AUTHOR=Oliveira Luana Caroline , Kretzschmar Gabriela Canalli , dos Santos Andressa Cristina Moraes , Camargo Carolina Maciel , Nisihara Renato Mitsunori , Farias Ticiana Della Justina , Franke Andre , Wittig Michael , Schmidt Enno , Busch Hauke , Petzl-Erler Maria Luiza , Boldt Angelica Beate Winter 

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

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02585

DOI=10.3389/fimmu.2019.02585

ISSN=1664-3224

ABSTRACT=<p>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. <italic>CR1</italic> gene polymorphisms have been associated with susceptibility to complex diseases. In order to investigate the association of <italic>CR1</italic> 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 <italic>CR1</italic><sup>*</sup><italic>3B2B</italic> (with the York antigen–encoded by p.1408Met) and <italic>CR1</italic><sup>*</sup><italic>3A2A</italic> (with p.1208Arg) were associated with protection against FS (OR = 0.57, <italic>P</italic> = 0.027, and OR = 0.46, <italic>P</italic> = 0.014, respectively). In contrast, the <italic>CR1</italic><sup>*</sup><italic>1</italic> haplotype (with the McCoy antigen – encoded by p.1590Glu) was associated with FS susceptibility (OR = 4.97, <italic>P</italic> &lt; 0.001). Heterozygote <italic>rs12034383</italic><sup>*</sup><italic>A/G</italic> individuals presented higher mRNA expression than homozygotes with the <italic>G</italic> allele (<italic>P</italic> = 0.04). The lowest sCR1 levels occurred in patients with active disease before treatment (<italic>P</italic> = 0.036). Patients in remission had higher levels of sCR1 than did healthy controls (<italic>P</italic> = 0.013). Among those under treatment, patients with localized lesions also presented higher sCR1 levels than those with generalized lesions (<italic>P</italic> = 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.</p>