Site- and size-dependent differences in pulmonary lymphocyte aggregates: an immunohistochemical and morphometric...

Pulmonary lymphoid aggregates are increasingly recognized as components of local immune responses in chronic lung diseases and infections. However, whether T- or B-lymphocytes predominate in non-tumorous peripheral pulmonary aggregates remains unclear. We aimed to identify site- and size-dependent patterns of lymphocyte composition. We examined 20 surgically obtained peripheral lung tissues located >50 mm from primary lung cancers in 20 patients. Immunoreactive cells, stromal cells, and lymph sinus-related structures were immunohistochemically analyzed. CD4-positive T-lymphocytes and CD20-positive B-lymphocytes were quantified in each aggregate and compared with aggregate size. We identified 138 lymphocyte aggregates, including spherical or nodular forms: 86 arteriole-associated, 28 subpleural, and 24 bronchiole-associated. Arteriole-associated aggregates were usually small (<100 μm) and located along arterioles 40-60 μm in diameter in the interalveolar septum, whereas subpleural aggregates measured 100-200 μm. The ratio of CD4-positive T-lymphocytes to CD20-positive B-lymphocytes (T/B ratio) ranged from 3.0-129.2 in arteriole-associated aggregates, 0.3-19.8 in subpleural aggregates, and 0.2-32.1 in bronchiole-associated aggregates. In 38 small arteriole-associated aggregates (<20,000 μm²), aggregate area weakly correlated with the T/B ratio (Spearman's ρ=0.328, P=0.044). Podoplanin-positive stromal cells were frequently observed, whereas dendritic cell-specific ICAM-3-grabbing nonintegrin-positive cells were few or absent. Pulmonary lymphoid aggregates may develop through site-dependent stages of organization, from small CD4-positive T-lymphocyte-rich aggregates to larger nodular structures containing follicle-like B-cell clusters.