A Role for the Lymphotoxin/LIGHT Axis in the Pathogenesis of Murine Collagen-Induced Arthritis

Abstract

A lymphotoxin-β (LTβ) receptor-Ig fusion protein (LTβR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTβR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTβR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTβR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.

Lymphotoxin Pathway-Directed, Autoimmune Regulator-Independent Central Tolerance to Arthritogenic Collagen

“…Although we have found that Ltbr Ϫ/Ϫ mice are more susceptible to CIA, others have described LT␤R-Ig fusion protein as an effective inhibitor of CIA development, arresting even established disease (23). There are several possible explanations.…”

“…4, a and b). Despite overt anti-CII autoimmunity, analysis of both Lta Ϫ/Ϫ and Ltbr Ϫ/Ϫ mice age Ͼ1 year revealed no evidence of spontaneously arising arthritis, presumably because the absence of peripheral LT signaling blocks disease pathogenesis, as demonstrated recently (23).…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…baminercept and pateclizumab) may prove effective in blocking ELF activity. Although clinically untested for ELF‐associated inflammation, targeting LT β has shown promise in pre‐clinical experimental models of disease 126, 127, 128, 129. Similarly, CXCL13 blockade has shown some promise in pre‐clinical studies for the treatment of experimental inflammatory arthritis, diabetes and Sjögren syndrome 130, 131, 132.…”

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

“…This includes an important role of LT signaling in the acceptance of donor stem cells, controlling cuprizone-induced demyelination, the progression of experimental autoimmune encephalomyelitis and the control of lipid metabolism or liver regeneration Lo et al, 2007;Plant et al, 2007;Markey et al, 2009;Ruddell et al, 2009;Tumanov et al, 2009). Studies with different mouse models revealed a role of LTbR signaling in atherosclerosis development (Schreyer et al, 2002;Grabner et al, 2009) and an involvement of LTbR signaling was discovered in the pathogenesis of RA (Fava et al, 2003). Blocking LTbR signaling using a LTbR-Ig fusion protein could prevent the onset of collagen-induced arthritis or reduce its severity, depending on the time point of LTbR-Ig treatment (Fava et al, 2003).…”

“…Studies with different mouse models revealed a role of LTbR signaling in atherosclerosis development (Schreyer et al, 2002;Grabner et al, 2009) and an involvement of LTbR signaling was discovered in the pathogenesis of RA (Fava et al, 2003). Blocking LTbR signaling using a LTbR-Ig fusion protein could prevent the onset of collagen-induced arthritis or reduce its severity, depending on the time point of LTbR-Ig treatment (Fava et al, 2003). On the basis of these results, clinical trials with patients suffering from RA have been initiated by Biogen Idec (Boston, MA, USA) to investigate the beneficial role of LTbR-Ig (Baminercept).…”