期刊
FRONTIERS IN IMMUNOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.01516
关键词
sarcoidosis; bronchoalveolar lavage fluid; autoantibodies; vimentin; Lofgren's syndrome; HLA-DRB1*03
类别
资金
- Swedish Heart Lung Foundation [20130321]
- Swedish Research Council [K2013-57X-14182-12-3]
- King Oscar II Jubilee Foundation
- King Gustaf V's and Queen Victoria's Freemasons' Foundation
- Karolinska Institutet [3-1818/2013]
- Stockholm County Council
- Karolinska Institutet
- NIH Autoimmunity Center of Excellence [AI082724, AR55646]
Vimentin has been implicated in pulmonary sarcoidosis as a T-cell autoantigen, particularly in the context of HLA-DRB1*03, the V alpha 2.3/V beta 22 T-cell receptor (TCR), and Lofgren's syndrome. As vimentin is a known antigenic target in B-cell-mediated autoimmunity, we investigated in situ humoral anti-vimentin responses in pulmonary sarcoidosis and their relationship with HLA-DRB1*03. Sarcoid and healthy control (HC) lung biopsies were analyzed by multi-color confocal microscopy for B-cells, T-cells, proliferation, and vimentin, and compared to tonsillectomy tissue. Bronchoalveolar lavage fluid (BALF) and serum from 48 sarcoidosis patients and 15 healthy volunteers were typed for HLA-DRB1*03 and titrated for antibodies to full-length vimentin, vimentin truncations, and total IgG and IgA by ELISA. Presence of extracellular vimentin in BALF was determined by mass spectrometry and T-cell populations measured by flow cytometry. Sarcoid lung samples, especially from HLA-DRB1*03(+) patients, contained vimentin-rich tertiary lymphoid structures and corresponding BALF was highly enriched for both IgG and IgA anti-vimentin antibody (AVA) titers. Furthermore, sarcoidosis patient BALF AVA concentrations (expressed as arbitrary units per milligram of total immunoglobulin isotype) correlated with the percentage of CD4(+) T-cells expressing the V alpha 2.3/V beta 22 TCR. BALF antibody reactivity to the vimentin N- terminus was most prominent in HCs, whereas reactivity to the C-terminus (Vim(C-term)) was enriched in the sarcoid lung. Specifically, HLA-DRB1*03+ patient BALF contained higher concentrations of anti-Vim(C-term) antibodies than BALF from both HCs and HLA-DRB1*03-patients. Consistent with the lung as a site of AVA production, the concentration of AVAs in BALF was dramatically higher than in matched serum samples. Overall, there was a poor correlation between BALF and serum AVA concentrations. Together, these studies reveal the presence of linked in situ recognition of vimentin by both T-and B-cells in HLA-DRB1(*)03(+) sarcoidosis patients, associated with a selective humoral immune response to the vimentin C-terminus.
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