The major histocompatibility complex (MHC) is the most gene-dense and polymorphic
region in the human genome with strong associations to many autoimmune disorders,
including rheumatoid arthritis (RA). However, even the genetic association between MHC
and RA was known more than 40 years ago, we still have not fully explained the functional
roles of the MHC genes and identified the underlying specific polymorphisms. This thesis
describes some of our research aimed for a better understanding of this topic, which can
largely be divided into three parts as follows.
First, we made use of a panel of MHC class II (MHC-II) congenic strains to evaluate the
functional roles of MHC-II polymorphisms in arthritis. By performing an extensive genetic
and functional analysis, we showed that MHC-II RT1-B (the rat orthologs of HLA-DQ)
determines the onset and severity of experimental arthritis, possibly due to the amino acid
variations in the P1 pocket of RT1-B. In addition, we showed that natural allelic variants in
Tap2, another gene in the MHC-II region, regulates the thymic selection of CD8+ T cells.
Second, in order to investigate whether other MHC genes also contribute to arthritis
susceptibility, we assessed arthritis development in congenic strains mapped to other parts
of the MHC region. We identified a second arthritis-regulatory QTL in the MHC class III
region, that regulates not only the onset and severity, but also chronicity of arthritis. We
subsequently mapped this effect to a conserved, 33-kb large haplotype Ltab-Ncr3
comprising five polymorphic genes. Interestingly, unlike other positionally-identified
arthritis genes in rats, Ltab-Ncr3 regulates only adjuvant arthritis models but not
autoimmunity triggered by specific tissue antigens, such as type II collagen. Furthermore,
we found that gene expression and alternative splicing of the Ltab-Ncr3 genes correlate
remarkably with arthritis severity and some of the gene expression differences were
reproduced in a cohort of RA patients and healthy controls.
Third, the MHC-II gene expression is regulated by class II transactivator (CIITA or C2TA),
and in humans, genetic variation in CIITA has been associated with differential expression
of MHC-II and susceptibility to autoimmune diseases. Using a congenic mouse strain with
an allelic variant in the type I promoter of C2ta, we demonstrate that whereas genetic
polymorphisms in C2ta promoter result in differential MHC-II expression and antigen
presentation, these do not necessarily have a strong impact on autoimmune diseases such as
arthritis.
In summary, these studies demonstrate how the congenic approach remains powerful to
conclusively identify and characterise genes regulating a complex disease like arthriti
