Project: Research project

Project Details


DESCRIPTION: (Adapted from the applicant's abstract) - In the current
paradigm, autoimmune disease evolves when "forbidden clones" recognize
a disease-inducing antigen and initiate an immune response. This
application presents a novel hypothesis on the involvement of T
lymphocytes in human autoimmune disease and plans to investigate this
novel disease model in patients with RA. The principal investigator
proposes that autoimmunity results from abnormalities in the formation
of the T cell repertoire and that more than 70% of the T cells present
in a patient are pathologically relevant. The rationale for this
hypothesis comes from preliminary data demonstrating that the repertoire
of CD4 T cells in patients with RA is extensively altered and is
characterized by widespread oligoclonality and loss in diversity. By
measuring the frequency of arbitrarily chosen TCR beta-chains in
circulating CD4 T cells, the principal investigator determined that, on
average, individual TCR beta-chains are present at tenfold higher
frequencies in RA patients than in age-matched controls, indicating
clonal proliferation. Telomere length analysis of CD4+ T cells
demonstrated that the vast majority of T cells in RA patients had an
extensive replicative history. Analysis of proliferating CD4 T cells
indicated an increased T cell turnover. These aberrations were not
present in patients chronically infected with hepatitis C virus,
suggesting that chronic antigenic stimulation cannot induce global
abnormalities in the repertoire. In the current project, this hypothesis
is to be tested with the ultimate goal of understanding mechanistic
principles inducing repertoire derangements. In the first specific aim,
the principal investigator will explore whether increase CD4 turnover
and loss of T cell diversity are found in multiple autoimmune diseases
or are specific for RA, and whether aberrations in the CD4 repertoire
are genetically controlled and can be detected in siblings and offspring
of patients. The second specific aim focuses on mechanisms inducing
widespread T cell proliferation, oligoclonality, and loss of diversity.
Such aberrations could be related to defects in T cell influx, an
imbalance of clonal expansion and clonal downsizing, or widespread
autorecognition. Accordingly, the repertoire of naive CD4 T cells will
be analyzed, the dynamics of antigen-specific T cell clones in vivo
after antigenic vaccination (influenza) will be studied, and the
precursor frequency of CD4 T cells reactive to diverse autoantigens will
be evaluated. The principal investigator anticipates that confirmation
of the unexpected preliminary findings will fundamentally change the way
for understanding RA and other autoimmune diseases, and open new
direction for therapy.
StatusNot started


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