Abstract
IntroductionSarcoidosis is a multisystem granulomatous disease for which the association with mycobacteria continues to strengthen. It is hypothesized that a single, poorly degradable antigen is responsible for sarcoidosis pathogenesis. Several reports from independent groups support mycobacterial antigens having a role in sarcoidosis pathogenesis. To identify other microbial targets of the adaptive immune response, we tested the ability of CD4+ and CD8+ T cells to recognize multiple mycobacterial antigens.MethodsFifty-four subjects were enrolled in this study: 31 sarcoidosis patients, nine non-tuberculosis mycobacterial (NTM) infection controls, and 14 PPD- controls. Using flow cytometry, we assessed for Th1 immune responses to ESAT-6, katG, Ag85A, sodA, and HSP.ResultsAlveolar T-cells from twenty-two of the 31 sarcoidosis patients produced a CD4+ response to at least one of ESAT-6, katG, Ag85A, sodA, or HSP, compared to two of 14 PPD- controls (p = 0.0008) and five of nine NTM controls (p = 0.44), while eighteen of the 31 sarcoidosis subjects tested produced a CD8+ response to at least one of the mycobacterial antigens compared to two of 14 PPD- controls (p = 0.009) and three of nine NTM controls (0.26). Not only did the BAL-derived T cells respond to multiple virulence factors, but also to multiple, distinct epitopes within a given protein. The detection of proliferation upon stimulation with the mycobacterial virulence factors demonstrates that these responses are initiated by antigen specific recognition.ConclusionsTogether these results reveal that antigen-specific CD4+ and CD8+ T cells responses to multiple mycobacterial epitopes are present within sites of active sarcoidosis involvement, and that these antigen-specific responses are present at the time of diagnosis.
Highlights
Sarcoidosis is a multisystem granulomatous disease for which the association with mycobacteria continues to strengthen
Together these results reveal that antigen-specific CD4+ and CD8+ T cells responses to multiple mycobacterial epitopes are present within sites of active sarcoidosis involvement, and that these antigen-specific responses are present at the time of diagnosis
Four of 17 sarcoidosis subjects responded to heat shock protein 70 (HSP), compared with one of seven Purified Protein Derivative negative (PPD)- subjects (p = 1) and one of three non-tuberculosis mycobacterial (NTM) subjects (p = 1)
Summary
Sarcoidosis is a multisystem granulomatous disease for which the association with mycobacteria continues to strengthen. Immunological studies have shown that there are oligoclonal T cells in sarcoid bronchoalveolar lavage (BAL), suggesting that the response is antigen-specific [1,2]. Investigation into T cell receptors in BAL fluid has shown an AV2S3+ T cell expansion in the lung of sarcoidosis patients with HLA-DRB1*0301 and HLADRB3*0101 supporting an antigen specific response. We have shown in a previous study that in peripheral blood mononuclear cells, multiple antigens induce IFN-g production [8], as well as that T cells from sarcoidosis BAL can produce an IFN-g response to both mycobacterial ESAT-6 and KatG [14]. We analyzed specific responses to mycobacterial early secreted antigenic target protein 6 (ESAT-6), catalase-peroxidase (katG), mycolyl transferase (Ag85A), superoxide dismutase A (sodA), and heat shock protein 70 (HSP) in BAL derived T cells
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