Complement Receptor 1 (CR1, CD35) Polymorphisms and Soluble CR1: A Proposed Anti-inflammatory Role to Quench the Fire of “Fogo Selvagem” Pemphigus Foliaceus

Abstract

Pemphigus foliaceus is an autoimmune disease that is sporadic around the world but endemic in Brazil, where it is known as fogo selvagem (FS). Characterized by autoantibodies against the desmosomal cadherin desmoglein 1, FS causes painful erosions, and crusts that may be widespread. The recognition of antigens, including exposed sugar moieties, activates the complement system. Complement receptor 1 (CR1, CD35), which is responsible for the Knops blood group on erythrocytes (York and McCoy antigens), is also expressed by antigen-presenting cells. This regulates the complement system by removing opsonized antigens, blocking the final steps of the complement cascade. Membrane-bound CR1 also fosters antigen presentation to B cells, whereas soluble CR1 has anti-inflammatory properties. CR1 gene polymorphisms have been associated with susceptibility to complex diseases. In order to investigate the association of CR1 polymorphisms with FS susceptibility, we developed a multiplex sequence-specific assay to haplotype eleven polymorphisms in up to 367 FS patients and 242 controls from an endemic area and 289 from a non-endemic area. We also measured soluble CR1 (sCR1) in the serum of 53 FS patients and 27 controls and mRNA levels in the peripheral blood mononuclear cells of 63 genotyped controls. The haplotypes CR1*3B2B (with the York antigen–encoded by p.1408Met) and CR1*3A2A (with p.1208Arg) were associated with protection against FS (OR = 0.57, P = 0.027, and OR = 0.46, P = 0.014, respectively). In contrast, the CR1*1 haplotype (with the McCoy antigen – encoded by p.1590Glu) was associated with FS susceptibility (OR = 4.97, P < 0.001). Heterozygote rs12034383*A/G individuals presented higher mRNA expression than homozygotes with the G allele (P = 0.04). The lowest sCR1 levels occurred in patients with active disease before treatment (P = 0.036). Patients in remission had higher levels of sCR1 than did healthy controls (P = 0.013). Among those under treatment, patients with localized lesions also presented higher sCR1 levels than those with generalized lesions (P = 0.0073). In conclusion, the Knops blood group seems to modulate susceptibility to the disease. Furthermore, corticosteroid treatment might increase sCR1 serum levels, and higher levels may play an anti-inflammatory role in patients with FS, limiting the distribution of lesions. Based on these results, we suggest CR1 as a potential new therapeutic target for the treatment of FS.

Immunoregulatory complement receptor-1 and leukocyte-associated Ig-like receptor-1 expression on leukocytes inPsoriasis vulgaris

“…26,27 Oliveira et al suggested an anti-inflammatory role for CR-1, claiming CR-1 as a potential new therapeutic target. 28 Furthermore, it was reported that CR-1 expression on phagocytes is involved in the binding of C3b/4bopsonised elements, which are then ingested, preventing the formation of C5 convertase. That would in turn block complement activation and the formation of the membrane attack complex.…”

“…18 Oliveira et al reported that the CR-1 haplotype with the major rs6656401*G allele of the Knops blood group was associated with increased susceptibility to Pemphigus foliaceus. 28 Sandri et al reported that the distinct CR-1 exon 29 variant affected CR-1 expression levels and increased susceptibility to Chagas disease. 19 Kretzschmar et al and Malik et al suggested a regulatory role for CR1 polymorphisms on mRNA and sCR1 levels.…”

Beyond the HLA polymorphism: A complex pattern of genetic susceptibility to pemphigus

“…The complement receptor 1 (CR1, or CD35) plays a major role in inhibiting the complement system, removing immune complexes, and activating B cells. The gene contains several functional polymorphisms that have been associated with different multifactorial diseases (please refer to Oliveira et al, 2019). In a study of FS, 11 CR1 SNPs were analysed.…”

“…The lowest soluble CR1 (sCR1) levels occurred in patients with active, more severe (generalized) disease, but treatment and remission resulted in the increase of median sCR1 levels. So, genetic variants of CR1 seem to modulate susceptibility to the disease and higher sCR1 levels may have an anti-inflammatory effect in patients with FS (Oliveira et al, 2019).…”

Variation in genes implicated in B‐cell development and antibody production affects susceptibility to pemphigus

“…The environmental factors that trigger the disease in the Brazilian endemic regions are not well established; however, they are possibly related to exposure to sunlight, mosquito bites, certain foods and poor living conditions. 8 In terms of susceptibility, several genetic variants have been identified as playing a role in the risk of developing PF, 9 including HLA (human leucocyte antigen) genes, [10][11][12][13] KIR (killer-cell immunoglobulin-like receptor) [14][15][16] genes and genes of the complement system, [17][18][19] among others. [20][21][22][23][24] Antibodies are immunoglobulin (Ig) molecules produced by B cells after a series of somatic rearrangements in immunoglobulin genes.…”