Pathogenesis and novel therapeutics of regulatory T cell subsets and interleukin-2 therapy in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous multisystem inflammatory disease with wide variability in clinical manifestations. Natural arising CD4+ regulatory T cells (Tregs) play a critical role in maintaining peripheral tolerance by suppressing inflammation and preventing autoimmune responses in SLE. Additionally, CD8+ regulatory T cells, type 1 regulatory T cells (Tr1), and B regulatory cells also have a less well-defined role in the pathogenesis of SLE. Elucidation of the roles of various Treg subsets dedicated to immune homeostasis will provide a novel therapeutic approach that governs immune tolerance for the remission of active lupus. Diminished interleukin (IL)-2 production is associated with a depleted Treg cell population, and its reversibility by IL-2 therapy provides important reasons for the treatment of lupus. This review focuses on the pathogenesis and new therapeutics of human Treg subsets and low-dose IL-2 therapy in clinical benefits with SLE.

Differences in the Clinical Characteristics and 1-Year Mortality Rates of Patients with Dermatomyositis with anti-Jo-1 and anti-MDA5 Antibodies.

Objective: Patients with anti-Jo-1 antibodies (Abs) and anti-melanoma differentiation-associated protein 5 (MDA5) Abs are at a higher risk of interstitial lung disease (ILD) and have a mortality rate higher than that of patients with anti-Jo-1 Abs. This study investigated differences in the clinical characteristics and prognosis of patients with anti-Jo-1 Abs and anti-MDA5 Abs with dermatomyositis (DM). Methods: We retrospectively reviewed the medical records of 38 patients with DM from January 2000 to December 2021. The patients were divided into anti-Jo-1 Abs and anti-MDA5 Abs groups. The basic demographic data, clinical manifestations, and 1-year mortality rates of the groups were compared. Results: Among the 38 patients, 30 were anti-Jo-1-Abs positive and 8 patients were anti-MDA5 Aba positive. The patients with anti-MDA5 Abs presented with more apparent cutaneous symptoms and aggressive pulmonary manifestations than did those with anti-Jo-1 Abs. The mortality rate in the anti-MDA5 Abs group (1.95/person-year (PY)) was much higher than that in anti-Jo-1 Abs group (0.094/PY), and most of the mortalities occurred within the first 1-3 months of follow-up. Conclusion: Distinct cutaneous and pulmonary manifestations were observed in the anti-Jo-1 Abs and anti-MDA5 Abs groups. The mortality rate in the anti-MDA5 Abs group was significantly higher than that in the anti-Jo-1 Abs group. Early recognition is crucial to ensuring higher chances of survival for patients with anti-MDA5 Abs.

Lupus nephritis with corticosteroid responsiveness: molecular changes of CD46-mediated type 1 regulatory T cells.

BACKGROUND: The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy. METHODS: We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients. RESULTS: We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells. CONCLUSIONS: Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN. IMPACT: In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17. These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 + Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment. Enhancing the expression of functional CD4 + CD46 + Tr1 cells may be a useful therapeutic approach for LN.

Association of serum interleukin-17 and interleukin-23 levels with disease activity in Chinese patients with ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic arthritis with a pathogenesis which is not fully understood. A third subset of IL-17-producing T helper cells, called Th17 cells, has been discovered and characterized. We investigated whether IL-17 and IL-23, two Th17-related cytokines, play any roles in the pathogenesis of, and have any correlations with, disease activity and clinical manifestations in AS. METHODS: This cross-sectional study included 49 AS patients and 25 healthy control subjects. The serum IL-17 and IL-23 levels were measured using enzyme-linked immunosorbent assay kits. At the same time, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Patient Global Score (BAS-G) levels were measured, and physical examinations were performed on study participants to determine their extent of physical mobility. RESULTS: The serum IL-17 and IL-23 levels of the AS patients were significantly higher than those of the healthy controls. In the AS patients, the BASDAI scores had a better correlation with the serum IL-17 or IL-23 levels (IL-17, r = 0.351, p = 0.014; IL-23, r = 0.398, p = 0.005) than with ESR (r = 0.078, p = 0.600) and CRP (r = 0.012, p = 0.993). IL-17 or IL-23 correlate to the BASFI, BAS-G and parameters related to physical mobility. In the receiver operating characteristic (ROC) analysis, the serum IL-17 and IL-23 levels act better in discriminating patients with BASDAI≥4 (AUC value 0.88, p = 0.001) than ESR and CRP (AUC value 0.727, p = 0.008). CONCLUSION: Serum IL-17 and IL-23 levels were significantly higher in AS patients than in healthy controls and the levels correlate to disease activity measured by BASDAI scores, but not parameters of functional ability and spinal mobility. These results suggest the existence of a role of IL-17 and IL-23 in the pathogenesis of inflammation in AS.