Specific autoimmunity in rheumatoid arthritis - T cells, antibodies and genetic regulation

Complex interactions between genes and environmental factors may result in
destruction of the body’s own cells and tissues by the immune system, i.e.
autoimmunity. Rheumatoid arthritis (RA) is a chronic joint inflammation mediated
by all arms of the immune system that can lead to tissue destruction and functional
disabilities. Many genetic variants and environmental factors that affect the
immune system in RA have been revealed in recent years, however it is still not
known precisely how they regulate and control autoimmunity. In this work I
studied the function and specificity of adaptive immunity in RA, and also addressed
influences from known genetic variants that predispose for disease.
First, autoantibody responses to several RA-associated citrullinated autoantigens
were studied in a cohort of patients with established RA. Antibody responses and
their interrelationships were examined, both in the whole study cohort and
following stratification to HLA-DRB1 types, since HLA-DRB1 alleles are the
strongest genetic risk factors known for RA. The autoantibodies were found to be
highly specific for RA and displayed only limited cross reactivity. HLA-DRB1*04
alleles strongly associated with the presence of these autoantibodies both in sera
and synovial fluid.
T cells are believed to be central mediators of RA pathogenesis, however studying
T cell specificity has been proven difficult. The stinking HLA-DRB1*04 association
with different anti-citrulline antibody responses encouraged us to revisit T cell
recognition and responses to citrullinated proteins. We identified an epitope from
vimentin that binds HLA-DRB1*0401 in its citrullinated but not in its native form
and T cell recognition and function were investigated. CD4 T cells from both HLADRB1*
0401 RA patients and healthy donors recognized citrullinated vimentin.
However, T cells derived from RA patients secreted higher levels of cytokines,
suggesting previous activation and/or cytokine dysregulation in RA. This study
required a development of an assay sensitive enough to allow detection of rare
antigen-specific CD4 T cells. Having such a tool, we further applied the same
method to functionally examine type-II collagen (CII)-reactive CD4 T cells from
peripheral blood and synovial fluid from HLA-DR*04 RA patients. T cells indeed
recognized different variants of the immunodominant T cell epitope of CII and
displayed epitope spreading throughout the disease. Synovial fluid derived T cells
produced higher levels of inflammatory cytokines as compared to blood suggesting
local reactivation.
Many more RA predisposing genetic variants have been identified outside the
HLA-DRB1 locus in recent years. We therefore continued to study the association
with autoantibody specificities in two independent cohorts of RA patients. Several
genetic variants were found to control autoantibodies formation; some associated
with several autoantibodies whereas others exclusively linked with a single fine
specificity.
In summary, our data suggest that both B and T cells selectively respond to
autoantigens in RA and are controlled by HLA and additional RA-predisposing
genes. This work emphasizes the importance of multidisciplinary investigation for
the understanding of interaction between genes and immunity in order to
functionally explain epidemiological findings. We further hope that our findings
regarding T and B cell specificities will encourage others to continue in this
direction, which may pave the road towards specific therapy in patients following
precise gene-immune investigation