Complement C4, Infections, and Autoimmune Diseases.

Hongbin Wang,Mengyao Liu

doi:10.3389/fimmu.2021.694928

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.

Highlights

Complement system plays a pivotal role in human innate immunity defending microbial infections, eliminating foreign pathogens, and maintaining tissue homeostasis
While the complement activation of the downstream of complement C3 resulting in inflammatory molecules, such as C3a, C5a, and the membrane attack complex (MAC), plays a less important role, the early components of the classical pathway, such as C1q, C4, and C2, are more critical in maintaining homeostasis and lack of some of early components of classical pathway will predispose an individual to autoimmune disorders
Those observations persuade us to speculate that infection-caused inflammation needs the containment that requires the immune modulation from the contribution of complement C4, otherwise it will be aggravated under the deficiency of C4

Summary

INTRODUCTION

Complement system plays a pivotal role in human innate immunity defending microbial infections, eliminating foreign pathogens, and maintaining tissue homeostasis. NRP1 was demonstrated to bind C4d in a concentration-dependent and saturable manner These data demonstrated NRP1 functions as a receptor for C4d that is covalently bound to target surfaces during complement activation, suggesting that NRP1 might be involved in regulation of the process of infections and autoimmune disorders by targeting the split product from classical or lectin complement pathway [77]. HCV NS5A protein can inhibit the expression of interferon regulatory factor 1 (IRF-1), which is important for IFNg-induced complement C4 expression These results highlight the roles of HCV proteins in establishing a chronic infection through the regulation of innate immunity by affecting the expression of complement C4 [90]. Another study by Mawatari et al demonstrated that HCV NS3/4A protease could cleave the g-chain of complement C4 in a concentration-dependent manner, suggesting that complement C4 is a novel cellular substrate of HCV N3/4A protease,

Streptococus

Findings

CONCLUDING REMARKS