Etiopathogenesis Of Systemic Lupus Erythematosus Research Articles

Physicochemical and immunological studies on mitochondrial DNA modified by peroxynitrite: implications of neo-epitopes of mitochondrial DNA in the etiopathogenesis of systemic lupus erythematosus

Recent evidence has demonstrated that mitochondria possess their own nitric oxide synthase (mtNOS) and can produce endogenous reactive-nitrogen-species (RNS) including peroxynitrite (ONOO(-)). This study was undertaken to investigate the role of mitochondrial DNA (mtDNA) damage by ONOO(-) in systemic lupus erythematosus (SLE) autoimmunity. MtDNA was isolated from fresh goat liver and modified by ONOO(-), generated by synergistic action of nitric oxide (NO) and superoxide (O (-) 2) donors. Modifications occurring in mtDNA were characterized by physicochemical techniques. SLE patients (n = 50) with varying disease activity according to the SLE Disease Activity Index (SLEDAI) and healthy controls (n = 34) were evaluated for antibodies to native and ONOO(-)-modified mtDNA by immunoassays. Gel retardation assays were performed to cross-examine the immunoassay results using affinity-purified SLE immunoglobulin G (IgG). Nitrosative stress in SLE patients was studied by measuring nitrotyrosine and inducible NO synthase (iNOS). The ONOO(-) caused extensive damage to mtDNA as evident by ultraviolet (UV) hyperchromicity and loss of florescence intensity. Thermal melting studies, agarose gel electrophoresis and nuclease S1 digestibility clearly indicate structural perturbation in mtDNA by ONOO(-). Quenching studies with specific NO or O (-) 2 quenchers confirmed that the damaging agent was ONOO(-). SLE autoantibodies exhibited enhanced binding with ONOO(-)-mtDNA as compared to their native analog. Interestingly, not only was there an increased number of subjects positive for ONOO(-) -mtDNA, but also the levels of anti-ONOO(-) -mtDNA antibodies were statistically significantly higher among SLE patients whose SLEDAI scores were ≥ 20 as compared with SLE patients with lower SLEDAI scores (SLEDAI < 20). Normal healthy controls showed negligible binding with either antigen. Furthermore, SLE patients had higher levels of nitrotyrosine and iNOS compared with their respective healthy controls. Our novel results provide an important insight into the immunological basis of anti-DNA autoantibody generation in SLE. Our data conclude that modification of mtDNA by ONOO(-) causes structural perturbations, resulting in the generation of neo-epitopes, and making it a potential immunogen in SLE. The mtDNA modified by ONOO(-) may be useful in evaluating the progression of SLE and in elucidating the mechanisms of disease pathogenesis.

TRAIL mRNA expression in peripheral blood mononuclear cells of Egyptian SLE patients

Although the definite etiopathogenesis of systemic lupus erythematosus (SLE) remains unclear, many different mechanisms may contribute to its pathogenesis. Tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family with pro-apoptotic activity. The accumulation of apoptotic cell debris has been hypothesized to induce the autoimmune inflammation in SLE, and TRAIL may trigger this programmed cell death. We investigated TRAIL mRNA expression levels in peripheral blood mononuclear cells (PBMCs) from 60 SLE patients and 40 controls using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), and we studied the association between the results and clinical and laboratory parameters of the patients. Expression levels of TRAIL mRNAs in SLE patients were significantly higher than in controls (p<0.001). A statistically significant association was detected between TRAIL mRNA expression and SLE activity (p=0.001).

Romatoid Artrit ve Sistemik Lupus Eritematozusta Parvovirüs B19’un Etiyolojik Rolünün İmmünolojik ve Moleküler Yöntemlerle Araştırılması

Objective: Genetic, hormonal, environmental factors and many infectious agents are thought to play role in the etiology of rheumatoid arthritis (RA). In this study, we aimed to investigate the role of Parvovirus B19 in etiology of RA and systemic lupus erythematosus (SLE). Material and Methods: Eighty-seven RA and 50 SLE patients diagnosed according to 1987 American College of Rheumatology (ACR) criteria and applied to Eskisehir Osmangazi University Medical Faculty, Internal Medicine Department, Division of Rheumatology between January 2007-January 2008, and a control group of 50 healthy blood donors were included in the study. In serum samples, Parvovirus B19 IgM, IgG (Focus Diagnostics Cypress, USA) were investigated by ELISA method. Genome presence and viral load were investigated by quantitative real-time polymerase chain reaction with Parvovirus B19 RG PCR kit (Qiagen, USA). The results were evaluated statistically by SPSS 20.0 program. Results: There was no significant difference between RA, SLE and healthy control groups in terms of Parvovirus B19 IgM (p=1.000). When Parvovirus B19 IgG positivity rate was considered, there was no difference between RA and SLE groups (p=0.277). Although there was no difference between RA and control groups (p=0.133), Parvovirus B19 IgG positivity rate was significantly higher in SLE group compared to the control group (p=0.016). Parvovirus B19-DNA was negative in all groups. Conclusion: We could not show any correlation between Parvovirus B19 and RA etiopathogenesis, there could be a relation between Parvovirus B19 and SLE etiopathogenesis. It is concluded that multicenter systematic investigations examining also synovial tissue and fluid samples are needed.

B lymphocytes enhance interferon‐α production by plasmacytoid dendritic cells

The type I interferon (IFN) system and B cells are activated in many autoimmune diseases, such as systemic lupus erythematosus (SLE). The IFNα produced by plasmacytoid dendritic cells (PDCs) stimulates several B cell functions, including autoantibody production. However, not much is known about how B cells influence PDC function. The aim of this study was to investigate the regulatory effect of B cells on IFNα production by PDCs. PDCs and B cells isolated from peripheral blood mononuclear cells from healthy blood donors were stimulated with RNA-containing immune complexes (ICs) consisting of U1 small nuclear RNP and SLE IgG, herpes simplex virus, or oligonucleotide (ODN) 2216, alone or in cocultures. IFNα, several other cytokines, and PDC- or B cell-associated surface molecules were analyzed using immunoassays or flow cytometry. B cells enhanced IFNα production by PDCs up to 47-fold, and the effect was most pronounced for PDCs stimulated with RNA-containing ICs. Anti-CD31 antibody reduced RNA-containing IC-induced IFNα production by 80% but had no effect on IFNα production when ODN 2216 was used as an inducer. Supernatants from ODN 2216-stimulated B cells promoted IFNα production by PDCs, while supernatants from RNA-containing IC-stimulated B cells did not. Our results showed that a novel function of B cells is enhancement of type I IFN production by PDCs. Because B cells are activated by type I IFN, this PDC-B cell cross-talk might be of fundamental importance in the etiopathogenesis of SLE and contribute to long-term immune activation in SLE and other systemic rheumatic diseases.

Physicochemical and immunological studies on 4-hydroxynonenal modified HSA: Implications of protein damage by lipid peroxidation products in the etiopathogenesis of SLE

4-Hydroxynonenal (HNE) is the most abundant and toxic aldehyde generated by the oxidation of plasma membrane polyunsaturated fatty acids. Systemic lupus erythematosus (SLE), a chronic autoimmune disease, is primarily characterized by increased levels of autoantibodies, predominantly against ds-DNA. However, the initial antigenic stimulus for the disease etiopathogenesis has remained elusive. HNE has been extensively used as a biomarker of oxidative stress. It can form adduct with proteins, making them highly immunogenic. Increased levels of such aldehyde-protein adducts have been reported in various pathological states, including autoimmune disorders like SLE and arthritis. In the present study, HNE-mediated structural changes in human serum albumin (HSA) were characterized by UV, fluorescence, CD and FT-IR spectroscopy as well as by polyacrylamide gel electrophoresis. Furthermore, immunogenicity of native and HNE-modified HSA was probed in female rabbits. The HNE-modified HSA was highly immunogenic eliciting high titre immunogen specific antibodies. Binding of SLE anti-DNA antibodies was analyzed by direct binding and competition ELISA. The data show preferential binding of SLE autoantibodies to HNE-modified HSA as compared to native HSA or native DNA. Our results suggest that HNE modification generates neoepitopes on HSA causing enhanced autoantibodies production. The results point towards the possible role of HNE-modified HSA in SLE etiopathogenesis.

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Increasing evidences suggest that the type I interferon α (IFN α) plays a critical role in the etiopathogenesis of systemic lupus erythematosus (SLE), which makes it a promising therapeutic target for the treatment of the disease. By screening a large size non-immune human antibody library, we have developed a human single-chain antibody (ScFv) AIFN α 1bScFv01 and corresponding whole antibody AIFN α 1bIgG01 to human interferon α 1b (IFN α 1b) with high specificity and high affinity. The IgG antibody could down-regulate the expression of ISG15 and IFIT-1 induced by either recombinant IFN α 1b or naïve IFN α from SLE patients' sera, and reduced total serum IgG and IgM antibodies level in a pristane-primed lupus-like mouse model. The crystal structure of AIFN α 1bScFv01-IFN α 1b complex solved to 2.8 Å resolution revealed that both Pro26-Gln40 region in loop AB and Glu147-Arg150 region in helix E of IFN α 1b contribute to binding with AIFN α 1bScFv01. Four residues of above two regions (Leu30, Asp32, Asp35 and Arg150) are critical for the formation of antigen-antibody complexes. AIFN α 1bScFv01 shares partial epitopes of IFN α 1b with its receptor IFNAR2 but with much higher binding affinity to IFN α 1b than IFNAR2. Thus, AIFN α 1bIgG01 exhibits its neutralizing activity through competition with IFNAR2 to bind with IFN α and prevents the activation of IFN α-mediated signaling pathway. Our results highlight the potential use of the human antibody for modulating the activity of IFN α in SLE.

Antibodies against 4-hydroxy-2-nonenal modified epitopes recognized chromatin and its oxidized forms: role of chromatin, oxidized forms of chromatin and 4-hydroxy-2-nonenal modified epitopes in the etiopathogenesis of SLE.

Objectives: This study was undertaken to investigate the role of lipid oxidative-by-product 4-hydroxy-2-nonenal (HNE)-modified human serum albumin (HSA), chromatin, reactive oxygen species (ROS)-modified chromatin and nitric oxide (NO)-modified chromatin in systemic lupus erythematosus (SLE). Methods: HSA was modified by HNE. Immunogenicity of modified HSA was probed by inducing polyclonal antibodies in rabbits. Chromatin was isolated from goat liver and modified by ROS or NO. Immunocross-reactions of Protein-A purified anti-HNE-HSA-IgG with chromatin, ROS-chromatin and NO-chromatin were determined. Autoantibodies from 74 SLE patients were screened. HSA was isolated from SLE patients (SLE-HSA) and immunocross-reactions of isolated SLE-HSA with HNE-specific antibodies were investigated. Results: HNE-HSA was found to be highly immunogenic in rabbits. The notable feature of anti-HNE-HSA-IgG showed cross-reactions with chromatin, ROS-chromatin and NO-chromatin (p < 0.01). High degree of specific binding to HNEHSA, chromatin, ROS-chromatin or NO-chromatin was observed with antibodies from 55% of SLE patients. SLE anti-native/oxidized chromatin antibodies showed specificity towards HNE-HSA. Furthermore, SLE-HSAshowed binding with HNE-specific antibodies. Conclusions: This is the first study to demonstrate that chromatin and its oxidized forms have been recognized by antibodies against HNE modified epitopes. Our results provide an important insight into the immunological basis of the reported HNE-modified epitopes in SLE.

Antibodies against 4-Hydroxy-2-nonenal Modified Epitopes Recognized Chromatin and Its Oxidized Forms: Role of Chromatin, Oxidized Forms of Chromatin and 4-Hydroxy-2-nonenal Modified Epitopes in the Etiopathogenesis of SLE

Objectives:This study was undertaken to investigate the role of lipid oxidative-by-product 4-hydroxy-2-nonenal (HNE)-modified human serum albumin (HSA), chromatin, reactive oxygen species (ROS)-modified chromatin and nitric oxide (NO)-modified chromatin in systemic lupus erythematosus (SLE).Methods:HSA was modified by HNE. Immunogenicity of modified HSA was probed by inducing polyclonal antibodies in rabbits. Chromatin was isolated from goat liver and modified by ROS or NO. Immunocross-reactions of Protein-A purified anti-HNE-HSA-IgG with chromatin, ROS-chromatin and NO-chromatin were determined. Autoantibodies from 74 SLE patients were screened. HSA was isolated from SLE patients (SLE-HSA) and immunocross-reactions of isolated SLE-HSA with HNE-specific antibodies were investigated.Results:HNE-HSA was found to be highly immunogenic in rabbits. The notable feature of anti-HNE-HSA-IgG showed cross-reactions with chromatin, ROS-chromatin and NO-chromatin (p&lt; 0.01). High degree of specific binding to HNEHSA, chromatin, ROS-chromatin or NO-chromatin was observed with antibodies from 55% of SLE patients. SLE anti-native/oxidized chromatin antibodies showed specificity towards HNE-HSA. Furthermore, SLE-HSAshowed binding with HNE-specific antibodies.Conclusions:This is the first study to demonstrate that chromatin and its oxidized forms have been recognized by antibodies against HNE modified epitopes. Our results provide an important insight into the immunological basis of the reported HNE-modified epitopes in SLE.

Current views on etiopathogenesis of systemic lupus erythematosus

The article is a review of information concerning etiopathogenesis of systemic lupus erythematosus (SLE). Due to the risk of serious complications, including death, the clarification of etiology could result in substantial improvement or even complete cure of the disease. Progress in scientific research of observed disorder mechanisms together with implementation of appropriate therapies contributed to a higher detection rate, improved course and decreased mortality in SLE. However, there are still many doubts, which legitimate the need of further research. A significant role in development of the disease and further exacerbations is played by environmental factors. Therefore, decreased exposure to UV light, female sex hormone and microbial antigens is associated with improved course and decreased frequency of exacerbations. Less is known about the genetic basis of SLE, which results from a multigene disease background and complex hereditary mechanisms. It is estimated that the disease may be conditioned by around 100 genes, that only in part are functionally determined. Only part of them is already functionally characterized. The role played by most of them is still unknown. Research currently being conducted is aimed at detecting genetic polymorphism in large and genetically diverse populations. It will allow evaluation of the role of a particular gene in protein biosynthesis, which is responsible for development of regulatory process disturbances, commonly observed in the course of SLE. The article presents current directions of research and the latest advances in epidemiology as well as environmental and genetic risk factors of SLE.

Parvovirus B19–associated Systemic Lupus Erythematosus: Clinical Mimicry or Autoimmune Induction?

To the Editor: Recent research has focused on the role of parvovirus B19 in the etiopathogenesis of systemic lupus erythematosus (SLE). The acute manifestations of B19 infection, including symmetric polyarthritis, cytopenia, and macular erythema, bear striking similarity to those found in SLE. Further, infection with B19 elicits autoantibodies to antigens commonly found in patients with SLE, including nuclear antigens, dsDNA, and phospholipids1. These symptoms and laboratory abnormalities are transient in some cases, yet persist in others, sparking debate over whether the similarities observed between acute B19 infection and SLE are mere coincidence, or whether the virus does in fact induce chronic autoimmunity. We describe a case of SLE possibly triggered by parvovirus B19, and we conducted a literature search to identify other cases in which B19 infection induced either transient or persistent SLE symptoms. To identify potential prognostic factors for the development of persistent disease, we performed a 2-tailed t test (p value for statistical significance = 0.05) to analyze differences in mean antinuclear antibody (ANA) titers in patients with transient versus persistent symptoms. A 59-year-old woman was referred for a history of urticarial plaques in the setting of fatigue, facial flushing, and polyarthritis of the hands and elbows. Her joint symptoms first developed 2 years ago; at the time, she was treated for presumed rheumatoid arthritis. However, she subsequently developed urticarial plaques on the torso, back, and arms. Biopsy of a plaque revealed an upper dermal angiocentric mixed polynuclear and mononuclear cell inflammatory infiltrate with … Address correspondence to M.T. Hession; E-mail: mth2114{at}columbia.edu

Allogenic bone-marrow-derived mesenchymal stem cells transplantation as a novel therapy for systemic lupus erythematosus

Importance of the field: Bone-marrow-derived mesenchymal stem cells (BMMSC) are multipotent non-hematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases including systemic lupus erythematosus (SLE).Area covered in this review: Our aim is to discuss recent progress in understanding the role of malfunctioning BMMSC in etiopathogenesis of SLE and to explore allogenic BMMSC transplantation as a potential therapy for SLE.What the reader will gain: Recent evidence suggests that the functions of BMMSC are disrupted in SLE pathology. This malfunction may result as a corollary of the disease, or may play a more fundamental role in its etiopathogenesis. We provide a brief characterization of BMMSC immunomodulatory effects, and describe our current understanding of the mechanisms by which it plays a part in treating SLE. We also present our clinical trial using allogenic BMMSC in this context.Take home message: Allogenic BMMSC appear to be a safe therapeutic option for treatment-resistant SLE as illustrated in our clinical trial.

HMGB1 containing nucleosomes from apoptotic cells induce inflammation and immune activation via TLR2 – implications for the etiopathogenesis of systemic lupus erythematosus

Nucleosomes (NCs) are the major primary autoantigens in systemic lupus erythematosus (SLE) and autoantibodies against dsDNA and NCs are a serological hallmark of SLE. However, it is still unknown why...

Circulating Surfactant Protein D Is Decreased in Systemic Lupus Erythematosus

Deficiencies of innate immune molecules like mannan binding lectin (MBL) have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Surfactant protein D (SP-D) and MBL belong to the same family of innate immune molecules - the collectins, which share important structural and functional properties. We aimed to compare concentrations of serum SP-D in patients with SLE and in healthy controls, and to investigate if SP-D is associated with selected disease indicators. We investigated the possible association of the Met11Thr polymorphism with disease, since this polymorphism is an important determinant for serum level, oligomerization pattern, and function of SP-D. Serum SP-D was measured using a 5-layer ELISA in 70 SLE patients and 1476 healthy subjects. DNA was genotyped for the Met11Thr variant. Median SP-D level in serum was 911 ng/ml (95% CI 776-1118) in patients and 1068 ng/ml (95% CI 901-1246) in controls (p = 0.0004). Circulating SP-D did not differ significantly in patients with high, intermediate, or low SLE disease activity. Similarly, SP-D did not correlate with C-reactive protein, erythrocyte sedimentation rate, and anti-dsDNA seropositivity. Genetic analysis did not support an association of the Met11Thr genotype with SLE. These findings suggest that low SP-D, unrelated to conventional disease indicators, represents an aspect of SLE etiopathogenesis.

Evaluation of C1q genomic region in minority racial groups of lupus.

Complement cascade plasma proteins play a complex role in the etiopathogenesis of systemic lupus erythematosus (SLE). Hereditary C1q deficiency has been strongly related to SLE; however, there are very few published SLE studies that evaluate the polymorphisms of genes encoding for C1q (A, B and C). In this study, we evaluated 17 single nucleotide polymorphisms (SNPs) across 37 kb of C1QA, C1QB and C1QC in a lupus cohort of individuals of the African-American and Hispanic origin. In a case-only analysis, a significant association at multiple SNPs in the C1QA gene was detected in African Americans with kidney nephritis (best P=4.91 x 10(-6)). In addition, C1QA was associated with SLE in African Americans with a lack of nephritis and accompanying photosensitivity when compared with that in normal controls (P=6.80 x 10(-6)). A similar trend was observed in the Hispanic subjects (P=0.003). Quantitative analysis showed that some SNPs in C1q genes might be correlated with C3 complement levels in an additive model among African Americans (best P=0.0001). The C1QA gene is associated with subphenotypes of lupus in the African-American and Hispanic subjects. Further studies with higher SNP densities in this region and other complement components are necessary to elucidate the complex genetics and phenotypic interactions between complement components and SLE.

Oxygen free radical modified DNA: Implications in the etiopathogenesis of Systemic lupus erythematosus.

The present study was designed to probe the possible role of singlet oxygen and superoxide anion radical modified DNA in the etiopathogenesis of Systemic lupus erythematosus. These species were generated by the exposure of riboflavin to 365 nm UV light. Modified DNA showed single strand breaks, hyperchromicity at 260nm and decrease in Tm. The modified DNA induced high titer antibodies in experimental animals. The antibodies showed reactivity with various nucleic acid polymers, a property commonly associated with Systemic lupus erythematosus anti-DNA autoantibodies. Systemic lupus erythematosus sera showed preferential binding of modified DNA over native DNA in direct binding and competitive binding solid phase immunoassays and band shift assays. The results suggest for the possible involvement of the singlet- superoxide modified DNA as a potential trigger for anti- DNA autoantibody production in SLE and thus in the etiopathogenesis of the disease.

IFNα kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model

A major involvement of IFNalpha in the etiopathogenesis of systemic lupus erythematosus has been suggested by clinical observations, including the increase of serum levels of this cytokine in patients with active disease. Supporting this hypothesis, we have shown that expression of IFNalpha from a recombinant adenovirus (IFNalpha Adv) precipitates lupus manifestations in genetically susceptible New Zealand Black (NZB) x New Zealand White (NZW)F(1) mice (NZB/W) but not in BALB/c mice. In the present investigation, we have prepared an IFNalpha immunogen, termed IFNalpha kinoid, which, appropriately adjuvanted, induces transient neutralizing antibodies (Abs) but no cellular immune response to the cytokine and without apparent side effects. Using this preparation, we also showed that, in kinoid-vaccinated NZB/W mice, lupus manifestations, including proteinuria, histological renal lesions, and death triggered by IFNalpha Adv challenge were delayed/prevented as long as an effective threshold of anti-IFNalpha inhibitory capacity was present in the serum.

Enhanced binding of circulating SLE autoantibodies to catecholestrogen-copper-modified DNA

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by circulating and tissue fixed autoantibodies reactive with self-antigens, including nucleic acid and other nuclear components. The pathways by which these autoantibodies act as a pathogenic factor remain elusive. Present study has investigated the role of estrogens in SLE etiopathogenesis. Estrogen-modified DNA [4-OHE(2)-Cu(II)-DNA] showed single- and double-strand breaks, hyperchromicity, decrease in Tm, and modification of bases. The 4-OHE(2)-Cu(II)-DNA exhibited increased binding with naturally occurring anti-DNA autoantibodies as compared to the unmodified native form (P < 0.001) as assessed by ELISA, quantitative precipitin titration, and gel retardation assay. The relative affinity of anti-DNA antibodies for modified and native DNA was in the order of 2.1 x 10(-7) M and 1.3 x 10(-6) M, respectively. The data suggested that DNA modified with 4-OHE(2) and Cu(II) may be one of the factors for the induction of circulating anti-DNA autoantibodies in SLE.

Role of apoptosis failure in etiopathogenesis of systemic lupus erythematosus and murine lupus

Apoptosis serves many functions in the homeostasis of multicellular organisms. Defects in apoptosis may lead to clonal expansion and accumulation of autoreactive lymphocytes, which may result in the rare human autoimmune lymphoproliferative syndrome, a mild autoimmune reaction against cells in the blood. Defects in the clearance of apoptotic cells lead to accumulation of dying cells, which may enter later stages of cell death and release their contents, thereby critically contributing to the etiopathogenesis of the autoimmune disease systemic lupus erythematosus. For an efficient therapy of systemic lupus erythematosus, it is necessary to analyze apoptosis and clearance defects and to unravel factors leading to its onset.

Autoimmune disease: is it a disorder of the microenvironment?

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease that involves several vital organs including the cardiovascular system, joints, and kidneys. The pathology is characterized by accumulation of autoreactive lymphocytes that attack the patients' own tissues, secretion of autoantibodies and deposition of immune complexes in vital organs. Chronic widespread inflammation is the hallmark of SLE and the target of current therapy. According to recent theories, intonating immune circuits of inflammatory cytokines and immune cells constitute highly specialized targets for SLE therapy, which nonetheless consists for the most part of anti-inflammatory medications and cytotoxic drugs. For advanced autoimmune disorders, cell therapy aiming at introducing "healthy" stem cells has been promising, keeping in mind that in its current state, stem cell therapy is reserved for the most advanced diseases refractory to traditional therapy. Ongoing studies in our laboratories examined the role of the bone marrow microenvironment, in particular, mesenchymal stem cells (MSCs) in the etiopathogenesis of SLE. Specifically, we are testing the hypothesis that, in human SLE mouse model, marrow MSCs are defective structurally and functionally. Preliminary data indicate that structural and functional defects in MSC population from an autoimmune mouse model for human SLE may contribute to this pathology and consequently present a target for cell therapy.

MTR 2756 A &gt; G polymorphism is associated with the risk of systemic lupus erythematosus in the Polish population

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by overexpression of cytokines and T cell accessory molecules, which is due to a reduction of DNA regulatory region methylation in T cells. It has been shown that polymorphic variants of genes encoding key enzymes of folate and methionine metabolism may have an effect on DNA methylation. Therefore, in patients with SLE (n = 106) and controls (n = 141) we examined the distribution of polymorphisms of genes encoding methionine synthase (MTR); 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1); and methylenetetrahydrofolate reductase (MTHFR). We found that MTR 2756AG (919DG) or GG (919GG) genotype exhibited 2.005-fold increased risk of SLE (95% CI = 1.177-3.416, P = 0.0146). However, MTHFR 677C > T (A222V) and MTHFD1 1958G > A (R653Q) allele and genotype frequencies did not exhibit statistical differences between SLE patients and controls. Since MTR is located on 1q43, our findings confirm the significance of the role of 1q region and the methyl cycle in etiopathogenesis of SLE.