Autoreactive T and B Cells Induce the Development of Bronchus-Associated Lymphoid Tissue in the Lung

Abstract

Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Studies in humans have found that the incidence of bronchus-associated lymphoid tissue (BALT) correlates with the severity of lung injury. However, the mechanisms underlying the development of BALT during systemic autoimmunity remain unknown. We have determined whether systemic autoimmunity in a murine model of autoimmune arthritis can promote the development of BALT by generating a novel murine model derived from K/BxN mice. Transgenic mice with the KRN T-cell receptor specific for the autoantigen, glucose-6-phosphate isomerase (GPI), were crossed with GPI-specific immunoglobulin heavy and light chain knock-in mice, producing mice with a majority of T and B cells specific for the same autoantigen. We found that 67% of these mice demonstrated lymphocytic infiltration in the lungs, localized to either the perivascular or peribronchial regions. Fifty percent of the mice with lymphocytic infiltration manifested lymphoid-like lesions resembling BALT, with distinct T and B cell follicles. The lungs from mice with lymphoid infiltrates had increased numbers of cytokine-producing T cells, including IL-17A1 T cells and increased major histocompatibility complex Class II expression on B cells. Interestingly, challenge with bleomycin failed to elicit a significant fibrotic response, compared with wild-type control mice. Our data suggest that systemic autoreactivity promotes ectopic lymphoid tissue development in the lung through the cooperation of autoreactive T and B cells. However, these BALT-like lesions may not be sufficient to promote fibrotic lung disease at steady state or after inflammatory challenge.

Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses

“…As in human RA patients, auto-Abs are crucial for disease pathogenesis in K/BxN mice (5). Importantly, K/BxN mice have previously been shown to develop inducible bronchus-associated lymphoid tissue (iBALT)-like structures in their lungs (6), ectopic lymphoid tissues that are known to correlate with lung tissue damage in RA patients (7). T follicular helper (Tfh) cells are a crucial subset of CD4 + T cells that help B cells produce high-affinity and high-titer Abs (8–10), and an excessive Tfh cell response can lead to many autoimmune conditions including RA (11).…”

The Immune Microenvironment: A Major Player in Human Cancers

“…TLS arise in non-lymphoid tissues in response to chronic inflammation that can occur in autoimmunity, chronic allograft rejection and microbial infection [31]. Because of their plasticity and close proximity to antigenic sites, TLS are considered to be a privileged site for the generation of anti-infectious [32,33], anti-allogenic [34] and anti-self reactions [35,36,37,38,39] . However, the TLS impact is unique for each situation.…”

Structure, Organization, and Development of the Mucosal Immune System of the Respiratory Tract

“…Moreover, citrullinated proteins are observed in lymphoid areas of the lungs of RA patients (Bongartz et al, 2007), suggesting that autoantigens are located inside BALT areas. Interestingly, a 2013 study shows that BALT forms in arthritis-prone autoimmune K/BxN mice, which have glucose-6-phosphate isomerase-specific B cells and T cells (Shilling et al, 2013). Surprisingly, however, when challenged with bleomycin to induce pulmonary fibrosis, the K/BxN mice failed to elicit a significant fibrotic response (Shilling et al, 2013), suggesting that the presence of BALT actually reduced pulmonary pathology.…”

“…Interestingly, a 2013 study shows that BALT forms in arthritis-prone autoimmune K/BxN mice, which have glucose-6-phosphate isomerase-specific B cells and T cells (Shilling et al, 2013). Surprisingly, however, when challenged with bleomycin to induce pulmonary fibrosis, the K/BxN mice failed to elicit a significant fibrotic response (Shilling et al, 2013), suggesting that the presence of BALT actually reduced pulmonary pathology. Thus, it is not clear whether the BALT found in patients with RA is exacerbating pulmonary pathology or may actually be preventing more severe disease.…”