Altered Tregs and oxidative stress in pregnancy associated lupus

Abstract

Aim: SLE is a systemic autoimmune disease generally affecting woman in the reproductive age. It is associated with an altered level of Tregs and oxidative stress while an increase in Tregs, and different antioxidant mechanisms to combat oxidative stress are essential for successful pregnancy. Hence, this study aims to determine the level of CD4 + and CD8 + Tregs and oxidative stress in pregnant lupus patients. Methods: Ten healthy and 10 pregnant lupus volunteers from the North Indian population, within the age group of 20-30 years were enrolled in the study. All the patients were non-smokers, non-alcoholics and were not associated or undergoing therapy for any other disease. They had a SLEDAI of 37.4 ± 7.32 with 5.2 ± 1.93 years of disease duration. Oxidative stress was determined by measuring the enzyme activity of anti-oxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) and the level of reduced glutathione and lipids peroxidised, spectrophotometrically. Flowcytometry was performed for immunophenotyping to determine CD8 + and CD4 + Tregs.Results: Elevated CD8 + Tregs and diminished CD4 + Tregs were observed in pregnant lupus patients. Oxidative stress was significantly increased as the activities of anti-oxidant enzymes and level of reduced glutathione was considerably diminished. There was a substantial increase in the amount of lipids peroxidised.Conclusion: Pregnant lupus patients undergo considerable level of oxidative stress in comparison to healthy pregnant woman. The decreased level of CD4 + Tregs and an increase in CD8 + Tregs might be another important factor responsible for pregnancy associated complications. Hence, lupus leads to alterations in the necessary conditions for a successful pregnancy, which might eventually cause higher mortality, morbidity and associated complications.

The Complement System, T Cell Response, and Cytokine Shift in Normotensive versus Pre-Eclamptic and Lupus Pregnancy

“…Unwarranted complement activation in lupus patients, particularly through an alternative pathway, as well as low serum levels of circulating complement and its activation fractions are significant biomarkers of disease activity. Complement deposition on immune cells with subsequent organ damage and decreased levels of C1q, C3, and C4 strongly correlates with disease activity and precedes clinically evident flare [1,[16][17][18][19][20][21][22]. Despite the well-known dysregulation and variability in complement levels throughout pregnancy, there is a lack of agreement on complement levels as biomarkers in lupus pregnancies [39]; different studies have pointed out correlations between complement and its activation products and adverse pregnancy outcomes as well as specific lupus manifestations, while others failed to demonstrate any association.…”

“…Recent studies focused on altered Tregs and oxidative stress in lupus, since both are involved in immune system dysregulation, abnormal activation and processing of celldeath signals, and autoantibody production [1,19,22]; moreover, while an increase in Tregs and different antioxidant mechanisms to combat oxidative stress are essential for successful pregnancy, decreased Tregs may be associated with a loss of fetal tolerance and a pre-term cessation of pregnancy [1,2,22]. Interestingly, CD8 + CD25 + Tregs appear to be increased in women with lupus in comparison to healthy gestation, while CD4 + CD25 + Tregs are decreased in lupus pregnancy; the explanation relies on an altered IL-2 profile during pregnancy that is able to activate CD8 + Tregs more potently than CD4 + Tregs, higher levels of CD8 + Tregs subpopulation being necessary to maintain pregnancy [19,22]. In addition, lupus pregnancy is associated with high oxidative stress.…”

“…In addition, lupus pregnancy is associated with high oxidative stress. Since low oxidative stress and altered CD4 + CD25 + Tregs are essential for safe pregnancy, lupus pregnancies are at high risk for potential complications such as pre-eclampsia and miscarriage [19,22].…”

“…As the prototype of autoimmune conditions, systemic lupus remains a multifaceted and multifactorial disease resulting from a complex interplay between environmental factors, hormonal status, as well as overwhelming immunological abnormalities acting on a specific genetic background (polygenic disease). Aberrant immune regulation comprises the activation of both innate and adaptive immunity with impaired clearance of self-nucleic acids related to the induction of type I interferon, lym-phocyte activation and signaling, defective T regulatory processes, autoantibody synthesis, complex immune formation and deposition, and multivisceral tissue damage [16][17][18][19][20][21][22]. Several pathways are actually proposed to explain the aberrant immunity in SLE, focusing on the imbalance between production and clearance of apoptotic debris, activated innate and adaptive immunity, inflammatory cell recruitment and tissue injury mediated by the augmented synthesis of pro-inflammatory cytokines derived from activated macrophages (TNFα, IL-6, IL-8), T cells (IL-17) and B cells (IL-10 and IL-6 as a result of IL-21 costimulation), loss of T and B cell tolerance and, finally, excessive autoantibody synthesis partially dependent on a specific type I IFN signature [16][17][18][19].…”

“…Several pathways are actually proposed to explain the aberrant immunity in SLE, focusing on the imbalance between production and clearance of apoptotic debris, activated innate and adaptive immunity, inflammatory cell recruitment and tissue injury mediated by the augmented synthesis of pro-inflammatory cytokines derived from activated macrophages (TNFα, IL-6, IL-8), T cells (IL-17) and B cells (IL-10 and IL-6 as a result of IL-21 costimulation), loss of T and B cell tolerance and, finally, excessive autoantibody synthesis partially dependent on a specific type I IFN signature [16][17][18][19]. Extreme patient heterogeneity as well as lupus endotypes rely on immunological heterogeneity comprising the activation of different cell subtypes (B and T cells, plasmablasts, NK cells, neutrophils, and myeloid cells), type I interferon response, and aberrant cytokine profile [16][17][18][19][20][21][22].…”