C4c

Background

Complement component C4 is a critical player in the human immune system, functioning as a multifunctional β1-globulin present in plasma. Composed of α-, β-, and γ-chains, C4 plays a pivotal role in the classical pathway of complement activation, where it is hydrolyzed to C4a and C4b by serine proteases C1s. Similarly, the lectin complement pathway relies on the activation of C4 by the mannan-associated serine protease-2 (MASP-2), yielding the same C4a and C4b products. These breakdown products of C4 are instrumental in complement system activation, phagocytosis facilitation, immune complex deposition prevention, and viral neutralization. C4c, a breakdown product of C4b, is considered a reliable biomarker of complement activation in both the classical and lectin pathways.

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

Fig.1 The three pathways of complement activation.¹

Complement C4 in Microbial Infections

The classical pathway of the complement system plays a crucial role in anti-microbial defense by engaging with anti-pathogenic antibodies. Additionally, the lectin complement pathway contributes to this defense mechanism through direct binding to bacterial surface sugar components. Studies have demonstrated that pathogenic microorganisms employ a range of sophisticated mechanisms to circumvent the complement system, including the following main modes.

• Binding with C4-binding proteins to inhibit C4 complement effectors (Staphylococcus aureus).
• Secreting active protease to cleave C4 from the bacterial surface (Bordetella pertussis, Aspergillus fumigatus).
• Binding with C4 enhances its cleavage and reduces C4b deposition as well as C3 convertase activity (dengue virus, West Nile virus, and yellow fever virus).
• Regulating the expression of upstream stimulatory factor 1 (USF-1) and interferon regulatory factor 1 (IRF-1) to inhibit C4 transcription (hepatitis C virus).

C4c in Lung Cancer

C4d, another C4b breakdown product, is significantly elevated in biological fluids of lung cancer patients, making it a candidate biomarker for diagnostic or prognostic purposes. In contrast to C4d (adhering to the plasma membrane), C4c is released into the extracellular environment after C4 fragmentation, making it potentially more accessible for detection in plasma. Consequently, C4c may serve as a valuable marker for the early diagnosis of lung cancer. A recent study has constructed a multivariate diagnostic model that incorporates the detection of C4c, CYFRA 21-1, and CRP. The model had high specificity and positive predictive value, enabling effective differentiation between plasma samples from control and lung cancer patients.

Fig.2 The proteolytic formation of C4-derived fragments.²

C4c in Diabetic Kidney Disease (DKD)

Complement components and relative fragment deposition are intimately linked to the pathogenesis of autoantibody-associated glomerulopathy. Studies have shown that glomerular C4c deposition is closely associated with the deterioration of renal function in patients with type 2 diabetic kidney disease (T2DKD). The involvement of the classical and lectin pathways of the complement system in the development of DKD may contribute to C4c deposition, which triggers an inflammatory response and leads to direct glomerular injury. These findings indicate that C4c may serve as a promising novel biomarker, complementary to other components of the complement system, for predicting the prognosis of DKD.

As a leading provider of cutting-edge biomedical research solutions, Creative Biolabs offers 14 distinct anti-C4c antibody products to our global customers. These antibodies can be labeled with a variety of markers and are suitable for six different applications, including WB, ELISA, IF, IP, FC, and IHC. Additionally, we offer complement C4c-related assay kits, natural protein, and recombinant protein to support diverse needs. Please feel free to contact us for more details.

References

1. Beltrame, Marcia Holsbach, et al. "The lectin pathway of complement and rheumatic heart disease." Frontiers in pediatrics 2 (2015): 148.
2. Ajona, Daniel, et al. "A model based on the quantification of complement C4c, CYFRA 21-1 and CRP exhibits high specificity for the early diagnosis of lung cancer." Translational Research 233 (2021): 77-91.
3. Duan, Suyan, et al. "Association of glomerular complement C4c deposition with the progression of diabetic kidney disease in patients with type 2 diabetes." Frontiers in Immunology 11 (2020): 2073.