Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice

• OBJECTIVE: To identify genetic factors driving pathogenic autoantibody formation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), in order to better understand the etiology of RA and identify possible new avenues for therapeutic intervention. METHODS: We performed a genome-wide analysis of quantitative trait loci controlling autoantibody to type II collagen (anti-CII), anti-citrullinated protein antibody (ACPA), and rheumatoid factor (RF). To identify loci controlling autoantibody production, we induced CIA in a heterogeneous stock-derived mouse cohort, with contribution of 8 inbred mouse strains backcrossed to C57BL/10.Q. Serum samples were collected from 1,640 mice before arthritis onset and at the peak of the disease. Antibody concentrations were measured by standard enzyme-linked immunosorbent assay, and linkage analysis was performed using a linear regression-based method. RESULTS: We identified loci controlling formation of anti-CII of different IgG isotypes (IgG1, IgG3), antibodies to major CII epitopes (C1, J1, U1), antibodies to a citrullinated CII peptide (citC1), and RF. The anti-CII, ACPA, and RF responses were all found to be controlled by distinct genes, one of the most important loci being the immunoglobulin heavy chain locus. CONCLUSION: This comprehensive genetic analysis of autoantibody formation in CIA demonstrates an association not only of anti-CII, but interestingly also of ACPA and RF, with arthritis development in mice. These results underscore the importance of non-major histocompatibility complex genes in controlling the formation of clinically relevant autoantibodies.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

Nyckelord

Animals

Arthritis

Experimental/*genetics/*immunology

Arthritis

Rheumatoid/genetics/immunology

Autoantibodies/blood/*genetics/*immunology

Collagen Type II/immunology

Disease Models

Animal

Female

Genome-Wide Association Study

Immunoglobulin G/blood/genetics/immunology

Male

Mice

Mice

Inbred A

Mice

Inbred AKR

Mice

Inbred BALB C

Mice

Inbred C3H

Mice

Inbred C57BL

Mice

Inbred CBA

Mice

Inbred DBA

Peptides

Cyclic/immunology

Quantitative Trait Loci/immunology

Rheumatoid Factor/immunology

Species Specificity

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)