- Systemic immunization of Balb/C mice with human aggrecan (high-density cartilage proteoglycan) induces progressive polyarthritis. This murine model (PG-induced arthritis (PGIA)) shares certain similarities with rheumatoid arthritis (RA) as indicated by clinical assessments, laboratory tests, histopathology of diarthrodial joints, and recessive inheritance of disease susceptibility dictated by both MHC- and non-MHC-associated genes. Development of disease is based upon cross-reactive immune responses between the immunizing (human) and self (mouse) cartilage aggrecan. Recently, the principal investigator conducted epitope-mapping studies on human aggrecan and identified a total of 27 T-cell determinants that belong to three functionally distinct groups. T-cell responses to at least 3 of the 27 epitopes are clearly associated with the onset of arthritis in Balb/C mice. The dominant (arthritogenic) T-cell epitopes were located in the G1 domain of aggrecan. Some peptides representing aggrecan core epitopes, induced either cytokine (IL-2, IFNgamma) production or T-cell proliferation in vitro, but not both. This partial activation of T cells might be associated with an altered peptide ligand (APL) effect. More importantly, certain T-cell epitopes (peptides) induced the production of Th1-type cytokines, whereas the homologous mouse self peptides induced mostly Th2-type cytokine secretion. The principal investigator hypothesizes that T cell maturation, the balance of Th1/Th2 regulation, and T-cell recognition of aggrecan core peptides are substantially altered by the sequence of the peptide (non-self versus self), and that an epitope hierarchy may dictate the onset of aggrecan-induced autoimmune arthritis. The functions of the arthritogenic/dominant epitope sequences, in context with TCR and MHC-binding, will be studied in three specific aims utilizing the PGIA model.
In Aim 1, T cell responses to immunodominant (arthritogenic) epitopes of aggrecan core protein will be studied using the capacity of APLs to modulate immune responses and T cell differentiation and in vitro (Aim 1A) and the clinical appearance of PGIA in vivo (Aim 1B).
In Aim 2 mutations in the immunodominant determinants of the G1 domain of the human aggrecan core protein will be performed to elucidate the function of immunodominant, and possibly some subdominant/cryptic T cell epitopes, when these antigenic determinants are components of an immunogenic macro-molecule.
Aim 3 will study aggrecan-specific T cell responses and arthritis susceptibility in HLA-DRB1 transgenic mice to reveal the pathological potential of cartilage aggrecan in human RA. Fine epitope mapping will be performed in aggrecan-responder transgenic mice and arthritis susceptibility studied in their HLA-DRB1/Balb/C congenic offspring.
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