Complement Component C4

Complement component 4 (C4) is a vital protein within the complement system. This article delves into the structural, functional, and clinical significance of C4, emphasizing its indispensable role in immune defense, homeostasis, and disease pathogenesis.

What is C4 Complement?

C4 is a glycoprotein encoded by the C4A and C4B genes located on chromosome 6 within the human leukocyte antigen (HLA) region. It is a key molecule in the classical and lectin pathways of the complement system, serving as a bridge between antigen recognition and effector responses. The protein exists in two isoforms, complement component C4a and C4b, which differ in their biochemical properties and functional specializations.

Fig. 1 Schematic illustration of fragmentation of complement C4 activation.^1,3

C4 is synthesized as a precursor protein (~200 kDa) and undergoes proteolytic cleavage by serine proteases - C1s in the classical pathway and MASP-2 in the lectin pathway. This cleavage generates two fragments:

• C4a (~9 kDa): A small anaphylatoxin involved in inflammatory responses.
• C4b (~191 kDa): A larger fragment that covalently binds to pathogen surfaces or immune complexes via an internal thioester bond.

Subsequent cleavage of C4b by Factor I produces intermediate fragments (iC4b) and ultimately yields C4c (~146 kDa) and C4d (~45 kDa). Among these, C4d serves as a biomarker for complement activation due to its stable deposition on tissues.

C4 Pathway

C4 plays a crucial role in the classical and lectin pathways of the complement system, a key part of innate immunity.

Table 1 C4 plays a key role in the complement cascade.

The C4 pathway is a critical component of the complement system, bridging innate and adaptive immunity through its role in pathogen recognition, opsonization, and initiation of the complement cascade.

C4 Protein Function

C4 is a key mediator in the classical and lectin pathways, linking pathogen recognition to immune effector mechanisms.

Fig. 2 Consumption or inhibition of complement C4 through classical, lectin, and undefined pathways.^1,3

C4 Protein Deficiency

Partial or complete deficiency of C4 is associated with increased susceptibility to:

• Infections: Impaired conditioning and complement activation predispose individuals to bacterial and viral infections.
• Autoimmune diseases: Reduced levels of C4 are associated with systemic lupus erythematosus (SLE), rheumatoid arthritis, and other autoimmune diseases due to defective clearance of immune complexes.

Fig. 3 Diseases involving the complement system.^2,3

Complement C4 Test

C4 is an important component of the complement system and is widely involved in immune defense and influenza regulation. The detection of complement C4 is of great significance and can provide key data for disease diagnosis, immune function assessment and scientific research.

The main laboratory methods currently used to detect complement C4 include the following:

• ELISA is a highly similar quantitative assay that is widely used to determine the concentration of C4 in serum, blood serum or other biological fluids.
• Immunoturbidimetric assay is a rapid and indispensable assay technique for the quantitative determination of C4 by the formation of an antibody-precursor response to changes in the turbidity of immune complexes.
• Flow cytometry combined with fluorescently labeled antibodies is used to detect complement fragments, such as C3 and C4, deposited on the surface of red blood cells.

This test can often be used for health diagnosis and monitoring.

Table 2 Interpretation of C4 test results.

In addition to this, C4 testing can be used for complement activation studies, which are used to assess the level of complement activation induced by anti-erythrocyte induction and provide data support for the development of complement.

C4 Target

The importance of C4 is not limited to basic immune function, but may be a therapeutic target for a variety of diseases, including autoimmune, neurodegenerative, and infectious diseases.

Table 3 Therapeutic potential of targeting C4.

Targeting C4 involves regulating its activation or interaction with other complement components.

• Activation inhibition: Blocking proteases that cleave C4 (e.g. C1s or MASP-2) prevents its activation in the classical or lectin pathways.
• Neutralize anaphylatoxin: Inhibitors targeting C4a can reduce local inflammation without disrupting downstream complement activation.
• Enhancing clearance: Therapies designed to enhance C4b deposition on pathogens can improve both conditioning and immune clearance.

Biological agents such as monoclonal antibodies and small molecule inhibitors targeting specific epitopes on C4 have shown promise in preclinical studies. Creative Biolabs is at the forefront of complement therapy development, providing customized solutions to harness the power of C4 in research applications worldwide.

• Individual Components Activity Test
• Antibodies
• Sera and Plasmas
• Proteins
• Reagents

If you want more information, please feel free to contact us.

References

1. Wang, Hongbin, and Mengyao Liu. "Complement C4, infections, and autoimmune diseases." Frontiers in immunology 12 (2021): 694928. https://doi.org/10.3389/fimmu.2021.694928
2. Panelius, Jaana, and Seppo Meri. "Complement system in dermatological diseases - fire under the skin." Frontiers in medicine 2 (2015): 3. https://doi.org/10.3389/fmed.2015.00003
3. under Open Access license CC BY 4.0, without modification.

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