T Cell Signaling in Rheumatoid Arthritis

Summary

Principal Investigator: Jorg J Goronzy
Abstract: DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests predominantly as a destructive arthropathy. In spite of the prominence of the synovial inflammation, autoantibodies are not tissue-specific and are directed against global antigens such as Ig Fc determinants and neoantigens of citrullinated peptides. Additional systemic immunological abnormalities include a defect that can best be summarized as accelerated immune aging. A putative role of age-dependent immune dysfunction in RA pathogenesis resonates with epidemiological data that RA is a disease of the second half of life with increasing incidence in the elderly. We have hypothesized that a defect in regulating T cell activation thresholds contributes to the tolerance failure and possibly also to the accelerated cellular aging. T cell activation thresholds are regulated by the signal strength originating from T-cell receptor (TCR) stimulation and by signals from costimulatory and coinhibitory cell surface receptors. We have found an increased responsiveness of the ERK pathway in RA T cells that is central to TCR calibration and amplifying signal strength and have proposed that mechanisms controlling the Raf-MEK-ERK module in T cells from RA patients have been reset to favor sustained signaling, thereby impairing peripheral immune tolerance. Our preliminary studies have identified several possible mechanisms causing this hyperresponsiveness including the increased transcription of B-RAF and K-RAS and the induction of a positive feedback loop induced by the homeostatic cytokines IL7 and IL15. The objective of the current application is to determine whether a characterization of these signaling abnormalities in individual RA patients is useful for patient classification and treatment design. Specific Aim 1 will explore the hypothesis that subsets of RA patients can be defined which differ in their mechanism to hyperstimulate the ERK pathway. Specific Aim 2 will determine whether the findings are limited to RA or also extend to other frequent arthritides such as psoriatic arthritis. In Specific Aim 3, we will determine whether existing standard (methotrexate, leflunomide or TNF inhibition) and newly emerging treatment approaches such as JAK3 inhibition are able to correct the signaling abnormalities In Specific Aim 4, we will examine the functional consequences of increased ERK responsiveness for T cell tolerance and T cell differentiation.
Funding Period: 2012-04-01 - 2016-03-31
more information: NIH RePORT

Research Grants

  1. Structure-function of HLA-DR, peptides, and T cells in autoimmune arthritis
    Edward F Rosloniec; Fiscal Year: 2013
  2. TSH RECEPTOR MULTIMERIZATION
    TERRY FRANCIS DAVIES; Fiscal Year: 2013
  3. B7-based, CD28 or CTLA-4-specific agonists and antagonists for tolerance inductio
    Roland K Strong; Fiscal Year: 2013
  4. CYTOKINE REGULATION IN EXPERIMENTAL ARTHRITIS
    Alison Finnegan; Fiscal Year: 2013
  5. Citrullinated Antigens Bridge Innate and Adaptive Immunity in RA
    Jeremy Sokolove; Fiscal Year: 2013
  6. Effects of miR-21 and miR-155 inhibition in SLE
    Marianthi Kiriakidou; Fiscal Year: 2013
  7. Oklahoma Autoimmunity Center of Excellence
    Judith A James; Fiscal Year: 2013
  8. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
  9. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Structure-function of HLA-DR, peptides, and T cells in autoimmune arthritis
    Edward F Rosloniec; Fiscal Year: 2013
    ..VA Public ..
  2. TSH RECEPTOR MULTIMERIZATION
    TERRY FRANCIS DAVIES; Fiscal Year: 2013
    ....
  3. B7-based, CD28 or CTLA-4-specific agonists and antagonists for tolerance inductio
    Roland K Strong; Fiscal Year: 2013
    ....
  4. CYTOKINE REGULATION IN EXPERIMENTAL ARTHRITIS
    Alison Finnegan; Fiscal Year: 2013
    ..These studies aim to develop novel insights into the autoimmune disease process that will facilitate the diagnosis and treatment of RA. ..
  5. Citrullinated Antigens Bridge Innate and Adaptive Immunity in RA
    Jeremy Sokolove; Fiscal Year: 2013
    ....
  6. Effects of miR-21 and miR-155 inhibition in SLE
    Marianthi Kiriakidou; Fiscal Year: 2013
    ..To our knowledge HITS-CLIP has not been previously performed in SLE and the combined results of HITS-CLIP and RNAseq will offer a panoramic view of all genes directly regulated by miRNAs in cells of the immune system in mouse lupus. ..
  7. Oklahoma Autoimmunity Center of Excellence
    Judith A James; Fiscal Year: 2013
    ..With our rich Native American heritage and large rural populations, the patients provided by the Oklahoma ACE will be previously understudied and provide unique insights for therapeutic trials. ..
  8. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
  9. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013
    ..Such an integrated interdisciplinary approach is possible only through continued support of this PPG. ..