Downregulation of the phosphatase JKAP/DUSP22 in T cells as a potential new biomarker of systemic lupus erythematosus nephritis

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is characterized by systemic inflammation and multiple organ failures. Dysregulation of T cells plays a critical role in SLE pathogenesis. Our previous study indicates that JKAP (also named DUSP22) inhibits T-cell activation and that JKAP knockout mice develop spontaneous autoimmunity; therefore, we investigated whether JKAP downregulation is involved in SLE patients. JKAP protein levels in purified T cells were examined by immunoblotting using blood samples from 43 SLE patients and 32 healthy controls. SLE patients showed significantly decreased JKAP protein levels in peripheral blood T cells compared to healthy controls. JKAP protein levels in peripheral blood T cells were inversely correlated with SLE disease activity index (SLEDAI) and anti-dsDNA antibody levels. JKAP downregulation in T cells was highly correlated with daily urinary protein amounts and with poor renal outcome in lupus nephritis patients. Notably, the diagnostic power of JKAP downregulation in T cells for active lupus nephritis was higher than those of serum anti-dsDNA antibody, C3, and C4 levels. Moreover, T-cell-specific transgenic mice expressing a dominant-negative JKAP mutant developed spontaneous autoimmune nephritis. Furthermore, JKAP-deficient T cells overproduced complement components, soluble ICAM-1, and soluble VCAM-1 in the kidney; these cytokines have been reported to be involved in lupus nephritis. Taken together, JKAP downregulation in T cells is a novel diagnostic and prognostic biomarker for SLE nephritis.

Gene Expression Profiles of Human Phosphotyrosine Phosphatases Consequent to Th1 Polarisation and Effector Function

“…Interestingly, low expression of DUSP22 in human T cells has been proposed to be a potential biomarker for systemic lupus erythematosus nephritis [45]. Thus, it seems that this protein is relevant in controlling T cell responses in order to prevent autoimmune diseases.…”

Downregulation of JKAP is correlated with elevated disease risk, advanced disease severity, higher inflammation, and poor survival in sepsis

“…6,15 For example, a study reveals that JKAP in peripheral blood T cells is downregulated in SLE patients compared to health controls; besides, its downregulation is correlated with increased SLE disease activity index in SLE patients and is associated with higher daily urinary protein amounts and poorer renal outcomes in SLE-nephritis patients. 9 In another study, JKAP in mucosa is decreased in active IBD patients compared to IBD patients at remission and health controls and is negatively correlated with disease activity as well as systemic inflammation in IBD patients; also, JKAP is observed to suppress CD4 + T-cell activation and Th1/Th17 Cell differentiation in IBD. 8 Given that SLE and IBD both belong to immune and inflammatory diseases, we speculated that the expression of JKAP might also be dysregulated and play a critical role in sepsis.…”

“…7 It is expressed in various types of human cells such as T cells, B cells, and natural killer cells, suggesting that JKAP is possibly involved in immune and inflammation response of human diseases. 8,9 Moreover, evidence reveals that JKAP is downregulated and negatively correlates with inflammation level and disease activity in systemic lupus erythematosus (SLE) as well as inflammatory bowel disease (IBD). 8,9 Considering the above-mentioned data which indicate that JKAP is a key factor in regulating immune, inflammation and is closely involved in the etiology of several inflammatory diseases, we hypothesize it might participate in the development and progression of sepsis.…”

AhR–ROR‐γt complex is a therapeutic target for MAP4K3/GLK high IL‐17A high subpopulation of systemic lupus erythematosus

“…Primary human T cells were freshly isolated and negatively selected from the PBLs of clinical samples using a cocktail of biotin-conjugated anti-CD19, anti-CD14, and anti-CD11b antibodies (BioLegend) on a magnetic cell separation column (Miltenyi Biotec, Bergisch Gladbach, Germany) (26). In addition, primary murine T cells were negatively selected from the spleens of mice using magnetically coupled antibodies against CD11b, B220, CD49b, CD235, and TER-119 (Miltenyi Biotec) (18).…”