The role of dead cell clearance in the etiology and pathogenesis of systemic lupus erythematosus: dendritic cells as potential targets

Abstract

Overwhelming apoptosis combined with a deficiency in clearing apoptotic cells is thought to be an important etiopathogenic event in the autoimmune disease systemic lupus erythematosus (SLE). Lazy macrophages, complement or DNase I deficiency as well as insufficient natural IgM might be important factors leading to such a clearance deficiency. A defective clearance of apoptotic cells leads to the activation and maturation of plasmacytoid and myeloid dendritic cells (DCs) by material derived from secondary necrotic cells carrying modified autoantigens. This results in the presentation of autoantigens to autoreactive T and B cells in an immunogenic manner, thereby leading to autoantibody production, chronic inflammation and severe tissue damage. Since DC activation and IFN-α production by plasmacytoid dendritic cells play a critical role in the course of SLE pathogenesis, therapeutic intervention to end this vicious cycle might be a promising approach for treating the disease.

Keywords::

• apoptosis
• autoimmunity
• clearance deficiency
• dendritic cells
• IFN signature
• NETosis
• secondary necrosis
• systemic lupus erythematosus
• tolerance
• toll-like receptor

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Apoptosis is a vitally important process in the organism’s development and in maintenance of tissue homeostasis. It is a well-organized process that does not trigger an inflammatory response.

• Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by systemic and chronic inflammation, autoantibody production and severe tissue damage.

• Overwhelming apoptosis, for example, after injury, oxidative stress or infection by pathogens in combination with an intrinsic deficiency in clearing the normal daily turnover of apoptotic cells is thought to be an important etiopathogenic event in SLE.

• A deficiency in the clearance of apoptotic cells and its remnants (NETs) can result from various causes such lazy macrophages, deficiency of complement or DNase I or insufficient natural IgM.

• NETosis in the presence of defective clearance is considered to represent an emerging factor contributing to the development of SLE.

• The accumulation of apoptotic and secondary necrotic cell-derived material with immunogenic modification of autoantigens might lead to the activation and maturation of dendritic cells (DCs). This results in a challenge of tolerance by the secretion of pro-inflammatory cytokines and subsequent presentation of autoantigens to autoreactive T and B cells.

• DCs are professional sensors of pathogen-associated molecular patterns through Toll-like receptors Modified apoptotic cell remnants can be recognized under appropriate conditions by DCs highlighting their role in the pathogenesis of SLE.

• Autoimmune activation occurs by accidental encounter of cell debris and DCs in the context of challenged tolerance. Pro-inflammatory cytokine production and especially an IFN-α signature drive the pathological course of the disease.

• Therapeutic intervention to end this vicious cycle might to be a promising approach to ameliorate or even abolish disease symptoms. Several studies targeting type I IFN, for example, by monoclonal antibodies or anti-IFN-α immunization, are currently on trial.

• Moreover, supporting natural back-up mechanisms of cell debris clearance may help to exclude the participation of DCs in both initiation and perpetuation of autoimmunity.

Notes