and Ger JM Pruijn. “NETosis, complement, and coagulation: a triangular relationship.” <em><i>Cellular & molecular immunology</i></em>1 (2019): 19-27.</span></li> </ol> ]]></content:encoded> </item> <item> <title>Complement Receptor Protein CD35</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/complement-receptor-protein-cd35/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Tue, 02 Apr 2024 03:52:48 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[C3b/C4b]]></category> <category><![CDATA[Complement Receptor]]></category> <category><![CDATA[Complement Therapy]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=335</guid> <description><![CDATA[CD35, also known as complement receptor 1 (CR1), plays a crucial role in the complement system. The complement system is part of the immune system that recognizes and removes pathogens, promotes inflammatory<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/complement-receptor-protein-cd35/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">CD35, also known as <a href="/complement-therapeutics/category-complement-receptor-type-1-cr1-cd35-559.htm">complement receptor 1</a> (CR1), plays a crucial role in the complement system. The complement system is part of the immune system that recognizes and removes pathogens, promotes inflammatory responses, and regulates immune function through a series of cascading reactions. CD35, a type I membrane glycoprotein expressed on the surface of erythrocytes and immune cells, is a central regulator of the classical, lectin, and alternative pathways of the complement system, and is a receptor for C3b/C4b <a href="/complement-therapeutics/category-peptides-46.htm">complement peptides</a>, which binds the complement C4b and C3b fragments and acts on phagocytes to promote the uptake of particles that activate complement by these cells. It is a cell membrane immunoadhesion receptor that plays a key role in the capture and clearance of complement-conditioned pathogens by erythrocytes and monocytes/macrophages, mediating the binding of these cells to particles of activated complement and immune complexes that remove complement from the circulation.</span></p> <p><img decoding="async" loading="lazy" class="aligncenter wp-image-336" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040201.png" alt="" width="451" height="459" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040201.png 727w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040201-295x300.png 295w" sizes="(max-width: 451px) 100vw, 451px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 Cells express complement proteins.<sup>1</sup></span></p> <p><span style="font-size: 15px;"><strong>CD35 Composition and Distribution</strong></span></p> <p><span style="font-size: 15px;">CD35 exists in the following forms: a membrane-bound form, which functions on the cell surface and is involved in the regulation of the complement system, helping to clear immune complexes and C3b/C4b-encapsulated particles from plasma, as well as regulating the inflammatory response. Another form is the non-membrane-bound soluble form of CR1 (sCR1) found in plasma, which is produced by proteolytic cleavage and released into circulation from leukocytes (especially polymorphonuclear leukocytes). It has an immune function in body fluids, binds to complement fragments, and may be involved in the regulation of local immune responses and inflammatory processes. Levels of soluble CD35 may change in certain disease states, making it a potential biomarker for certain pathologies.</span></p> <p><span style="font-size: 15px;">Distribution of CD35: CD35 is mainly found in erythrocytes, CD4+ T cell subsets, mature B cells, follicular dendritic cells, monocytes, and eosinophils.</span></p> <p>For CD35/CR1 research, we can offer the following related products:</p> <ul> <li><a href="/complement-therapeutics/target-cr1-51.htm">CR1 Antibody</a></li> <li><a href="/complement-therapeutics/target-cr1-51.htm">CR1 Protein</a></li> <li><a href="/complement-therapeutics/target-cr1-51.htm">CR1 Assay Kit</a></li> <li><a href="/complement-therapeutics/target-cr1-51.htm">CR1 Peptide</a></li> </ul> <p><span style="font-size: 15px;"><strong>CD35 Structure</strong></span></p> <p><span style="font-size: 15px;">CD35 is a transmembrane protein. The extracellular domain of CD35 consists of 30 short complement regulatory (SCR) structural domains, also known as short consensus repeats, Sushi or complement control protein structural domains. Each SCR structural domain contains 61 amino acid residues with two conserved disulfide bonds and a buried conserved tryptophan residue. Of the CR1 sequences, the first 28 are organized into four long homologous repeat sequences (LHRs), each with seven contiguous SCRs. The functional domains of the CR1 proteins are specifically distributed among the different LHRs. The LHR-A region of CD35 binds predominantly to C4b, whereas the LHR-B and LHR-C regions bind to C3b/C4b and PfEMP1 and have cofactor activity for cofactor I-mediated cleavage of C3b and C4b. The LHR-D region has binding sites for mannose-binding lectin (MBL) and C1q. SCR-25 has binding sites for the Swain-Langley (Sl) and McCoy (McC) Knops blood group antigens in LHR-D. The LHR-D region also has binding sites for the C3b/C4b antigen. Soluble CD35 (sCR1) contains 30 short consensus repeat (SCR) structural domains that are identical to the extracellular domains of CR1, but because sCR1 lacks transmembrane and cytoplasmic tails, it is structurally different from CR1 immobilized on the cell surface.</span></p> <p><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-337" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040202.png" alt="" width="1647" height="447" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040202.png 1647w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040202-300x81.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040202-1024x278.png 1024w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040202-768x208.png 768w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040202-1536x417.png 1536w" sizes="(max-width: 1647px) 100vw, 1647px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 2 The structure, genetic polymorphisms, expression ofCR1/CD35.<sup>2</sup></span></p> <p><span style="font-size: 15px;"><strong>CD35 Signaling Pathway and Regulation</strong></span></p> <p><span style="font-size: 15px;">CD35 is involved in regulatory T cell activation and proliferation: binding of CD35 enhances IL-10 production and reduces IFNγ production, contributing to the transformation of CD4+ T cells into a regulatory T cell (Treg) phenotype. Additionally, the co-binding of CD35 and CD46 synergistically enhances the proliferation of CD4+ T cells. Furthermore, the combination of CD35 and CD46 enhances granzyme B expression in activated CD4+ T cells. Overall, CD35 plays an important role in regulating the function and phenotypic transformation of CD4+ T cells.</span></p> <p><span style="font-size: 15px;">CD35 is also involved in the regulation of complement system activation: it regulates the degradation-accelerating activity (DAA) of C3 and <a href="/complement-therapeutics/complement-therapeutic-target-c5-convertases.htm">C5 convertases</a> of the classical and alternative pathways through its different structural domains (e.g., LHR-A, LHR-B, LHR-C). Different structural domains of CR1 contribute differently to the DAA of C3 and C5 convertases of the classical pathway. For example, for the C3 convertase of the classical pathway, the LHR-A structural domain plays a major role in DAA, while the LHR-B and LHR-C structural domains contribute to a lesser extent. In contrast, for the C5 convertase of the classical pathway, the LHR-A, LHR-B, and LHR-C structural domains are all required, acting synergistically to provide complete activity. Additionally, CR1 exerts cofactor activity (CFA) by binding to C3b and C4b and facilitating cleavage of C3b and C4b by complement factor I. CR1 has more cleavage activity on C3b than on C4b, correlating with its binding affinity for C3b and C4b. Thus, CR1 regulates the activities of C3 and C5 convertases of the classical and alternative pathways through the action of its different structural domains, participating in the regulatory mechanism of the signaling pathway.</span></p> <p><img decoding="async" loading="lazy" class="aligncenter wp-image-338" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040203.png" alt="" width="536" height="453" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040203.png 933w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040203-300x253.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/04/2024040203-768x649.png 768w" sizes="(max-width: 536px) 100vw, 536px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 3 A model of the molecular mechanisms of soluble CD35.<sup>3</sup></span></p> <p><span style="font-size: 15px;"><strong>CD35 Clinical Value</strong></span></p> <p><span style="font-size: 15px;">Diagnosis: The expression level of CD35 can be used as a diagnostic marker for certain hematologic diseases, especially in differentiating chronic lymphocytic leukemia (CLL) from other B-chronic lymphoproliferative disorders (B-CLPDs). Studies have shown that low expression of CD35 correlates significantly with the diagnosis of CLL, especially in the differential diagnosis with other B-CLPDs such as MCL.</span></p> <p><span style="font-size: 15px;">Disease monitoring: Changes in CD35 expression may reflect disease progression or response to therapy. In some cases, changes in CD35 levels may be used to monitor a patient’s response to therapy, particularly in immunotherapy or <a href="/complement-therapeutics/therapeutic-antibody-development.htm">complement therapies</a>.</span></p> <p><span style="font-size: 15px;">Immunomodulation: CD35 plays a key role in regulating the activation of the complement system and suppressing inflammatory responses. It is involved in regulating the activation of the complement system by binding to the complement fragment C3b/C4b and plays a role in clearing immune complexes and modulating the inflammatory response in particular.</span></p> <p><span style="font-size: 15px;">Therapeutic target: Due to its role in a variety of diseases, CD35 may be a potential target for therapy. Regulating the <a href="/complement-therapeutics/complement-function-activity-test.htm">complement activity</a> by targeting CD35 may provide new avenues for the treatment of certain inflammatory and autoimmune diseases.</span></p> <p><span style="font-size: 15px;">In conclusion, CD35, as an important complement receptor, plays a key role in the development of many diseases, and its in-depth study can help understand disease mechanisms and provide new strategies for clinical treatment.</span></p> <p><span style="font-size: 15px;">References:</span></p> <ol> <li><span style="font-size: 15px;">Washburn, Rachel L., and Jannette M. Dufour. “Complementing testicular immune regulation: the relationship between sertoli cells, complement, and the immune response.” <em>International Journal of Molecular Sciences</em>4 (2023): 3371.</span></li> <li><span style="font-size: 15px;">Liu, Dong, and Zhong-Xiang Niu. “The structure, genetic polymorphisms, expression and biological functions of complement receptor type 1 (CR1/CD35).” <em>Immunopharmacology and immunotoxicology</em>4 (2009): 524-535.</span></li> <li><span style="font-size: 15px;">Hardy, Matthew P., <em>et al</em>. “The Molecular Mechanisms of Complement Receptor 1—It Is Complicated.” <em>Biomolecules</em> 13.10 (2023): 1522.</span></li> </ol> ]]></content:encoded> </item> <item> <title>Complement Bomb – Complement Negative Regulatory Factor H</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/complement-bomb-complement-negative-regulatory-factor-h/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Fri, 01 Mar 2024 08:09:07 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[Complement Factor H]]></category> <category><![CDATA[Complement Therapy]]></category> <category><![CDATA[COVID-19]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=326</guid> <description><![CDATA[Structure of Complement Regulatory Protein Factor H Complement Factor H, also known as Factor H and CFH, is a sialic acid-containing glycoprotein that plays an integral role in regulating the complement-mediated immune<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/complement-bomb-complement-negative-regulatory-factor-h/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;"><strong>Structure of Complement Regulatory Protein Factor H</strong></span></p> <p><span style="font-size: 15px;"><a href="/complement-therapeutics/category-complement-factor-h-cfh-544.htm">Complement Factor H</a>, also known as Factor H and CFH, is a sialic acid-containing glycoprotein that plays an integral role in regulating the complement-mediated immune system. The human CFH gene is located in the region of the complement activation gene cluster where the regulatory factors reside. It contains 25 exons and 24 introns, 94 kb and 91.4 kb bases long, respectively, encoding a total of 1,231 amino acids. The CFH gene encodes Factor H protein, a Factor H-like protein 1 (FHL-1), and five Factor H-associated proteins (FHR1-5) with a molecular weight of 155 kDa. Factor H proteins belong to the β1H globulins. They are the most characterized members of the Factor H protein family and serve as important negative regulators of alternative complement pathway activity. Factor H proteins contain several structural domains that interact with ligands such as C3, C3b, heparin, and <a href="/complement-therapeutics/category-c-reactive-protein-580.htm">C-reactive protein</a> (CRP), with three binding sites for C3b and three for heparin. CFH protects its own cells from complement activation but not bacteria and viruses. Misregulation of CFH may adversely affect the ability to deal with foreign infections or to reduce the <a href="/complement-therapeutics/complement-function-activity-test.htm">complement activity</a> of the host cell, leading to various effects.</span></p> <p><span style="font-size: 15px;">Creative Biolabs is dedicated to providing monoclonal antibodies, polyclonal antibodies, recombinant proteins, ELISA kits, etc., for CFH research. Example:</span></p> <ul> <li><a href="/complement-therapeutics/sheep-anti-human-complement-factor-h-polyclonal-antibody-348.htm"><span style="font-size: 15px;">Sheep anti-human complement factor H polyclonal antibody</span></a></li> <li><a href="/complement-therapeutics/pig-complement-factor-h-elisa-kit-1273.htm"><span style="font-size: 15px;">Pig complement factor H ELISA kit</span></a></li> <li><a href="/complement-therapeutics/human-complement-factor-h-autoantibody-igg-elisa-kit-1277.htm"><span style="font-size: 15px;">Human complement factor H autoantibody ELISA kit</span></a></li> <li><a href="/complement-therapeutics/category-complement-factor-h-related-protein-1-545.htm"><span style="font-size: 15px;">Complement factor H-related protein 1</span></a></li> <li><a href="/complement-therapeutics/category-complement-factor-h-related-protein-2-546.htm"><span style="font-size: 15px;">Complement factor H-related protein 2</span></a></li> </ul> <p><span style="font-size: 15px;">Mutations in the Factor H gene have been associated with a variety of serious diseases, including rare kidney diseases (HUS) and membranoproliferative glomerulonephritis (MPGN), as well as the more common age-related macular degeneration (AMD). Structure determines function, and the complex physiology of CFH underlies the complex diseases that result.</span></p> <p><span style="font-size: 15px;"><strong>Function of Complement Regulatory Protein Factor H</strong></span></p> <p><span style="font-size: 15px;">CFH is a multistructural and multifunctional plasma glycoprotein present in normal serum, whose primary role is to bind to host surfaces to prevent them from being activated by complement. CFH stabilizes complement activity in the blood at a concentration of 400-800 µg/ml, thereby targeting the immune response. It binds to C3b, accelerating the breakdown of the alternative pathway <a href="/complement-therapeutics/complement-therapeutic-target-c3-convertases.htm">C3 convertase</a> and helping to inactivate C3b, thereby protecting the body from unwanted tissue damage. This plasma protein is mainly produced by the liver, and small amounts of CFH can also be produced by other types of cells, such as retinal pigment epithelial cells, peripheral blood lymphocytes, fibroblasts, neurons, and glial cells.</span></p> <p><span style="font-size: 15px;">Factor H and/or FHL-1 are important negative regulators in the complement paracrine activation pathway, which starts to function at the early stage of the immune response. Therefore, CFH plays a crucial role in inhibiting early complement activation, inhibiting the formation of the complement paracrine C3 converting enzyme, thereby inhibiting the activation of the complement paracrine pathway on the surface of circulating cells, and attenuating the subsequent lysogenic effect and inflammatory response. Specifically:</span></p> <ul> <li><span style="font-size: 15px;">CFH protein binds complement C3b and inhibits the formation of the C3 converting enzyme of the bypass pathway.</span></li> <li><span style="font-size: 15px;">It displaces C3b from the formed C3 converting enzyme of the bypass pathway, accelerates the degradation of the C3 converting enzyme, and interferes with the generation and stabilization of the C3 converting enzyme of the complement bypass pathway.</span></li> <li><span style="font-size: 15px;">In addition, there is also a binding site on CFH for CRP, which plays a role in the negative regulation of inflammation</span></li> <li><span style="font-size: 15px;">Meanwhile, CFH protein, as an important effector of innate immunity, recognizes self and foreign bodies and plays an important role in innate immunity.</span></li> </ul> <p><span style="font-size: 15px;"><strong>Complement Regulatory Protein Factor H and COVID-19</strong></span></p> <p><span style="font-size: 15px;">COVID-19 may cause long-lasting sequelae, so research on its pathogenesis remains a topic of high interest. The clinicopathologic manifestations of COVID-19 are consistent with an innate immune host response. Hyperactivation of the blood-borne complement system is a major component of innate immunity and plays a key role not only in inflammatory syndromes but also in the microvascular and macrovascular thrombosis that usually occurs. Several soluble and membrane-anchored proteins, including CFH, prevent excessive <a href="/complement-therapeutics/complement-activation-definition.htm">complement activation</a>. Reduced functional expression of one or more of these negative regulators increases the risk of atypical hemolytic uremic syndrome (aHUS) with microvascular thrombosis, inflammation, and multiorgan damage, a syndrome with characteristics similar to COVID-19.</span></p> <p><span style="font-size: 15px;">Literature indicates that data from screening by the complement system showed that AP was activated in all COVID-19 patients, and serum CFH levels were significantly lower in COVID-19 patients compared to healthy controls. Thus, reduced functional levels of the negative AP regulator FH led to overactivation of the AP pathway, C3a generation, and C3 fragmentation deposition, and a significant increase in C5a serum levels, as well as providing the idea that inhibition of C3 and C5 could be used to treat patients.</span></p> <p><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-328" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/03/20240229.png" alt="" width="1017" height="562" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/03/20240229.png 1017w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/03/20240229-300x166.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/03/20240229-768x424.png 768w" sizes="(max-width: 1017px) 100vw, 1017px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 Markers of complement pathway activation or complement proteins in serum from healthy general population controls and critically ill COVID-19 patients admitted to the ICU.<sup>1</sup></span></p> <p style="text-align: left;"><span style="font-size: 15px;"><strong>Complement Regulatory Protein Factor H and AMD</strong></span></p> <p><span style="font-size: 15px;">AMD is a senile alteration of macular structures. The main manifestation is that the retinal pigment epithelial cells have decreased phagocytosis and digestion of the disc membrane of the outer segment of the optic cells. As a result, the residual vesicles of the disc membrane that have not been completely digested are retained in the cellular plasma of the base and are discharged to the outside of the cell, and are deposited in the Bruch’s membrane, forming vitreous membrane warts. Such changes are more pronounced due to the structural and functional peculiarities of the macula. Vitreous warts are also seen in elderly people with normal vision, but the resulting pathological changes lead to macular degeneration.</span></p> <p><span style="font-size: 15px;">Polymorphisms in FH have been identified in genome-wide association studies as a key susceptibility factor for AMD, and binding of CFH to <a href="/complement-therapeutics/category-complement-receptor-3-cd11b-cd18-561.htm">CR3 receptor</a> inhibits the activation of the integrin-related receptor CD47 by platelet-responsive protein-1, which is necessary for the homeostatic elimination of subretinal phagocytes. This inhibition is potentiated by the AMD-associated CFH variant H402Y, which results in the pathological accumulation of subretinal phagocytes.</span></p> <p><span style="font-size: 15px;"><strong>Complement Regulatory Protein Factor H and Atherosclerosis</strong></span></p> <p><span style="font-size: 15px;">Atherosclerosis (AS) is a major cause of coronary heart disease, cerebral infarction, and peripheral vascular disease. Impaired lipid metabolism is the basis of atherosclerosis. Because of the yellow, atheromatous appearance of the lipids that accumulate in the lining of the arteries, it is called atherosclerosis. Over the past decades, it has been found that activation of the bypass pathway of the complement system produces a large number of unstable C3 converting enzymes, as well as a variety of inflammatory mediators produced during complement activation, such as C5a and <a href="/complement-therapeutics/category-complement-c5b-9-540.htm">complement C5b-9</a>, which cause damage to vascular endothelial cells, aggregation of inflammatory mediators, platelet aggregation, and hyperplasia of vascular smooth muscle cells, affecting the development of atherosclerosis. Compared with normal arteries, C3b/iC3b and C5b-9 deposition were significantly increased in arteries with atherosclerotic lesions. This is, of course, very much related to the reduction of CFH, which leads to the overactivation of the complement system.</span></p> <p><span style="font-size: 15px;">This demonstrates that CFH, as an important negative regulator of the complement system, plays an important regulatory role in preventing atherosclerosis. CFH accelerates the inactivation of the C3 converting enzyme in the bypass pathway by binding to C3b in the artery’s endothelium, reduces the generation of the end-product of complement activation, C5b-9, and inhibits complement activation in the superficial layer of the artery’s endothelium, thus slowing down the development of atherosclerotic plaques.</span></p> <p><span style="font-size: 15px;">Reference:</span></p> <ol> <li><span style="font-size: 15px;">Leatherdale, Alexander, <em>et al</em>. “Persistently elevated complement alternative pathway biomarkers in COVID-19 correlate with hypoxemia and predict in-hospital mortality.” <em>Medical Microbiology and Immunology</em> (2022): 1-12.</span></li> </ol> ]]></content:encoded> </item> <item> <title>Complement Therapy Newcomer: Dianthus Therapeutics</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/complement-therapy-newcomer-dianthus-therapeutics/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Wed, 31 Jan 2024 08:54:15 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[News]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[C1s]]></category> <category><![CDATA[Classical Pathway]]></category> <category><![CDATA[Complement Therapy]]></category> <category><![CDATA[gMG]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=318</guid> <description><![CDATA[Dianthus Therapeutics’ (DNTH) primary asset is DNTH103, a selective monoclonal antibody targeting the active form of complement C1s. The main focus is a me-better version of Sanofi’s already-marketed C1s monoclonal antibody, Sutimlimab.<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/complement-therapy-newcomer-dianthus-therapeutics/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Dianthus Therapeutics’ (DNTH) primary asset is DNTH103, a selective monoclonal antibody targeting the active form of <a href="/complement-therapeutics/category-complement-c1s-513.htm">complement C1s</a>. The main focus is a me-better version of Sanofi’s already-marketed C1s monoclonal antibody, Sutimlimab. DNTH103 completed a Phase I study showing favorable safety and PK. DNTH plans to initiate multiple Phase II trials for autoimmune neuromuscular disorder indications in 2024.</span></p> <p><strong><span style="font-size: 15px;">Classical Complement Pathway – An Introduction to C1s Targets</span></strong></p> <p><img decoding="async" loading="lazy" class="aligncenter wp-image-320" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/01/Complement-signaling-pathways.png" alt="" width="785" height="368" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/01/Complement-signaling-pathways.png 1108w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/01/Complement-signaling-pathways-300x141.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/01/Complement-signaling-pathways-1024x480.png 1024w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2024/01/Complement-signaling-pathways-768x360.png 768w" sizes="(max-width: 785px) 100vw, 785px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 Complement signaling pathways.<sup>1</sup></span></p> <p><span style="font-size: 15px;">Many autoimmune diseases, especially those associated with pathogenic autoantibodies, have been shown to be connected with abnormal activation of the complement pathway. The <a href="/complement-therapeutics/complement-therapeutic-target-c1-complex.htm">complement C1 complex</a> (C1q, C1r, C1s) is the most upstream component of the classical pathway of complement. Upon binding to immune complexes formed by autoantigen-antibody, it prompts sequential cleavage of C3 and C5 through a series of reactions. This, in turn, triggers subsequent reactions such as the generation of <a href="/complement-therapeutics/complement-anaphylatoxin.htm">C3a and C5a</a> for recruiting and activating effector cells, the deposition of C3-conditioning hormones that mediate phagocytosis and lymphocyte activation, and the eventual formation of the membrane attack complex.</span></p> <p><span style="font-size: 15px;">Alexion’s Soliris and Ultomiris, developed based on the C5 target, were great successes, and have been approved for several self-immunization indications such as PNH, NMO, and gMG. However, because C5 is located furthest downstream of the classical pathway of complement, antagonizing C5 does not ameliorate C3-mediated pathological changes. Many drug companies have attempted to target the C1 complex upstream of the classical pathway to address this issue.</span></p> <p><span style="font-size: 15px;">Unlike complement therapies such as Soliris, Ultomiris, and Pegcetacoplan, targeting the C1 complex inhibits only the complement classical pathway and has no blocking effect on the lectin pathway or the alternative pathway. This could potentially lead to a safety advantage. Interestingly, congenital defects in C1q in the C1 complex are the predominant genetic risk factor for lupus. 85%-90% of individuals deficient in C1q develop symptoms of SLE, possibly because the complement classical pathway is responsible for the regulatory effects of antibody complexes, cellular debris, and apoptotic cells. Unlike C1q, inhibition of C1s has a minimal effect on phagocytosis to uptake apoptotic cells. Thus, inhibiting C1s to control the overactivated complement pathway became a new option.</span></p> <p>Creative Biolabs offers a wide range of products for C1s research.</p> <ul> <li><a href="/complement-therapeutics/target-c1s-29.htm">C1s antibodies</a></li> <li><a href="/complement-therapeutics/target-c1s-29.htm">C1s assay kits</a></li> <li><a href="/complement-therapeutics/target-c1s-29.htm">C1s proteins</a></li> <li><a href="/complement-therapeutics/target-c1s-29.htm">C1s peptides</a></li> <li><a href="/complement-therapeutics/target-c1s-29.htm">C1s lysate</a></li> <li><a href="/complement-therapeutics/target-c1s-29.htm">C1s vectors</a></li> </ul> <p><strong><span style="font-size: 15px;">Sanofi Lays Out Two Targeted Drugs for C1s Targets</span></strong></p> <p><span style="font-size: 15px;">(1) Sutimlimab</span><br /> <span style="font-size: 15px;">Sutimlimab, a humanized C1s monoclonal antibody of the IgG4 subtype, is the first and only marketed C1s monoclonal antibody approved by the FDA in 2022 for the treatment of Cold Agglutinin Disease (CAD). It is the first approved therapy for CAD.</span></p> <p><span style="font-size: 15px;">CAD is a rare autoimmune hemolytic anemia, a disease in which an excessive immune response is triggered by the binding of cold agglutinins (cold-reactive anti-red blood cell antibodies) to the surface of red blood cells, and affects approximately 5,000 patients in the United States.</span></p> <p><span style="font-size: 15px;">There are still some problems with Sutimlimab. Complement is mostly present in the body in an inactive form, and Sutimlimab targets both active and inactive forms of C1s. The concentration of inactive forms of C1s in the body is much higher than that of active forms, resulting in higher dosages of the drug in patients. Sanofi has responded to these problems with the launch of its second-generation monoclonal antibody to C1s, SAR445088.</span></p> <p><span style="font-size: 15px;">(2) SAR445088</span><br /> <span style="font-size: 15px;">SAR445088 is Sanofi’s second-generation C1s monoclonal antibody. Compared to Sutimlimab, which targets both active and inactive C1s, SAR445088 is highly selective for the active form of C1s and has a longer half-life for intravenous/subcutaneous administration in humans. This supports a longer dosing cycle and a more convenient mode of subcutaneous administration.</span></p> <p><span style="font-size: 15px;">According to public disclosure, SAR44588 is in clinical phase II for the indications of antibody-mediated rejection and chronic inflammatory demyelinating polyneuropathy (CIDP), a rare autoantibody-mediated polyneurological disorder with key features including nerve demyelination and inflammation of the peripheral nervous system leading to impaired motor and sensory function, with approximately 15,000 patients in the United States. Existing standard therapies have significant side effects and high costs, and there are no new mechanism drugs on the market. Thus, there is a large unmet need for CIDP. SAR44588 has shown promising preliminary clinical results in an ongoing Phase II clinical trial for CIDP.</span></p> <p><strong><span style="font-size: 15px;">DNTH103</span></strong></p> <p><span style="font-size: 15px;">DNTH103 Phase I clinical trials have been completed and demonstrated good PK properties and safety with a half-life of 60 days, supporting a biweekly subcutaneous dosing regimen with a favorable safety profile and no SAE events. DNTH103 is expected to undergo a generalized myasthenia gravis (gMG) trial in the 1st quarter of 2024, followed by a multifocal motor neuropathy (MMN) trial in the second half of 2024 and a CIDP clinical trial in the second half of 2024.</span></p> <p><span style="font-size: 15px;">Conventional therapies for gMG (including acetylcholinesterase inhibitors, corticosteroids, non-steroidal immunotherapies, IVIg, and PLEX) are effective in controlling symptoms, but are slow-acting and have serious side effects. <a href="/complement-therapeutics/complement-component-inhibitor-development.htm">Complement inhibitors</a> and anti-FcRn therapies have greatly improved the treatment of gMG, and targeting the complement pathway or IgG has been shown to be effective in gMG.</span></p> <p><span style="font-size: 15px;"><a href="/complement-therapeutics/mouse-anti-human-complement-c1s-monoclonal-antibody-m241-159.htm">C1s antibodies</a> promise a breakthrough in gMG indications, particularly in AchR+ MG, where the classical pathway is initiated when IgG1 or IgG3 (and less frequently IgG2) autoantibodies attached to the AChR bind to C1q. This is the primary pathogenetic mechanism of AChR+ MG. DNTH103 has also been shown in the preclinical setting using sera from patients with AChR+ MG, demonstrating that DNTH103 may have better efficacy compared to C5 antibodies.</span></p> <p><span style="font-size: 15px;">DNTH103 has the potential to offer greater advantages in terms of avoiding the risk of serious infections, low dosage, and less frequent dosing.</span></p> <p><strong><span style="font-size: 15px;">Summary and Prospects</span></strong></p> <p><span style="font-size: 15px;">C1s, as an upstream component of the classical complement pathway, is a very promising target in autoimmune IgG-mediated self-immune diseases. The current safety data are excellent. Both the C1s target and DNTH as a company have multiple challenges ahead:</span></p> <p><span style="font-size: 15px;">1) According to statistical analysis of epidemiology, inhibition of targets in the C1 complex still carries a theoretical risk of increasing the probability of developing lupus.</span><br /> <span style="font-size: 15px;">2) Theoretically, targeting the classical pathway can treat autoimmune diseases mediated by autoantibodies of IgG1/IgG3 subtypes, but there is not enough clinical evidence to prove the effectiveness of merely inhibiting the classical pathway in autoimmune diseases other than CAD. Admittedly, as C3 and C5 act as downstream components of the complement pathway, and inhibition of C3/C5 can inhibit all three pathways simultaneously to play a role.</span><br /> <span style="font-size: 15px;">3) It is difficult to demonstrate the efficacy of anti-C1s antibodies in gMG with preclinical evidence on animal models due to the lack of a better animal model, in contrast to the higher clinical risk of gMG.</span></p> <p><strong><span style="font-size: 15px;">Reference:</span></strong><br /> <span style="font-size: 15px;">1. Kolev, Martin, Gaelle Le Friec, and Claudia Kemper. “Complement—tapping into new sites and effector systems.” <em>Nature Reviews Immunology</em> 14.12 (2014): 811-820.</span></p> ]]></content:encoded> </item> <item> <title>Specific Discussions of the Molecular Mechanisms of Complement Receptors</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/specific-discussions-of-the-molecular-mechanisms-of-complement-receptors/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Wed, 27 Dec 2023 02:20:36 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[News]]></category> <category><![CDATA[C3a]]></category> <category><![CDATA[C5a]]></category> <category><![CDATA[C5aR]]></category> <category><![CDATA[Complement Activation]]></category> <category><![CDATA[Complement Test]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=303</guid> <description><![CDATA[Cascade activation of the complement system is one of the key mechanisms of the immune system against pathogenic infections. It is a complex network of plasma proteins, including inflammatory peptides, proteases, and<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/specific-discussions-of-the-molecular-mechanisms-of-complement-receptors/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Cascade activation of the complement system is one of the key mechanisms of the immune system against pathogenic infections. It is a complex network of plasma proteins, including inflammatory peptides, proteases, and integral membrane receptors that function together in a synergistic manner. Once the complement system is activated, it effectively removes microorganisms by forming a membrane attack complex (MAC). The complement system is cleaved by different proteases to produce a number of peptides, and these complement factors activate the corresponding receptors or effectors. Abnormally activated complement systems are closely associated with the development of various diseases, such as immunodeficiency and autoimmune disorders. In this process, the peptide fragments<a href="/complement-therapeutics/complement-anaphylatoxin.htm"> C3a and C5a</a> produced from the cleavage of complement C3 and C5 amplify the immune response by recruiting immune cells, also known as anaphylatoxins.</span></p> <p><span style="font-size: 15px;">C3a and C5a function mainly by activating their responsive receptors <a href="/complement-therapeutics/category-complement-3a-receptor-c3ar-563.htm">C3aR </a>and C5aR1/C5aR2, which are typical G protein-coupled receptors. Under agonist activation, C3aR can act through different signaling pathways such as downstream Gi/Gq/βarrs, whereas C5aR1 is also able to activate the downstream Gi and βarrs signaling pathways, and C5aR2 is unable to activate the G-protein signaling pathway, but only the βarrs signaling pathway.</span></p> <p><span style="font-size: 15px;">In addition, human C3a and C5a contain 77 and 74 amino acids, respectively, and previous studies have shown that they can activate the corresponding receptors through a two-site binding mode and associate with the N-terminal end of the receptor, the second extracellular loop (ECL), and the periplasmic core. In addition, the C-terminal hydrolysis of C3a and C5a produces peptides that can also activate the corresponding receptors, such as the peptides EP54 and EP67 produced by the hydrolysis of C5a, as well as the artificially designed peptide C5apep. Meanwhile, the last amino acids of C3a and C5a can be physiologically regulated to be excised to produce C3ades-Arg and C5ades-Arg, which have a reduced ability to activate the corresponding receptors. Although researchers understand the function of C3a and C5a in activating the corresponding receptors, little is known about their ligand-recognition mechanisms.</span></p> <p><span style="font-size: 15px;">On October 17, 2023, Arun K. Shukla and his collaborator Ramanuj Banerjee from IIT, along with Cornelius Gati’s team from the University of Southern California, published their latest research results in <em>Cell</em> under the title “Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors”. They analyzed the complexes of C3aR or C5aR1 with downstream G proteins in the presence of ligand activation by cryo-electron microscopy. They revealed the binding modes of the corresponding ligand-activated receptors. In addition, the researchers have also analyzed the structural basis for the activation of the receptors by C3ades-Arg, C5ades-Arg, and a biased agonist, providing a detailed molecular basis for the development of drugs targeting C3aR and C5aR1/2 in the corresponding diseases.</span></p> <p><span style="font-size: 15px;">The researchers first examined the activation of downstream signaling pathways by C3aR as well as C5aR1 in the presence of different ligands. The researchers found that EP54 from C3a was able to activate the Gi signaling pathway and βarr1/2 signaling pathway of C3aR. Human-derived C5apep and C5a were able to activate mC5aR1 and inhibit cAMP, although they were slightly less potent in activating mC5aR1 than in activating hC5aR1. In addition, C5a is a full agonist of mC5aR1, whereas C5apep is only partially agonistic for hC5aR1 and mC5aR1.</span></p> <p><span style="font-size: 15px;">C3a and C5a share 35% sequence homology, and they both consist of four helices linked together by disulfide bonds, as well as a terminal arginine residue located at the tail end of the helix (Arg77 in C3a and Arg74 in C5a). Through structural analysis and base mutation activity detection, the researchers confirmed that both C3a-C3aR and C5a-C5aR1 have a two-site model, in which one site of the ligand binds to the ECL2 of the receptor, and the second site interacts with multiple amino acid residues in the membrane-penetrating structural domain. In addition, the N-terminal domain of C5aR1 is also involved in <a href="/complement-therapeutics/receptor-ligand-binding-assay.htm">C5a binding</a>. While the ECL2 of C3aR is long, functional experiments show that a large part of it is not related to C3a binding.</span></p> <p><span style="font-size: 15px;">Upon binding to the receptor, C3a and C5a retained their helical folded structures, but also underwent some changes from the original structures, such as 30° and 45° tilting of the H3 helices of C3a and C5a. In addition, the distal carboxyl terminus of C3a underwent a significant rotation, whereas the distal carboxyl terminus of C5a changed from a short helix in the basal state to an extended conformation. The overall position of C3a in C3aR differs dramatically from that of C5a in C5aR1, with the globular structural domains of C3a and C5a both tilted 120° relative to their distal carboxyl terminus. Unlike the C3a and C5a, which are oriented in opposite directions on the outside of the receptor at an angle of approximately 90°, the carboxyl termini of C3a and C5a, on the other hand, form a hook-like conformation that buries them in a binding pocket.</span></p> <p><span style="font-size: 15px;">Both C3a and C5a have a natural modulation of their activity by removing the last arginine via a hydrolyzing enzyme, resulting in a diminished ability to activate the corresponding receptor.</span></p> <p><span style="font-size: 15px;">In summary, the researchers resolved the structures of the complexes of C3aR and C5aR1 with downstream G proteins under multiple ligand activation scenarios by cryo-electron microscopy and analyzed the activation mechanisms, as well as the naturally occurring mechanisms of activity regulation and the molecular mechanisms of biased agonist activation of C3aR. This provides a theoretical basis for understanding the molecular mechanisms by which the <a href="/complement-therapeutics/complement-function-activity-test.htm">complement functions</a>.</span></p> <p><span style="font-size: 15px;">References:</span></p> <p><span style="font-size: 15px;">1</span>. <span style="font-size: 15px;">Yadav, Manish K., <em>et al</em>. “Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.” <em>Cell</em> 186.22 (2023): 4956-4973.</span></p> <p><span style="font-size: 15px;">2. Hawksworth, Owen A., <em>et al</em>. “New concepts on the therapeutic control of complement anaphylatoxin receptors.” <em>Molecular immunology</em> 89 (2017): 36-43.</span></p> <p><span style="font-size: 15px;">3. Pandey, Shubhi, <em>et al</em>. “Emerging insights into the structure and function of complement C5a receptors.” <em>Trends in biochemical sciences</em> 45.8 (2020): 693-705.</span></p> ]]></content:encoded> </item> <item> <title>Structurally Revealing the Coupled Mechanism of Complement Receptor Activation and Signal Transduction</title> <link>https://www.creative-biolabs.com/blog/complement-therapeutics/structurally-revealing-the-coupled-mechanism-of-complement-receptor-activation-and-signal-transduction/</link> <dc:creator><![CDATA[biolabs]]></dc:creator> <pubDate>Tue, 28 Nov 2023 03:19:04 +0000</pubDate> <category><![CDATA[Complement Pathways]]></category> <category><![CDATA[News]]></category> <category><![CDATA[Related Diseases]]></category> <category><![CDATA[C3a]]></category> <category><![CDATA[C5a]]></category> <category><![CDATA[Complement Cascade]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/complement-therapeutics/?p=297</guid> <description><![CDATA[The complement system plays a crucial role in the body’s defense against harmful invaders. It is an essential component of the innate immune response, and its end products, C3a and C5a, exert<a class="moretag" href="https://www.creative-biolabs.com/blog/complement-therapeutics/structurally-revealing-the-coupled-mechanism-of-complement-receptor-activation-and-signal-transduction/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The complement system plays a crucial role in the body’s defense against harmful invaders. It is an essential component of the innate immune response, and its end products, C3a and C5a, exert their physiological and pathological responses primarily through two G protein-coupled receptors, <a href="/complement-therapeutics/category-complement-3a-receptor-c3ar-563.htm">C3aR</a> and <a href="/complement-therapeutics/category-complement-c5a-receptor-1-c5ar1-565.htm">C5aR1</a>. However, the molecular mechanisms underlying the recognition, activation, and signaling bias of these receptors remain largely unknown.</span></p> <p><span style="font-size: 15px;">In a new study, researchers from USC, India, Australia, and Switzerland have shed light on these proteins’ mysteries. Their research has the potential to pave the way for innovative treatments for various diseases, including severe COVID-19, rheumatoid arthritis, neurodegenerative diseases, and cancer.</span></p> <p><span style="font-size: 15px;">The complement cascade lies at the core of our immune response, a series of events triggered when a potential threat is detected. This process produces C3a and C5a, which activate specific receptors on the cell surface, initiating internal signals. The exact mechanism of these receptors, particularly C5aR1, has always been a mystery.</span></p> <p><span style="font-size: 15px;">Using advanced cryo-electron microscopy (cryo-EM) techniques, the authors of this study have provided nine cryo-EM structures of C3aR and C5aR1, activated by natural and synthetic agonists. These structures reveal different binding pocket topologies fo <a href="/complement-therapeutics/anaphylatoxin-receptor-antagonist-development.htm">complement allergenic toxins</a>, providing valuable insights into receptor activation and signal transduction coupling. The author also elucidates the structural basis of naturally occurring inhibition of the C5a inflammatory response through protein hydrolysis-mediated cleavage of terminal arginine, as well as the G protein signaling bias induced by a C3aR peptide agonist. Their study sheds light on the internal structure of complement allergy toxin receptors and contributes to structure-driven drug discovery for targeting these receptors in a range of diseases.</span></p> <p><img decoding="async" loading="lazy" class="aligncenter wp-image-299" src="http://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2023/11/16975830548712185383.png" alt="" width="443" height="442" srcset="https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2023/11/16975830548712185383.png 620w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2023/11/16975830548712185383-300x300.png 300w, https://www.creative-biolabs.com/blog/complement-therapeutics/wp-content/uploads/sites/9/2023/11/16975830548712185383-150x150.png 150w" sizes="(max-width: 443px) 100vw, 443px" /></p> <p style="text-align: center;"><span style="font-size: 15px;">Fig. 1 Inner workings of C3aR and C5aR1.<sup>1</sup></span></p> <p><span style="font-size: 15px;">As the global community continues to grapple with diseases that affect millions of people, understanding the intricacies of the immune system becomes increasingly essential. This study enhances a deeper understanding of this issue and sets the stage for future research aimed at harnessing the body’s natural defenses.</span></p> <p><span style="font-size: 15px;">Reference:</span></p> <ol> <li><span style="font-size: 15px;">Yadav, Manish K., <em>et al</em>. “Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.” <em>Cell</em> 186.22 (2023): 4956-4973.</span></li> </ol> ]]></content:encoded> </item> </channel> </rss>