BACKGROUND: Sarcoidosis is a multisystem disorder that predominantly involves the lungs, characterised by a T-helper 1 (Th1) biased CD4-positive T-cell response and granuloma formation, for which the explanation is unknown. A newly identified subset of T-cells with immunoregulatory functions, CD1d-restricted natural-killer T (NKT) cells, has been shown to protect against disorders with increased CD4-positive Th1 responses in animals. We explored whether abnormalities in these cells are implicated in the pathogenesis of sarcoidosis. METHODS: We generated fluorescence-labelled CD1d-tetrameric complexes and used them, with monoclonal antibodies to Valpha24 and Vbeta11 T-cell receptor, to assess the frequency of CD1d-restricted NKT cells in the peripheral blood of 60 patients with histologically proven sarcoidosis (16 with Lofgren's syndrome) and 60 healthy controls. Lung lymphocytes were also analysed in 16 of the patients with sarcoidosis. FINDINGS: CD1d-restricted NKT cells were absent or greatly reduced in peripheral blood from all patients with sarcoidosis, except those with Lofgren's syndrome (median proportion of lymphocytes 0.01% [IQR 0-0.03] vs 0.06% [0.03-0.12] in controls; p=0.0004). The deficiency was found in both acute and resolved disease and was unrelated to systemic corticosteroid therapy. There was no difference in the proportion of CD1d-restricted NKT cells between peripheral blood and lungs in patients, suggesting that the peripheral-blood deficiency is not due to sequestration of these cells in the lungs. The NKT cells were not observed in mediastinal lymph nodes or granulomatous lesions. CD1d expression on antigen-presenting cells of patients was normal, thus the deficiency of CD1d-restricted NKT cells is not explained by abnormal CD1d expression. INTERPRETATION: Loss of immunoregulation by CD1d-restricted NKT cells could explain the amplified and persistent T-cell activity that characterises sarcoidosis. RELEVANCE TO PRACTICE: Our findings give new insight into the pathogenesis of sarcoidosis and draw attention to a potential target for therapeutic modulation in sarcoidosis.
BACKGROUND:Sarcoidosis is a multisystem disorder that predominantly involves the lungs, characterised by a T-helper 1 (Th1) biased CD4-positive T-cell response and granuloma formation, for which the explanation is unknown. A newly identified subset of T-cells with immunoregulatory functions, CD1d-restricted natural-killer T (NKT) cells, has been shown to protect against disorders with increased CD4-positive Th1 responses in animals. We explored whether abnormalities in these cells are implicated in the pathogenesis of sarcoidosis. METHODS: We generated fluorescence-labelled CD1d-tetrameric complexes and used them, with monoclonal antibodies to Valpha24 and Vbeta11 T-cell receptor, to assess the frequency of CD1d-restricted NKT cells in the peripheral blood of 60 patients with histologically proven sarcoidosis (16 with Lofgren's syndrome) and 60 healthy controls. Lung lymphocytes were also analysed in 16 of the patients with sarcoidosis. FINDINGS:CD1d-restricted NKT cells were absent or greatly reduced in peripheral blood from all patients with sarcoidosis, except those with Lofgren's syndrome (median proportion of lymphocytes 0.01% [IQR 0-0.03] vs 0.06% [0.03-0.12] in controls; p=0.0004). The deficiency was found in both acute and resolved disease and was unrelated to systemic corticosteroid therapy. There was no difference in the proportion of CD1d-restricted NKT cells between peripheral blood and lungs in patients, suggesting that the peripheral-blood deficiency is not due to sequestration of these cells in the lungs. The NKT cells were not observed in mediastinal lymph nodes or granulomatous lesions. CD1d expression on antigen-presenting cells of patients was normal, thus the deficiency of CD1d-restricted NKT cells is not explained by abnormal CD1d expression. INTERPRETATION: Loss of immunoregulation by CD1d-restricted NKT cells could explain the amplified and persistent T-cell activity that characterises sarcoidosis. RELEVANCE TO PRACTICE: Our findings give new insight into the pathogenesis of sarcoidosis and draw attention to a potential target for therapeutic modulation in sarcoidosis.
Authors: Laura Denney; Celia Aitken; Chris Ka-Fai Li; Eleri Wilson-Davies; Wai Ling Kok; Colin Clelland; Kevin Rooney; Duncan Young; Tao Dong; Andrew J McMichael; William F Carman; Ling-Pei Ho Journal: PLoS One Date: 2010-05-18 Impact factor: 3.240