Restricted V_α2.3 gene usage by CD4⁺ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA‐DR3

Abstract

The alpha/beta T cell receptor (TcR) V gene usage of bronchoalveolar lavage (BAL) lymphocytes and peripheral blood lymphocytes (PBL) from 11 sarcoidosis patients and 4 healthy controls was investigated, using eight alpha/beta TcR V gene product-specific monoclonal antibodies (mAb). Twenty-seven percent (3/11) of the sarcoidosis patients had a highly significant increase in V alpha 2.3+CD4+ T lymphocytes in the bronchoalveolar space, while displaying normal frequencies of these T cells in peripheral blood. The reactivities with the remaining seven TcR mAb were normal. In the control group, no compartmentalization of any T cells was seen. Four of the patients expressed the HLA-DR3 (w17), DQw2 haplotype. Interestingly, the three patients with distinct signs of compartmentalized V alpha 2.3+CD4+ T cells all expressed this HLA haplotype. Additionally, a fourth patient with pronounced, although less significant, accumulation of V alpha 2.3+CD4+ T cells in the lung, was also HLA-DR3(w17), DQw2+. Expression of V alpha 2.3+CD4+ T cells in BAL of these patients correlated with clinical disease, as revealed on re-analyzing the four patients after 6 months or longer. Predominant TcR V alpha 2.3 gene usage in compartmentalized CD4+ BAL T lymphocytes, linked to HLA-DR3(w17), DQw2 haplotype, may thus indicate presence of a specific antigen localized to the lungs of sarcoidosis patients.

Limited heterogeneity of biased T‐cell receptor Vβ gene usage in lung but not blood T cells in active pulmonary sarcoidosis

“…6 Since the aetiology of sarcoidosis is unknown, efforts to understand the mechanisms underlying the accumulation of T cells in affected organs have concentrated on evaluating T cells at sites of disease and in the peripheral blood for preferential usage of specific T-cell receptor genes. [7][8][9][10][11][12][13][14] This approach is based on the knowledge that antigen-specific immune responses can be associated with biases in the usage of specific -chain are seen in antigen-specific T cells specific for cytochrome-c, myelin basic protein, mycobacterial heat shock proteins, influenza virus and tetanus toxoid. [15][16][17][18][19][20][21] Biases in the usage of Va TCR gene segments have also been reported for selected antigen-specific T cells.…”

“…[7][8][9][10][11][12][13][14] For example, using a panel of monoclonal antibodies directed against a small number of Vb genes, our previous study detected a subgroup of individuals with sarcoidosis who had biased accumulation of Vb8 T cells in either the lung or blood. 7 In order to evaluate the diversity and longevity of this Vb8 T-cell response in sarcoidosis, the present study presents a detailed clonal analysis and serial evaluation of Vb8 Tcell populations present in individuals with sarcoidosis characterized by preferential expansion of Vb8 T cells.…”

“…10 Although Va gene usage was not analysed in the current study, it is likely that such an analysis, when combined with evaluation of Vb gene usage, may identify additional patients with clonal expansions of select T cells at sites of disease. The use of different Vb genes in the oligoclonal expansion of select Vb T-cell subsets in sarcoidosis may reflect different MHC haplotypes in different individuals.…”

Human leukocyte antigen genes may outweigh racial background when generating a specific immune response in sarcoidosis

“…AV2S3z CD4z T-cells accumulating in the lungs, was previously identified only in HLA-DR17 positive Scandinavian Caucasian sarcoidosis patients [20,22]. In fact, the association between lung accumulated CD4z AV2S3z T-lymphocytes and HLA-DR17 in Scandinavian patients with pulmonary sarcoidosis is extremely strict, provided there is an active disease [20,22]. Moreover, BAL AV2S3z T-cells were recently found to correlate with clinical features of the disease [23] and to express a panel of activation markers indicative of select stimulation of this particular subset [24].…”

“…AV2S3z CD4z T-cells accumulating in the lungs, was previously identified only in HLA-DR17 positive Scandinavian Caucasian sarcoidosis patients [20,22]. In fact, the association between lung accumulated CD4z AV2S3z T-lymphocytes and HLA-DR17 in Scandinavian patients with pulmonary sarcoidosis is extremely strict, provided there is an active disease [20,22].…”