Enhanced autoimmune arthritis in IFN-gamma receptor-deficient mice is conditioned by mycobacteria in Freund's adjuvant and by increased expansion of Mac-1+ myeloid cells.
Induction of experimental autoimmune diseases often relies on immunization with the organ-specific autoantigens in CFA, which contains heat-killed mycobacteria. In several of these models, including collagen-induced arthritis, endogenous IFN-gamma acts as a disease-limiting factor in the pathogenesis of the disease. Here we show that in collagen-induced arthritis the protective effect of IFN-gamma depends on the presence of mycobacteria in the adjuvant. Omission of mycobacteria inverts the role of endogenous IFN-gamma to a disease-promoting factor. Thus, the mycobacterial component of CFA opens a pathway by which endogenous IFN-gamma exerts a protective effect that supersedes its otherwise disease-promoting effect. Extramedullary hemopoiesis and expansion of the Mac-1+ cell population accompanied the accelerated and more severe disease course in the IFN-gamma receptor knockout mice immunized with CFA. Treatment of such mice with Abs against the myelopoietic cytokines IL-6 or IL-12 inhibited both disease development and the expansion of the Mac-1+ population. We postulate that mycobacteria in CFA stimulate the expansion of the Mac-1+ cell population by a hemopoietic process that is restrained by endogenous IFN-gamma. These results have important implications for the validity of animal models of autoimmunity to study the pathogenesis and to evaluate cytokine-based therapy of autoimmune diseases.
Matthys
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Rega Institute, University of Leuven, Belgium. Patrick.Matthys@reg.kuleuven.ac.be
Vermeire
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Mitera
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Heremans
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Huang
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Schols
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De Wolf-Peeters
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Billiau
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D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D003094:Collagen / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology*; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006411:Hematopoiesis, Extramedullary / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology; D007106:Immune Sera / Q000494:pharmacology; D007115:Immunization Schedule; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009161:Mycobacterium / Q000276:immunology*; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D000096743:Interferon gamma Receptor
D001323:Autoantibodies; D003094:Collagen; D005620:Freund's Adjuvant; D007106:Immune Sera; D007371:Interferon-gamma; D018664:Interleukin-12; D015850:Interleukin-6; D016177:Macrophage-1 Antigen; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor