RESUMEN
Rheumatoid arthritis is a joint-specific autoimmune inflammatory disease of unknown etiology. The K/BxN mouse is a model of rheumatoid arthritis that is thought to be mainly due to autoantibody-mediated inflammatory responses. We showed previously that homeostatic proliferation of autoreactive CD4(+) T cells is required for disease initiation in the K/BxN mice. In this study, we show that the homeostatically proliferating CD4(+)CD25(-) T cells produce IL-21. We generated IL-21R-deficient (IL-21R(-/-)) K/BxN mice and found that these mice were completely refractory to the development of spontaneous arthritis. They contained fewer CD4(+) T cells with a reduced proportion of homeostatically proliferating cells, fewer follicular Th cells, and, surprisingly, more Th17 cells than their control counterparts. They also failed to develop IgG1(+) memory B cells and autoantigen-specific IgG1 Ab-secreting cells. IL-21 induced expression of receptor activator of NF-kappaB ligand (RANKL) a regulator of osteoclastogenesis, and few RANKL-expressing infiltrates were found in the synovia of IL-21R(-/-) K/BxN mice. Thus, our results demonstrate that IL-21 forms a positive feedback autocrine loop involving homeostatically activated CD4(+) cells and that it plays an essential role in the development of autoimmune arthritis by mechanisms dependent on follicular Th cell development, autoreactive B cell maturation, and RANKL induction but independent of Th17 cell function. Consistent with this, in vivo administration of soluble the IL-21R-Fc fusion protein delayed the onset and progression of arthritis. Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis.
Asunto(s)
Artritis/inmunología , Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/inmunología , Homeostasis/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Interleucinas/inmunología , Transducción de Señal/inmunología , Animales , Formación de Anticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación de la Expresión Génica/inmunología , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/inmunología , Interleucina-17/inmunología , Interleucinas/deficiencia , Interleucinas/genética , Interleucinas/metabolismo , Ratones , Ratones Noqueados , Receptores de Interleucina-21/deficiencia , Receptores de Interleucina-21/genética , Receptores de Interleucina-21/inmunología , Receptores de Interleucina-21/metabolismoRESUMEN
OBJECTIVE: K/BxN-transgenic mice are a model of autoimmune arthritis, similar to rheumatoid arthritis. This study was undertaken to determine whether inhibition of lymphopenia-provoked homeostatic expansion can prevent spontaneous development of disease in the K/BxN model. METHODS: To inhibit homeostatic expansion of autoreactive T cells, K/BxN mice with disease in the preclinical stage were adoptively transferred with CD4+ T cells purified from nontransgenic BxN or Thy1.1+ BxN mice. To observe the profile of proliferation of CD4+ T cells derived from the hosts, carboxyfluorescein diacetate succinimidyl ester-labeled autologous CD4+ T cells were cotransferred to K/BxN mice together with BxN CD4+ T cells. Disease onset and progression were scored, and the dynamics and phenotypes of recipient CD4+ T cells were determined by flow cytometry, before and after cell infusion. RESULTS: During the preclinical phase of disease, K/BxN mice exhibited CD4+ T lymphopenia, which was followed by a compensatory expansion of these cells during the early clinical phase. The majority of CD4+ T cells acquired a memory phenotype (CD44(high),CD62L(low),CD25-), which is a hallmark of homeostatically expanding cells. Importantly, K/BxN mice subjected to syngeneic T cell transfer did not develop symptoms of arthritis and also possessed fewer transgenic T cell receptor-encoded Vbeta6+,CD4+ T cells. This effect was associated with decreased proliferation of recipient-derived CD4+ T cells but not with the function of CD25+ T regulatory cells present in donor cells. CONCLUSION: These results provide the first evidence that lymphopenia-associated homeostatic proliferation of autoreactive CD4+ T cells potentiates autoimmune arthritis, and that inhibition of this process protects mice from the development of this pathologic condition.