The pathogenic role of T lymphocytes in vasculitis.
Several disease mechanisms have been studied in the model of GCA. GCA patients exhibit a genetic susceptibility which has been mapped to the HLA-DRB1 gene. Polymorphic amino acid residues localized at the floor of the antigen binding site are highly selected in GCA patients suggesting a role for antigen binding and presentation in the disease. This and other genetic risk factors might actually be a surrogate for the distinct geographic distribution of the disease with a marked preference for Northern Europe. Studies on functional aspects of T cells accumulating in the vasculitic foci have demonstrated a strong bias for Th1 helper T cells which locally release IL-2 and IFN-gamma. IFN-gamma appears to be a key cytokine in this vasculitis. IFN-gamma producing T cells represent a minority of the tissue infiltrating cell population suggesting that very few cells have disease relevance and the majority of T cells is recruited as bystanders. IFN-gamma secreting CD4 T cells preferentially localize to the adventitial-medial junction and are thus placed distant from the center of pathology, the intima and internal media. TCRs expressed by T cells accumulated in the affected tissue are not randomly distributed but are biased toward selected specificities. These selected T cells undergo proliferation in the tissue and can be isolated from nonadjacent and independent sites of the vasculitis. This distribution pattern indicates a common driving factor, suspected to be a tissue residing antigen [8]. Further support for an antigen driving this pathological T cell response comes from the finding that temporal artery specimens engrafted into SCID mice continue to show the typical disease process indicating that all components relevant for the disease are contained in the temporal artery wall. So far no shared TCR utilized by different patients has been identified, raising the question whether distinct antigens can elicit GCA as a common pathway of reactivity. Besides its role in investigating pathomechanisms the SCID mouse model of GCA provides the unique opportunity to study the therapeutic effects of established and novel treatments. It can be expected that some of the pathogenic rules established for GCA can be applied to other vasculitic syndromes.
Weyand
C M
CM
Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Goronzy
J J
JJ
D000818:Animals; D013700:Giant Cell Arteritis / Q000209:etiology* / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology*; D014657:Vasculitis / Q000209:etiology / Q000235:genetics
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains