C4d

Background

The complement fragment C4d is a significant product of the classical pathway of complement activation. Emerging from the cleavage of the highly abundant complement component C4, C4d has a molecular weight of approximately 45 kDa and can also be generated through the lectin pathway. In humoral immunity, the formation of antigen-antibody complexes is a crucial driver of the classical pathway, leading to the hydrolysis of C4 into the larger C4b fragment and the smaller C4a fragment. Further hydrolysis of C4b produces the C4d fragment, which possesses a thioester site that allows it to bind firmly to the basement membrane and endothelial cells. This stable and long-lasting presence of C4d serves as a reliable "footprint" of complement system activation, making it a valuable diagnostic marker in various clinical applications.

Its Gene ID: 721, UniProtKB ID: P0C0L5, and OMIM ID: 120820.

C4d in Organ Transplantation

In the assessment of antibody-mediated allograft rejection, C4d has become a useful biomarker. Many transplant centers routinely incorporate C4d staining into the pathological evaluation of allograft biopsies, particularly for heart, kidney, and pancreas transplants. However, the utility of C4d in diagnosing rejection for other transplanted organs, such as the lung, remains a subject of ongoing investigation. In addition, C4d can provide valuable insights into the treatment course and prognosis of transplant recipients. Some studies have shown that the C4d-positive group has a higher rate of both hormone therapy resistance and graft loss than the opposing group, making it promising as an effective prognostic indicator for kidney transplantation.

C4d in Autoimmune Diseases

In autoimmune disorders, C4d has also emerged as a valuable biomarker, especially in the investigation of systemic lupus erythematosus (SLE). Excessive complement activation is a hallmark feature of SLE. Several studies have demonstrated that erythrocyte-bound C4d (EC4d) and platelet-bound C4d (PC4d) hold potential as diagnostic biomarkers for SLE. Furthermore, the fluctuation of reticulocyte-bound C4d (RC4d) levels has been found to correlate closely with clinical disease activity measured by the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus Activity Measure (SLAM), suggesting its promise as a biomarker for monitoring SLE disease progression.

Signaling Pathways of C4d

The Ig-like transcript (ILT) 4 and ITL5v2 have been identified as cellular receptors for the complement fragment C4d. The binding of cell surface ILT4 with C4d leads to the endocytosis of C4d, which is involved in the control of autoreactivity, the induction of graft tolerance, and the maintenance of maternal-infant tolerance during pregnancy. Furthermore, the interaction of C4d with its receptor appears to act as an inhibitory agent capable of blocking inflammatory responses triggered by chemokines, cytokines, and allergenic toxins (e.g., C3a).

Fig.1 C4d’s role in modulating inflammatory responses.^{1, 3}

Creative Biolabs offers a comprehensive range of C4d-related products to support the advancement of customer programs, including anti-C4c antibodies, assay kits, and recombinant proteins. These versatile products can be utilized in a diverse array of immunoassays, such as WB, FC, IF, IA, IHC, and ELISA. Contact us for more detailed information.

C4d Functional Service

Creative Biolabs provides an extensive selection of C4d-targeted products, featuring tailored C4d-specific antibodies, ELISA kits designed for C4d detection, and C4d proteins. These carefully developed reagents are indispensable for investigating the interactions between C4d proteins and diverse moleculars, thereby contributing to research focused on crafting therapeutic strategies for a broad range of diseases.

Fig.2 Cross-sectional study reveals elevated plasma C4d levels in SLE patients, establishing C4d as a reliable marker for assessing increased disease activity.^{2, 3}

In this study, researchers aimed to assess the usefulness of the complement activation product C4d as a biomarker for lupus nephritis in patients with systemic lupus erythematosus (SLE). Utilizing a novel enzyme-linked immunosorbent assay to detect a specific short linear cleavage neoepitope, C4d levels were measured in plasma samples from 98 SLE patients, stratified by disease activity. The findings suggested that C4d serves as a valuable marker for monitoring SLE and correlated significantly with the SLE disease activity index, especially for tracking lupus nephritis, elevated C4d levels have the potential to predict forthcoming lupus nephritis flares, thereby guiding patient treatment strategies.

Creative Biolabs provides an extensive array of services centered on C4d functionality, including assays tailored for C4d interactions and custom functional assessments. These thoughtfully crafted solutions are designed to aid our distinguished clients in furthering their clinical and research endeavors.

References

1. Wang, Hongbin, and Mengyao Liu. "Complement C4, infections, and autoimmune diseases." Frontiers in immunology 12 (2021): 694928.
2. Martin, Myriam, et al. "Plasma C4d as marker for lupus nephritis in systemic lupus erythematosus." Arthritis research & therapy 19 (2017): 1-9.
3. Distributed under Open Access license CC BY 4.0, without modification.