T helper type 2-biased natural killer cell phenotype in patients with pemphigus vulgaris.
Pemphigus vulgaris (PV) is an autoantibody-mediated bullous disease, but the role of natural killer (NK) cells in its pathogenic process has never been examined in detail. Circulating CD56+ CD3- NK cells as well as CD69+-activated NK cells were increased in PV patients compared with healthy controls and patients with other autoantibody-mediated autoimmune diseases, including immune thrombocytopenic purpura and myasthenia gravis. Gene expression analysis of highly purified NK cells demonstrated an increased expression of IL-10 and decreased expression of IL-12Rbeta2, perforin, and granzyme B ex vivo in PV patients versus healthy controls. The NK cells from PV patients also showed impaired signal transducer and activator of transduction4 phosphorylation upon in vitro IL-12 stimulation. Moreover, NK cells from PV patients exhibited reduced IL-10 production in response to in vitro stimulation with IL-2/IL-12. Finally, IL-5 expression in NK cells was exclusively detected ex vivo in PV patients with active disease, and was lost in subsequent analyses performed during disease remission. Together these findings suggest that NK cells contribute to a T helper type 2-biased immune response in PV patients through impaired IL-12 signaling and an upregulation of IL-10 and IL-5.
Takahashi
Hayato
H
Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Amagai
Masayuki
M
Tanikawa
Akiko
A
Suzuki
Shigeaki
S
Ikeda
Yasuo
Y
Nishikawa
Takeji
T
Kawakami
Yutaka
Y
Kuwana
Masataka
M
D000328:Adult; D000368:Aged; D015536:Down-Regulation; D005260:Female; D053804:Granzymes / Q000235:genetics; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015848:Interleukin-5 / Q000235:genetics; D007694:Killer Cells, Natural / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D010392:Pemphigus / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D053707:Receptors, Interleukin-12 / Q000235:genetics; D015398:Signal Transduction; D018418:Th2 Cells; D015854:Up-Regulation
D007376:Interleukin-2; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D020033:Protein Isoforms; D053707:Receptors, Interleukin-12; D054353:Perforin; D016753:Interleukin-10; D018664:Interleukin-12; D053804:Granzymes