Complement C4, Infections, and Autoimmune Diseases

Abstract

Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading microbes, plays an essential role for the functions of both classical (CP) and lectin (LP) complement pathways. Complement C4 is the most polymorphic protein in complement system. A plethora of research data demonstrated that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders. In this review, we will discuss the diversity of complement C4 proteins and its genetic structures. In addition, the current development of the regulation of complement C4 activation and its activation derivatives will be reviewed. Moreover, the review will provide the updates on the molecule interactions of complement C4 under the circumstances of bacterial and viral infections, as well as autoimmune diseases. Lastly, more evidence will be presented to support the paradigm that links microbial infections and autoimmune disorders under the condition of the deficiency of complement C4. We provide such an updated overview that would shed light on current research of complement C4. The newly identified targets of molecular interaction will not only lead to novel hypotheses on the study of complement C4 but also assist to propose new strategies for targeting microbial infections, as well as autoimmune disorders.

Keywords: C4; C4a; C4d; autoimmune diseases; complement; infections.

Figure 1

Schematic illustration of fragmentation of complement C4 activation. Complement C4 (~200 kDa) is activated by the serine protease C1s or MASP2 from classical and lectin complement pathway, respectively, to form the activation fragments C4a (~9 kDa) and C4b (~191 kDa). C4b (~191 kDa) is then inactivated and cleaved by the factor I together with cofactors to generate intermediate product iC4b and then further to generate the thioester linked C4d (~45 kDa) and C4c (~146 kDa).

Figure 2

Interactions of various microorganisms (including viruses and E. coli.) and pathological conditions with complement C4 to cause consumption or inhibition of complement C4 through classical, lectin, and undefined pathways. HCV, hepatitis V virus; HBV, hepatitis B virus; IR, ischemia reperfusion; RA, rheumatoid arthritis. Black solid arrow represents the activation of complement C4; Blue dash line represents the inhibition of complement C4.

Figure 3

Anti-inflammatory functions by complement C4 activation fragments C4a and C4d. On the surface of pathogens, the activation of complement C4 is triggered through classical (antibody) or lectin (sugar) pathways that will activate C1s or MAPSs, which will rapidly cleave C4 to generate C4a and C4b. C4b will be further fragmented by factor I and cofactors to generate C4d and C4c. C4b will associate with C2a to form a complement C3 cleavage enzyme (C3 convertase), C4b2a, which will cleave C3 to generate C3a and C3b. C3b will be associated with C4b2a to converge to C5 convertase (C4bC2aC3b), which will cleave C5 to generate C5a and C5b. C5b will associate with C6, C7, C8, and C9 to form membrane attack complexes (MAC) C5b-9 on the surface of pathogens. For the alternative pathway, C3b is spontaneous C3 turnover or generated by classical or lectin pathways. C3b bound to factor B (B). The complex is converted by factor D (D) to C3-cleaving enzyme C3bBb that is stabilized by properdin (P) and further form C3bBbC3b, which can cleave C5 to generate C5a and C5b. Plasma membrane (blue) represents the surface of pathogen cells.