title: T-cell specific defect in expression of the NTPDase CD39 as a biomarker for lupus.
abstract: Regulatory T cells (T(regs)) are critical for maintenance of peripheral tolerance via suppression of T-cell responses, and absence of T(regs) results in autoimmunity. The role of aberrations in the T(reg) pool for the development of systemic lupus erythematosus (SLE, lupus) remains uncertain. T(reg)-mediated generation of adenosine, dependent on the ectonucleotidase CD39, is an important mechanism for suppression of T-cell responses. We tested whether decreases in numbers of T(regs), and specifically CD39-expressing T(regs), are associated with human lupus. We studied 15 SLE patients, six patients with rheumatoid arthritis (RA) and 24 healthy controls. T(reg) phenotypic markers, including CD39 expression, were studied by flow cytometry. Varying numbers of sorted T(regs) cells were co-cultured with responder T (T(resp)) cells, with proliferation assessed by (3)H-thymidine incorporation. The proportion of T(regs) as defined by Foxp3(+) CD25(+high) CD127(-/low) was similar in lupus and control populations. CD39-expressing T(regs) comprised 37±13% of the T(reg) population in healthy controls and 36±21% in lupus subjects using nonsteroidal immunosuppressants to control active disease, but was nearly absent in five of six lupus subjects with minimally active disease. In contrast to healthy controls and lupus subjects without the CD39 defect, in SLE subjects with the CD39 defect, adenosine-dependent T(reg)-mediated suppression was nearly absent. These results suggest that functional defects in T(regs), rather than reduced T(reg) numbers, are important for the loss of peripheral tolerance in lupus. Presentation of this defect may serve as a biomarker for untreated disease.
authors.affiliation: Center for Human Genomics, Wake Forest University Health Sciences, Winston-Salem, NC, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Loza
authors.forename: A Shane
authors.initials: AS
authors.lastname: Anderson
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: O'Rourke
authors.forename: James
authors.initials: J
authors.lastname: Wood
authors.forename: Islam U
authors.initials: IU
authors.lastname: Khan
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D007166:Immunosuppressive Agents; D014970:Xanthines; C051869:8-(4-((2-aminoethyl)aminocarbonylmethyloxy)phenyl)-1,3-dipropylxanthine; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine