1.2. Pathophysiology

The chaos in biology associated with SLE, the involvement of multiple body organs along with the release of a wide array of autoantibodies has definitely challenged the advancement in understanding the disease pathophysiology. Such a comprehension is highly essential for the identification of novel biomarkers, for efficient classification of SLE patients, and in exposing specific pathways prone for targeting to help guiding personalized therapies [1, 4, 5]. Nevertheless, great insights have been achieved through the use of mouse models of lupus and multiple genetic and epigenetic investigations [19–24] through which a mechanism for disease development has been proposed to proceed as illustrated in Figure 1 [4].

Two important events set the basis for SLE pathophysiology: first is the loss of immune tolerance in which the immune system acquires autoantigen recognition and second the persistent release of autoantibodies that mainly target endogenous nucleic acids and associated proteins [1, 4]. A cascade of events has been postulated to underlie such two events and comprise impaired disposal of apoptotic cells, accumulation and immune recognition of nucleic acid material, deregulated lymphocyte signaling, and sustained production of interferons and other cytokines [1, 4].

Removal of apoptotic cell debris is normally a silent process. However, with impaired elimination of dead cells as in SLE, nucleic acid material becomes vastly accumulated and can acquire immunogenic properties through sustained exposure to the extracellular

Figure 1. Underlying immune deregulation in SLE pathogenesis. Accumulated nucleic acid material containing DNA, RNA, and associated proteins that is released from apoptotic cells and neutrophils via NETosis can acquire immunogenic properties through their sustained availability in the extracellular surrounding in addition to the co-association with stimulatory molecules such as HGB1 protein. The accumulated nucleic acid material is engulfed by PCDs which in turn activate intracellular TLRs that stimulate potent release of type I INFs from PDCs which stimulate expression of BAFF that stimulates B-cell production of autoantibodies targeted against endogenous nucleic acids and associated proteins. T cells are important key players in SLE pathogenesis as they induce the release of inflammatory cytokines such as IL-17 and mediate tissue injury and destruction. Furthermore, T-cell and B-cell interactions stimulate B-cell differentiation and consequent release of pathogenic autoantibodies [4].

environment and the association with immune-stimulatory molecules such as IL-1 and the DNA-binding protein HMG-1 [25–27]. The innate immune cells plasmacytoid dendritic cells (PDCs) act by engulfing apoptotic remains containing nucleic acid material which stimulates the intracellular nucleic acid receptors Toll-like receptors (TLRs) particularly TLR7 and TLR9 [28–30]. When TLRs engage DNA or RNA, they elicit a strong release of type I interferons (IFNs) such as IFN-α which in addition to other cytokines induce autoantibody production through stimulating B-cell maturation and differentiation and can promote loss of immune tolerance and impaired immune responses [31, 32]. The activation of B cells via type I INFs has also been demonstrated by the increased expression of the B-cell-activating factor (BAFF) in response to IFN-α which stimulates B-cell activation and generation of autoantibodies [33–36]. Released autoantibodies bind their target antigens which are mainly nuclear components and form immune complexes that are recognizable by PDCs and further stimulate the release of type I IFNs amplifying INF signaling in a process known as "IFN signature" [1, 4, 27]. Many of the gene products that become actively expressed in response to type I INFs are engaged in immunoregulatory functions and were found to be highly elevated in many SLE patients with strong association of autoantibody release specifically those targeting RNA-binding proteins such as RNP, Sm, Ro, and La [37]. TLR7 specifically binds single-stranded RNA and was found to be strongly associated with the release of anti-Sm autoantibodies [38, 39]. On the other hand, TRL9 binds CpG-rich DNA sequences, was found to be highly expressed in B cells isolated from patients with severe SLE activity with an association of potent release of anti-double-stranded DNA (dsDNA) antibodies [38]. In addition to apoptotic cell death, neutrophil extracellular traps that are rich in DNA released from neutrophil cell death (NETosis) and other immunostimulatory molecules induce type I interferons through stimulating TLRs [40]. Impaired T-cell signaling is also a significant contributor to SLE pathogenesis where overly activated T cells of lupus were able to stimulate autoantibody production from B cells, activate dendritic cells, and stimulate the release of inflammatory cytokines and can thus mediate widespread tissue injury and inflammation [4, 41].
