Fine Mapping and Functional Characterization of Complement Receptor 1 (Cr1/Cd35) Genetic Variations and Contribution to Taiwanese Autoimmune Diseases

Human complement receptor 1 (CR1; the C3b/C4b receptor, CD35) belongs to the family of complement inhibitors and regulator of complement activation family (RCA) is widely recognized to play functional roles in innate immunity recognition and immune cells responses contribute to disease pathophysiology. CR1 gene exists structural copy number variations (CNVs) carry the different long homologous repeats coding for different functional CR1 protein isoforms and Single nucleotide polymorphisms (SNPs) may affect the efficient disposal of immune complexes and contribute to development of infectious and autoimmune diseases. SLE is characterized by dysregulation of self-reactive B cells, complement activation, and formation of ICs. The reduced level of CR1 on erythrocytes is speculated as a key mechanism contributing to immune complex (IC) overload and exaggerated complement cascade activation in SLE. Total leukocyte CR1 expression may impair the phagocyte mediated immune complex clearance and contribute to SLE complement consumption. The over-activation of the complement system (CS) is the cause of RA disease exacerbation. RA patients, have identified an elevated expression of CD35 in monocyte and neutrophil and correlated with disease activity. Leucocyte CR1 (L-CR1) transcript levels were decreased in RA that correlated negatively with DAS28, CIC and C3d. We have identified novel SNPs through deep sequencing and distinct method to identify CNVs in CR1. Also, we have identified the CR1 critical cytoplasmic domain, interacting proteins and functional signaling disturbance. The overall goals of this proposal are to define CR1 functions in human autoimmune diseases and characterize the following hypothesis: Aim #1: To explore CR1 novel SNPs and identification of CNVs distribution in Taiwanese. Aim #2: To determine the CR1 length polymorphism (CNVs) and novel SNPs genotypes involved in susceptibility and clinical phenotypes in SLE, and RA. Aim #3: To determine whether expression of CR1 on peripheral blood, monocytes, neutrophils and B cells is altered in persons with SLE, RA and related to CR1 genetic variations. Aim #4: To characterize CR1 cytoplasmic interacting molecules and elucidate CR1 signaling mechanisms where this receptor plays key roles during immune responses.

Project ID:PC10901-0058
External Project ID:MOST107-2314-B182-059-MY3