Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis

Abstract

Bronchus-associated lymphoid tissue (BALT) was originally described as a mucosal lymphoid organ in the lungs of some species. However, while the lungs of naive mice and humans typically lack BALT, pulmonary infection in mice leads to the development of inducible BALT (iBALT), which is located in peribronchial, perivascular, and interstitial areas throughout the lung. Here we investigated whether iBALT forms in patients with a variety of interstitial lung diseases. We show that while iBALT can be found in the lungs of patients suffering from multiple diseases, well-developed iBALT is most prevalent in patients with pulmonary complications of RA and Sjögren syndrome. In these patients, iBALT consisted of numerous B cell follicles containing germinal centers and follicular dendritic cells. A loosely defined T cell area surrounded the B cell follicles while lymphatics and high endothelial venules were found at the B cell/T cell interface. Increased expression of lymphoid-organizing chemokines, such as CXCL13 and CCL21, as well as molecules involved in the immunopathology of RA, such as B cell-activating factor of the TNF family (BAFF), ICOS ligand, and lymphotoxin, correlated with more well-developed iBALT. Finally, the presence of iBALT correlated with tissue damage in the lungs of RA patients, suggesting that iBALT participates in local RA pathogenesis.

Thy1+IL-7+lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

“…This is consistent with the previous findings that influenza virus infection-induced iBALT areas have Lyve-1 + lymphatic vessels (8), and robust lymphangiogenesis occurs after iBALT formation in the lungs of mice (55). In addition, increased M2A + lymphatic vessels were observed in lung biopsies from patients with rheumatoid arthritis (13). In summary, our study demonstrates a new paradigm for how inflammatory pathogenic memory Th2 cells (i.e., Tpath2 cells) are maintained at local sites of inflammation, particularly within ectopic lymphoid tissues in the airway.…”

“…Moreover, mice deficient in the chemokine receptor CCR7 appear to spontaneously develop BALT together with excessive formation of secondary lymphoid organs without being exposed to immunological stimulation (12). In humans, iBALT formation has been identified in patients with chronic inflammatory diseases such as rheumatoid arthritis, tuberculosis, and chronic obstructive pulmonary diseases (13)(14)(15). Despite increasing evidence of the correlation between iBALT formation and the severity of chronic inflammatory diseases in the lung, the pathophysiological roles of iBALT remain unknown.…”

The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation

“…1). In the lung, similar, less organized lymphoid tissue that does not meet the conventional criteria of secondary and tertiary lymphoid tissue has been reported (13). However, the functional significance of such anatomical variations among intrapulmonary lymphoid tissue remains unclear.…”

“…In the lung, TLO is considered to be represented by an inducible form of bronchus-associated lymphoid tissue (BALT), namely iBALT (1,11). Formation of iBALT has been reported in various chronic inflammatory lung diseases such as emphysema (12), pulmonary fibrosis (13), and chronic hypersensitive pneumonitis (14). In contrast, Hasegawa et al demonstrated a negative result regarding the relationship between OB/BOS and BALT, which should theoretically include iBALT (15).…”

Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation

“…iBALT develop postnatally, are evident in many autoimmune/inflammatory disorders (e.g., rheumatoid arthritis, Sjogren's disease, chronic obstructive pulmonary disease [COPD]), and may contribute to immunopathology through the production of autoantibodies or allergen-specific Abs (1,2). In contrast, iBALT can limit immunopathology and can contribute to host defense against respiratory pathogens (3,4) via the creation of a local niche to facilitate immune cell crosstalk and accelerated T cell priming (5).…”