Autoantibodies specific to D4GDI modulate Rho GTPase mediated cytoskeleton remodeling and induce autophagy in T lymphocytes

Highlights

• Defective autophagy is a key actor in the pathogenesis of SLE.

• Autoantibodies to D4GDI are detected in sera from patients with SLE.

• Anti-D4GDI antibodies induce autophagy in T lymphocytes.

• Anti-D4GDI antibodies can select autophagy-resistant T cell clones in SLE patients.

• Anti-D4GDI antibodies can play a role in the pathogenesis of SLE.

Abstract

T lymphocytes from patients with Systemic Lupus Erythematosus (SLE) display multiple abnormalities, including increased cell activation, abnormal cell death by apoptosis and impairment of autophagy pathway. In the present study we report the presence of specific antibodies to D4GDI, a small GTPase family inhibitor, in a significant percentage (46%) of SLE patient sera. We also found a significant association between the presence of these autoantibodies and hematologic manifestations occurring in these patients. Investigating the possible implication of anti-D4GDI autoantibodies in SLE pathogenesis or progression, we found that these antibodies were capable of binding D4GDI expressed at the lymphocyte surface and triggering a series of subcellular events, including Rho GTPase activation. These antibodies were also able to induce autophagy in T cells from both healthy donors and SLE patients, but only those negative to these antibodies. We can conclude that anti-D4GDI autoantibodies could be capable of triggering important responses in T cells such as cytoskeleton remodeling and autophagy pathway and that, in SLE patients, the chronic exposure to these specific autoantibodies could lead to the selection of autophagy-resistant T cell clones contributing to the pathogenesis of the disease.

Introduction

Systemic lupus erythematosus (SLE) is a multifactorial and highly polymorphic systemic autoimmune disorder that affects multiple organs, including skin, muscles, joints, kidneys and heart [1]. The etiology of SLE remains still unknown. However, it is likely that the complex interaction between genetic, environmental (e.g., infectious agents, UV light, drugs), and hormonal factors promotes the immune dysfunction underlying the pathogenesis of the disease. SLE is characterized by autoantibody production by deregulated B cells, target organ infiltration by inflammatory T cells and aberrant immune cell activation due to abnormal antigen-presenting cell function [2], [3]. Among the cells that participate in the initiation, progression, and perpetration of the disease, T lymphocytes play a key role in all stages [4]. This is at least partially due to the production of pathogenic autoantibodies in a T-cell-dependent process. However, as major contributors to the disease, T cells also display multiple abnormalities, such as increased cell activation and abnormal cell death by apoptosis [5], [6]. More recently, autophagy, the lysosome-mediated catabolic process involved both in basal turnover of cellular components and in response to stressful conditions, has been reported to play a key role. In fact, genetic studies have linked some mutations of autophagy regulators with SLE disease [7], [8], [9], [10], [11], and a deregulation of autophagy has been described either in T cells from lupus-prone mice or from patients with SLE [12]. In addition, the activation of the mammalian target of rapamycin (mTOR), a metabolic regulator of autophagy, has been documented in SLE T cells [13], [14], and its blockade with rapamycin improved the clinical conditions of these patients [15]. We added further insights in this scenario since we discovered that serum IgG from patients with SLE were able to induce autophagy in T lymphocytes from healthy donors, suggesting a role for anti-lymphocyte antibodies as autophagy inducers [16]. Even though it is well known that the majority of patients with SLE develop autoantibodies to lymphocyte surface antigens able to inhibit T-cell activation and proliferation, few data are available so far as concerns the antigenic target of these antibodies [17], [18]. The present study deals with the mechanism underlying autophagy modulation in SLE patients. We identified the small GTPase family inhibitor D4GDI as a possible key antigenic determinant implicated in the pathogenesis of the disease.