Chronic Inflammation: A Common Promoter in Tertiary Lymphoid Organ Neogenesis

Abstract

Tertiary lymphoid organs (TLOs) frequently develop locally in adults in response to non-resolving inflammation. Chronic inflammation leads to the differentiation of stromal fibroblast cells toward lymphoid tissue organizer-like cells, which interact with lymphotoxin ${\alpha }_1{\beta }_2^{+}$ immune cells. The interaction initiates lymphoid neogenesis by recruiting immune cells to the site of inflammation and ultimately leads to the formation of TLOs. Mature TLOs harbor a segregated T-cell zone, B-cell follicles with an activated germinal center, follicular dendritic cells, and high endothelial venules, which architecturally resemble those in secondary lymphoid organs. Since CXCL13 and LTα₁β₂ play key roles in TLO neogenesis, they might constitute potential biomarkers of TLO activity. The well-developed TLOs actively regulate local immune responses and influence disease progression, and they are thereby regarded as the powerhouses of local immunity. In this review, we recapitulated the determinants for TLOs development, with great emphasis on the fundamental role of chronic inflammation and tissue-resident stromal cells for TLO neogenesis, hence offering guidance for therapeutic interventions in TLO-associated diseases.

Keywords: adventitia; atherosclerosis; immunity; inflammation; tertiary lymphoid organs.

Figure 1

TLO stage classification. Stage 0, normal tissue without TLO formation; Stage I, early TLOs with mixed T/B-cell aggregates; Stage II, pre-TLOs with segregated T/B-cell area with lymph vessels and conduits; Stage III, well organized TLOs containing segregated T-cell area and B-cell follicles with germinal centers and follicle DC network.

Figure 2

ATLO location in atherosclerotic aorta. Oil red O/Hematoxylin staining showing ATLO position in the abdominal aorta adventitia relative to media (dashed lines) and intimal plaque in aged Apoe^−/− mice.