Chronic inflammation caused by lymphotoxin is lymphoid neogenesis.

Abstract

SummaryIn presenting a unifying concept for chronic inflammation and lymphoid organogenesis, we suggest that lymphotoxin's (LT, LT-ot, TNF-J3) crucial role in these processes is pivotal and similar. Chronic inflammatory lesions that developed in the kidney and pancreas at the sites of transgene expression in rat insulin promoter-LT (RIP-LT) mice resembled lymph nodes with regard to cellular composition (T cells, B cells, plasma cells, and antigen-presenting cells), delineated T and B cell areas, primary and secondary follicles, characteristic morphologic and antigenic (ICAM-1, VCAM-1, MAdCAM-1, and PNAd) features of high endothelial venules, and ability to respond to antigen and undergo Ig class switching when obtained from mice immunized with SRBC. The vascular changes, with the exception of PNAd, appear to be the direct consequence of transgene derived LT expression, as they were also observed in RIP-LT mice lacking mature T and B cells. These data show that LT-induced chronic inflammation has the characteristics of organized lymphoid tissue.

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…The role of LT in the context of lymphoid neogenesis, development of autoimmune diseases and inflammatory disorders was further investigated in vivo (Picarella et al, 1992;Kratz et al, 1996;Luther et al, 2000;Drayton et al, 2003Drayton et al, , 2006Gommerman and Browning, 2003;Martin et al, 2004;Heikenwalder et al, 2005Heikenwalder et al, , 2008Haybaeck et al, 2009). These studies revealed that ectopic LT expression suffices to generate lymphoid-like structures (Picarella et al, 1992;Kratz et al, 1996;Gommerman and Browning, 2003;Heikenwalder et al, 2005;Haybaeck et al, 2009), also termed tertiary lymphoid organs or tissues.…”

“…These studies revealed that ectopic LT expression suffices to generate lymphoid-like structures (Picarella et al, 1992;Kratz et al, 1996;Gommerman and Browning, 2003;Heikenwalder et al, 2005;Haybaeck et al, 2009), also termed tertiary lymphoid organs or tissues. LTa or LTab expression under the control of the rat insulin promoter II (RIP) induces chemokine expression and follicular lymphocytic infiltrations with mature follicular dendritic cell networks, resulting in chronic insulitis and glomerulonephritis (Picarella et al, 1992;Kratz et al, 1996;Drayton et al, 2003). Inflamed sites in RIPLTa or RIPLTab mice are vascularized with endothelia showing morphologic characteristics of high endothelial venules (Picarella et al, 1992;Cuff et al, 1999;Drayton et al, 2003).…”

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

“…These chemokines induce lymphocyte immigration into the perivascular space, causing enlarged KNA, and the eventual neogenesis of a tertiary lymphoid organ, with discrete T and B cell zones (42)(43)(44)(45)(46)(47), therefore sharing many similarities with NZB thymi. The possibility that abnormal intrathymic LT signals were driving the degeneration of the medullary epithelial network was thus investigated.…”

Targeting tumors with LIGHT to generate metastasis-clearing immunity

“…Binding of LTα1β2 and TNF to their respective receptors, LTβR and TNFR1, induces the expression of chemokines and adhesion molecules, which directly mediate lymphocyte migration and homing [29]. The first evidence that the generation of TLS could involve the same signaling pathways that regulate lymphoid organogenesis came from studies of transgenic mice [24], in which the ectopic expression of LTα and LTβ in pancreatic islets induced the formation of in-situ TLS [30][31][32][33]. Extrapolating from this earlier experiment, stimulation of LTβR or TNFR expressed by tumor stromal cells may promote the formation of lymphoid-like structures inside the tumor tissues, which in turn may facilitate tumor destruction.…”