Genetischer Hintergrund der Vaskulitiden

Genetic association studies have been of great value in the past by contributing to the understanding of pathophysiological mechanisms of chronic inflammatory and autoimmune diseases. Many genetic risk factors have been identified which confer susceptibility for one or several (autoimmune) disease(s). Using a candidate-gene approach, the first genetic risk factors and polymorphisms of vasculitides have been identified. Due to the rarity of autoimmune vasculitides often only small sample numbers have been generated and analysed, leading to inconsistent results. Furthermore, differences in ethnic background may complicate analysis. Only few of the detected risk factors have been reliably replicated in larger cohorts, such as the association of the PTPN22*620W allele with WG and MPA, the deficiency allele Pi*Z of the alpha1 antitrypsin gene and the HLA-DPB*04041 allele with WG and the HLA-DRB3/DRB4 with CSS. Genome-wide association studies (GWAS) offer the advantage of screening the whole genome for risk factors rather than relying on disease models postulated by the investigator; however, they require even larger sample sizes. Initial results from GWA studies are available for Beh?et??s disease and Kawasaki syndrome, which identified new genetic associations but require replication, especially since some of the identified risk factors could not be linked to pathophysiological pathways to date.     

Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene

OBJECTIVE: The protein tyrosine phosphatase N22 (PTPN22) gene exhibits regulatory activities for both T cells and B cells. A missense single-nucleotide polymorphism (SNP) within this gene (rs2476601) has recently been associated with 4 autoimmune diseases: rheumatoid arthritis (RA), systemic lupus erythematosus, autoimmune thyroid disease, and type 1 diabetes mellitus, all of which are T cell-mediated and associated with the elaboration of autoantibody. The aim of this study was to investigate associations of the missense SNP of PTPN22 in a number of autoimmune diseases in the UK population, including RA, juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis (PsA), and multiple sclerosis (MS), some of which have not been examined previously. METHODS: The PTPN22 missense SNP was genotyped in 886 RA, 661 JIA, 279 psoriasis, 455 PsA, and 379 MS patients and in 595 healthy controls. Association with the PTPN22 SNP was analyzed by chi-square test as implemented in Stata software. RESULTS: There was a significant association between the PTPN22 SNP and RA (P = 1.8 x 10(-8)) and JIA (P = 0.0005). In contrast, no association with psoriasis, PsA, or MS was detected. CONCLUSION: We replicated the findings of a previous association with RA and identified a novel association with JIA. Together with previous data showing associations with other autoimmune diseases, our findings provide further evidence that the PTPN22 gene plays a role in the pathogenesis of a subgroup of autoimmune diseases.     

The PTPN22 620W allele confers susceptibility to systemic sclerosis: findings of a large case-control study of European Caucasians and a meta-analysis

OBJECTIVE: To determine whether genetic variants of the PTPN22 gene, including the R620W (1858C>T) missense single-nucleotide polymorphism (SNP), are associated with systemic sclerosis (SSc). Since PTPN22 is involved in multiple autoimmune diseases, we also examined the occurrence of a concomitant autoimmune disease. We then conducted a meta-analysis of the most recent studies of SSc in order to verify the association or lack of association between the PTPN22 1858C>T variant and SSc. METHODS: Seven PTPN22 SNPs were analyzed in a French Caucasian cohort of 659 SSc patients and 504 healthy controls. All SSc patient sera were tested for the presence of autoantibodies against topoisomerase I (anti-topo I) and for anticentromere antibodies (ACAs). RESULTS: The co-occurrence of an autoimmune disease was observed in 22% of the 416 SSc patients who were exhaustively screened. In 33 of the 416 patients (8%), the concomitant autoimmune disease was known to be associated with PTPN22 1858T; these patients were excluded prior to analysis. No association was detected for any of the SNPs tested. PTPN22 haplotype analysis identified a strong association between SSc and the presence of a risk haplotype carrying the 1858T allele (P = 1.52 x 10(-7)) and a protective haplotype carrying the 1858C allele (P = 2.20 x 10(-16)) in our French Caucasian population. The meta-analysis provided evidence that the PTPN22 1858T allele is involved in the genetic susceptibility to SSc in Caucasian (P = 8.39 x 10(-3), OR 1.08 [95% CI 1.02-1.15]) and mixed (P = 3.11 x 10(-3), OR 1.09 [95% CI 1.04-1.16]) populations, particularly in the anti-topo I-positive subset. CONCLUSION: Our results indicate that PTPN22, a shared genetic factor of multiple autoimmune diseases, also contributes to the genetic background of SSc.     

Association of the PTPN22 R620W polymorphism with increased risk for SLE in the genetically homogeneous population of Crete

Autoimmune diseases affect approximately 5% of the population, but much work remains to define the genetic risk factors and pathogenic mechanisms underlying these conditions. There is accumulating evidence that common genetic factors might predispose to multiple autoimmune disorders. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune disorders with multiple susceptibility genes. The functional R620W (C1858T) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, a member of the PTPs that negatively regulate T-cell activation, has been recently associated with susceptibility to various autoimmune diseases. The aim of this study was to assess whether the C1858T polymorphism of PTPN22 also confers increased risk for SLE and RA in the genetically homogeneous population of Crete. It was found that the minor T allele of the PTPN22 C1858T SNP was more common in SLE patients than in control individuals (odds ratio [OR]?=?1.91, 95% confidence interval [CI]?=?1.11 to 3.9, p?=?0.017). No significant difference was observed in the frequency of this allele when RA patients were compared with controls (OR?=?1.14, 95% CI?=?0.65 to 1.9, p?=?0.64). Although the PTPN22 1858?T allele is found at decreased frequency in Southern Europe, including Crete, an association was found between this allele and SLE in the population studied.     

Common genetic factors in autoimmunity

Autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) among others, are characterized by a complex etiology in which the combination of several genetic and environmental factors leads to an altered immune response. Several lines of evidence, such as the presence of chromosomal regions associated with several AIDs and the existence of similar gene expression patterns in autoimmune disorders, suggest that different AIDs share common genetic factors. The identification of common genetic factors associated with autoimmunity is of great relevance, since it will allow a better understanding of disease pathogenesis and could help for the development of molecular diagnosis tools and new therapeutic targets. In the past few years, a great progress has been made in the knowledge of the common genetic factors associated with autoimmunity. The PTPN22 gene, an important regulator of T cell response, has been identified as a relevant genetic marker for AIDs. This gene is implicated in the susceptibility to autoimmune disorders such as, RA, SLE, and type 1 diabetes (T1D). In the case of RA the association with the PTPN22 gene is the most replicated after association with HLA genes. In addition, genes implicated in the altered balance between cytokines, such as MIF and IRF5, have been identified as genetic factors predisposing to AIDs.     

The genetic basis of thyroid autoimmunity.

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are prevalent autoimmune diseases, affecting up to 5% of the general population. AITDs arise due to interplay between environmental and genetic factors. In the past decade, significant progress has been made in our understanding of the genetic contribution to the etiology of AITDs. Excitingly, several AITD susceptibility genes have been identified and characterized. Some of these susceptibility genes are specific to either GD or HT, while others confer susceptibility to both conditions. The first AITD susceptibility gene locus identified was the Human-Leukocyte-Antigen DR (HLA-DR) gene locus. Subsequently, a quintet of non-HLA genes, including the cytotoxic T lymphocyte antigen (CTLA-4), CD40, protein tyrosine phosphatase-22 (PTPN22), thyroglobulin, and thyroid-stimulating hormone receptor (TSHR) gene, has been shown to contribute to the susceptibility to AITDs. Recently, the mechanisms by which these new AITD genes predispose to AITDs have been dissected. In this review, we overview and highlight the recent data on the genes predisposing to AITDs and the putative mechanisms by which they confer susceptibility to disease.     

Associations of the PTPN22 and CTLA-4 genetic polymorphisms with Taiwanese ankylosing spondylitis

Ankylosing spondylitis (AS) is an autoimmune disease, and the imbalance of peripheral tolerance is involved in its pathogenesis. Importantly, the negative signal of activated T cells plays a crucial role in the balance of peripheral tolerance. It has been postulated that human protein tyrosine phosphatase nonreceptor 22 (PTPN22) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) genes encode proteins that are actively involved in regulating T-cell activation. Therefore, we evaluated the effects of PTPN22 and CTLA-4 genotypes on the occurrence of AS. Genetic polymorphisms of PTPN22 -1123G/C and CTLA-4 +49A/G were identified by polymerase chain reaction for 391 AS patients and 391 healthy controls. Subjects with PTPN22 CC and GC genotypes had a greater risk of AS occurrence than those with PTPN22 GG genotype [relative risk = 1.39, 95 % confidence interval (95 % CI) 1.03–1.88]. Further, subjects with PTPN22 CC/CTLA-4 AA or PTPN22 GC/CTLA-4 AA genotypes had 1.90-fold (95 % CI 1.02–3.49) greater risk of AS development than those with other combinations of PTPN22 and CTLA-4 genotypes. Our findings indicated that PTPN22 -1123G/C and CTLA-4 +49A/G genetic polymorphisms have a combined effect on the development of AS.     

Lack of association between the protein tyrosine phosphatase non-receptor 22 (PTPN22)*620W allele and systemic sclerosis in the French Caucasian population

The minor allele of the R620W missense single-nucleotide polymorphism (SNP; rs2476601) in the PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been reported to be associated with multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis and vitiligo. Systemic sclerosis (SSc) is a connective tissue disease with some autoimmune abnormalities. The aim of our study was to test for association of the PTPN22*620W allele with SSc in a French Caucasian cohort with a case-control study of 121 patients with SSc and 103 controls. All patients and controls were genotyped for the PTPN22*R620W SNP. No association was found between the PTPN22*620W allele and SSc (7% v 9.2%, p = 0.39). The frequency of genotypes carrying at least one 620W allele was similar in both groups (13% v 17%, p = 0.38). The PTPN22*620W allele was also not associated with autoantibody patterns. Thus, the PTPN22*R620W polymorphism cannot be regarded as a genetic susceptibility factor for SSc in the French Caucasian population.     

Study of PTPN22 1858C/T polymorphism in rheumatoid arthritis patients from Western India

BackgroundRheumatoid arthritis (RA) is an inflammatory autoimmune disorder with etiologies including genetic and environmental factors. Protein tyrosine phosphatase non-receptor type22 (PTPN22) 1858C/T polymorphism is widely suspected to be a susceptibility gene for RA in the non-HLA genes group.AimThis study aimed at determining whether PTPN22 1858C/T polymorphism is associated with RA patients from Western India and to evaluate its possible association with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies.MethodsA total of 130 Indian RA patients and 100 age and sex matched normal controls were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP) for the PTPN22 1858C/T polymorphism.ResultsRF positivity was seen among 73.8% RA patients studied and the overall incidence of anti-CCP antibodies was 86.2%. The homozygous genotype (T/T) was absent in both groups. Among RF positives, C/C homozygosity was 90.6% whereas 9.4% patients were C/T heterozygous. Among anti-CCP positives, 89.1% had C/C genotype while the remaining 10.9% have the C/T genotype. Statistically significant association was obtained between the polymorphism and anti-CCP positivity in RA patients (OR: 2.939, ‘p’ value = 0.0595).ConclusionOur study suggested that a positive autoantibody status may predispose an individual to RA. PTPN22 may act as a susceptibility gene only in certain ethnic groups and there is no direct association between PTPN22 C1858 polymorphism and RA patients from Western India. Still a larger study is needed to understand whether this polymorphism predisposes individual to disease-associated antibodies among Indian RA patients.     

Airway innate lymphoid cells in the induction and regulation of allergy

The recent discovery of innate lymphoid cells has revolutionized our understanding of the pathogenesis of immune diseases including allergy and asthma. Innate lymphoid cells (ILCs) are a heterogeneous collection of lymphocytes that lack antigen-specificity (non-T, non-B cells) and potently produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). ILCs are divided into group 1 (ILC1s), group 2 (ILC2s), or group 3 (ILC3s). Similar to Th2 cells, ILC2s produce IL-4, IL-5, and IL-13, among others, and are present in increased numbers in samples from patients with many allergic disorders including asthma and chronic rhinosinusitis (CRS). Animal models have identified that ILC2s contribute to eosinophilic tissue infiltration, airway hyperresponsiveness, mucus production, as well as coordinate adaptive immune responses. Finally, recent studies support regulation of ILC2s by neuro-immune mechanisms as well as demonstrate a significant degree of plasticity between ILC subsets that may impact the immune responses in asthma and allergic airway diseases. Here, we review the current literature on ILC2s in human asthma and allergic airway diseases, as well as highlight some recent mechanistic insights into ILC2 function from in vitro studies and in vivo animal models.     

Association of PTPN22 1858T/T genotype with type 1 diabetes, Graves' disease but not with rheumatoid arthritis in Russian population

The protein tyrosine phosphatase nonreceptor 22 gene (PTPN22) is an important negative regulator of signal transduction through the T-cell receptors (TCR). Recently a single-nucleotide polymorphism (SNP) 1858 C/T within this gene was shown to be a risk factor for several autoimmune diseases, such as rheumatoid arthritis (RA), Graves' Disease (GD), systemic lupus erythematosus (SLE), Wegener's granulomatosis (WG) and type 1 diabetes mellitus (T1D). The aim of this study was to analyze a possible association between 1858 C/T SNP and a number of autoimmune diseases, including RA, GD and T1D in Russian population. Patients with T1D, GD, RA and healthy controls were genotyped for the 1858 C/T SNP in PTPN22 gene. We found a significant association between PTPN22 1858 C/T SNP and T1D and GD. 1858T/T genotype was observed more frequently in T1D and GD patients compared to control subjects. No such association was observed for RA. In concordance with a previous data establishing PTPN22 1858 C/T SNP association with several autoimmune diseases, our findings provide further evidence that the PTPN22 gene may play an important role in the susceptibility to some autoimmune diseases.     

The codon 620 single nucleotide polymorphism of the protein tyrosine phosphatase-22 gene does not contribute to autoimmune thyroid disease susceptibility in the Japanese.

The etiology of the autoimmune thyroid diseases (AITDs), Graves' disease (GD), and Hashimoto's thyroiditis (HT) is largely unknown. However, genetic susceptibility is believed to play a major role. The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyrosine phosphatase-22 (PTPN22) gene, is a powerful inhibitor of T cell activation. Recently, a single-nucleotide polymorphism (SNP), encoding a functional arginine to tryptophan residue change at PTPN22 codon 620 in Caucasians has been shown to be associated with GD and other autoimmune diseases. We have used a polymerase chain reaction (PCR)-restriction fragment (XcmI) assay to examine genotypes at the codon 620 polymorphism in 334 unrelated patients with AITD and 179 controls. None of the patients with AITD and controls had the tryptophan allele. These data suggest that the codon 620 polymorphism of the PTPN22 gene does not have a causal role for AITD in the Japanese. However, we cannot exclude the PTPN22 region as harboring another susceptibility locus for AITD in linkage disequilibrium with the Trp/Arg SNP.     

Genetik bei Kollagenosen

Genetic risk factors are known to exist for all collagen vascular diseases. They are most important for systemic lupus erythematosus (SLE) and systemic scleroderma (SSc), as shown by the systematic analysis of family data. Both diseases to date share most of the validated risk factors (PTPN22, STAT4, BANK1, TNFAIP3, IRF5, BLK) underlining once again their relationship. Moreover, most of these factors were also shown to be associated with other autoimmune diseases. Many additional risk factors exist, but need further analysis. The HLA complex is of special interest, as many loci within this region, some highly polymorphic, may contribute to the total genetic risk.     

PTPN22 -1123G > C polymorphism is associated with susceptibility to primary immune thrombocytopenia in Chinese population

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by autoantibody-mediated platelet destruction. Multiple factors have been implicated in ITP pathogenesis, including T-lymphocyte dysfunctions. The protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene encodes lymphoid-specific phosphatase (LYP), a critical negative regulator of T cell activation. Single nucleotide polymorphisms (SNPs) of PTPN22 have been broadly associated with susceptibilities to various autoimmune disorders. Here we conducted a case-control study investigating whether the PTPN22 -1123G?>?C SNP contributes to the risk of ITP in Chinese population. The study included 191 ITP cases and 216 ethnically matched normal controls. Genotyping of -1123G?>?C SNP was performed using a single-base extension (SBE) and mass spectrometry method. Allelic and genotypic frequencies were compared between the case-control groups by the chi-square test. We observed significant overrepresentation of -1123G allele (p?=?0.034, odds ratio (OR)?=?1.374, 95% confidence interval (CI) [1.024–1.843]) and GG genotype (P?=?0.038, OR?=?1.951, 95% CI [1.031–3.694]) in the patients compared with the controls. Stratified analysis by gender and age of disease onset revealed comparable observations in both male and adult ITP cohorts. These data suggest a moderate association of PTPN22 -1123G?>?C SNP with susceptibility to ITP. Together with previous reports, our finding provides further evidence for PTPN22 being a general autoimmunity gene.     

The association of the PTPN22 620W polymorphism with Behcet's disease

Objectives

A single nucleotide polymorphism (SNP) of the gene encoding protein tyrosine phosphatase type 22 (PTPN22 620W) has recently been described as a strong common genetic risk factor for human autoimmune disease. We have analysed the association of PTPN22 620W in patients with Behçet''s disease (BD).

Methods

Genomic DNA was obtained from 270 patients with BD from the UK and the Middle East. Normal controls (n  =  203) were collected from the same populations. Patients with idiopathic retinal vasculitis from the UK (n  =  136) were used as disease controls. PTPN22 620W was detected by SSP–PCR analysis and agarose gel electrophoresis.

Results

The results showed an inverse correlation between the presence of PTPN22 620W and Behçet''s disease in either patient group tested. There was a greatly reduced prevalence in Middle Eastern compared to UK patients and controls. Finally, there was no association with either UK patients with retinal vasculitis compared with UK controls.

Conclusions

The presence of PTPN22 620W was inversely associated with BD and the distribution of the SNP in the Middle East supports previous findings in the global prevalence.     

The functional <Emphasis Type="Italic">PTPN22</Emphasis> C1858T polymorphism confers risk for rheumatoid arthritis in patients from Central Mexico

Rheumatoid arthritis (RA) is a complex genetic disease. Human leukocyte antigen (HLA) and non-HLA genes are reportedly associated with an increased risk of RA. The protein tyrosine phosphatase non-receptor 22 gene (PTPN22), which encodes the lymphoid tyrosine phosphatase (LYP) protein, is one of the best examples of a non-HLA gene associated with a risk for RA in several populations. The functional PTPN22 C1858T (R620W) non-synonymous polymorphism is widely associated with an increased risk for RA in Europeans and non-Europeans. The aim of this study was to determine if the PTPN22 C1858T polymorphism confers susceptibility to RA in a sample of patients from Mexico. This study included 364 RA patients and 387 non-related controls from Central Mexico. Genotyping of the PTPN22 C1858T (rs2476601) polymorphism was performed using allelic discrimination assays with TaqMan probes. The functional PTPN22 C1858T polymorphism was associated with an increased risk for RA in our study population. The CC vs CT genotype in RA patients versus healthy controls had an odds ratio (OR) of 4.17 (95 % CI 1.79–9.74, p?=?0.00036), while T allele had an OR of 4.06 (95 % CI 1.75–9.41, p?=?0.00043). PTPN22 is a genetic risk factor for developing RA in the Mexican population.     

Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene

The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF+). No interaction was shown with HLA-DRB1, the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of approximately 5% on average and large variations of population allele frequencies (2.1-15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22-1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 "trio" families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF+ families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF+ RA for the French Caucasian population and the susceptibility genotype (1858T/T or T/C) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2-2.8)]. In conclusion, we provided the linkage proof for the PTPN22-1858T allele and RF+ RA. With diabetes and RA, PTPN22 is therefore a "linkage-proven" autoimmunity gene. PTPN22 accounting for approximately 1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.     

Innate and adaptive immunological insights into HIV pathogenesis

The human immunodeficiency virus is notorious for its ability to evade the immune system. As well as its ability to escape from cell-mediated and humoral immune responses, new insights are detailing its subversive, pernicious interactions with the innate immune system. The molecular mechanisms underlying these processes highlight potential therapeutic and vaccination strategies.     

Bases immunogénétiques du lupus systémique chez l'homme

Immunogenetics basis of human systemic lupus erythematosus.Introduction. — Systemic lupus erythematosus (SLE) is an autoimmune disease, of unknown pathogenesis. Familial studies and concordance rates among affected twins suggest that human SLE has a strong genetic basis.Current knowledge and key points. — Recent studies have emphasized that SLE, like other autoimmune diseases, is a complex genetic trait with contributions of both major histocompatibility complex (MHC) associated genes and multiple non-MHC genes. Recent significant advances have been made in the genetic analysis of complex traits, which allow the identification of new candidate genes in SLE. Among the genes rewieved in this article, some polymorphisms of Fc gamma receptor genes and other genes or loci localized on the long arm of the human chromosome 1 appear to be very promising.Future prospects and projects. — The identification of new susceptibility genes in SLE will certainly provide important insights into the breakdown of self-tolerance mechanisms leading to autoimmune diseases. To achieve this objective, the recruitment of a large number of genetic traits of multiplex families presenting with SLE is therefore essential. More than 125 multiplex families have been collected to date in France.     

PTPN22 620W allele is not associated with aplastic anemia

The 1858C/T variant in PTPN22 imparts a gain of function mutation dysregulating T-cell stimulation and is associated with an array of autoimmune diseases. Using a case-control design, we compared the frequency of this polymorphism in 91 patients with acquired aplastic anemia to 132 ethnically matched controls. Representation of the PTPN22 variant was not significantly different between the two populations, suggesting that this gene polymorphism does not contribute to the etiology of aplastic anemia. Aplastic anemia thus joins a list of autoimmune diseases that commonly lack a major humoral disease component and do not associate with the PTPN22 variant.