The role of FoxP3+CD4+CD25hi Tregs in the pathogenesis of myasthenia gravis.
CD4(+)CD25(+) regulatory T cells (CD4(+)CD25(+) Tregs) play a critical role in the maintenance of peripheral self-tolerance and the regulation of immune responses. Genetic defects that primarily affect the development and/or function of CD4(+)CD25(+) Tregs result in severe autoimmune diseases and inflammatory disorders. In this study, we investigated whether the peripheral pool and the function of CD4(+)CD25(+) Tregs are altered in patients of myasthenia gravis (MG), a chronic autoimmune disorder that results in progressive skeletal muscle weakness. Here we showed that both mRNA and protein expression level of FoxP3 in CD4(+)CD25(+) Tregs are dramatically down-regulated, accompanied by an severe functional defect in CD4(+)CD25(+) Tregs regulatory activity when cocultured with autologous CD4(+)CD25(-) T cells, although the reservoir of CD4(+)CD25(+) Tregs is not changed in peripheral blood from MG patients. Since FoxP3 is a pivotal transcription factor that indispensable for the generation and the regulatory function of CD4(+)CD25(+) Tregs, our data suggested that the functional activity of CD4(+)CD25(+) Tregs is inhibited in MG patients and that MG might originate from the dysfunction of CD4(+)CD25(+) Tregs. Although the underlying molecular basis for the reduced expression of FoxP3 in CD4(+)CD25(+) Tregs from MG patients remains unknown, this study provided a potential target for MG therapy.
Zhang
Ying
Y
Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Helongjiang 150086, PR China.
Wang
Hua-bing
HB
Chi
Li-jun
LJ
Wang
Wei-zhi
WZ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015704:CD4 Antigens; D049109:Cell Proliferation; D002648:Child; D018920:Coculture Techniques; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007165:Immunosuppression Therapy; D053645:Interleukin-2 Receptor alpha Subunit; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000097:blood / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit