Immunogenetics of Collagen Induced Arthritis in Mice

Project: Research project

Project Details

Description

PROJECT SUMMARY\ABSTRACT
Predisposition to develop Rheumatoid arthritis (RA) is associated with the presence of certain HLA alleles
while others offer resistance. HLA-DQ8 and DRB1*0401 molecules render humans and mice susceptible to
develop arthritis while DQ6/DR2 and DRB1*0402 provide protection. Collagen-induced arthritis (CIA)
susceptible HLA transgenic mice produce rheumatoid factor and anti-cyclic citrullinated peptide (CCP)
antibodies similar to that in RA patients. Similar to humans, the HLA-DR4 transgenic mice develop CIA more
often in females than males. Our hypothesis is that DR4 has a role in gender-bias of arthritis, where DR4
expression, presentation of antigen by various APCs and ensuing responses are different in males and
females. Female sex hormone, estrogen, is involved in pathogenesis by enhancing production of peptidyl
arginine deiminase (PAD) enzyme that leads to citrullination of synovial proteins. These citrullinated proteins
are presented with greater efficiency by HLA-DR4 leading to an autoreactive T and B cell response and
disease. Smoking and aging can result in higher amounts of citrullination. On the other hand, DQ8 can present
native and de-amidated peptides thus generating a robust immune response to an antigen. In this proposal we
will investigate the mechanism of association of DR/DQ with arthritis by studying its interaction with receptors
involved in innate and adaptive immunity via 1) binding to calreticulin, an established innate immunity receptor,
and triggering signaling, 2) by selection of regulatory cells and 3) by selection/ deletion of autoreactive T cells.
In addition, we will use DRB1*0401 and DRB1*0402 mice to determine the mechanism of protection to
understand how 3 amino acids difference in both molecules lead to protection by the latter. In aim1, we will
define the mechanism of predisposition by using mice expressing RA susceptible and resistant HLA class II
molecules. In aim 2 we will test role of shared epitope in protection versus susceptibility by studying interaction
of *0401 and *0402 with calreticulin, and role of T regulatory cells and Th17 cytokines. As a corollary, we will
study mechanism of remission during pregnancy by studying function of T regulatory cells and antigen
presenting cells. Recent literature has shown a protective/ susceptible effect of non-inherited maternal antigen
(NIMA) on the development of arthritis. In aim3, we will use various matings to generate mice that have been
exposed in utero to one NIMA. These mice will be evaluated for in vivo arthritis, autoantibodies and function of
T and B cells. The proposed experiments will test several new, original and innovative theories on the role of
MHC genes in predisposition, onset, progression, severity and modulation in arthritis. The findings would shed
light on the role of immune system in health and disease and may identify new therapeutic approaches for
arthritis.
StatusFinished
Effective start/end date1/1/835/31/16

ASJC

  • Medicine(all)