Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease

Abstract

Much of the efficiency of the immune system is attributed to the high degree of spatial and temporal organization in the secondary lymphoid organs. Signalling through the lymphotoxin (LT) pathway is a crucial element in the maintenance of this organized microenvironment. The effect of altering lymphoid microenvironments on immune responses remains relatively unexplored. Inhibitors of the LT and LIGHT pathways have been shown to reduce disease in a wide range of autoimmune models. This approach has provided a tool to probe the effect of manipulation of the microenvironment on both normal and pathological immune responses.

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

“…In most of these diseases, elevated expression of LT or its target genes has been detected, supporting LT's role in lymphoid neogenesis (Drayton et al, 2006). Suppression of LTbR signaling by injection of LTbR-Ig was efficacious in the treatment of various inflammatory or autoimmune disease models (Gommerman and Browning, 2003;Ware, 2005;Drayton et al, 2006;Browning, 2008;Haybaeck et al, 2009). …”

“…LTbR is mainly expressed on parenchymal and stromal cells-but apparently also on myeloid cells (Norris and Ware, 2007). Its signaling might enable the communication between lymphocytes and stromal cells, thereby influencing various biological processes (Gommerman and Browning, 2003;Ware, 2005;Lo et al, 2007;Tumanov et al, 2009).…”

“…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).…”

Regulation of cell fate by lymphotoxin (LT) receptor signalling: Functional differences and similarities of the LT system to other TNF superfamily (TNFSF) members

“…LTα is secreted by activated lymphocytes, resting B cells, nonhematopoietic and myeloid lineage cells. Like TNFα, LTα secretion has been found in some immortalised T cell lines including Jurkat and Hut78 (87). It is also found to be secreted following stimulation of Raji B lymphocytes with phorbol ester (88).…”