Target organ localization of memory CD4+ T cells in patients with chronic beryllium disease

Abstract

Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace, and it remains an important public health concern. Evidence suggests that CD4(+) T cells play a critical role in the development of this disease. Using intracellular cytokine staining, we found that the frequency of beryllium-specific CD4(+) T cells in the lungs (bronchoalveolar lavage) of 12 CBD patients ranged from 1.4% to 29% (mean 17.8%), and these T cells expressed a Th1-type phenotype in response to beryllium sulfate (BeSO(4)). Few, if any, beryllium-specific CD8(+) T cells were identified. In contrast, the frequency of beryllium-responsive CD4(+) T cells in the blood of these subjects ranged from undetectable to 1 in 500. No correlation was observed between the frequency of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells as detected by intracellular staining and lymphocyte proliferation in culture after BeSO(4) exposure. Staining for surface marker expression showed that nearly all BAL T cells exhibit an effector memory cell phenotype. These results demonstrate a dramatically high frequency and compartmentalization of antigen-specific effector memory CD4(+) cells in the lungs of CBD patients. These studies provide insight into the phenotypic and functional characteristics of antigen-specific T cells invading other inaccessible target organs in human disease.

Identification of Multiple Public TCR Repertoires in Chronic Beryllium Disease

“…1). We focused on IFN-γ since it is the predominant cytokine expressed by Be-specific CD4 + T cells (14, 15). Similar to patient 1332, CD4 + T cell lines derived from BAL of patients 1056 and 1435 also expressed Vβ5.1 + T cell expansions as measured by an increased frequency (10-30%) of IFN-γ-producing Vβ5.1 + cells compared to non-IFN-γ producing cells (<6%) (Fig.…”

“…The onset of CBD is associated with the accumulation of Be-specific, Th1 cytokine-secreting CD4 + T cells in the lung (14, 15). With a known antigen and access to pathogenic CD4 + T cells from the lung, CBD is an important organ-specific immune-mediated disease, characterized by a CD4 + T cell alveolitis and lung fibrosis.…”

p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation

“…Once an adaptive immune response to beryllium is established, Be-stimulates activation and proliferation of a subset of Be-specific CD4+ pathogenic T cells and secretion of pro-inflammatory cytokines that in-turn amplifies granuloma formation in CBD [5, 47]. To investigate the role of p38MAPK in this process of Be-related disease, we evaluated the impact of the p38MAPK inhibitor SB203580 on the Be-specific adaptive immune response.…”

“…While BeS precedes CBD, the immune changes that cause progression from BeS to CBD are unclear. However, at some point accumulation of CD4+ T cells are noted in the lung, and once these Be-specific CD4+ T cells are activated, they clonally proliferate and secrete cytokines such as IL-2, IFN-γ, and TNFα but not IL-4 [5–7]. This process results in granulomatous inflammation and perpetuation of this Be-immune response.…”

Molecular mechanisms for contribution of MHC molecules to autoimmune diseases

“…The disease has an association with DPβ 69 Glu expressing DP alleles, of which DPB1 *02:01 is the most prevalent [42]. The patients have Bespecific CD4 T cells in the lungs [43] which are restricted by disease-associated MHC molecules [44,45]. The crystal structure of a Be 2+ specific T cell receptor (TCR) bound to a complex of HLA-DP2, self-peptide and Be 2+ was recently solved **[46].…”