Dysregulation and chronicity of pathogenic T cell responses in the pre-diseased stage of lupus

Abstract

In the normal immune system, T cell activation is tightly regulated and controlled at several levels to ensure that activation occurs in the right context to prevent the development of pathologic conditions such as autoimmunity or other harmful immune responses. CD4+FoxP3+ regulatory T cells (Treg) are crucial for the regulation of T cell responses in the peripheral lymphatic organs and thus for the prevention and control of autoimmunity. In systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease with complex etiology, a disbalance between Treg and pathogenic effector/memory CD4+ T cells develops during disease progression indicating that gradual loss of control over T cell activation is an important event in the immune pathogenesis. This progressive failure to adequately regulate the activation of autoreactive T cells facilitates chronic activation and effector/memory differentiation of pathogenic T cells, which are considered to contribute significantly to the induction and perpetuation of autoimmune processes and tissue inflammation in SLE. However, in particular in humans, little is known about the factors which drive the escape from immune regulation and the chronicity of pathogenic T cell responses in an early stage of autoimmune disease when clinical symptoms are still unapparent. Here we briefly summarize important findings and discuss current views and models on the mechanisms related to the dysregulation of T cell responses which promotes chronicity and pathogenic memory differentiation with a focus on the early stage of disease in lupus-prone individuals.

Graft survival and mortality outcomes after kidney transplant in patients with lupus nephritis: a systematic review and meta-analysis

“…Our analysis showed an increased risk of graft failure in patients with LN. This finding is in agreement with previous studies and further underscores the complex immune milieu associated with LN, which might impact graft viability [ 2 , 26 , 29 ]. Autoimmune processes and ongoing immune activity in LN patients could potentially contribute to chronic graft inflammation [ 10 ] and dysfunction [ 2 , 29 ].…”

Low-dose interleukin-2 therapy: a promising targeted therapeutic approach for systemic lupus erythematosus

“…IL-2 is predominantly produced by activated T cells and is nowadays acknowledged as an essential and nonredundant factor for the growth, differentiation, and survival of Treg [7,23,24]. Preclinical studies in SLE patients as well as SLE-related mouse models could identify an acquired perturbation of IL-2 production as a key factor in the pathogenesis of SLE promoting the impairment and exhaustion of the Treg population [4,[8][9][10][11][12][25][26][27][28][29][30][31]. Patients with SLE have improper Treg, characterized by reduced expression of the IL-2R a chain (CD25) and an impaired proliferative capacity in relation to the proliferation of CD4 þ conventional T cells (Tcon) [9,32].…”

“…Systemic lupus erythematosus (SLE) is a severe chronic and relapsing autoimmune disease with complex pathogenesis [1,2]. Among various cells of the innate and adaptive immune system, autoreactive effector T cells (Teff) are particularly involved in the initiation, perpetuation, and progression of the pathologic processes in SLE [3,4]. Under homeostatic conditions, autoreactive Teff are under check by FoxP3 þ regulatory T cells (Treg), which is resembled by a delicate balance between Treg and Teff that impedes pathogenic immune responses against self-antigens and tissues [5][6][7].…”

“…Under homeostatic conditions, autoreactive Teff are under check by FoxP3 þ regulatory T cells (Treg), which is resembled by a delicate balance between Treg and Teff that impedes pathogenic immune responses against self-antigens and tissues [5][6][7]. In SLE, an acquired deficiency of the cytokine interleukin-2 (IL-2), an essential growth and survival factor for Treg, leads to Treg insufficiency and a Treg/Teff imbalance that promotes loss of immune tolerance against several nuclear auto-antigens resulting in tissue inflammation and injury [3,4,[8][9][10][11][12]. Despite growing insights into the immune pathogenesis of SLE, many promising treatment strategies have failed in clinical trials, and unselective immunosuppressive therapies are still the main treatment modality, which contributes to increased morbidity and mortality in SLE patients.…”

Vaccination in the Era of Immunosuppression

“…Autoantigens have been implicated in the immune dysregulation of various autoimmune diseases. In systemic lupus erythematosus (SLE), nucleic acid self-antigens derived from dying cells are presented to dysregulated T cells, leading to aberrant patterns of differentiation characterized by decreased regulatory T cell production and unchecked CD4+ T cell expansion [ 18 ]. Autoreactive B cells are stimulated by CD4+ T cells, resulting in the production of anti-nuclear antibodies that cause downstream organ dysfunction through complement activation, immune complex deposition, and altered immune effector cell function [ 19 ].…”