*4.3.3 Role of BALT in response to particles*

The lungs are exposed to a wide range of particles, many of which are naturally inflammatory because they cannot be metabolized and persist in phagocytes or because their components bind to specific receptors that trigger an inflammatory response. Silicosis, for example, is a chronic diffuse parenchymal lung disease caused by prolonged exposure to inhaled crystalline silica particles. Pulmonary silica exposure reportedly results in nodules of mononuclear cell infiltration at the location of silica deposition, leading to pulmonary fibrosis [101]. It has been proposed that pulmonary exposure of rats to silica causes silica-loaded alveolar macrophages to migrate across the epithelium and accumulate in BALT [102]. This is analogous to the kinetic observation of virus-activated DCs in the airways migrating from the epithelium to BALT [40].

#### *4.3.4 Role of BALT in autoimmune diseases*

Rheumatoid arthritis (RA) and Sjögren's syndrome (SS) are autoimmune disorders characterized by the formation of ectopic lymphoid follicles in target tissues. Ectopic lymphoid follicles in the joints are common in patients with RA [103]; whereas ectopic follicles in the salivary and lacrimal glands are common in those with SS [104]. These follicles are hypothesized to contain separate B- and T-cell domains, germinal centers, FDCs, and HEVs, and they contribute toautoimmunity by generating high-affinity autoreactive B cells and sparing autoreactive effector T cells. BALT areas are observed in lung biopsies from a subset of patients with RA and SS who develop lung disease. It has been suggested to range from very small isolated lymphoid follicles to large, highly organized clusters of B-cell follicles [61].

#### *4.3.5 Role of BALT in pulmonary malignancy*

BALT formation is frequently linked to lung inflammation and exposure to a variety of inflammatory stimuli. Therefore, it is not surprising that experimental exposure to an inflammatory agent via the pulmonary route results in BALT hyperplasia in rats. However, it is possible that an inflammatory agent, which has been linked to tumorigenesis, could also cause pulmonary adenocarcinoma [105]. Therefore, inflammatory responses in the lung can promote BALT and neoplasia at the same time. Indeed, considering the links between chronic inflammation and cancer development [106], it seems probable that BALT formation precedes tumorigenesis in such cases [48].

Local immune responses to pulmonary pathogens and antigens are clearly associated with BALT formation; thus, it is predicted that BALT development adjacent to pulmonary malignancies would also be beneficial for antitumor immune responses. A study demonstrated tertiary lymphoid tissue neogenesis induced by lymphotoxin: antitumor antibody fusion protein with the accumulations of CD4+ and CD8+ T cells, B cells, and PNAd-expressing HEVs [107]. Thus, it was hypothesized that the immune response necessary for tumor eradication was produced locally in tertiary lymphoid tissues [108]. Therefore, it is concluded that local BALT induction surrounding pulmonary metastases may be beneficial in inducing antitumor immunity and tumor regression [48].

In addition, it is suggested that the development of a lymphoid environment surrounding tumors may trigger antitumor immunity or immunological tolerance due to some unknown factors. Further, some studies indicate that lymphoid-like stromal elements surrounding tumors can impair antitumor immunity and lead to tolerance [109]. Despite the discrepancies and gaps in the literature, the ability of BALT to be spontaneously developed as a clear response to the development of pulmonary tumors or metastasis of other tumors to the lung as well as to boost immunity against lung tumors is an intriguing and research-worthy topic.
