Several passages in the manuscipt need to be improved.
The writer needs to should give the full name for abbreviated terms (ATG5….., TREX1…., L1) when they occur the first time in the text.
A list of the abbreviations used should be made.
There are a little errors in table 2, reference 31, “IFN-α stimulates neutrophils is SLE patients” would be “IFN-α stimulates neutrophils in SLE patients”. Please check the manuscript carefully for such errors.
– Some passages are difficult to understand without detailed knowledge of the literature. In my opinion this review article should lead to a basic understanding of pathogenic mechanism by reading the text. Therefore the following passages would need a more clear explanation and rewording:
Please better explain the following text parts and reword them to get the manuscript better readable:
in the introduction page 4 it is described that DNaseI destroys DNA in endosomes and cytoplasm (of necrotic and apoptotic cells). This needs to be corrected as DNAse I destroys DNA in the extracellular space whereas endosomal and cytoplasmic DNA is degraded by DNAse II and III.
Please better explain the following text parts numbered from 1 to 11 and reword them to get the manuscript better readable:
1.Introduction:… DNAse I enzyme, an endonuclease cleaves dsDNA thus cleaves chromatin in necrotic cells as well as apoptotic cells [3, 4]. The chromatin in necrotic cells is not sufficiently engulfed prompting DNase activity. It is the inefficient clearance of dying cells (normally cleared by apoptosis) that results to necrosis which is associated with inflammation. Failure of the MerTK receptor induction results to cytokine production due to accumulation of dead cells prompting necrosis which is associated with inflammation [1, 2].
2 In cell necrosis, tissue damage in SLE is caused by reactive oxygen species induced stress, exhaustion of ATP and heat-shock proteins which destroy the plasma membrane. It’s the loss of plasma membrane integrity that triggers production of autoantigens [5].
3. NF-κB-inducing kinase (an enzyme encoded by the MAP3K14 gene) (NIK) has been implicated in mediation of tumor necrosis factor (TNF) proteins that play a role in SLE pathogenesis, hence its inhibition leads to improved quality of life by alleviating SLE manifestation [3, 31 and,32].
4. Complex mechanisms are involved in the activation of the abnormal lupus T cells. More specifically, the genes related to lupus T cells activation are directly regulated by lupus-associated isoform PBX1-d which has unique molecular functions [36]. PBX1-d is an isoform of pre-B-cell leukemia homeobox 1 (PBX1); it has a deficiency of DNA-binding and Hox-binding domains, hence chromatins of dying cells will be inaccessible by the DNase 1 enzyme for degradation [36]. The un-degraded un-engulfed dsDNA stimulates an autoimmune response in SLE patients [37, 38]. PBX –d directly stimulates production of autoreactive CD4 +T cells [36]. Moreover, dual-specificity protein phosphatase 23 (DUSP23) in CD4+ T cells is significantly higher in people with SLE and that the expression of DUSP23 is positively correlated with the transcript levels of different DNA methylation-related enzymes [39, 40]. DUSP23 activates the interferon and interleukin pathways via desphosphorylation [39].
5 In summary, this understanding of the role of T cell activation in SLE etiopathogenesis has led to the invention of T cell vaccination which efficaciously alleviates SLE manifestation [43].
6 Absence of Melanoma 2 (AiM2) promote the suppression of Type I interferons (IFN-α/β) hence it is associated with SLE susceptibility by initiating NETosis [26, 45]. Further, the expression of L1 induces IFN-α/β pathway in patients with SLE hence contributing to the initiation and progression of SLE [45].
7. Inhibition of interaction of IR5 with RNA polymerase II, HDAC3, DNA Sp1 and p300 by TSA in children with SLE suggests SLE is associated with defects in DNA degradation and erroneous removal of cellular debris [46].
8 The transcriptional repressor growth factor independence 1 (Gfi1) can help in preventing lupus autoimmunity by restraining TLR7 signaling [48].
9. . This is the reason why PK201/CAT plasmid (PK) DNA and histone 4 (H4) assays are reliable in the differential diagnosis of SLE [58].
10 Finally, oligosaccharyltransferase (OST) inhibition can suppress autoantibody production in the TREX1 frame-shift mutant mice hence therapeutically potential [67]. Mutations in TREX1 D272fs have been shown to result into an inactive DNase in SLE mice resulting to defective chromatin degradation hence elevated levels of cf-DNA [67].
11. In addition to drug factors, the diagnosis of SLE exclusively depends on the detection of autoantigen-specific autoantibodies in serum. A recent study, reported that Poly-L-Lysine a Capture Agent enhances the detection of SLE autoantibodies in ELISA [68]. Detection of ds-DNA, histones, RNP, SSA, and SSB; all nuclear components in sera of SLE patients using this assay suggests that SLE pathogenesis is associated with abnormal DNA degradation [68].
– Some passages need more stringent formulation to avoid replication (numbered from 1-3) :
1 Additionally, the low density granulocytes in the peripheral blood mononuclear cells in SLE patients have been shown to form NETs [30].
2. The formed NETs, normally are degraded by the action of DNase I which acts by hydrolyzing dsDNA in an endonucleatic manner thus breaking down chromatins during cell apoptosis [30]. Incomplete degradation of NETs by DNase I results to accumulation of remaining NETs which react with other proteins to form complexes which are involved in autoimmune SLE disorder [9, 12, 13, 30, and, 31]. Elevated levels of un-degraded residual NETs is the major source of serum dsDNA also called circulating cell-free DNA in SLE patients [29]. Clearance of NETs entirely depends on an efficient and active DNase 1 enzyme. A defective DNAse 1 implies un-degraded chromatins which is positively related with SLE disease activity [9, 12, and, 29]. 3 The absence of DNASE1L3 enzyme, the DNA degrading enzyme results to production of anti-ds antibodies to serum ds-DNA hence defective DNA degradation is associated with SLE disease [51].When it reaches a point where autoantibodies are produced as a result of
defective clearance of NETs and apoptotic remains, it is said that the person has a global loss of self-tolerance [51]. This is the point where impaired DNA degradation plays a role in the etiopathogenesis of SLE.