apyrase and Lupus-Erythematosus--Systemic

Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with periods of exacerbation and remission. SLE is characterized by the irreversible breakdown of immunological self-tolerance, where there is deregulation of multiple aspects of the immune system. SLE immune dysfunction is characterized by activation of autoreactive T lymphocytes, and hyperactivity of B lymphocytes with consequent production of several autoantibodies. ATP is a purinergic mediator released into the extracellular space in response to cell and tissue damage which operates as a danger signal to modulate immune and inflammatory responses. ATP binds to P2 receptors and its levels are regulated by NTPDase (CD39). SLE patients exhibit increased levels of ATP which binds to P2X receptors resulting in activation of the inflammasome and consequent release of IL-1β and IL-18, cytokines associated with disease pathogenesis. CD39 is upregulated in SLE representing an important immunoregulatory mechanism by controlling inflammation and favoring the production of adenosine. The aim of this review is to clarify the effects of ATP on the modulation of the inflammatory process and immune responses via P2 receptors as well as the role of NTPDase in the immunopathogenesis of SLE.

Topics: Adenosine Triphosphate; Animals; Antigens, CD; Apyrase; CD4-Positive T-Lymphocytes; Humans; Inflammation; Lupus Erythematosus, Systemic; Receptors, Purinergic P2X; Self Tolerance; Signal Transduction

Topics: 5'-Nucleotidase; Apyrase; Biomarkers; Disease Susceptibility; Humans; Lupus Erythematosus, Systemic; Purines

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease, where there is irreversible breakdown of immunological self-tolerance. Extracellular adenosine triphosphate (ATP) and adenosine are signaling molecules that play an important part in the immune response. During inflammation and the immune response, a group of enzymes control these molecules, including ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), E-5'-nucleotidase, and ecto-adenosine deaminase (E-ADA). We determined the activity and expression of E-NTPDase, the expression of E-5'-nucleotidase, the activity of E-ADA in lymphocytes and serum of SLE patients.. This study involved 35 patients with SLE and 30 healthy subjects as a control group. E-NTPDase activity and expression were increased in lymphocytes from SLE patients (31% and 37% for activity and expression, respectively) compared with the control group.. An approximately 42% increase in E-ADA activity in lymphocytes was observed in SLE patients compared with the control group, in serum the ADA activity was decreased by 57% in SLE patients. Expression of E-5'-nucleotidase was not changed in SLE patients.. E-NTPDase and E-ADA perform key functions in the modulation of the immune and inflammatory response in SLE.

Topics: 5'-Nucleotidase; Adult; Apyrase; Female; GPI-Linked Proteins; Humans; Lupus Erythematosus, Systemic; Lymphocytes; Male

The quantitative identification and enrichment of viable regulatory T cells (Treg) requires reliable surface markers that are selectively expressed on Treg. Foxp3 is the accepted marker of nTreg, but it cannot be used to isolate cells for functional studies. In this study, we compared four staining profiles of Treg, including CD4(+)CD25(high) T cells, CD4(+)CD39(+) T cells, CD4(+)CD73(+) T cells, and CD4(+)CD25(+)CD127(low/-) T cells. We found that CD4(+)CD25(+)CD127(low/-) T cells expressed the highest level of Foxp3 and had the strongest correlation with CD4(+)CD25(+)Foxp3(+) T cells, the accepted identifying characteristics for "real" nTreg cells. Moreover, functional data showed that CD4(+)CD25(+)CD127(low/-) T cells could effectively suppress the proliferation of CD4(+)CD25(-) T cells, suggesting that compared with the other three populations, CD4(+)CD25(+)CD127(low/-) T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood. Finally, we showed that CD4(+)CD25(+)CD127(low/-) can be used to quantitate Treg cells in individuals with systemic lupus erythematosus supporting the use of CD4(+)CD25(+)CD127(low/-) to identify human Treg cells.

Topics: 5'-Nucleotidase; Adult; Antigens, CD; Apyrase; Biomarkers; CD4 Antigens; Cell Proliferation; Coculture Techniques; Female; Forkhead Transcription Factors; Humans; Immunosuppression Therapy; Interleukin-2 Receptor alpha Subunit; Interleukin-7 Receptor alpha Subunit; Lupus Erythematosus, Systemic; Male; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory

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.

Topics: Adenosine; Adult; Aged; Antigens, CD; Apyrase; Biomarkers; Cell Proliferation; Cells, Cultured; Flow Cytometry; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Middle Aged; T-Lymphocytes; T-Lymphocytes, Regulatory; Xanthines