Involvement of C4 allotypes in the pathogenesis of human diseases

Abstract

The complement system is an important humoral defense mechanism that plays a relevant role against microbial agents, inflammatory response control, and immunocomplex clearance. Classical complement pathway activation is antibody-dependent. The C4 component participates in the initial step of activation, and C4 expression is determined by 2 pairs of allotypes: C4A and C4B. Deficiencies in C4 allotypes have been associated with several diseases. The aim of the present review is evaluate the reported data in the literature regarding specific C4A and C4B deficiencies and characterize their clinical relevance. We searched the MEDLINE and LILACS databases. Papers referring to total C4 deficiency without allotype evaluation and case reports of primary C4 deficiency were not included. Deficiencies in C4 allotypes have been associated with Mycobacterium leprae infection, erythema nodosum, systemic sclerosis with anti-topoisomerase I antibodies, intermediate congenital adrenal hyperplasia with DR5 genotype, diabetes mellitus type 1 with DR3,4 genotype, and diabetes mellitus with antibodies against islet cells. C4 allotype deficiency is also related to C4B deficiency and autoimmune-associated diseases, such as systemic lupus erythematosus, or diseases with an autoimmune component, such as autism. Some reports associate C4A with thyroiditis after delivery as well as limited and systemic sclerosis without anti-topoisomerase I antibodies. However, the studies with C4A and C4B have been concentrated in isolated populations, and some of the studies could not be reproduced by other authors.

Complement Activation via Alternative Pathway Is Critical in the Development of Laser-Induced Choroidal Neovascularization: Role of Factor B and Factor H

“…We next used mice with a genetic deficiency in C4, as well as siRNA directed against C1q and factor B, to determine precisely which complement pathway(s) is important in the development of laser-induced CNV in mice. C4 molecule is a component of both the classical and lectin pathways (28) and mice with a homozygous deficiency of complement component C4 have been useful in defining the role of classical and lectin pathways in the pathogenesis of various complement-mediated diseases (29,30). We found that mice with targeted deletion of C4 gene developed CNV following laser, thus suggesting that classical and/or lectin pathways may not play a key role in the development of laser-induced CNV.…”

CD59, a Complement Regulatory Protein, Controls Choroidal Neovascularization in a Mouse Model of Wet-Type Age-Related Macular Degeneration

“…These animals have provided valuable information in efforts to understand the role of complement and CRegs in vivo (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). We used gene-deleted mice deficient in CD59a (Cd59a Ϫ/Ϫ ) because CD59a is the primary regulator of MAC formation in mice (16,17).…”

HLA-DRB1 allele frequencies and C4 copy number variation in Finnish sarcoidosis patients and associations with disease prognosis

“…Most Caucasians have 2 copies of C4A and C4B genes. Interestingly, the variation of C4 gene copy numbers (C4A; 0 -4 copy numbers, C4B; 0 -4 copy numbers) and the deficiency of C4 proteins (less than 2 copies of the gene) have been associated with a variety of bacterial and viral infections, which made the C4 genes functional and potential candidate genes for sarcoidosis [25,26].…”