Th1 and Th2 cytokines regulate proteoglycan-specific autoantibody isotypes and arthritis.
BALB/c mice immunized with human cartilage proteoglycan (PG) develop arthritis accompanied by the production of autoantibodies to mouse cartilage PG. To determine whether the autoantibody isotype contributes to the onset and severity of arthritis, PG-specific serum IgG1 (Th2, IL-4-cytokine-supporting) and IgG2a (Th1, IFN-gamma-controlling) concentrations were monitored during immunization with PG in IL-4-deficient and IFN-gamma-deficient mice. Paradoxically, despite elevated IFN-gamma, the PG-specific IgG1 isotype was significantly higher than the PG-specific IgG2a response, and the PG-specific IgG1 isotype was independent of IL-4. In contrast, the serum concentration of PG-specific IgG2a isotype was six times higher in IL-4-deficient mice than in wild-type controls. Moreover, the high concentration of PG-specific IgG2a isotype in IL-4-deficient mice corresponded to an increased severity of arthritis. The concentration of PG-specific IgG2a isotype was lower in IFN-gamma-deficient mice than in wild-type mice, and the incidence and severity of arthritis also were significantly lower. Concentrations of PG-specific IgG2a isotype autoantibody correlated with the onset and severity of arthritis, suggesting a pathological role of this isotype, probably locally in the joint.
Kaplan
Charles
C
Department of Medicine, Section of Rheumatology, Rush Presbyterian-St Luke's Medical Center, Chicago, IL 60612, USA. afinnega@rush.edu
Valdez
Juan C
JC
Chandrasekaran
Raman
R
Eibel
Hermann
H
Mikecz
Katalin
K
Glant
Tibor T
TT
Finnegan
Alison
A
D053674:Aggrecans; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001323:Autoantibodies; D002358:Cartilage, Articular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005260:Female; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics; D037181:Lectins, C-Type; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011509:Proteoglycans / Q000008:administration & dosage / Q000276:immunology*; D051381:Rats; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
C508320:Acan protein, mouse; C508321:Acan protein, rat; D053674:Aggrecans; D001323:Autoantibodies; D016326:Extracellular Matrix Proteins; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D037181:Lectins, C-Type; D011509:Proteoglycans; D015847:Interleukin-4; D007371:Interferon-gamma