Gisela Orozco

Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease.

OBJECTIVES:Genome-wide association studies have reported the role of the interleukin (IL) 2–IL21 chromosomal region at 4q27 in several autoimmune conditions. Mice deficient in IL-2 develop a disease with clinical and histological similarity to ulcerative colitis (UC) in humans. Modest evidence of linkage with UC was tentatively proposed for the IL2 gene more than a decade ago. Therefore, we decide to investigate the association of polymorphisms in the IL-2 axis (IL2, IL2RA, and IL2RB genes) with inflammatory bowel diseases (IBDs).METHODS:Seven hundred and twenty-eight white Spanish unrelated IBD patients (356 Crohns disease (CD) and 372 UC) and 549 ethnically matched controls were included in a case–control study. In addition, a Spanish replication cohort with 562 CD and 430 UC patients and 1,310 controls were analyzed. Eight single-nucleotide polymorphisms previously associated with different autoimmune diseases were analyzed using TaqMan chemistry.RESULTS:The IL2-rs6822844 polymorphism modified CD predisposition (P=0.002; odds ratio, OR (95% confidence interval, CI)=0.61 (0.44–0.84)); this was replicated in the other Spanish cohort, resulting in a strong protective effect of the minor allele in the merged samples (P=0.0002; OR (95% CI)=0.70 (0.58–0.85)). A similar effect of rs6822844 was detected for UC. Another marker, rs11938795, also showed evidence of an association with CD (P=0.006; OR (95% CI)=0.73 (0.58–0.92)).CONCLUSIONS:Polymorphisms within the IL2–IL21 linkage disequilibrium (LD) block show a novel association with IBD, this is concordant with suggestive previous results of whole genome analyses in CD and type 1 diabetes. Our data agree with the effect previously observed for other conditions and delineate a shared underlying mechanism.

Protein tyrosine phosphatase gene (PTPN22) polymorphism in multiple sclerosis.

Sirs: Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS) with a complex pathogenesis involving multiple genetic and environmental contributions. Alterations in the signalling pathway that regulate T-cell tyrosine phosphorylation play an important role in MS [6]. Tyrosine phosphorylation is regulated by the equal and balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) [1]. The lymphoid-specific phosphatase (LYP), encoded by the PTPN22 gene, is important in negative control of T-cell activation and in T-cell development. A functional polymorphism at nucleotide 1858 in codon 620 (Arg620Trp) in the PTPN22 gene has been associated with type 1 diabetes mellitus (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) in humans [3, 4, 7, 8]. In the present study, we tested the possible role of the 1858C→T variant of the PTPN22 gene in MS predisposition. We examined the distribution frequency of the PTPN22 1858C→T polymorphism of 120 patients with clinically defined MS and 200 healthy controls by a TaqMan 5’ allelic discrimination [8]. The frequencies of 1858C/C, 1858C/T and 1858T/T genotypes were 87.5 %%, 12 % and 0.5 % respectively in controls and 83.3 %, 15.8 % and 0.9 % in the patient group. The allele and genotype distribution frequencies were similar in MS patients and controls and were in Hardy-Weinberg equilibrium. Indeed, stratification of MS patients according to their clinical phenotypes (RR and SP) and genus revealed no significant differences (data not shown). This lack of association of the PTPN22 1858C→T polymorphism with MS should be interpreted cautiously. Because of the relatively small sample size, slight effects may be not uncovered and therefore these results do not completely rule out the possibility of an association with MS. The association of RA, T1D and SLE susceptibility with the PTPN22 1858C→T polymorphism suggests that the PTPN22 1858T allele predisposes individuals to developing autoimmune diseases. However, the PTPN22 1858C→T polymorphism seems not to be a critical point in the susceptibility to MS. Given the expression of this molecule in many immunological relevant cell types, our data support the hypothesis that PTPN22 may act in different ways in different autoimmune diseases. It is possible that different genetic backgrounds could condition the effect of the PTPN22 polymorphism, but this seems not to be the reason since the PTPN22 polymorphism confers susceptibility to other autoimmune diseases such as RA and SLE with the same genetic background [8]. Furthermore, there are no significant differences between 1858C→T genotype distribution of control groups from North America, where an association of the PTPN22 1858C→T polymorphism with RA and SLE has been described [3, 7], and South Spain populations. It is worth mentioning that the Sardinia population has a high MS prevalence (150/100,000) [10]). However, they have the lowest proportion of 1858 T allele which is associated with susceptibility to autoimmune diseases [4]. This is in concordance with the absence of PTPN22 1858 T polymorphism association with MS. Similar contradictory findings have been reported concerning the influence of CTLA-4 gene in autoimmunity. While the CTLA-4CT60 marker has been associated with a range of autoimmune diseases, such as T1D, Graves’ disease, thyroiditis and SLE [5, 11], no linkage was observed with RA [9, 2] These findings support the notion that common susceptibility alleles are not shared among all autoimmune diseases, but rather among groups of these conditions. In conclusion, our data suggest that the PTPN22 1858 SNP has no, or only a negligible effect on MS susceptibility in the Spanish population. However, a minor effect of the PTPN22 SNP cannot be ruled out, and this may only be verifiable in an extremely large data set.

Genetic association of vasoactive intestinal peptide receptor with rheumatoid arthritis: altered expression and signal in immune cells.

OBJECTIVE Vasoactive intestinal peptide (VIP) has been shown to be one of the endogenous factors involved in the maintenance of immune tolerance. Administration of VIP ameliorates clinical signs in various experimental autoimmune disorders. This study was undertaken to investigate whether the exacerbated inflammatory autoimmune response in rheumatoid arthritis (RA) might result directly from altered expression and/or signaling of VIP receptors in immune cells. METHODS The effect of specific agonists of different VIP receptors on collagen-induced arthritis in mice was investigated by clinical and histologic assessment and measurement of cytokine and chemokine production. Expression of VIP receptor type 1 (VPAC1) in synovial cells and monocytes from RA patients was determined by flow cytometry. Potential associations of VPAC1 genetic polymorphisms with RA susceptibility were investigated. RESULTS A VPAC1 agonist was very efficient in the treatment of experimental arthritis, and deficient expression of VPAC1 in immune cells of RA patients was associated with the predominant proinflammatory Th1 milieu found in this disease. Immune cells derived from RA patients were less responsive to VIP signaling than were cells from healthy individuals and showed reduced VIP-mediated immunosuppressive activity, rendering leukocytes and synovial cells more proinflammatory in RA. A significant association between multiple-marker haplotypes of VPAC1 and susceptibility to RA was found, suggesting that the reduced VPAC1 expression in RA-derived immune cells is associated with the described VPAC1 genetic polymorphism. CONCLUSION These findings are highly relevant to the understanding of RA pathogenesis. They suggest that VIP signaling through VPAC1 is critical to maintaining immune tolerance in RA. In addition, the results indicate that VPAC1 may be a novel therapeutic target in RA.

Study of the role of functional variants of SLC22A4, RUNX1 and SUMO4 in systemic lupus erythematosus.

Background: Functional polymorphisms of the solute carrier family 22, member 4 (SLC22A4), runt related transcription factor 1 (RUNX1) and small ubiquitin-like modifier 4 (SUMO4) genes have been shown to be associated with several autoimmune diseases. Objective: To test the possible role of these variants in susceptibility to or severity of systemic lupus erythematosus (SLE), on the basis that common genetic bases are shared by autoimmune disorders. Methods: 597 SLE patients and 987 healthy controls of white Spanish origin were studied. Two additional cohorts of 228 SLE patients from Sweden and 122 SLE patients from Colombia were included. A case–control association study was carried out with six single nucleotide polymorphisms (SNP) spanning the SLC22A4 gene, one SNP in RUNX1 gene, and one additional SNP in SUM04 gene. Results: No significant differences were observed between SLE patients and healthy controls when comparing the distribution of the genotypes or alleles of any of the SLC22A4, RUNX1, or SUMO4 polymorphisms tested. Significant differences were found in the distribution of the SUMO4 genotypes and alleles among SLE patients with and without nephritis, but after multiple testing correction, the significance of the association was lost. The association of SUMO4 with nephritis could not be verified in two independent SLE cohorts from Sweden and Colombia. Conclusions: These results suggest that the SLC22A4, RUNX1, and SUMO4 polymorphisms analysed do not play a role in the susceptibility to or severity of SLE.

Factores genéticos comunes en autoinmunidad

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.Las enfermedades autoinmunitarias, entre las que se incluyen la artritis reumatoide (RA) o el lupus eritematoso sistemico (LES), se caracterizan por tener una etiologia compleja, en la que varios factores geneticos de susceptibilidad y factores ambientales interaccionan y resultan en una respuesta inmunitaria alterada. Hay diversos indicios de que existen elementos geneticos comunes de predisposicion a las enfermedades autoinmunitarias, como la existencia de regiones cromosomicas asociadas a numerosas enfermedades autoinmunitarias y que haya patrones de expresion genica similares en varias de ellas. La identificacion de factores geneticos comunes asociados con autoinmunidad es de gran relevancia, ya que contribuiria a comprender mejor la patogenia de estas enfermedades, desarrollar nuevas estrategias de diagnostico a escala molecular e identificar posibles nuevas dianas terapeuticas. En los ultimos anos se ha producido un gran avance en el conocimiento de los marcadores geneticos comunes asociados a las enfermedades autoinmunitarias. El gen PTPN22, importante regulador de la respuesta de los linfocitos T, se ha perfilado como un importante marcador genetico de autoinmunidad. Este gen esta implicado en la susceptibilidad a diversas enfermedades autoinmunitarias como el LES, la diabetes mellitus tipo 1 (DM1) y la RA, en la que la asociacion con el gen PTPN22 se ha convertido en la mas solida y repetida despues de la asociacion con los genes HLA. Tambien se han identificado como nuevos marcadores geneticos de susceptibilidad a las enfermedades autoinmunitarias genes implicados en la alteracion del equilibrio de citocinas como los genes MIF e IRF5.