Inflammatory etiopathogenesis of systemic lupus erythematosus: an update

Abstract

The immune system struggles every day between responding to foreign antigens and tolerating self-antigens to delicately maintain tissue homeostasis. If self-tolerance is broken, the development of autoimmunity can be the consequence, as it is in the case of the chronic inflammatory autoimmune disease systemic lupus erythematosus (SLE). SLE is considered to be a multifactorial disease comprising various processes and cell types that act abnormally and in a harmful way. Oxidative stress, infections, or, in general, tissue injury are accompanied by massive cellular demise. Several processes such as apoptosis, necrosis, or NETosis (formation of Neutrophil Extracellular Traps [NETs]) may occur alone or in combination. If clearance of dead cells is insufficient, cellular debris may accumulate and trigger inflammation and leakage of cytoplasmic and nuclear autoantigens like ribonucleoproteins, DNA, or histones. Inadequate removal of cellular remnants in the germinal centers of secondary lymphoid organs may result in the presentation of autoantigens by follicular dendritic cells to autoreactive B cells that had been generated by chance during the process of somatic hypermutation (loss of peripheral tolerance). The improper exposure of nuclear autoantigens in this delicate location is consequently prone to break self-tolerance to nuclear autoantigens. Indeed, the germline variants of autoantibodies often do not show autoreactivity. The subsequent production of autoantibodies plays a critical role in the development of the complex immunological disorder fostering SLE. Immune complexes composed of cell-derived autoantigens and autoantibodies are formed and get deposited in various tissues, such as the kidney, leading to severe organ damage. Alternatively, they may also be formed in situ by binding to planted antigens of circulating autoantibodies. Here, we review current knowledge about the etiopathogenesis of SLE including the involvement of different types of cell death, serving as the potential source of autoantigens, and impaired clearance of cell remnants, causing accumulation of cellular debris.

Keywords: NETosis; apoptosis; autoimmunity; cell death; clearance deficiency; systemic lupus erythematosus.

Figure 1

The role of neutrophils in the etiopathogenesis of SLE. Notes: Activated neutrophils release NETs covered with α-NE, α-LF, α-MPO, or α-LL-37. Chromatin and associated compounds are hallmark antigens of the autoimmune response of patients with SLE. Decreased activity of DNase I combined with a general (anti-inflammatory) clearance deficiency leads to the accumulation of NETs covered with proinflammatory and cytotoxic intracellular constituents. Opsonization of NETs with autoantbodies comes with immune complex formation followed by inflammatory clearance by blood-borne phagocytes. This process causes inflammation and tissue damage, thus stimulating pDC to secrete IFN-α and IL-6, ultimately resulting in the so-called “IFNα signature” typical of SLE. The pro-inflammatory cytokines secreted by pDCs induce long-lived plasma cell formation and massive autoantibody production. Abbreviations: α-NE, antibodies against neutrophil elastase; α-MPO, antibodies against myeloperoxidase; α-LF, antibodies against lactoferrin; NET, neutrophil extracellular trap; IFN-α, interferon-alpha; IL-6, interleukin-6; pDC, plasmacytoid dendritic cells; SLE, systemic lupus erythematosus; NETosis, neutrophil extracellular trap formation; NETs, neutrophil extracellular traps; MΦ: macrophage.

Figure 2

The vicious cycle of SLE. Notes: A deficiency in the clearance of apoptotic cells leads to autoimmunity and chronic inflammation (1). when apoptotic cells fail to be cleared in time, they get secondary necrosis, leading to the accumulation of SNEC (2). Self-tolerance is broken when SNEC-derived autoantigens (Aag) are presented to autoreactive B cells by fDC. with help from autoreactive helper T cells, these B cells undergo affinity maturation and differentiate into memory B cells, thus establishing autoimmunity (3). IC are formed when autoantibodies (AAb) encounter SNEC in circulation or tissue (4). Newly formed SNEC-IC are then processed by blood-borne phagocytes and dendritic cells (DC) accompanied by the secretion of pro-inflammatory cytokines (5). This in turn leads to severe organ damage and cell death fueling the vicious cycle that maintains chronic inflammation (6). Abbreviations: SNEC, secondary necrotic cell-derived material; fDC, follicular dendritic cells; IC, immune complex; SLE, systemic lupus erythematosus; DC, dendritic cells; MΦ: macrophage, PMN: polymorphonuclear leukocytes.