Changes in Frequency and Activation Status of Major CD4+ T-Cell Subsets after Initiation of Immunosuppressive Therapy in a Patient with New Diagnosis Childhood-Onset Systemic Lupus Erythematosus

Abstract

BackgroundSeveral studies suggest that defects of regulatory T-cells (Tregs) and impaired cellular immunity are secondary to an imbalance between auto-aggressive T-cells and Tregs in lupus patients. Discrepancies in Tregs and effector T-cells (Teff) in active lupus patients are shown to be restored in patients upon receiving immunosuppressive therapy. Therefore, our main aim was to observe frequencies of these CD4+ T-cell subsets and Tregs/Teff ratio in a new diagnosis of childhood-onset systemic lupus erythematous (cSLE) before and after initiation of therapy. In addition, we monitored T-cell exhaustion status by examining responses to super-antigen staphylococcal enterotoxin B (SEB) and PD-1 expression in this patient.MethodsPhenotyping of CD4+ T-cell subsets was carried out under basal conditions and after SEB stimulation using flow cytometry in one inactive (I-cSLE) and one active cSLE (A-cSLE) patient, as well as a healthy control (HC). The A-cSLE patient was a new diagnosis. Variables were measured at three consecutive time points in the active patient, reflecting various stages of disease activity. Activation status of CD4+ T-cells in the A-cSLE patient was compared to that of the I-cSLE patient and HC. Disease activity was measured by calculating the systemic lupus erythematous disease activity index.ResultsWe found that the A-cSLE patient was not Tregs deficient. The patient had increased frequency of Tregs, and the Tregs/Teff ratio increased when the disease activity became less severe. CD4+ T-cells in the I-cSLE patient and in the A-cSLE patient with milder disease activity had heightened responsiveness to SEB, whereas T-cells were relatively hypo-responsive to SEB in the A-cSLE patient when disease activity was higher. The active patient exhibited higher frequencies of PD-1+ expressing Tregs, Teff, and Tnaïve/mem cells under basal conditions compared to the HC and I-cSLE patient.ConclusionIn the A-cSLE patient, changes in Tregs/Teff ratio correlated better with clinical improvement compared to Tregs frequencies alone and might reflect the restoration of immune homeostasis with therapy. SEB hypo-responsiveness in the A-cSLE patient when disease activity was higher paralleled with findings of greater frequencies of PD-1+ expressing Tregs, Teff, and Tnaïve/mem cells, suggests a possible global exhaustion status of CD4+ T-cells in this patient.

Regulation of CD4+CD25+FOXP3+ Treg Cells in Systemic Lupus Erythematosus (SLE): Association With miRNAs Expression

“…Our study observed a substantial increase in Treg cells in both active and inactive SLE patients compared to controls, with the most signi cant increase in active ones. This result agreed with Singla et al's(2017) [43] results, who reported a signi cant increase in Tregs in childhood SLE and mentioned that active lupus patients had a higher percentage than inactive lupus patients do. A previous study by Suarezet al (2006) [44] also observed a signi cant elevation in both active and inactive SLE patients with a maximum increase in inactive ones.…”

“…The equilibrium between the effector and regulatory T cells determines whether an autoimmune response can be triggered and propagated by autoreactive cells or not [12]. While a great deal of effort has been made to shed some light on the Treg imbalance in SLE, contradictory results have been shown [15][16][17][18][19][20][21][22][23][24].…”

An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus

“…The failure of T cells to produce IL-2 leads to a reduction in regulatory T cells and increased effector T cells, especially the T helper 17 (Th17) phenotype. This imbalance contributes to a pro-inflammatory status in adult-onset SLE and cSLE [64][65][66]. Additionally, changes in T-cell receptors observed in SLE result in hyperactivation of their signaling pathway [64,67].…”

Cell activation, PD-1 expression and in vitro cytokine production in patients with juvenile systemic lupus erythematosus

“…The only study published in jSLE was a case report of a patient with active disease where the authors demonstrated higher frequencies of PD-1 expressed in regulatory CD4 T cells, effector T cells, and naive/memory T cells. 25 After stimulation of peripheral blood cells in vitro, we observed a decrease in the production of IL-10, an antiinflammatory cytokine, and an increase in IL-23. The reduced production of IL-10 after stimulation with PHA in vitro in patients with jSLE, unlike what was observed in the control group, may suggest immune exhaustion despite the low disease activity score and the absence of clinical symptoms.…”

“…The only study published in jSLE was a case report of a patient with active disease where the authors demonstrated higher frequencies of PD-1 expressed in regulatory CD4 T cells, effector T cells, and naive/memory T cells. 25…”