Adaptive Immunity in Pulmonary Sarcoidosis and Chronic Beryllium Disease.

Sarah A Greaves,Andrew P Fontenot,Shaikh M Atif

doi:10.3389/fimmu.2020.00474

Sarah A Greaves, Andrew P Fontenot + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2020.00474

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Abstract

Pulmonary sarcoidosis and chronic beryllium disease (CBD) are inflammatory granulomatous lung diseases defined by the presence of non-caseating granulomas in the lung. CBD results from beryllium exposure in the workplace, while the cause of sarcoidosis remains unknown. CBD and sarcoidosis are both immune-mediated diseases that involve Th1-polarized inflammation in the lung. Beryllium exposure induces trafficking of dendritic cells to the lung in a mechanism dependent on MyD88 and IL-1α. B cells are also recruited to the lung in a MyD88 dependent manner after beryllium exposure in order to protect the lung from beryllium-induced injury. Similar to most immune-mediated diseases, disease susceptibility in CBD and sarcoidosis is driven by the expression of certain MHCII molecules, primarily HLA-DPB1 in CBD and several HLA-DRB1 alleles in sarcoidosis. One of the defining features of both CBD and sarcoidosis is an infiltration of activated CD4+ T cells in the lung. CD4+ T cells in the bronchoalveolar lavage (BAL) of CBD and sarcoidosis patients are highly Th1 polarized, and there is a significant increase in inflammatory Th1 cytokines present in the BAL fluid. In sarcoidosis, there is also a significant population of Th17 cells in the lungs that is not present in CBD. Due to persistent antigen exposure and chronic inflammation in the lung, these activated CD4+ T cells often display either an exhausted or anergic phenotype. Evidence suggests that these T cells are responding to common antigens in the lung. In CBD there is an expansion of beryllium-responsive TRBV5.1+ TCRs expressed on pathogenic CD4+ T cells derived from the BAL of CBD patients that react with endogenous human peptides derived from the plexin A protein. In an acute form of sarcoidosis, there are expansions of specific TRAV12-1/TRBV2 T cell receptors expressed on BAL CD4+ T cells, indicating that these T cells are trafficking to and expanding in the lung in response to common antigens. The specificity of these pathogenic CD4+T cells in sarcoidosis are currently unknown.

Highlights

Granulomatous lung diseases represent a diverse set of disorders that are caused by both infectious and non-infectious agents that induce granuloma formation in the lung
Sarcoidosis and chronic beryllium disease (CBD) are both non-infectious granulomatous lung diseases defined by the presence of non-caseating granulomas, comprised primarily of lymphocytes, epithelioid cells, giant cells, and macrophages [2,3,4]
Increased Th1 polarized cytokines including IFN-γ, TNF-α, IL-2, IL-1 CD4+ T cell alveolitis Majority Th1 polarized No evidence of Th2 or Th17 CD4+ T cells present Increased PD-1 and CTLA-4 expression Predominantly effector memory phenotype TRBV5.1 beryllium specific TCRs are expressed in majority of HLA-DP2 patients Public TCRs recognize HLA-DP2/beryllium/plexin A peptide complex beryllium exposure has a crucial effect on innate cell function that contributes to disease development and progression

Summary

INTRODUCTION

Granulomatous lung diseases represent a diverse set of disorders that are caused by both infectious and non-infectious agents that induce granuloma formation in the lung. Certain MyD88 polymorphisms are associated with the development of sarcoidosis [30] While these studies have led some to speculate that the abnormal inflammation in sarcoidosis is caused by aberrant monocyte and macrophage activity and TLR responses, the evidence for specific antigenic stimuli, as discussed below, indicates that there is an interplay between the innate and adaptive immune responses that drives the inflammation and granuloma formation. Beryllium exposure and the development of granulomatous inflammation in CBD patients results from activation of both innate and adaptive immunity. Increased Th1 polarized cytokines including IFN-γ, TNF-α, IL-2, IL-1 CD4+ T cell alveolitis Majority Th1 polarized No evidence of Th2 or Th17 CD4+ T cells present Increased PD-1 and CTLA-4 expression Predominantly effector memory phenotype TRBV5.1 beryllium specific TCRs are expressed in majority of HLA-DP2 patients Public TCRs recognize HLA-DP2/beryllium/plexin A peptide complex beryllium exposure has a crucial effect on innate cell function that contributes to disease development and progression

B CELL INVOLVEMENT IN CBD AND SARCOIDOSIS

Findings

CONCLUSIONS