T-regs in autoimmune hepatitis-systemic lupus erythematosus/mixed connective tissue disease overlap syndrome are functionally defective and display a Th1 cytokine profile

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• 作者：Maria Serena Longhi^a ; ^{maria.longhi@kcl.ac.uk} ; Yun Ma^a ; ^{yun.ma@kcl.ac.uk} ; Charlotte R. Grant^a ; ^{charlotte.r.grant@kcl.ac.uk} ; Marianne Samyn^a ; ^b ; ^{marianne.samyn@nhs.net} ; Patrick Gordon^c ; ^{patrick.gordon2@nhs.net} ; Giorgina Mieli-Vergani^a ; ^b ; ^{giorgina.vergani@kcl.ac.uk} ; Diego Vergani^a ; ^b ; ^{diego.vergani@kcl.ac.uk}
• 关键词：Autoimmune hepatitis ; Systemic lupus erythematosus ; Mixed connective tissue disease ; Regulatory T-cells ; Th1 immunity
• 刊名：Journal of Autoimmunity
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：41
• 期：Complete
• 页码：146-151
• 全文大小：241 K

文摘

Autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinaemia, autoantibodies and interface hepatitis, is occasionally associated with systemic autoimmune manifestations [systemic lupus erythematosus (SLE); mixed connective tissue disease (MCTD)]. In both AIH and SLE/MCTD numerical and/or functional impairment of regulatory T-cells (T-regs) is believed to favour autoimmunity. To investigate whether immune-tolerance breakdown profiles differ in patients with AIH and SLE/MCTD, isolated AIH or systemic autoimmunity, we studied phenotypic and functional features of T-regs in 10 patients with AIH-SLE/MCTD, 22 with AIH, 12 with SLE and 20 healthy subjects. Compared to health, CD4^posCD25^pos cells were decreased in number and expressed high levels of the CD127 activation marker in all three disease groups; in AIH-SLE/MCTD and in SLE they displayed low levels of FOXP3. In AIH-SLE/MCTD, they also contained a high proportion of IFN¦Ã positive cells, indicating a Th1 profile. Similarly, in AIH-SLE/MCTD, CD4^posCD25^posCD25^high T-regs were reduced in number and contained an increased proportion of activated CD127^pos and IFN¦Ã^pos cells. Such skewing towards a Th1 profile was also present at effector level, as a high frequency of IFN¦Ã-producing cells was observed within AIH-SLE/MCTD CD4^posCD25^neg responder cells. Impairment in suppressor function both of CD4^posCD25^pos cells and CD4^posCD25^posCD127^neg T-regs was observed in all three autoimmune conditions, but while addition of CD4^posCD25^posCD127^neg T-regs decreased CD4^posCD25^neg responder cell proliferation in healthy subjects and partially in AIH patients, it had no effect in AIH-SLE/MCTD and SLE patients.

In conclusion, in AIH-SLE/MCTD T-regs display a distinctive phenotypic and functional signature, characterized by marked activation, elevated IFN¦Ã production and by a profound impairment of suppressive function, suggesting that multiple autoimmune manifestations may derive from a complex defect of immune-regulation.