Increased numbers of T lymphocytes with gamma delta-positive antigen receptors in a subgroup of individuals with pulmonary sarcoidosis.

Balbi, Bruno; Möller, David R.; Kirby, Martha; Holroyd, Kenneth J.; Crystal, Ronald G.

doi:10.1172/jci114579

Cited by 95 publications

(39 citation statements)

References 80 publications

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“…Indeed, the blood findings alone appeared to be misleading in terms ofidentifying diseaserelated T cells. Thus, in concert with a prior report ( 19), we also noted that some patients with sarcoidosis have an elevated proportion of circulating T cells bearing y/6 TCR. The elevated percentage, however, did not reflect a true increase in number, but was apparently secondary to a proportional reduction in a/fl# (CD4+ and CD8 +) cells.…”

Section: Discussionsupporting

confidence: 89%

“…We found that the Vy9/V62 subset is selectively excluded from the lung T cell pool or is diluted out by the large influx ofpredominantly CD4+, a/f3' cells. Other investigators have also failed to demonstrate an increase in the proportion of total y/6 cells in the lungs and in other involved tissues of patients with sarcoidosis ( 19,40). More importantly, we noted that in patients with detectable lung -y/6 cells, a higher proportion expressed VS1 segments compared with blood cells.…”

Section: Discussionsupporting

confidence: 49%

“…The second most frequent blood subset, expressing VA 1 and a Vy other than Vy9, appears to be nonresponsive to mycobacterial antigens. Interestingly, a recent study in patients with pulmonary sarcoidosis demonstrated an increased percentage of peripheral blood 'v/6 T cells expressing Vy9 (19,20). However, the involvement ofthese cells in the lung lesions of the same patients was unclear.…”

Section: Introductionmentioning

confidence: 99%

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Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis.

Forrester

Newman²,

Wang³

et al. 1993

J. Clin. Invest.

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Sarcoidosis is a multisystem disease of unknown etiology characterized by the presence of noncaseating granulomas in involved tissues. To investigate a potential role for y/6 T cells in the pathogenesis of pulmonary sarcoidosis, we studied lung and blood T cells from patients for preferential expression of particular 'y/6 T cell receptors. An abnormally high percentage of 'y/6 cells was found in the blood of some patients. However, the increased percentage did not reflect an increase in absolute number, and appeared to be secondary to a decrease in T cells expressing a/, receptors. Furthermore, as in normals, the circulating 'y/6 cells in patients predominantly expressed V-y9 /V52 receptors, a subset that was not enriched at the site of disease. In contrast, in the lung, an increased percentage of 7a/6 cells expressing VS1 was found in a subset of patients. Importantly, these cells demonstrated evidence of prior activation by selectively expanding in vitro in the presence of interleukin 2. Furthermore, an analysis of junctional region sequences revealed their clonal nature. These clonal expansions of V1 + cells in pulmonary sarcoidosis provide evidence for a disease process that involves specific recognition of a local antigen by T cells, and contributes new information regarding the nature of the as yet undefined antigenic stimulus. (J. Clin. Invest. 1993. 91:292-300.)

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

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Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis.

Forrester

Newman²,

Wang³

et al. 1993

J. Clin. Invest.

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“…In this regard, it is intriguing that one of a panel of M. leprae-specific T cell clones responsive to the 65-kD heat shock polypeptide expressed a # chain with a V/i5 gene member and a junctional region sequence with an RGGR sequence similar to the junctional region motif seen in sarcoidosis (11). Although any correlation of CDR3 region motifs to T cell specificity remains highly speculative, the hypothesis that a subset of biased sarcoid T cell clones may have specificity for either exogenous or endogenous heat shock proteins is enhanced by reports of 65-kD heat shock protein expression at sites of sarcoid granulomatous inflammation and from studies of y7+ T cells in sarcoidosis (25,(33)(34)(35)(36). It is conceivable that the preferential use of specific V/i genes in sarcoidosis reflects an autoimmune process to self-antigens such as endogenous stress proteins or other autoantigens with homology to infectious agents (36).…”

Section: Methodsmentioning

confidence: 99%

Selective activation and accumulation of oligoclonal V beta-specific T cells in active pulmonary sarcoidosis.

Forman¹,

Klein²,

Silver³

et al. 1994

J. Clin. Invest.

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102

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Sarcoidosis is a granulomatous disease in which activated T cells, responding to an unidentified stimulus, accumulate at sites of disease such as the lung. To evaluate the hypothesis that active sarcoidosis is characterized by a selective activation and expansion of a limited repertoire of T cell receptor (TCR) specific T cells, we analyzed TCR VB gene expression in lung and blood T cells of patients with active sarcoidosis and, for comparison, normal individuals using polymerase chain reaction amplification of 20 VB gene families. Analysis of normal bronchoalveolar lavage T cells revealed TCR V,8 distributions similar to that of normal blood, providing evidence for a lack of generalized skewing of the T cell repertoire in the normal, noninfected lung. Compared to normnal lung and blood, subgroups of individuals with sarcoidosis demonstrated biased expression of one or more Vfi genes in either the lung or blood. Five Vfi gene families (Vfi5, Vp8, Vfi15, Vfi16, and V1318) were most frequently utilized in a biased fashion by sarcoid lung or blood T cells. Furthermore, dramatic skewing of the T cell repertoire was apparent when sarcoid lung and blood T cells were expanded by short-term culture with IL-2. Sequence analysis demonstrated a bias in V,3 gene expression was usually due to expansion of select VB-specific clones, some of which contained a similar V(D)J junctional region motif. These observations provide evidence for a selective activation and accumulation of antigen-specific Vf8-expressing T cells in sarcoidosis. (J. Clin. Invest. 1994Invest. . 94:1533Invest. -1542

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

1996

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Sarcoidosis is a multisystem disorder characterized by non‐caseating granulomas and the accumulation of CD4+ T cells in involved tissues such as the lung. To evaluate the diversity of the CD4+ T‐cell repertoire in this disorder, a detailed clonal analysis was performed in five individuals with active sarcoidosis who demonstrated preferential accumulation of T cells expressing the T‐cell receptor variable gene family Vβ8 in either the lung or blood. In three individuals, analysis of unselected samples of nucleotide sequences derived from Vβ8+ lung T cells demonstrated degrees of clonality ranging from 11% to 46%, indicating the expansion of limited numbers of Vβ8+ T‐cell clones in the lung. Analysis of the corresponding deduced amino acid sequences demonstrated common VDJ junctional amino acid residues in the dominant Vβ8+ T‐cell clones derived from two oligoclonal Vβ8+ lung T‐cell populations, consistent with an antigen‐specific T‐cell response. In contrast, analysis of Vβ8+ CD4+ T cells from the blood of an individual with a marked bias for peripheral blood Vβ8+ T cells demonstrated no evidence of oligoclonality, suggesting that the stimulus for circulating biased Vβ‐specific T cells in sarcoidosis may derive from a different, perhaps superantigenic, origin. Clinical improvement in the disease either in response to treatment with corticosteroids or as a result of spontaneous resolution was associated with a decrease in the proportion of Vβ8‐specific T cells in the biased lung and/or blood T‐cell compartments. Together, these observations are consistent with a role for this T‐cell subset in the clinical manifestations of active granulomatous disease.

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Increased numbers of T lymphocytes with gamma delta-positive antigen receptors in a subgroup of individuals with pulmonary sarcoidosis.

Cited by 95 publications

References 80 publications

Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis.

Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis.

Selective activation and accumulation of oligoclonal V beta-specific T cells in active pulmonary sarcoidosis.

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

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