title: Abnormalities of CD4 T cell subpopulations in ANCA-associated vasculitis.
abstract: In patients with ANCA-associated vasculitis (AAV), CD25 expression is increased on circulating T cells. Although in animal experiments the role of CD4(+) CD25(+) T-regulatory-cells (T(reg)) in protection against autoimmunity is well established, the role of these cells in AAV is unknown. To investigate the hypothesis that an increased expression of CD25 on T cells is related to persistent T cell activation and not to disturbances in T(reg) cells in AAV (34 patients, six of them after renal transplantation), we investigated CD25 expression in different subpopulations of CD4(+) cells and FOXP3 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). In addition, T cell proliferation and cytokine secretion after stimulation with anti-CD3 and anti-CD28 and intracellular cytokine production after stimulation with phorbol myristate acetate (PMA)-ionomycin was determined. Controls were non-vasculitic renal transplant patients (n = 9) and healthy controls (HC) (n = 13). In AAV the total number of lymphocytes, CD4(+) lymphocytes and the percentage of naive T cells are lower than in HC and RTX. An increased percentage of CD25(+) cells was found in AAV and AAV/RTX, irrespective of disease activity, but not in HC or RTX. This was confined to the naive (CD4(+) CD45RB(high)) population only. FOXP3 mRNA expression in CD4(+) T cells did not differ between AAV patients and healthy controls. In vitro T cell proliferation was enhanced in AAV patients compared to HC (P < 0.01). PBMC of AAV patients produced significantly less interleukin (IL)-10 and interferon (IFN)-gamma after anti-CD3/CD28 stimulation. The percentage of IL-10 and IL-12, but not IFN-gamma, IL-4 or tumour necrosis factor (TNF)-alpha-producing cells was significantly higher in patients compared to HC. These findings were confined to the memory population of CD4(+) cells. We conclude that AAV patients are lymphopenic and have low numbers of CD4(+) T cells, which seem to be in a persistent state of activation.
authors.affiliation: Fifth Department of Medicine, University Hospital Mannheim, University of Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Marinaki
authors.forename: I
authors.initials: I
authors.lastname: Neumann
authors.forename: A-I
authors.initials: AI
authors.lastname: Kälsch
authors.forename: P
authors.initials: P
authors.lastname: Grimminger
authors.forename: A
authors.initials: A
authors.lastname: Breedijk
authors.forename: R
authors.initials: R
authors.lastname: Birck
authors.forename: W
authors.initials: W
authors.lastname: Schmitt
authors.forename: R
authors.initials: R
authors.lastname: Waldherr
authors.forename: B A
authors.initials: BA
authors.lastname: Yard
authors.forename: F J
authors.initials: FJ
authors.lastname: Van Der Woude
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D051858:Forkhead Transcription Factors; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D007668:Kidney / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000276:immunology; D014657:Vasculitis / Q000276:immunology*
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007378:Interleukins; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens