SLE

SLE is a heterogenous autoimmune disease with an elusive etiology. Mucocutaneous initial symptoms and constitutional symptoms affect multiple organs such as skin, lungs, kidneys, joints, and nervous system in SLE. Genetic, hormonal, immunologic, and environmental factors are combined in the progress of this disease. Among the genomic elements, L1 retrotransposons play an important role in SLE pathogenesis. L1-expressing and virus-infected cells share the same hallmarks with specific cellular and humoral immune responses. Immunogenic ORF1p and ORF2p proteins are produced by L1 retroelements, which causes generation of type I IFN. Additionally, ORF1p and ORF2p take place in RNA-rich macromolecular structures including SLE autoantigens such as Ro60, a 60 kDa RNA-binding protein [5, 19, 20]. Expression of at least one of the L1 proteins in the organs affected in SLE was demonstrated. Additionally, IFN-β and IFN-α were detected in L1-transfected plasmacytoid dendritic cells (pDCs) or monocytes, showing the production of type I IFN [16].

Common markers of SLE include antinuclear antibody (ANA) as well as the autoantibodies targeting double-stranded DNA (dsDNA), rheumatoid factor (RF), Smith (Sm), ribosomal P, histones, ribonucleoproteins (RNPs), Ro/Sjögren’s syndrome A (SSA) and La/SSB [21]. High titers of anti-La/SSB and anti-Ro/SSA antibodies were detected in the sera of SLE patients [22]. Additionally, expression of type I IFNs and retrotransposons, such as IFN-β1 and L1, was found to be coordinated in SLE [23].

Ro60-associated RNAs were investigated in human cell lines, and it was found that Ro60 binds to an Alu-derived RNA motif. Type I IFN also affects the expression of Alu elements, and proinflammatory cytokine response is stimulated. Ro60 deficiency induces the expression of Alu RNAs and genes regulated by IFN. Expression of Alu elements was shown to be up-regulated in SLE, and related immune complexes containing anti-Ro60 also included Alu RNAs [24].

Frequently, multicomponent complexes made of nucleic acid(s) and proteins act as the autoantigens, such as spliceosomal, nucleolar, or Ro/La RNPs as well as aminoacyl-tRNA synthetase and tRNA complexes [21, 25]. RNP and chromatin particles can trigger antigen-specific immune responses because of resemblance to viral particles structurally. Therefore, SLE pathogenesis might include pseudoviral immunity driven by self nucleic acids. For instance, the mechanism that protects RNP and chromatin particles from receptor recognizing viral nucleic acids is abnormal in SLE [19].

In monogenic SLE, the most common cause is the loss-of-function in cytosolic endoplasmic reticulum (ER)-associated deoxyribonuclease III (DNase III), termed three prime repair exonuclease 1 (TREX1), which is a ubiquitous DNase for the degradation of retroelements. TREX1 is an important negative regulator of the IFN-stimulatory DNA (ISD). Digestion of single-stranded DNA (ssDNA) substrates with methylated, deaminated, or oxidized bases, as well as an abasic site at the 3’ end by TREX1 was shown. Additionally, TREX1 degrades reverse-transcribed DNA and dsDNA with methylated or deaminated bases [26–28].

Heterozygous mutations were identified in TREX1 in SLE patients [29]. TREX1-deficient mice also develop sterile inflammatory myocarditis. Anti-retroviral drugs would be expected to prevent or treat the disease; however, azidothymidine (AZT), a reverse transcription inhibitor, did not protect the TREX1-deficient mice from lethality. It was proposed that TREX1 deficiency might lead to activation of AZT-resistant reverse transcriptases, or some of the retroelements might be rescued from AZT. On the other hand, combination of the reverse transcriptase inhibitors Truvada and Viramune was shown to reduce mortality in TREX1-deficient mice [17, 28–30]. Moreover, hypomethylation of endogenous retroelements results in their activation. Therefore, the drugs such as procainamide contributing to DNA hypomethylation by blocking DNA (cytosine-5)-methyltransferase 1 (DNMT1) might be effective against autoimmune diseases [31].

Moreover, a null mutation, homozygous 2 bp-deletion c.289_290delAC (NM_004944.2) resulting in loss-of-function, in the Dnase1L3 (Dnase γ) gene causes an autosomal recessive, pediatric and rare form of SLE [32, 33]. DNA from circulating apoptotic bodies is not digested in the absence of Dnase1L3, and autoantibody responses are delayed [34].

AGS

AGS is an inflammatory encephalopathy which is heritable, and has symptoms similar to congenital brain infections of viruses, such as neurological dysfunction, skin inflammation, and psychomotor retardation. Characteristic induction of type I IFN in serum and cerebrospinal fluid in AGS is due to the alteration of sensing or metabolism of endogenous nucleic acids in response to mutations in genes encoding TREX1, RNA-specific adenosine deaminase 1 (ADAR1), sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1), and three subunits of the ribonuclease H2 (RNase H2). These proteins have inhibitory effect on L1 retrotransposition, and their loss-of-function because of mutations leads to accumulation of cytosolic nucleic acids. Thus, overproduction of type I IFN is triggered by ADAR1 in RNA-dependent as well as by TREX1, SAMHD1 and RNase H2 in DNA-dependent manner action [2, 7, 35].

The genes encoding these proteins in AGS have an action throughout the replication steps to inhibit the reverse transcription products. SAMHD1 degrades cellular deoxynucleoside triphosphates (dNTPs), thus depleting the nucleotide pool available for the reverse transcription. TREX1 digests DNA molecules produced after reverse transcription, and RNase H2 degrades phosphodiester backbone of RNA molecules in RNA/DNA hybrids, thus the retrotransposition is blocked [4, 7]. TREX1-deficient cells were shown to accumulate different sizes of ssDNA fragments generated during DNA replication in AGS [36].

MS

MS is an autoimmune disease with involvement of endogenous retroelements. Analysis of the MS-associated retrovirus (MSRV) obtained from plasma of MS patients revealed a new family of HERVs, named as HERV-W, composed of gag, pol, and env genes, a primer binding site, RU5 and U3R LTRs, and a polypurine tract [37]. A total of 213 elements were discovered in HERV-W family, and grouped into three categories according to portion of LTRs and formation mechanism: 65 proviruses, 135 processed pseudogenes and 13 undefined elements [38].

Involvement of HERV-W family of retroelements in MS was shown by various studies. Serum samples obtained from 103 MS patients were analyzed by enzyme-linked immunosorbent assay (ELISA) to reveal the presence of envelope (Env) protein, and 73% of the sera were shown to contain Env antigen of HERV-W. Additionally, expression and copy number of env were found to be increased significantly in peripheral blood mononuclear cells (PBMC) of MS patients compared to healthy controls, revealed by quantitative polymerase chain reaction (qPCR). Moreover, presence of Env protein was detected via immunohistology analysis in macrophages within brain lesions of MS patients [39]. Altered expression of individual HERV-W copies in PBMC of clinically isolated syndrome (a precursor to MS) patients compared to controls was also shown by next-generation sequencing analysis [6].

Prevalence of MS is higher in women compared to men, at a ratio of 2:1 to 3:1 depending on the region. Involvement of the X chromosome in this higher ratio was investigated by mapping a 3 kb region in Xq22.3, covering the HERV-W locus, and three polymorphisms were identified as rs6622139 (T/C), rs6622140 [guanine/adenine (G/A)] and rs1290413 (G/A). Moreover, rs6622139 T/C polymorphism was found to be related to MS susceptibility and severity in women as CC structure showed lower scores than CT or TT carrying patients. Also, association between rs6622139*T genotype and higher expression of MSRV was revealed [40].

HERV-W Env interacts with Toll-like receptor 4 (TLR4) on the cells of immune system, and a pro-inflammatory and autoimmune response is activated. Therefore, blocking the interaction between Env and TLR4 using a monoclonal antibody was proposed as an effective therapeutic strategy against MS [41].