Endocrine, Metabolic & Immune Disorders - Drug Targets, 2018, 18, 000-000 1
REVIEW ARTICLE
1871-5303/18 $58.00+.00 © 2018 Bentham Science Publishers
An Insight on the Pathogenesis and Treatment of Systemic Lupus Erythe- matosus
Murtaza Ali
1, Chelapram K. Firoz
2, Nasimudeen R. Jabir
2, Mohd Rehan
2, Mohd S. Khan
3and Shams Tabrez
2,*1
Department of Biosciences, Jamia Millia Islamia, New Delhi, India;
2King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia;
3Protein Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
A R T I C L E H I S T O R Y Received: March 23, 2017 Revised: August 13, 2017 Accepted: August 23, 2017
DOI:
10.2174/1871530318666171207145003
Abstract: Background and Objective: Systemic lupus erythematosus (SLE) is a diverse autoimmune disorder, evoked in response to self-immune system that leads to immune complex depositions and organ damage. The exact mechanism of SLE pathogenesis is still unclear but certain genetic and envi- ronmental factors have been suggested that could influence its pathogenesis.
Discussion: The modulation in B- and T- cell responses and genetic variations could lead to abnormal lymphocyte functions and the production of antibodies against the indigenous proteins and the immune complex depositions.
Conclusion: The present review highlights the various causatives of SLE, particularly the genetic al- teration in B- and T-cell-related proteins. We have also delineated some of the available therapeutic strategies for the treatment of SLE.
Keywords: Cytokines, inflammation, interferons, polymorphism, pathogenesis, systemic lupus erythematosus.
1. INTRODUCTION
Systemic lupus erythematosus (SLE) is a multifarious autoimmune disorder evoked in response to self-immune system. Typically, SLE is marked by the onset of auto- antibody formation against host antigen leading to immune complex depositions and organ damage [1]. The exact mechanism of SLE pathogenesis is still unclear. However, certain genetic and environmental factors have been sug- gested in the literature that could influence its pathogenesis.
Currently, it is one of the most common autoimmune dis- eases affecting millions of people worldwide [2]. Females (especially during pregnancy), are more prone to SLE com- pared with males; with a 15:1 noted ratio [3]. A person with SLE suffers from skin lesions in reaction to sunlight. Oral ulcers, joint pain and swellings, serositis, renal disorders and neurological dysfunction including seizures and psychosis are among the common symptoms of SLE [4, 5]. In SLE patients, haematological disorders are marked by the condi- tions like anaemia, leukopenia, lymphopenia or thrombocy- topenia [4]. Single nucleotide polymorphism (SNP) in im- mune-related genes and human leucocyte antigen (HLA) variants are the classical hallmarks of this diseases [6]. In addition, the genome-wide association studies (GWASs) provided the evidence of association of some novel genes with SLE [7]. Several genes related to B- and T-cell
*Address correspondence to this author at the King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; E-mail: [email protected]
responses have also been suspected to have roles in the pathophysiology of SLE. Variations in these genes could lead to abnormal lymphocyte functions which ultimately result into auto-immune responses, antibodies formation against indigenous proteins and immune complex deposi- tions [8].
The purpose of the current article was to summarize the various causatives of SLE via genetic alteration in B- and T- cell-related proteins and also provide a glance on the avail- able therapeutic strategies against SLE in a single article.
2. ETIOPATHOGENESIS OF SLE
SLE is a typical systemic auto-inflammatory disorder of unknown etiology, marked by the dysregulation of T-cells and increased production of autoantibodies. T-cell dysfunc- tion activates auto-reactive B-cells and evokes inflammatory injury of target organs through excessive secretion of cytoki- nes [7, 9]. An understanding of the molecular defects under- lining the T-cells could pave the way for identifying poten- tial therapeutics for SLE treatment. The etiopathology of SLE is partially understood, although, it depends upon both environmental and genetic factors.
3. INVOLVEMENT OF GENETIC FACTORS IN SLE PATHOGENESIS
Complement system plays significant roles in conferring
innate immunity by enhancing the potential antibodies and
phagocytic cells to clear pathogens. Deficiency of C1qa complement component has been reported to be associated with periodic commencement of infections with high preva- lence of SLE. Botto et al. (1998) reported that deletion of C1qa in mice model leads to glomerulonephritis along with immune deposits and apoptotic cells in the glomeruli [10].
Another study subjected to deletion of serum amyloid P component (SAP) unexpectedly confers antinuclear autoim- munity and severe glomerulo-nephritis (a typical phenotypic character in human SLE patients) [5]. A genetic polymor- phism in the Fc receptor gene FcgRIIa has also been noted to affect the metabolism of immune complexes and affects SLE pathogenesis [11]. Conclusively, these studies clearly indi- cate that SLE pathogenesis took place via some genetic de- fects which leads to impaired clearance of apoptotic cells, eventually leading to immune-mediated organ damage.
4. INVOLVEMENT OF T CELLS IN SLE PATHOGE- NICITY
T-cells are the key player of SLE pathophysiology and are involved in the initiation and perpetuation of immune- mediated organ damage [12]. Affinity maturation, isotype switching and memory formation are some of the complex functions governed by these cells. Autoantigens are the in- digenous source of proteins, which on reaction with the autoreacitve T-cells, recognises as foreign material. On the other hand, anti-nucleosome response takes place by the epi- topes present on histones and DNA. The epitopes for B-cell specific response are present on the DNA, while T-cell epi- topes are provided by histones. Consequently, the production of anti-double stranded DNA (anti-dsDNA) occurs due to co-incubation of T-cells acquainted DNA-binding proteins with autologous B-cells [13-15].
5. PHAGOCYTOSIS OF APOPTOTIC AND NECROTIC CELLS
Under normal conditions, apoptotic cells are proficiently swallowed by the macrophages in the early stage of apop- totic cell death without triggering inflammation or immune response [14, 16]. An inefficient dying cells clearance is the key event in the etiopathogenesis of SLE [10, 17]. Upon dif- ferentiation, the macrophages from SLE patients show com- promised phagocytosis of apoptotic cells [18]. During necro- sis and apoptosis, various potential autoantigens are often modified along with their components resulting in an in- creased immunogenicity.
6. GENETIC ALTERATIONS IN B- AND T-CELL- RELATED PROTEIN FUNCTIONS
B- and T-cell responses play the major regulatory role in immunological response. A number of genes have been iden- tified which are associated with SLE etiology [19]. Func- tional mutation in any of these B- and T-cell-related proteins can cause serious implications through auto-antibody forma- tion. In the following section, we have covered some of the specific genes and related proteins which have been impli- cated with SLE pathogenesis.
7. CDKN1B
The CDKN1B gene plays a vital role in the mammalians innate immune system. Numerous studies highlighted their role in providing autoimmune balance. CDKN1B gene is located at 12
thchromosome (12p13.1-p12) and contains the SNP site rs34330, resulting in a change of C allele located in the 5 untranslated region (5 UTR). The genetic alteration in CDKN1B is frequently observed in SLE patients. Specifi- cally down-regulation of CDKN1B has been noted in the individuals with SLE [19]. A cyclin dependent kinase (CDK) inhibitor, p27kip1 protein is encoded by CDKN1B and is involved in the inhibition of cell-cycle progression, espe- cially in T-lymphocytes. Moreover, p27kip1 has also been suggested to cause apoptotic death of dendritic cells and plays an important role in the susceptibility of SLE [20].
8. INTERLEUKIN 10 (IL-10)
Interleukin 10 (IL-10) is an important immune-modulator involved in various inflammatory responses [21]. It is se- creted by almost all type of leucocytes especially by T-helper cells, dendritic cells and macrophages [22-23]. It suppresses the activity of pro-inflammatory cytokines like IL-1, IL-6, IL-8, IL-12, tumour necrosis factor (TNF)- and inhibit the T-cell function. On the other hand, IL-10 also increases the survival rate, differentiation and proliferations of B-cells.
Genetic polymorphism in the promoter region of IL-10 gene and unusual production of IL-10 has been reported to cause several clinical implications of SLE in Asiatic and Caucasian populations [24-28].
9. TET3
TET3 is a ubiquitously expressed zinc finger binding protein, located on chromosome 10 (10q21.3) and has been associated with SLE susceptibility. The high expression of this protein has been noted in myeloid and monocytic hema- topoietic cells [29]. TET3 catalyses the conversion of 5- methylcytosine to 5-hydroxymethylcytosine and plays a cru- cial role in DNA demethylation [30]. Hypo-methylation is involved in the early accusation of inflammatory disorders and has been noted in CD4 helper T cells in SLE individuals [31]. In addition, TET3 has also been reported to be associ- ated with DNA and histone modification which regulates the gene expression in T- and B-lymphocytes.
10. AT-RICH INTERACTIVE DOMAIN-CONTAINING PROTEIN 5B (ARID5B)
It is a component of a histone-demethylase protein com- plex, involved in B-cell signalling pathway and is located on chromosome 10 (10q21.2). The genetic polymorphism in this gene affects the growth and differentiation of B-lymphocyte progenitors. Study on knockout ARID5B mice reported the prevalence of transient immune abnormalities which clearly suggests its role in immune system [32].
11. CD80
CD80 is a membrane receptor on antigen presenting cells
expressed by T- and B-lymphocytes [33]. These are found on
dendritic cells which have important function in the modula- tion of monocytes and B-cells and also provide essential co- stimulatory signals for T-cell activation [34]. This receptor works with CD86 and is localized on chromosomes 3 (q13.33). During T-cell activation, it works as ligand for two different proteins namely CD28 and CTLA-4 leading to downstream signal regulations. The prolonged down- regulation of CD80 has been reported in SLE-affected indi- viduals which attenuates T- and B-cell responses [35, 36].
The association of CD80 has also been noted with multiple sclerosis, celiac disease and primary biliary cirrhosis (all of which have high autoimmune components) [37, 38].
12. PROGRAMMED CELL DEATH 1 (PDCD1)
Programmed cell death 1 (PDCD1) is one of the impor- tant immunoregulatory receptor present on T- and B- lym- phocytes. It helps in the activation of T- and B- lymphocytes, through an immuno-inhibitory domain by the development of immune receptor tyrosine based inhibition motif (ITIMs).
Upon cellular activation, this motif gets phosphorylated re- sulting into inhibition of the downstream signalling, trigger- ing B- and T-cells responses. PDCD1 belongs to CD28 fam- ily of receptors [39].
Several studies reported the association of genetic poly- morphism in PDCD1 gene with SLE pathogenesis [40].
Variations in intronic region 2 of PDCD1 gene at 7146 and 7209 positions have been suggested to be associated with SLE. However, several studies reported great deal of varia- tions among different geographical regions, for instance the SNP at position 7146 has been reported to be allied with SLE venerability in Mexican, Swedish and European population [40-44]. Concomitantly, SLE occurrences in Taiwanese and Polish population have been subjected to SNP at 7209 site [21, 45]. Genetic alterations within single or multiple locus compromise the binding of NF-B and RUNX1 and decrease the expression of PD-1 that contributes lymphocytic hyper- activity and autoimmunity.
13. PRL GENE
Sex hormones play important roles in the biological devel- opment, immuno-regulation, sex characterisation and meta- bolic functioning of the body [46]. An alteration in the genetic makeup of these hormones could lead to the improper func- tioning of the system. The prolactin hormone is secreted by the anterior pituitary gland in combination with extra-pituitary tissues including T-lymphocytes [47]. Prolactin is encoded by the PRL gene, which resides on chromosome 6 (6p22.2- p21.3). Prolactin acts like cytokine, and has a role in immuno- modulation cytokine type 1 receptor [48]. Treadwell et al.
(2015) reported the association of high levels of prolactin with SLE [49]. SNP analysis reveals higher expression of prolactin in African, American and European women’s with lupus [50].
The functional polymorphism present in the promoter region at -1149 G>T (rs1341239) of the extra-pituitary form of PRL gene has been associated with SLE [50].
14. LYMPHOID-SPECIFIC TYROSINE PHOSPHATASE (LYP)
Lymphoid-specific tyrosine phosphatase (LYP) is en- coded by PTPN22 (Protein tyrosine phosphatase non-
receptor type 22) gene and is placed on chromosome 1 (posi- tion 1p13). LYP negatively regulates T-cell signalling by de- phosphorylating kinases such as Lck, Fyn and ZAP70. Dur- ing cellular activation, it binds with C-terminal poly-proline (P1) region through SH3 domain of CSK tyrosine kinase, leading to deactivation of downstream signalling [51]. Muta- tion in the P1 region (1858 C>T) results into substitution of amino acid from arginine to tryptophan. This mutation dis- turbs the physiological interaction and hinders T-cell recep- tor signalling [52]. Linkage between polymorphism in this gene and SLE pathogenesis has been reported in individuals from Europe and other parts of the world [44, 53-58]. The mutated PRL gene alters T-cell signalling and affects disease susceptibility by various mechanisms including disturbed thymic selection, T-helper activity and distribution in the number or function of regulatory T-cells [59]. In a study by Zhang et al. (2011) involving PEP-R619W knock in mice (a murine mutant similar to LYP-R620W) noted swelling of thymus and spleen and a decline in the level of PEP protein [60].
15. FYB GENE
FYB gene encode Fyn binding protein located on chro- mosome 5 (5p13.1) and is involved in T-cell signal transduc- tion pathway. Garcia et al. (2009) reported down-regulation of this gene in SLE patients [61]. Their implications with SLE pathogenicity has been associated by the polymorphism in this gene at rs6863066 (C>T) and rs358501 (T>C). In addition, these polymorphism has also been noted to be as- sociated with SNP bearing IDs rs379707 (A>C) and rs2161612 (A>G) which affect the production of anti- dsDNA and protection of haematological variations [62].
The SNP bearing ID rs379707 is present on exon 15 of FYB gene and causes phenylanine to valine substitution. This sub- stitution could results into functional impairment of FYB protein that leads to synthesis of anti-DNA antibodies. How- ever, another SNP bearing ID rs2161612 are situated in the 5’ UTR of the FYB gene and is believed to shield the SLE patients from extreme inflammation [63].
16. ATG5
Genetic polymorphism near ATG5 (MIM 604261) has been suggested to be linked with SLE pathogenesis [64-66].
ATG5 are localized on long arm of chromosome 6 (q21) and has a role in autophagy and also work as FYN binding pro- tein, which encodes a protein involved in LCP2-signalling cascades in T-cells and IL-2 expression [67]. The low ex- pression of IL-2 has also been noted in SLE individuals.
17. TUMOUR NECROSIS FACTOR LIGAND SUPERFAMILY MEMBER 4 (TNFSF4)
Tumour necrosis factor ligand superfamily member 4
(TNFSF4) belongs to TNF ligand family and is involved
with the differentiation and proliferation of T- and B- lym-
phocytes. It is a key player in the regulation, survival and
development of CD4
+T-cells at inflammation sites and
influence the production of pro-inflammatory cytokine of
pro-inflammatory cytokines [45, 68]. Several studies re-
ported the role of TNFSF4 and its association with SLE
pathogenesis in Asian, Caucasian and African-American population [1, 65-66, 69-73]. Several genetic variants are observed in the UTR of the TNFSF4 gene bearing IDs rs844644, rs2205960, rs10489265, rs844648 and rs1234315 and have been reported to be associated for SLE pathogene- sis. Although these variations are present in the promoter region, however, these are believed to shift gene regulation that may result in the predisposition of SLE.
18. RASGUANYL NUCLEOTIDE RELEASING PROTEINS 3 (RASGRP3)
Rasguanyl nucleotide releasing proteins 3 (RASGRP3) is expressed in B-cells and is located on the chromosome 2 (2p25.1–p24.1). It is known to regulate Ras activators that promote procurement of guanosine triphosphate (GTP) to maintain the active state and also provide association be- tween cell surface receptors and Ras [74]. Ras is a membrane bound GTPase which are involved in the signaling of B-cell receptor. The conversion of Ras-GDP to Ras-GTP could lead to the initiation of numerous downstream pathways such as RAF-ERK kinase cascade that results into fluctuations in the transcription and other cellular responses [75]. The polymor- phism in this gene at intronic region leading to SLE has been reported in Chinese and Swedish population [65, 76].
19. B-CELL SCAFFOLD PROTEIN WITH ANKYRIN REPEATS 1 (BANK 1)
B-cell scaffold protein with ankyrin repeats 1 (BANK1) is an important protein engaged in B-cell signalling. It acts like an adaptor protein molecule which gets phosphorylated upon stimulation of B-cell receptor and induces inositol 1, 4, 5 trisphosphate receptors phosphorylation through Src tyrosine kinase such as Lyn. Eventually, this phosphorylation leads to Ca
2+recruitment from intracellular stores [77, 78]. Addition- ally, the B-cell receptor stimulation augments the interaction of BANK1 and B- lymphoid tyrosine kinase interceding cellu- lar kinases [33]. Three of the BANK1 gene variants bearing IDs rs10516487, rs3733197 and rs17266594 have been re- ported to be associated with SLE in Swedish, German, Scan- dinavian, Spanish, Argentinian and Italian population [34].
This result has been consistently observed in Asian, African- Americans and other European population [38, 68, 79, 80].
Antinuclear antibodies (ANA) are produced by the body against indigenous components. The ANA and anti- Sjögren's-syndrome-related antigen A production in SLE patients are reported to be associated with SNPs located at rs10516487 and rs17266594 in Han Chinese and European SLE patients [38, 81]. The mutations in BANK1 gene might lead to continuous B-cell receptor signalling and consequent B-cell hyperactivity which ultimately results in to SLE ex- pansion and the production of autoantibodies.
20. VITAMIN D RECEPTOR (VDR)
Vitamin D receptor (VDR) is also known as NR111 (nu- clear receptor family 1, group 1, member 1), located on chromosome 12 (p47-p84) and has a central role in trans- repression of specific gene products [82]. In the past few decades, a number of targets have been identified for immu-
nological regulation of vitamin D. The down-regulation of T helper1 Th1 response to immune system depresses activated proliferation of B-cells and up-regulation of T-cells. On the other hand, a decreased level of vitamin D has been noted in several immunological disorders including SLE [83-86].
Vitamin D operates through numerous immune cells like T, B and dendritic cells. These cells express 1-hydroxylase and VDR which enables the production of vitamin D in their vicinity. The complex formed due to interaction of vitamin D and VDR leads to the inhibition of pro-inflammatory cytoki- nes such as interferon- (IFN-) and IL-12 (increased serum levels are reported in SLE patients) [87]. The VDR gene is extremely polymorphic but till now, only four SNPs namely TaqI (rs731236), FokI (rs2228570), BmsI (rs1544410), and ApaI (rs7975232) are studied. The functional role for the SNP variants (BmsI, ApaI and TaqI) is linked with the in- crease in the stability of messenger RNA. The variant FokI- can alter the transcription initiation site of VDR and synthe- sizes truncated VDR protein [87, 88]. In a study, Luo et al.
(2012) reported the linkage of BsmI polymorphism with SLE susceptibility in Chinese population [86].
21. CYTOTOXIC T-LYMPHOCYTE ASSOCIATED ANTIGEN-4 (CTLA-4)
CTLA-4 is a cell surface receptor associated with the tight control of T cells over a pathway of unresponsiveness and resistance. It is a member of immunoglobulin superfa- mily which refers antigen-specific apoptosis of T-cells and subdues proliferation of T-lymphocytes self-reactiveness [89]. These are exhibit sequence homology with CD28 and both (CD28 and CTLA-4) bind to the same ligands B7.1 (CD80) and B7.2 (CD86), but perform opposite functions [90]. In human, this gene is located at chromosome 2 (posi- tioned at 2q33) while in mouse it is located at chromosome number 1. Several studies reported linkage of CTLA-4 gene polymorphisms with SLE [91-93]. Ahmed et al. (2001) re- ported the linkage of CTLA-4 exon 1 polymorphism at +49 with SLE but not with CD28 which signifies that SNPs in CTLA-4 gene might be directly associated with the develop- ment of SLE [91].
22. ROLE OF DNA REPAIR GENES IN SLE PATHOGENESIS
Several environmental factors, particularly, ultraviolet light have profound effects on DNA repair mechanism. Ex- ternal stimulus disrupts cellular integrity by introducing dou- ble strand breaks (DSBs) and oxidative DNA damage [94].
These damages could lead to the array of pathology related
with autoimmunity, metabolic dys-functioning and hyperac-
tive responsiveness [95]. Although DNA is a poor immuno-
genic molecule, yet DSBs may evoke immune response. In
addition, mutations in DNA repair genes may also hinder
nucleotide excision repair pathway. The flaws in the DSBs
repair may cause accretion of genomic variations and pro-
mote apoptosis [96]. This compromised genetic stability in
SLE patients, leads to the loss of molecular machinery via
apoptotic or autophagic pathways [94, 97, 98]. Additionally,
polymorphic sites in DNA repair genes are also linked with
clinical manifestations of SLE and production of anti-DNA
antibody [94, 99].
23. X-RAY REPAIR CROSS COMPLEMENTING (XRCC) 1, 3 AND 4
X-ray repair cross complementing (XRCC) is a DNA repair protein encoded by XRCC gene family, located on chromosome 19 (19q13.2-13.3) and form complex with DNA ligase III [100]. They are involved in the efficient re- pair mechanism and protect DNA damage against ionizing radiation [100]. The DNA damage might produce nucleopro- tein complexes which stimulates auto-reactive immune re- sponses and induces SLE susceptibility in individuals [96, 100]. XRCC gene modifications are not only associated with SLE pathogenesis but also with some other autoimmune dis- orders [101]. There are more than 300 SNPs sites reported in XRCC1 gene, out of which only three have been associated with SLE pathogenicity. The amino acid switches at codon 280 (at position 27466 on exon 9, rs25489), codon 194 (at position 26304 on exon 6, rs1799782), and codon 399 (at position 28152 on exon 10, rs25487) are SNP hotspots that have been associated with SLE pathogenicity. These non- essential amino acid modifications might lead to a dimin- ished repair kinetics prompting immune system imbalance [102]. Despite their important role in providing the DNA stability, not enough studies have been performed concern- ing autoimmune disorder specifically in context of SLE pathogenesis. SLE susceptibility and occurrence in the Bra- zilian population has been reported to be associated with genetic polymorphism in XRCC 1, 3 and 4 genes.
24. SERINE/THREONINE KINASE 17 A (STK17A) Serine/threonine kinase 17 A (STK17A) is a member of DAP kinase and related with apoptosis inducing protein. One study suggested association of SLE vulnerability with three DNA repair genes (LIG4, RAD52 and STK17A) [61]. On the other hand, Silva et al. (2013) didn’t find any linkage of LIG4 and RAD52 with SLE development [103]. In addition to SLE, arthritis, cutaneous and immunological modifica- tions have also been reported to be linked with STK17A polymorphism [104]. They are localized on chromosome 7 (7p13) and known to regulate several nuclear processes viz.
DNA damage stimulus, regulation of apoptotic progression, reactive oxygen species and intracellular protein kinase cas- cade [105, 106]. The external stimulus such as UV radiation and certain cytotoxic drugs can also trigger STK17A [62].
The recruitment of STK17A takes place by DNA dependent protein kinase catalytic subunit for the repair of DSBs which could be caused by the endogenous damage or environ- mental factors [105, 107, 108].
25. INTERFERON REGULATORY GENES
The role of interferon type 1 system in SLE pathogenesis was the first described by Bengtsson et al. [109]. Later, Baechler et al. (2003) demonstrated profound interferon sig- natures in the peripheral blood cells of lupus patients [110].
Based on their significant role, IFN type 1 (IFNI) system is considered as one of the root molecule in SLE pathogenesis [109, 111]. However, some studies reveal that the IFNI sig- natures are not only exclusively associated with SLE, but are also observed with other autoimmune diseases [112]. IFNI includes interferon alpha and interferon beta, both of them
signal through type I interferon receptor [113]. The IFNs are the cytokines that intercede the reactions of Th1 to maintain survival of activated T- and B-cell [16, 114]. Th1 reactions communicate pro-inflammatory cytokines and contribute to the chronic inflammation and tissue damage [113, 114]. Sev- eral polymorphic sites in IFN-genes have been linked with the SLE susceptibility.
26. INTERFERON-INDUCED HELICASE C DOMAIN 1 (IFIH1)
IFIH1 is another gene that participate in the programmed cell death via IFNI response modulation by the secretion of pro-inflammatory cytokines [115]. These genes activate apoptosis in viral dsRNA infected cells provoking immune- regulatory responses. The flawed initiation of these proteins by auto-derived and intracellular nucleic acids might trans- form immune function. IFN1 plays a crucial role in the pathogenesis of SLE, enhances autoimmune progressions and disease complications [116, 117]. The IFIH1 gene is located at chromosome 2 (2q24). Scientific literature high- lighted the role of INF-induced genes that regulate mecha- nisms involved in SLE development [118]. IFIH1 gene polymorphism at rs2068330, rs2111485 and rs984971 have been associated with SLE pathogenicity and have variable frequency distribution in different populations [116]. Gateva et al. (2009) for the first time reported the linkage of IFIH1 polymorphism with SLE [66]. Meta-analysis data by Silva et al. (2013) further confirmed the linkage of this polymor- phism with SLE [119].
27. INTERFERON REGULATORY FACTOR (IRF-5) Interferon regulatory factor-5 (IRF-5), located at chromo- some 7 (7q32), is expressed by B- and dendritic cells. They play an important role in the transcription and regulate the expression of a wide range of genes. IRF-5 works as tran- scription inducer of IFN-mRNA and are also involved in the activation of IFN and pro-inflammatory cytokines [120].
Several studies reported polymorphism in IRF5 gene as a risk factor for SLE vulnerability in various populations [121, 122]. Sigurdsson et al. (2005) and Graham et al. (2009) re- ported the association of IRF5 polymorphism (rs2004640) with SLE [123, 124]. SLE pathogenesis and disease´s sever- ity is also marked by the production of anti-Ro auto- antibodies which are synthesized against nuclear antigens [125]. Studies also suggested the production of these auto- antibodies that could leads to the stimulation of IFN levels in humans through the activation of endosomal toll like recep- tor (TLR) system. Auto-antibodies play a key role in the progression of glomerular inflammation, particularly anti- dsDNA antibodies that have been related with lupus nephri- tis (a common clinical feature of SLE pathogenesis) [126]. In one study, Qin et al. (2010) reported the association of IRF5 gene polymorphism (rs2004640) with lupus nephritis onset in Chinese population [127].
28. TYROSINE KINASE 2 (TYK2)
Tyrosine kinase 2 (TYK2) plays a pivotal role in the pro-
duction of IFN-1 responsive genes and the progression of
SLE [117]. It is located on chromosome 19 (19p13.2), as a
part of the janus kinase (JAK). During cellular activation, TYK2 binds with interferon receptor-/ (IFNAR-/) pre- sent on the cell surface of IFN producing cells. This binding leads to phosphorylation which ultimately results in the acti- vation of TYK2. Phosphorylated TYK2 at that point phos- phorylates IFNAR to permit binding of signal transducer and activator of transcription (STAT) 3 and 5. Moreover, the increase in the expression of type I IFN and IFN-inducible genes regulation play an important role in SLE aetiology.
Furthermore, an elevated level of IFN-1 is also a distin- guished feature of SLE patients which is highly associated with both disease manifestation and severity [128]. Meta- analysis study by Lee et al. (2012) reported four SNP hot- spots viz. rs12720270, rs2304256, rs280519 and rs12720356 in TYK2 gene have been associated with SLE pathogenicity [129].
29. TOLL LIKE RECEPTORS (TLR 7, 8 AND 9)
TLRs are the family of proteins that play a vital role in innate immune response and chiefly regulate self-tolerances caused by the activation of auto-reactive B cells and plas- macytoid dendritic cells via TLR ligands [130-132]. TLRs are expressed by sentinel cells such as macrophages and dendritic cells, and are widely studied as pattern-recognition molecules [132]. During cellular activation, TLR receptors recruit an adopter molecule which evokes antigen-specific acquired immunity. TLR7 and TLR8 can recognize single stranded RNA, while TLR9 recognizes bacterial and viral DNA [131, 133]. TLR7 is expressed by B-cells and plas- macytoid dendritic cells. It is encoded by TLR7 gene, which is located at X chromosome (Xp22.3-p22.2) and contains the SNP site rs179008. The substitution of glutamine (A allele) with leucine (T allele) takes place in this peptide at position 11 which leads to the truncated N region of TLR7 protein [62]. TLR8 is expressed in monocyte-derived cells for ex- ample myeloid dendritic cells (mDC) and macrophages [131]. TLR8 gene is also located at chromosome X, 16kb apart from TLR7 and is also referred as CD288 [134]. TLR8 gene encodes two variants (TLR8v1 and TLR8v2) with op- posite translation start sites. TLR8 confers innate immunity by regulating protein phosphorylation, cytokine secretion, interferons and MyD88-dependent TLR signalling [130, 134]. TLR9 gene is also referred as CD289 and located at chromosome 3 (3p21.3). They preferentially bind with the bacterial and viral DNA and has two polymorphic sites namely rs5743836 and rs352140 [135]. TLR9 gene is highly expressed by immune rich tissues such as spleen, bone mar- row and lymph nodes [136]. TLRs are expressed inside the kidney cells of SLE patients, particularly in lupus nephritis.
The elevated level of TLR9 and their possible role in SLE development has been suggested in literature [137]. Altera- tions in TLR 7/8/9 gene are frequently associated with SLE pathogenesis.
30. SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 4 (STAT4)
STAT4 is a transcription activator, belongs to the STAT family of proteins and expressed in T- and B-lymphocytes, natural killer cells, macrophages, monocytes and dendritic cells [138-140]. They are responsible for the differentiation
of immune cells, production of cytokines, and inhibition of autoantibodies apoptosis and autoantigens presentation which may lead to the onset of autoimmune activation [138].
STAT4 gene is located at chromosome 2 (2q32.2–2q32.3) and its distribution is limited to myeloid cells, thymus and spleen [141]. The polymorphisms in STAT4 gene have also been associated with other autoimmune disorders [139]. The polymorphic site rs7574865 in STAT4 gene is located at 3
rdintronic region and has a strong correlation with autoimmu- nity. This SNPs are not associated with linkage disequilib- rium which explains its association with SLE pathogenesis [139]. To summarize our article, we have listed different genes involved in SLE pathogenicity, location and their mechanism of action in Table 1.
31. CURRENTLY AVAILABLE THERAPEUTIC STRATEGIES FOR THE TREATMENT OF AUTOIMMUNE LUPUS
In the following section, we have covered some of the therapeutic strategies available for the treatment of lupus.
32. STEROID MEDIATED THERAPY
In severe condition, corticosteroids are used to treat SLE under a particular dose regimen [142-144]. For the treatment of proliferative nephritis, cyclophosphamide, azathioprine along with corticosteroid are usually used [144]. On the other hand, the continuous search of suitable medicine for the treatment of lupus nephritis led to the identification of mycophenolate mofetil which could work as a suitable sub- stitute for intravenous cyclophosphamide [145-147]. The combined use of mycophenolate mofetil and corticosteroid reduces renal inflammation and glomerulonephritis. The therapeutic effects of corticosteroid treatment are purely tis- sue specific. Blockage of mineralocorticoid receptors have been reported to reduces mortality of SLE patients. Recent studies also indicated therapeutic benefit of progesterone for the treatment of autoimmune diseases and arthritis [148, 149]. In addition, some studies also highlighted the disad- vantage of glucocorticoid therapy which could cause steroid psychosis in individuals with lupus [150]. Kanik et al.
(2000) reported association of sex steroids estrogen, andro- gen and corticosteroids with the reduction of inflammatory immune responses in autoimmune arthritis [151]. Further- more, a selective inhibitor of NF-B, non-steroidal estrogen receptor ligand WAY-169916, has also been reported for its potential in the treatment of autoimmune rheumatoid arthritis [37]. In addition, the determination of steroid family, steroid hormone receptor modulators, streamlining dosage and dura- tion are critical parameters ensuring management of tissue specific complications in immune system lupus [152].
33. IFN-MEDIATED THERAPIES
IFNs are emerging targets for the treatment of SLE pathogenesis. They play a central role in inducing an array of biological effects that can enhance the dysfunctioning of effector cells such as B-cells, T-cells and dendritic cells.
They do so by activating several pattern recognition mole-
cules such as TLR receptors, antagonists, and by inducing
inflammatory responses. In humans, 13 subtypes of IFN 1
family has been reported with wide range of properties like
Table 1. Genes, chromosome location, SNPs sites and possible mechanism of action.
Genes Involved
in SLE Synonyms Chromosome
Location SNP’s Family Mechanism of Action References
CDKN1B p27Kip1 12p13.1-p12 rs34330 Cip/Kip family Inhibitor of cyclin E and D [19]
TET3 . 10 (10q21.3) rs6705628
rs4852324
TET family-zinc finger binding protein
Dioxygenase cause DNA hydroxylation
[30, 31]
ARID5B Modulator recogni- tion factor 23.
10 (10q21.20 rs494849610 ARID Component of a histone demethylase complex
[32]
CD80 B7.1 3(q13.33) rs6804441 CD A membrane receptor on
antigen presenting cells, provide signal for T cell activation and survival
[35, 36]
IL-10 Human cytokine synthesis inhibitory
factor
1 (1q31-q32) rs1800896 rs1800871 rs1800872
Interleukin IL-10 induces STAT3 signalling through phos-
phorylation
[26, 27, 176]
PDCD1 PD-1 or CD279 2 (2q37.3) rs11568821
rs41386349
CD28 A cell surface receptor having immune-receptor tyrosine–based inhibition
motif
[42, 44, 45]
PRL Luteotropin 6(6p22.2- p21.3) rs13412390 Hormone Basically, regulate lacta- tion
[48, 50]
Lymphoid- specific tyrosine
phosphatase
PTPN22 1 (1p13) rs2476601 Protein tyrosine
phospatase
Regulates T cell signalling through direct dephosphorylation of Lck,
Fyn and ZAP70 kinases
[57-58]
FYB ADAP,
SLAP-130 Fyn binding protein
5 (5p13.1) rs6863066, rs358501, rs379707, rs2161612, rs379707, rs2161612
Protein Recruit adaptor protein and regulate T cell re-
sponse
[61, 63]
TNFSF4 TNFRSF4/OX40
ligand
1q25.1 rs2205960, rs844648,
rs844644, rs10489265 and
rs1234315
tumour necrosis fac- tor ligand family
Mediates adhesion of activated T cells to endo-
thelial cells
[69, 71, 177, 178]
RASGRP3 2p25.1p24.1 rs13385731 RAS family
Subfamily GTPase
RAS activation by phos- phorylation of Ras-GDP
[65, 179]
BANK 1 4q24 rs10516487,
rs17266594 rs3733197
Acts like an adaptor pro- tein molecule which gets phosphorylated upon BCR
stimulation
[69, 81]
VDR NR1I1 12p47-p84 rs7975232,
rs731236 rs1544410,
rs2228570 rs11168268,
rs3890733 rs2248098, rs4760648
Nuclear receptor family of transcrip-
tion factors
Trans repression of spe- cific gene products
[86, 180, 181]
CTLA-4 CD152 2q33 at position +49
A/G
Member of immuno- globulin superfamily
Negative controller of T- cell responses
[91-92]
Table (1) contd….
Genes Involved
in SLE Synonyms Chromosome
Location SNP’s Family Mechanism of Action References
XRCC 1, 3 and 4
XRCC1 at
19q13.2-13.3
XRCC1: rs25489 rs1799782,
rs25487 XRCC3:
Thr241Met XRCC4:
Ile401Thr
XRCC family Forms complex with DNA ligase and participate in efficient repair mechanism
[94, 101]
STK17A 7p13 DAP kinase related
apoptosis-inducing protein kinase family
DNA repair of double strand breaks
[61, 103]
IFIH1 MDA5 2q24 rs10930046,
rs1990760 rs2068330, rs2111485 rs984971
INF family Pattern recognition mole- cule.
DEAD box protein
[66, 117- 118]
IRF5 7q32 rs2004640,
rs10954213 rs10499631, rs1990760
IRF family Control macrophages [123-124]
TYK2 19p13.2 rs12720270,
rs2304256 rs280519, rs12720356
JAK family Activates cytokine recep- tors by phosphorylating receptor subunits, includ- ing type-I IFN receptors
[129, 182]
TLR7 CD288 Xp22.3 p22.2 rs179008 TLR family Expressed by B and plas-
macytoid dendritic cells
[131]
TLR 9 CD289 3p21.3 rs5743836,
rs352140 rs3764880
TLR family Expressed in B and plas- macytoid dendritic cells
[136]
STAT4 2q32.2–2q32.3 rs7574865 STAT family Transcription activator and
require for the activation of Th+CD4 – T sacells
[139]
antiviral, antiproliferative and immunoregulatory effects. On- going studies suggested a linkage between IFN- and SLE pathogenicity [153, 154]. Particularly, IFN- regulated activa- tion of the type I IFN pathway has been suggested to be linked with SLE occurrence. Several anti-type I IFN drugs have un- dergone in clinical assessment. Among those anti-IFN mAbs, sifalimumab and rontalizumab, have successfully completed phase II trials [50, 155, 156]. Till date, only anifrolumab has progressed to phase III clinical trial (NCT02446899). Another important therapeutic target for SLE treatment could be pDCs [a specialized dendritic cell with the ability to produce type I IFN rapidly]. They respond against viral infection where acti- vation of endosomal TLR7 and TLR9 took place [157].
Moreover, BIIB059 is in a phase I clinical trial (NCT02106897). The discerning reduction of pDCs has been reported in SLE patients which took place due to the inhibition of Bcl-2 [158]. A clinical trial of ABT-199, (an inhibitor of Bcl-2) has successfully completed a phase I clinical trial for the SLE treatment (NCT01686555).
34. MONOCLONAL BASED ANTIBODY THERAPY OF AUTOIMMUNE LUPUS
Monoclonal antibodies are the proteins raised against spe- cific B-cells targets. There are several humanized chimeric antibodies available in the market with SLE preventing poten- tial. Rituximab treatment causes reduction in CD20 positive
B-cells and control lipid profile of lupus patients. In addition, recent studies also suggested use of rituximab and other monoclonal antibodies for the treatment of CNS inflammation during lupus [159, 160]. Rituximab could also work as B- lymphocyte stimulator (Belimumab), which neutralizes BAFF (inhibitor of B-cell activating factor) instead depletion of B- cells [160-162]. This highlights another potential tactic for the treatment of lupus. Epratuzumab (monoclonal antibody) showed promising results in clinical trial against lupus and several other hematologic and rheumatic pathogenesis [51].
They influence many co-stimulatory molecules viz. CD28, CD80, CD86, CD154 (CD40 ligand), ICOS, B7RP-1, which have been involved with the beginning of lupus. The mono- clonal antibody treatment alone or in association with im- mune suppressing drugs gives advantage in diminishing in- flammatory responses in lupus. The cumulative treatment with tocilizumab (IL-6 blocking monoclonal antibody) and tacrolimus (macrolide, immunosuppressant) has been sug- gested as an effective treatment measure against autoimmune diseases [162, 163].
35. THERAPEUTIC PANORAMA OF ALEMTUZUMAB IN LUPUS TREATMENT
Alemtuzumab is an anti-CD52 monoclonal antibody used
for the treatment of hemophagocytic lymphohistiocytosis
during progressive lupus. It reduces mature CD52 bearing B-
and T-cells from circulation along these lines diminishes cell-mediated immune responses to auto-antigens [164]. Sci- entific study suggested its importance in delaying graft rejec- tion during kidney transplant [165]. Alemtuzumab along with other drugs have also been reported for their potential for the treatment of lupus. However, a strict regulation of dose and duration is required to avoid side effects as a result of long treatment procedure.
36. ESTROGEN MEDIATED THERAPY OF LUPUS Female hormones and their receptors are more suscepti- ble to SLE progression. Estrogen and its receptors (ER- and ER-ß) play an important role in B-cell development and im- munoglobulin class switch recombination [166]. On the other hand, estrogen signal regulates peripheral tolerance resulting into expansion of CD4 CD25 regulatory T-cells, via Th1attenuation [167]. Grimaldi and Diamond (2001) re- ported an increase in lupus like symptoms in response to the injection of estrogenin anti-DNA antibody [168]. An in- crease in calcium dependent serine-threonine phosphatase calcineurin took place by elevated ER- in lupus T-cells [169]. However, Ward et al. (2013) reported a decrease in the expression of calcium buffering protein calreticulin in T- cells of lupus patients [170]. Perry et al. (2012) suggested the regulation of Esrrg expression and orphan receptor ERR gamma autoimmune T- and B-cells is a way to mitigate lu- pus [171]. During cellular signalling, somatic hypermutation and activation, the induction of cytidine deaminase (AID) enzyme are critical checkpoints involved in the onset of B- cell mediated autoimmunity in lupus. An impaired AID gene causes allergy and autoimmune manifestations [87]. Estro- gen and its receptor guides AID expression and recombina- tion of immunoglobulin genes [172]. Thus, controlling es- trogen and its receptors mediated signal pathways could have major therapeutic benefits to attenuate autoimmune re- sponses. Several reports also suggested the therapeutic im- portance of NF-B, p65 inhibitors amid progression of im- mune system lupus nephritis [173, 174]. The transcription factor NF-B regulates immunoglobulin gene rearrangement and T-cell mediated inflammatory immune responses. In this way, dosage, duration and selective inhibition of peripheral NF-B activation could likewise be considered for reducing auto-reactive antibody production from B-cells. Simultane- ously, NF-B is also involved in the reduction of inflamma- tory responses by decreasing pro-inflammatory cytokine and chemokine gene expression [175]. However, an updated therapeutic intervention is still required in order to determine intracellular signal mechanisms involving estrogen receptors (ERs) and NF-B.
CONCLUSION
Based on our article, it is quite clear that several genetic and environmental factors are involved in the pathogenicity of SLE. These genes and/or some other novel genes could be exploited further to understand exact mechanism of SLE pathogenicity. Currently, several potential therapeutics against SLE are at different stages of clinical trial. However, the selection of inhibitor, its receptor modulators, optimiza- tion of dose and duration are critical parameters that needs to
be considered before finalizing any for the treatment of auto- immune lupus.
CONSENT FOR PUBLICATION Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENTS
The project was financially supported by King Saud Uni- versity, Vice Deanship of Research Chairs, Riyadh, KSA.
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