2.1. Antinuclear antibodies (ANAs)

ANAs are a large group of autoantibodies that target various nuclear antigens including DNA, RNA, proteins, or complexes of nucleic acid and proteins [44]. They can generally be categorized into two groups based on the targeted antigens, one group that recognizes DNA and DNA-associated proteins such as histones or DNA-protein complexes such as nucleosomes and another group that recognizes distinct proteins that exist in association with RNA and are thus called RNA-binding proteins (RBPs) including the small nuclear ribonucleoproteins (snRBPs) Sm, RNP, Ro, and La [47].

These nuclear antigens are normally enclosed within the nucleus. However, as described above, upon cell death, these antigens are released into the extracellular space where they elicit immune responses that lead to the generation of ANAs that target these antigens and form immune complexes that further stimulate the immune system [4]. In the context of SLE, ANA detection in patients' sera is an important diagnostic criterion where they are specified as a stand-alone criterion in SLE classification criteria that are used for SLE diagnosis [48–50] as will be described in more details in the next section.

Although, ANA positivity is detected in not less than 95% of SLE patients [44, 51], they exhibit low specificity to SLE as they are also detected in other autoimmune diseases including rheumatoid arthritis, Sjogren's syndrome, and mixed connective tissue disease [51, 52]. Furthermore, depending on the employed detection method, ANA positivity can be seen in 20– 30% of healthy individuals in the general population for yet unknown reasons [44]. Therefore, the value of ANA testing for SLE diagnosis is a debatable issue because of this diminished specificity despite of its inclusion in SLE classification criteria [53].
