Bias toward use of a specific T cell receptor beta-chain variable region in a subgroup of individuals with sarcoidosis.

Möller, David R.; Konishi, Kazuki; Kirby, Martha; Balbi, Bruno; Crystal, Ronald G.

doi:10.1172/jci113715

Cited by 150 publications

(82 citation statements)

References 57 publications

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“…A restricted usage of certain TCR gene products in active sarcoidosis at the site of inflammation has previously been reported [16,17]. The patients in this study were also characterised at BAL1 by such a restricted usage of the TCR gene segment, AV2S3.…”

Section: Discussionsupporting

confidence: 62%

Markers of activity in clinically recovered human leukocyte antigen-DR17-positive sarcoidosis patients

Planck

Eklúnd²,

Grünewald³

2003

Eur Respir J

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Markers of activity in clinically recovered human leukocyte antigen-DR17-positive sarcoidosis patients. A. Planck, A. Eklund, J. Grunewald. #ERS Journals Ltd 2003. ABSTRACT: Scandinavian human leukocyte antigen-DR17-positive (DR17z) sarcoidosis patients are characterised by a good prognosis. They also reveal an accumulation in bronchoalveolar lavage fluid of T-lymphocytes expressing the T-cell receptor V gene segment AV2S3 at disease onset. The authors of this study wished to establish whether AV2S3 T-lymphocyte accumulation changes from disease onset to clinically resolved disease and how this relates to other activity parameters.Bronchoalveolar lavage fluid and serum from nine DR17z sarcoidosis patients were examined at disease onset and after spontaneous resolution of clinical and radiographical signs of disease.Nine DR17z patients with lung accumulated CD4z AV2S3z T-cells were investigated after clinically recovery. At re-examination the percentage of CD4z AV2S3z lymphocytes in bronchoalveolar lavage fluid was normalised (29 versus 5.4%). A significant reduction in lymphocyte percentage (14 versus 4.4%) and a decrease in cellular concentration (179610?L -1 ) and CD4/CD8 ratio (5.2 versus 2.4) were also seen. In serum, the activity of angiotensin-converting enzyme (24.9 versus 14.0 U?mL -1 ) as well as the levels of neopterin (7.8 versus 5.3 nmol?L -1 ) decreased significantly after recovery.These results indicate that the locally accumulated AV2S3 positive T-lymphocytes in bronchoalveolar lavage are involved in the pathogenic process of sarcoidosis in this patient group.

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Section: Discussionsupporting

confidence: 62%

Markers of activity in clinically recovered human leukocyte antigen-DR17-positive sarcoidosis patients

Planck

Eklúnd²,

Grünewald³

2003

Eur Respir J

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“…7 Cells were >95% viable as determined by trypan blue exclusion. Blood mononuclear cells were isolated by Ficoll-Hypaque gradient centrifugation as described previously.…”

Section: Lung and Blood Mononuclear Cell Preparationsmentioning

confidence: 99%

“…Blood mononuclear cells were isolated by Ficoll-Hypaque gradient centrifugation as described previously. 7 Immunofluorescence analysis Evaluation of lung and blood mononuclear cells for the proportions of CD3 + , CD4 , CD8 + and Vb8 T cells was performed as described previously using flow cytometry and anti-CD3 (Leu-4), anti-CD4 (Leu-3), anti-CD8 (Leu-2) (Becton Dickinson Immunocytometry Systems, Mountain View, CA) and anti-Vb8 (5REX9H5; kindly provided by E. Reinherz, Dana-Farber Cancer Institute, Boston, MA) monoclonal antibodies (mAb) and stained with fluorescein isothiocyanate (FITC)-conjugated goat anti-mouse immunoglobulin (Tago Inc., Burlingame, CA). 7,25 Isolation of lung and blood T-cell RNA and preparation of cDNA Total lung cell RNA was extracted using guanidine isothiocyanate and ultracentrifugation through a caesium chloride gradient.…”

Section: Lung and Blood Mononuclear Cell Preparationsmentioning

confidence: 99%

“…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%

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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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“…Specific interactions between T cells and antigens may increase the frequency of T cells using selected TCR V gene segments, while superantigens stimulate T cells in a Vb-specific manner [15]. In certain inflammatory and autoimmune conditions, samples of affected sites show restricted or preferential expression of distinct Vb or Va families [30][31][32]. Moreover, T cells obtained from patients with various different disease states have different relative ratios of cytokine gene expression and/or secretion [33,34].…”

Section: Discussionmentioning

confidence: 99%

TCR usage and cytokine expression in peripheral blood and BAL T cells

Bakakos

Pickard

Smith

et al. 2002

Clinical and Experimental Immunology

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SUMMARY T cells are thought to play an important regulatory role in atopic asthma. We hypothesized that human blood and BAL T cell subsets bearing various TCR-Vβ genes might show selective differences in their cytokine profile. Peripheral blood (PB) and bronchoalveolar lavage (BAL) T cells from seven atopic asthmatic and six non-atopic non-asthmatic subjects were stimulated with PMA and ionomycin in the presence of monensin and analysed for TCR-Vβ expression and production of cytokines at the single cell level. The percentage of IFN-γ- and IL-2-producing BAL T cells was elevated compared with PB T cells from both the asthmatic subjects and the non-atopic, non-asthmatic controls. A small percentage of PB and BAL T cells produced IL-4 and IL-5, in asthmatic and normal subjects. In peripheral blood, the percentage of T cells expressing each cytokine was similar in the various TCR-Vβ subsets and in total CD3+ T cells in all normal and six of seven asthmatic subjects. However, there was a substantial degree of heterogeneity in the cytokine profile of BAL TCR-Vβ subsets compared with the total CD3+ T cells. This was more obvious in the asthmatic subjects with a reduction in the percentage of IFN-γ- and IL-2-expressing T cells (five of seven asthmatic subjects) and an increase in the percentage of IL-4- and IL-5-expressing T cells (two of seven asthmatic subjects). These data confirm previous findings of an elevated proportion of IFN-γ- and IL-2-producing BAL T cells while only a small proportion of PB and BAL T cells produce IL-4 and IL-5. Moreover, subsets of BAL T cells, defined by their TCR-Vβ usage, may differ in their cytokine profile compared with the total CD3+ T cells, implying that T cells expressing different Vβ elements may play different roles in regulating the airway inflammation in asthma.

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Bias toward use of a specific T cell receptor beta-chain variable region in a subgroup of individuals with sarcoidosis.

Cited by 150 publications

References 57 publications

Markers of activity in clinically recovered human leukocyte antigen-DR17-positive sarcoidosis patients

Markers of activity in clinically recovered human leukocyte antigen-DR17-positive sarcoidosis patients

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

TCR usage and cytokine expression in peripheral blood and BAL T cells

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