Abstract
Both the type I (IFN-alpha beta) and type II (IFN-gamma) IFNs have been heavily implicated in the pathogenesis of systemic lupus erythematosus. To test the relative roles of these systems, congenic lupus-prone MRL/CD95(lpr/lpr) (MRL/lpr) mice lacking the type I IFN receptor (IFN-RI), type II IFN receptor (IFN-RII), or both, were derived. As expected, deficiency for IFN-RII protected MRL/lpr mice from the development of significant autoimmune-associated lymphadenopathy, autoantibodies, and renal disease. However, deficiency for the IFN-RI surprisingly worsened lymphoproliferation, autoantibody production, and end organ disease; animals doubly deficient for IFN-RI and IFN-RII developed an autoimmune phenotype intermediate between wild-type and IFN-RII-deficient animals, all correlating with an ability of type I IFN to suppress MRL B cell activation. Thus, type I IFNs protect against both the humoral and end organ autoimmune syndrome of MRL/lpr mice, independent of IFN-gamma. These findings warrant caution in the use of type I IFN antagonists in the treatment of autoimmune diseases and suggest further investigation into the interplay between the types I and II IFNs during the ontogeny of pathogenic autoantibodies.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Antinuclear / biosynthesis
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Autoimmune Diseases / genetics
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Autoimmune Diseases / pathology
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Autoimmune Diseases / physiopathology
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Autoimmune Diseases / prevention & control*
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B-Lymphocytes / immunology
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Crosses, Genetic
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Disease Models, Animal
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Female
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Interferon-alpha / physiology*
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Interferon-beta / physiology*
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Kidney Glomerulus / pathology
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Liver / pathology
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Lung / pathology
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / pathology
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Lupus Erythematosus, Systemic / physiopathology
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Lupus Erythematosus, Systemic / prevention & control*
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Lupus Nephritis / pathology
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Lupus Nephritis / physiopathology
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Lupus Nephritis / prevention & control
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Lymphocyte Activation
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Lymphoproliferative Disorders / genetics
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Lymphoproliferative Disorders / physiopathology
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Male
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Membrane Proteins
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Mice
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Mice, Inbred BALB C
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Mice, Inbred MRL lpr
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Receptor, Interferon alpha-beta
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Receptors, Interferon / deficiency
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Receptors, Interferon / genetics
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Receptors, Interferon / physiology*
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Rheumatoid Factor / biosynthesis
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Salivary Glands / pathology
Substances
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Antibodies, Antinuclear
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Interferon-alpha
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Membrane Proteins
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Receptors, Interferon
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interferon receptor, type II
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Receptor, Interferon alpha-beta
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Interferon-beta
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Rheumatoid Factor