Distinct vascular lesions in giant cell arteritis share identical T cell clonotypes.

Abstract

SulTlmaryGiant cell arteritis (GCA) is a spontaneous vasculitic syndrome that specifically targets the walls of medium and large arteries. Vascular lesions are characterized by patchy granulomatous infiltrates composed of T cells, macrophages, histiocytes, and giant cells. To test the hypothesis that a locally residing antigen recruits T cells into the vessel walls, we have analyzed T cell receptor (TCR) molecules of tissue infiltrating T cells. A total of 638 CD4 + T cell clones were isolated from temporal artery specimens of three patients with GCA. Analysis of TCR molecules for the usage of V/31-VB20 revealed that all TCR V/3 elements were represented, demonstrating that interleukin 2 (IL-2)-responsive T cells infiltrating the tissue are highly diverse. To detect expanded T cell specificities, we made use of the patchy character of the inflammatory disease and compared the TCR repertoire ofT cells established from independent vasculitic foci of the same artery. Sequence analysis of TCR V/3 chains documented that individual TCR specificities were present in multiple copies, indicating clonal expansion. T cells with identical/3 chains were isolated from distinct inflammatory loci of the same patient. These specificities represented only a small fraction of tissue-infiltrating T cells and involved the V/35.3 gene segment in the two patients sharing the HLA-DRBI*0401 allele. The third complementarity determining region of clonally expanded TCR/3 chains was characterized by a duster of negatively and positively charged residues, suggesting that the juxtaposed antigenic peptide is charged. The sharing of identical T cell specificities by distinct and independent regions of the granulomatous inflammation suggests that these T cells are disease relevant and that their repertoire is strongly restricted. These data suggest that an antigen residing in the arterial wall is recognized by a small fraction of CD4 + T cells in the inflammatory process characteristic for GCA.

Disease patterns and tissue cytokine profiles in giant cell arteritis

“…Alternatively, a specific suppression of IFNy could be attempted, assuming that tissue IFNy production is a consequence of local antigen recognition (7,20,21). Experimental therapy exploring a targeted suppression of antigen-driven T cell stimulation should work best in patients whose vascular lesions secrete high concentrations of IFNy.…”

Functional profile of tissue-infiltrating and circulating CD68+ cells in giant cell arteritis. Evidence for two components of the disease.

“…We have provided evidence recently for clonal expansion of CD4+ T cells in the vascular lesions (5). A minority of tissue-infiltrating T cells were present in multiple copies, and CD4+ T cells with identical T cell receptor 83 chains were isolated from distinct vasculitic foci.…”

Therapeutic effects of acetylsalicylic acid in giant cell arteritis

“…CD4 T cell clones were generated from the temporal artery tissue of patients with GCA and from peripheral blood mononuclear cells (PBMC) of healthy controls, and maintained in culture as previously described (25). Monocytes were prepared from PBMC of patients with GCA by plastic adherence.…”