ROLE OF CYTOKINES IN RHEUMATOID ARTHRITIS

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by infiltration of T cells and antigen presenting cells (APC) from the blood into the synovial joint. Activation of both cell types results in destruction of tissue within the joint. This tissue destruction leads to an abundance of self proteins available for uptake by phagocytic APC. Presentation of self peptide:MHC complexes by APC is believed to lead to activation and expansion of autoreactive T cells. The most convincing evidence implicating a role for antigen presentation in RA is the observation that inheritance of certain subtypes of the HLA-DR4 allele predisposes people to developing RA. The nature of the self peptides being presented by these DR4 subtypes is currently not known, but studies performed in animal models have provided some candidate autoantigens. The following studies are proposed: Aim 1: Determine the array of epitopes derived from candidate autoantigens expressed by normal peripheral blood APC and determine how cytokines modulate presentation of these epitopes; Aim 2: Determine the array of epitopes derived from candidate autoantigens expressed by APC obtained from RA patients and determine how cytokines modulate presentation of these epitopes; Aim 3: Determine if mature dendritic cells obtained from rheumatoid synovia display enhanced ability to process and present soluble autoantigens due to the presence of inflammatory cytokines. T cell hybridomas which recognize peptides derived from human type II collagen HCgp39 and calreticulin in the context of DR4 have been generated by immunizing human DR4 transgenic mice with these candidate autoantigens. These T cell hybridomas can then be used to study presentation of these epitopes by APC from human DR4 donors with and without rheumatoid arthritis.