RESUMO
B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.
Assuntos
Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Imunoterapia/métodos , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adulto , Autoimunidade , Fator Ativador de Células B/sangue , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Estudos de Casos e Controles , Células Cultivadas , Estudos Transversais , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Interferon beta/análise , Masculino , Esclerose Múltipla/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
CCL19 and CCL21 bind to CCR7, which is crucial for both inducing an immune response and establishing immunological tolerance. We report that in the normal human brain CCL19, but not CCL21, is transcribed, and detectable as a protein in tissue lysates and in cerebrospinal fluid. In both active and inactive multiple sclerosis (MS) lesions CCL19 transcripts were elevated. In cerebrospinal fluid from MS and OIND patients CCL19 protein was increased. In relapsing-remitting and secondary progressive MS patients CCL19 correlated with intrathecal IgG production. This study suggests that CCL19 plays a role in both the physiological immunosurveillance of the healthy CNS and the pathological maintenance of immune cells in the CNS of MS patients.
Assuntos
Encéfalo/imunologia , Quimiocina CCL19/imunologia , Encefalite/imunologia , Esclerose Múltipla/imunologia , Adulto , Idoso , Encéfalo/fisiopatologia , Quimiocina CCL19/líquido cefalorraquidiano , Quimiocina CCL19/genética , Quimiocina CCL21/líquido cefalorraquidiano , Quimiocina CCL21/genética , Quimiocina CCL21/imunologia , Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , Encefalite/líquido cefalorraquidiano , Encefalite/fisiopatologia , Feminino , Humanos , Vigilância Imunológica/genética , Vigilância Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/fisiopatologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Recidiva , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
The effect of aging on the delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) in vivo and the interleukin-2 (IL-2) production capacity in vitro by spleen cells from young (17 weeks) and old (125 weeks) CBA/Rij and C57BL/Ka mice were investigated. For both CBA/Rij and C57BL/Ka mice an age-related decline in the DTH response to SRBC and the IL-2 production capacity was observed. Both parameters are mediated by Thy-1+,Lyt-2- spleen cells. For both mouse strains the proportion of Thy-1+,Lyt-2- spleen cells declined less strongly with aging than the DTH reactivity and the IL-2 production capacity. From this it was concluded that not only a quantitative but also a qualitative decrease of T-cell function occurs during senescence. It was also investigated whether the proportion of Thy-1+,Lyt-2- peripheral blood lymphocytes can be used as a predictive value with regard to the decline of DTH with aging of the corresponding mouse. This was indeed found to be the case in CBA/Rij mice, but not in C57BL mice.