A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis.
A lymphotoxin-beta (LTbeta) receptor-Ig fusion protein (LTbetaR-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 LTbetaR-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 LTbetaR-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 LTbetaR-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.
Fava
Roy A
RA
Department of Veterans Affairs Medical Center, White River Junction, VT 05001, USA.
Notidis
Evangelia
E
Hunt
Jane
J
Szanya
Veronika
V
Ratcliffe
Nora
N
Ngam-Ek
Apinya
A
De Fougerolles
Antonin R
AR
Sprague
Andrew
A
Browning
Jeffrey L
JL
D000818:Animals; D000936:Antigen-Antibody Complex / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D001323:Autoantibodies / Q000096:biosynthesis; D002478:Cells, Cultured; D003094:Collagen / Q000008:administration & dosage / Q000276:immunology*; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007116:Immunization, Passive; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D053308:Lymphotoxin-beta; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D051381:Rats; D011917:Rats, Inbred Lew; D017452:Receptors, IgG / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; C505886:LTB protein, human; C505697:LTBR protein, human; C505887:Ltb protein, mouse; C505888:Ltb protein, rat; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D017452:Receptors, IgG; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D005620:Freund's Adjuvant