Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis

Atamas, Sergei P.; Yurovsky, Vladimir V.; Wise, Robert A.; Wigley, Fredrick M.; Robinson, Courtland; Henry, Patricia A.; Alms, William J.; White, Barbara

doi:10.1002/1529-0131(199906)42:6<1168::aid-anr13>3.0.co;2-l

Cited by 198 publications

(177 citation statements)

References 38 publications

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“…Both SSc and cGVHD are characterized by skin, lung, and esophageal involvement and intense fibrosis (1,2). Immunologic similarities include lymphocytic infiltration of affected tissues, the presence of Scl-70 and PM-Scl serum autoantibodies, and up-regulation of a series of cytokines (1,2,(5)(6)(7)(8). Moreover, several reports have indicated that IL-4 production by CD4ϩ T cells infiltrating SSc and cGVHD lesions is prominent in both animal models and humans, suggesting a Th2-polarized phenotype of the specific immune response in both conditions (5)(6)(7)(8)10,11).…”

Section: Discussionmentioning

confidence: 99%

“…The selected CD4ϩ T cell population derived from fetal cell engraftment may be at least partially included in the population of T cells expressing IL-4 that are found in the skin of patients with SSc (5), and it is probably responsible for the enhanced levels of IL-4 in the biologic fluids of these patients (6)(7)(8). Thus, although the results of this study need further investigation, they provide support for the hypothesis that a fetal antimaternal cGVHD may be an immunopathogenic mechanism in the development of SSc in some women.…”

Section: Discussionmentioning

confidence: 99%

“…We and other investigators have reported the existence of a predominant activation of IL-4-producing Th2-like T cells in patients with SSc, which may account for the major alterations that occur in this disease (5)(6)(7)(8).…”

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confidence: 88%

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Th2‐oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens

Scaletti

Vultaggio

Bonifacio

et al. 2002

Arthritis & Rheumatism

122

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Objective. To characterize the cytokine production profile of male-offspring T cells reactive against maternal major histocompatibility complex (MHC) antigens present in the peripheral blood and/or skin from women with systemic sclerosis (SSc).Methods. T cell clones were generated from peripheral blood and/or skin biopsy specimens from 3 women with SSc of recent onset and from peripheral blood from 3 healthy women, all of whom had 1 male child. All clones were screened for their proliferative response in vitro to maternal MHC antigens by measuring 3 H-thymidine uptake and for their expression of Y chromosome by using fluorescence in situ hybridization. The concentrations of interferon-␥ and interleukin-4 (IL-4) released by T cell clones in response to maternal MHC antigens were evaluated in culture supernatants, using appropriate enzyme-linked immunosorbent assays.Results. Thirty-nine of 202 T cell clones generated from women with SSc and 11 of 312 from healthy women proliferated in vitro in response to maternal MHC antigens. Seven MHC-reactive T cell clones obtained from women with SSc and 1 obtained from healthy women exhibited the Y chromosome, thus indicating that the clones were derived from T cells of male offspring. All clones generated from male-offspring T cells of SSc women (but not from those of healthy women) produced significantly higher levels of IL-4 in response to stimulation with maternal MHC antigens than did all other clones generated from the same women. The other clones proliferated in response to maternal or allogeneic MHC antigens but did not exhibit the Y chromosome.Conclusion. Male-offspring T cells that are present in the blood and skin of women with SSc and react with maternal MHC antigens exhibit a Th2-oriented profile, supporting the possibility that a chronic graft-versus-host reaction attributable to longterm microchimerism plays a pathogenic role in SSc.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Th2‐oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens

Scaletti

Vultaggio

Bonifacio

et al. 2002

Arthritis & Rheumatism

122

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“…CD8ϩ T cells are seen in the pulmonary interstitium on lung biopsy specimens and are increased in the bronchoalveolar lavage fluid from SSc patients with active lung disease (alveolitis) compared with SSc patients with inactive lung disease or no lung disease (11). These T cells exhibit an activated phenotype (HLA-DRϩ), and their presence in the bronchoalveolar lavage fluid is quantitatively associated with progressive and more severe ILD (12,13). Similarly, activated T cells are described in skin biopsy specimens from SSc patients who have early active cutaneous involvement (14).…”

mentioning

confidence: 99%

“…Th2 cytokine expression and secretion are increased in T cells isolated from newly affected SSc skin (21,22). Activated CD8ϩ T cells in bronchoalveolar lavage fluid from SSc patients with alveolitis have higher type 2 cytokine (IL-4 and IL-5) messenger RNA (mRNA) expression (12,13). These data suggest that in SSc, a specific population of activated T cells exhibiting a profibrotic Th2/Tc2-polarized phenotype may be potentially relevant in mediating tissue fibrosis.…”

mentioning

confidence: 99%

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

Boin¹,

Fanis²,

Bartlett³

et al. 2008

Arthritis & Rheumatism

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Objective. Lung involvement is the leading cause of morbidity and mortality in systemic sclerosis (SSc; scleroderma), and interstitial lung disease (ILD) is the most common pulmonary manifestation. An abnormal profibrotic Th2/Tc2-polarized T cell response is postulated to mediate tissue damage and fibrosis. The aim of this study was to investigate whether a polarized T cell phenotype in SSc is associated with lung disease or other clinical manifestations of SSc.Methods. Circulating T cells were characterized by flow cytometry in 62 patients with SSc and 36 healthy control subjects, using antibodies against CD3, CD4, CD8, chemokine receptor CCR5 (Th1/Tc1-specific), and prostaglandin D 2 receptor CRTH2 (Th2/Tc2-specific). The ratio between CCR5 and CRTH2 T cell frequencies was used to quantify type 1 (high-ratio) or type 2 (low-ratio) immune polarization.Results. Patients with SSc exhibited lower CCR5/ CRTH2 T cell ratios than those exhibited by control subjects (P < 0.0001), indicating a Th2/Tc2-polarized phenotype. Markedly reduced CCR5/CRTH2 T cell ratios were observed in SSc patients with ILD compared with SSc patients without ILD (P < 0.0001), particularly in patients with active ILD (P < 0.0001) compared with those with stable lung function. Lower CCR5/ CRTH2 ratios were strongly associated with a lower value for the percent predicted forced vital capacity (P < 0.0001). In patients with an estimated right ventricular systolic pressure >35 mm Hg, suggestive of pulmonary vascular disease, a lower value for the percent predicted diffusing capacity (DLCO) was associated with higher CCR5/CRTH2 T cell ratios (Th1/Tc1) (P ‫؍‬ 0.009), while in those with right ventricular systolic pressure <35 mm Hg, a lower value for the percent predicted DLCO correlated with lower ratios (Th2/Tc2) (P < 0.0001), as observed for ILD.

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Th2-type cytokines and the Fas way to pulmonary fibrosis: Comment on the article by Atamas et al

Spinozzi

Agea

Russano

et al. 2000

Arthritis & Rheumatism

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Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis

Cited by 198 publications

References 38 publications

Th2‐oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens

Th2‐oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

Th2-type cytokines and the Fas way to pulmonary fibrosis: Comment on the article by Atamas et al

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