Genetic contributors and soluble mediators in prediction of autoimmune comorbidity
Introduction
Comorbidities in the setting of autoimmune disorders are increasingly recognized as a major problem with impact in morbidity and mortality. In particular, patients with Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) are at increased risk for accelerated atherosclerosis and lymphoma development, with the first being a major issue in lupus and the second in SS patients [1]. Of note, the latter have the highest susceptibility for lymphoma development amongst all autoimmune diseases [2,3]. Although chronic inflammation has been proposed as a major contributor of autoimmune-related atherogenesis and lymphomagenesis, the underlying biology remains poorly understood [4]. Moreover, fatigue in SS patients seems to originate by interplay between neuropsychological issues and a complex network of cytokines and neuropeptides [[5], [6], [7]]. In the present review, we will focus on our previous and ongoing work regarding soluble and genetic contributors in subclinical atherosclerosis in the setting of systemic lupus erythematosus and SS. Furthermore, new data on SS related fatigue, neuropsychological issues as well as lymphoproliferation will be discussed.
SLE is a multisystem autoimmune disease with a strong female predilection. Cardiovascular (CV) morbidity and mortality is a frequent complication, particularly in females aged 35–44 years, whose risk of myocardial infarction is raised 50-fold [8,9]. The mechanisms leading to the development of subclinical atherosclerosis and vascular injury in SLE are not fully elucidated. Traditional CV factors such as hypertension, diabetes mellitus (DM), obesity and hyperhomocystenemia are more common in SLE patients than in the general population. However, they do not completely account for the increased CV risk, implying that other factors related to lupus such as disease duration, activity and chronicity, chronic inflammation, impairment of immunological status, therapy with corticosteroids as well as psychosocial features, such as anxiety [10,11] may be involved. Though accelerated atherosclerosis was first established in lupus and rheumatoid arthritis (RA), over the last 15 years heightened rates of subclinical atherosclerosis have been recognized as a significant burden in SS as well [[12], [13], [14], [15], [16], [17]], identifying SS as an independent predictor for subclinical atherosclerosis [13,15].
Despite that exact pathogenesis of atherosclerosis in the setting of autoimmune diseases remains ill defined, an imbalance between endothelial damage caused by increased oxidative stress and immune mediated production of atheroprotective molecules seems to be a crucial event [18]. Briefly, increased oxidative stress results in the accumulation and oxidation of LDL particles (oxidized LDL/oxLDL) in the vascular intima. OxLDL is immunogenic, chemo-attracts monocytes that migrate and differentiate into macrophages, which by accumulation of oxLDL they transform into inflammatory foam cells forming the atherosclerotic lesion [19]. Subsequently, other immune cells including T and B cells, neutrophils and dendritic cells produce cytokines and chemokines leading to the initiation and perpetuation of an inflammatory response. Recent findings support the role of the cytokine B-cell activating factor (BAFF) in atherogenesis possibly through selective activation, survival and proliferation of B2 atherogenic cells (which produce anti-oxLDL autoantibodies of IgG isotype) over the atheroprotective IgM producing B1a cells, resulting in atherosclerotic disease [20,21].
In this context, IgG autoantibodies to oxLDL have been previously shown to be mediators of autoimmune atherogenesis [22], though some studies in the general population revealed an opposite role [23]. In our recent report, reduced anti-oxLDL levels were reported in SS and RA, but not in lupus patients compared to healthy controls (HC) implying a potential protective role. Interestingly, SS patients with high titers of antibodies to oxLDL were independently associated with reduced rates of carotid and/or femoral plaque formation [24]. Given the increasingly recognized role of B-cell activating factor (BAFF) in both autoimmunity [25] and atherosclerosis [26], in a prospective cohort of 250 SLE patients we have shown that patients with high serum BAFF levels (defined as the upper quartile level of the distribution) displayed increased rates of both plaque formation and arterial wall thickening [defined as intima media thickness (IMT) > 0.90 mm] compared to patients with low BAFF levels; this association remained significant after disease related features were taken into account [27]. Towards the same direction, BAFF mRNA expression was found to be significantly higher in the whole peripheral blood of SS patients with plaque formation compared to those without the presence of plaque [28].
In view of recent findings supporting genetic influences on serum BAFF levels [25,29], we screened our lupus cohort for five BAFF gene variants previously shown to be linked to lupus [30]. The presence of the AA genotype of the rs12583006 BAFF gene variant increased the susceptibility for both lupus and lupus related plaque formation, while the haplotype TTTAT (formed by rs1224141, rs12583006, rs9514828, rs1041569 and rs9514827 variants) was found to be protective for plaque formation among SLE patients [27]. Similarly, the TT genotype of the rs9514828 BAFF promoter variation was found to be significantly increased in SS patients with plaque formation independently of traditional CV risk factors [28].
Another molecule involved in CV heightened observed risk in both lupus and general population is homocysteine [31,32]. Hyperhomocysteinemia is strongly influenced by functional polymorphisms of the MTHFR gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase [33]. In our recent work of 150 SLE patients, both hyperhomocysteinemia and MTHFR (rs1801133) 677 TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional CV risk factors and disease related features [34].
Additional genetic aberrations associated with lupus related CV disease include variations of the interferon regulatory factor 8 (IRF8) [35], the mannose-binding lectin [36], the signal transducer and activator of transcription 4 (STAT4) [37] and recently the interleukin (IL)-19 and signal recognition particle 54-antisense 1 (SRP54-AS1) [38] as well as the FcγRIIA genes [39]. A summary of genetic variants previously found to be associated with both subclinical atherosclerosis and CV events in lupus patients are depicted in Table 1 [27,34,35,[37], [38], [39]].
Recent findings support an association of subclinical atherosclerosis and impaired bone health in autoimmune patients including lupus [[40], [41], [42]] and SS [13], in accord with previous observations in general population [43]. Thus, SLE and SS patients with evidence of plaque formation were also shown to display heightened rates of osteoporosis as well [13,40], with an inverse correlation between femoral neck bone mean density (BMD) values and total IMT scores reported for lupus patients. A plausible scenario could suggest the mobilization of calcium from osteoporotic/osteopenic bone to vascular wall leading to vascular tissue calcification and subsequently plaque formation [13,44]. In this setting, molecules traditionally involved in bone metabolism such as vitamin D, parathormone (PTH) and osteoprotegerin (OPG) attracted major interest over the last years in the pathogenesis of CV disease as well [[45], [46], [47]], though recent data failed to demonstrate a protective role for vitamin D supplementation in the reduction of CV risk [48]. In our lupus cohort, no associations between vitamin D serum levels and surrogate markers of subclinical atherosclerosis were detected. Nevertheless, PTH serum levels were found to be increased in lupus patients with both arterial wall thickening and plaque formation [40]. In SS patients, reduced serum levels of the Wnt mediator Dickkopf-related protein 1 (DKK1) have been associated with both plaque formation and lower BMD levels [13]. These findings are in accord with previously published findings supporting the emerging role of Wnt signaling pathway in both atherosclerosis and osteoporosis [[49], [50], [51]]. Α summary of soluble mediators involved in lupus related subclinical atherosclerosis over the last years are displayed in Table 2 [27,31,34,40,46,[52], [53], [54], [55], [56], [57], [58], [59]].
Lymphoproliferation in the setting of autoimmunity has been early recognized [[60], [61], [62], [63]]. In patients with SS, this association was first reported by Talal and Bunim in the early sixties [64], an observation confirmed later in a metaanalysis published in 2005, in which SS has been found to confer the highest susceptibility for lymphoma risk among all autoimmune disorders, with a standardized incidence ratio of 18.9 [2]. While the prevailing concept in SS related lymphoma development is the end result of a long lasting chronic polyclonal B cell activation, a growing body of data supports the distinct prognostic nature of SS, already present at time of SS diagnosis [65]. Thus, clinical features including salivary gland enlargement (SGE), lymphadenopathy, purpura [65], Raynaud's phenomenon [66] and tongue atrophy [67], diagnostic markers such as rheumatoid factor [66,68], autoantibodies against Ro/SSA and La/SSB [66], anticentromere antibodies [69], low complement C4 [65,70], mixed monoclonal cryoglobulinemia [71], increased β2-microglobulin levels along with increased free light chain κ/λ ratio levels [72] as well as histopathological features (focus score ≥3, germinal center formation) [73,74] could serve as reliable predictors for lymphoma development. Moreover, it has been also appreciated that patients with SS onset earlier in life display more aggressive clinical phenotypes [75]. Taken together, these data prompted us to explore the potential contribution of genetic contributors in the pathogenesis of SS related lymphoma.
Given that B cell activation and germinal center formation are key pathogenetic events in both SS and non-Hodgkin lymphoma (NHL), molecules implicated in these processes are candidate biomarkers [[76], [77], [78]]. Thus, serum BAFF levels [72,76,79,80] along with other B cell growth factors including FMS-like tyrosine kinase 3 ligand (Flt-3L) and chemokines involved in organization of ectopic lymphoid follicles, such as CXC chemokine ligand 13 (CXCL13) have been previously shown to be elevated in serum derived from SS patients complicated by lymphoma [[81], [82], [83]]. Increased frequency of the minor T allele of the rs9514828 BAFF variation was detected in the high risk for lymphoma development group, in contrast the minor A allele of the rs12583006 was more prevalent in the low risk group. Haplotypes in the 5′ regulatory region of BAFF gene (formed by rs1224141, rs12583006, rs9514828 and rs9514827 variants) could also discriminate SS patients at high risk for lymphoma development from SS low risk patients; patients with lymphoma display lower frequencies of the TACC and TTCT haplotypes compared to low risk SS and HC respectively, together with a higher frequency of the TTTC haplotype compared to the low risk SS [84]. Interestingly, an increased prevalence of the His159Tyr mutation of the BAFF receptor in patients with SS was also detected, particularly in those patients complicated by mucosa-associated lymphoid tissue (MALT) lymphoma whose disease onset occurred at a younger age, reaching 70%; activation of the alternate NF-κB pathway, as evidenced by increased nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NFκB2) expression levels in B cells derived from SS patients bearing the His159Tyr mutation was demonstrated [76].
Uncontrolled inflammatory responses have been previously linked to lymphoma development particularly of MALT type [[85], [86], [87], [88]]. As already mentioned, extensive lymphocytic infiltration [73] along with increased percentage of IL-18 producing macrophages [89] and heightened transcript levels of both interferon γ (IFNγ) [80] and inflammasome molecules [90] in minor salivary gland (MSG) tissues have been previously related to lymphoma development in the context of SS.·In line with these findings, serum levels of IL-18 and apoptosis-associated speck-like protein (ASC) were found to be increased in high risk SS patients and SS-lymphoma subsets [90]. One of the products of tissue macrophages is extracellular lipoprotein-associated phospholipase A2 (Lp-PLA2), which is found in the circulation associated with lipoproteins, playing an important role in both CV [91] and malignant diseases [92], including B-cell NHL lymphoma [93]. In a recent study from our group, serum Lp-PLA2 activity was found to be increased in primary SS-lymphoma compared to both primary SS patients without lymphoma and HC. Lp-PLA2 activity was determined by two different techniques (measuring [3H] PAF degradation products in liquid scintillation counter and a commercially available ELISA kit) in two independent SS cohorts including SS-lymphoma patients [94].
In view of the implication of the A20 protein in controlling the NFκB pathway, several studies explored the contribution of a functional tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) variant -the encoding gene for A20- in both inflammatory and malignant disorders [[95], [96], [97]]. In patients with SS of French [98,99], UK [99] and Greek origin [100], the prevalence of the coding rs2230926 TNFAIP3 variant, has been previously found to be increased in SS-lymphoma patients [99,100], increasing the risk by approximately 2.5-fold. In the Greek SS cohort the presence of the variant was associated with higher serum IgM and LDH levels, higher transcripts of the anti-apoptotic Bcl-XL molecule in peripheral blood as well as lower leucocyte and neutrophil counts [100]. Of interest, approximately one-fifth of SS-lymphoma cases with younger age at disease onset (≤40 years) carried the rs2230926 variant, supporting the concept of increased mutational load in SS patients with lymphoma presenting earlier in life. Similarly, the wild type variant of the immunoreceptor LILRA3 (Leukocyte immunoglobulin-like receptor A3) –previously related in chronic inflammatory disorders [101,102] was detected in all primary SS patients ≤40 years complicated by lymphoma in comparison to 81.8% in primary SS-non lymphoma patients and 83.2% in HC. As expected, LILRA3 protein serum levels were also found to be increased in this SS subset [103]. Another regulator of inflammation namely major histocompatibility complex P5 (HCP5) has been recently found to get involved in lymphoma development in the context of SS, in a Italian cohort, with the rs3099844 gene variation increasing lymphoma risk by approximately seven fold [104].
A defective immunosurveillant function in a setting of deregulated inflammatory responses has been postulated as a major mechanism for malignant transformation [105]. In salivary gland tissues derived from SS patients complicated by lymphoma, IFNα transcripts were found to be downregulated, implying a similar operating mechanism in SS related malignant transformation [80]. In order to explore potential genetic contributors for the dampened type I IFN responses observed in salivary glands from SS-lymphoma patients, genetic variants of the three-prime repair exonuclease 1 (TREX1) gene, previously found to increase susceptibility in lupus patients with neuropsychiatric manifestations [106] and also involved in type I IFN pathways [107], were tested in SS patients of Greek and Italian origin complicated or not by lymphoma [108]. While no differences in the rs3135941 and rs3135945 variants were detected between groups, the frequency of the rs11797 A minor allele was found to be remarkably reduced in SS-lymphoma patients of non-MALT type. Since the presence of the rs11797 AA genotype was found to be related with increased type I IFN inducible genes in MSG tissues, we postulate that genetically diminished type I IFN responses could offer an alternative explanation for SS related lymphomagenesis [108].
Finally, epigenetic alterations have been associated with NHL pathogenesis in general [109], as well as in the setting of SS with defective expression of miR200b-5p [110] and DNA methylating enzymes [111] in MSG tissues derived from SS patients with lymphoma. Variations of the MTHFR gene and particularly the rs1801133 (c.677C > T) TT genotype has been shown to display increased frequencies among primary SS patients complicated by non-MALT lymphoma in association with decreased methylation levels [112]. On the other hand, reduced prevalence of the rs11801131 (c.1298A > C) C minor allele in the primary SS non-MALT group compared to controls and SS patients without NHL was observed leading potentially to increased double-strand breaks, a marker of DNA damage. These findings imply defective DNA methylation and subsequent silencing of oncogenes together with genomic instability as additional operating mechanisms in SS related lymphomagenesis [113]. Genetic variations and potential soluble biomarkers associated with lymphoproliferative disease in the context of SS are summarized in Fig. 1 and Table 3 [72,76,79,80,[82], [83], [84],90,94,100,103,104,108,112,114,115].
Fatigue has been appreciated as a major burden in patients with SS compromising quality of life [5,[116], [117], [118], [119]]. In a previous study from our group, approximately one third of SS patients was affected [116]. Despite significant efforts, biomarker discovery for SS related fatigue has been limited. Thus, markers of B cell activation, such as serum BAFF levels and autoantibodies against organ‐specific and nonspecific antigens, as well as peripheral blood transcripts of the IFN‐inducible gene IDO‐1 -previously shown to be associated with depression and fatigue through induction of serotonin catabolism [120]- did not seem to contribute to increased sense of fatigue experienced by these patients [116]. While no association between fatigue scores and disease activity indices, low hemoglobin levels, impaired thyroid function, complication by lymphoma or medication use was detected; multivariate analysis revealed depression, neuroticism, and fibromyalgia as independent predictors of SS related fatigue [116]. Discrete personality spectrum and psychopathology features have been previously demonstrated in patients with primary SS [6]. A higher number of primary SS patients reported distinct personality traits (neuroticism, psychoticism and obsessiveness) and psychological distress compared to HCs, with autoantibodies against alpha-melanocyte-stimulating hormone (alpha-MSH), oxytocin and vasopressin being correlated with anxiety scores in these patients [6]. Despite that pro-inflammatory cytokines have been long considered as fatigue inducers, recent data confirmed an inverse relationship between serum TNFα and lymphotoxin (LT) α with fatigue scores in patients with SS [7]. In contrast, IL1β related molecules measured in cerebrospinal fluid (CSF) were found to be positively associated with fatigue levels in these patients [121]. In a recent work by Bodewes and colleagues [5] using a proteomic approach, 16 serum proteins were found to be differentially expressed between fatigued and non-fatigued SS patients including several neuropeptides, the proinflammatory mediator IL36a and complement components (upregulated); on the contrary, epidermal growth factor as well as an enzyme with potentially neurological effects namely formimidoyltransferase cyclodeaminase were found to be downregulated in fatigued SS patients. Finally, recent data revealed an association of severe fatigue in the setting of SS, with a reduced frequency of TT genotype of both rs9514828 and rs1224141 BAFF variations [122]. These associations remain to be confirmed in larger multicenter studies.
Section snippets
Conclusion
In conclusion, a comprehensive overview on genetic contributors and soluble biomarkers in comorbidities related to SLE and SS has been outlined revealing complex interactions between immune and/or neuroendocrine pathways in generation of fatigue and subclinical atherosclerosis. Deregulated inflammatory control, excessive B cell activation, impaired immune surveilling functions, as well as epigenetic alterations have been also shown to promote lymphomagenesis in the context of an otherwise
Disclosures
Harmonics European Union Project, Grant agreement ID: 731944, funded under: H2020-EU.3.1.1 and coordinated by: Ethniko and Kapodistriako Panepistimio Athinon, Athens, Greece.
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