Single nucleotide polymorphisms of the genes encoding IL-10 and TGF-ß1 in Iranian children with atopic dermatitis.

BACKGROUND: Atopic dermatitis is an inflammatory skin disease in which both genetic and environmental factors interact to determine the susceptibility and severity of the disease. OBJECTIVE: The aim of this study was to determine the association between atopic dermatitis and IL-10 and TGF-ß1 gene polymorphisms. METHODS: The allele and genotype frequencies of genes encoding for IL-10 and TGF-ß1 were investigated in 89 patients with atopic dermatitis in comparison with 138 in the control group using the PCR-SSP method. RESULTS: A significant increase was found in the frequency of the TGF-ß1 codon 10/C allele among patients (p<0.001, OR=6.77), whereas a significant decrease was observed in the frequency of the T allele at the same position (p<0.001, OR=0.14). The frequency of the TGF-ß1 codon 25/G allele in the control group was significantly higher than among patients (p<0.001, OR=0.08). A significant positive correlation was seen between CC (p<0.001, OR=15.10) and CG (p<0.001) genotypes and AD at codons 10 and 25, respectively. The most frequent haplotypes among patients was TGF-ß1 CG which was significantly higher than in the control subjects (50% in patients vs. 39.9% in controls, p=0.042). A significant increase was found in the frequency of TGF-ß CC (36% in patients vs. 7.6% in controls, p<0.001) and TC (14% in patients vs. 0% in controls, p<0.001) haplotypes among patients compared to controls. By contrast, the TGF-ß1 TG haplotype was significantly lower in patients than controls (0% in patients vs. 52.5% in controls, p<0.001). There were no significant differences in the frequency of alleles, genotypes and haplotypes of the IL-10 gene. CONCLUSIONS: We found a strong association between the polymorphisms of the TGF-ß1 gene at codon 10 and codon 25 positions and atopic dermatitis.

Gene expression and levels of IL-6 and TNFα in PBMCs correlate with severity and functional class in patients with chronic heart failure.

BACKGROUND: Evidence shows that proinflammatory cytokines are important determinants of assessment of severity and prognosis of chronic heart failure (CHF). AIMS: We investigated whether peripheral expression of the proinflammmatory factors, TNF-α and IL-6 can predict variable of clinical assessment of patients with CHF. METHODS: In this report, we used real-time PCR assay to compare relative gene expression of TNFα and IL-6 in PBMC from CHF patients with various heart diseases (n = 42, EF < 45%, NYHA I to IV) and matched healthy control subjects (n = 42).We also determined the TNFα and IL-6 concentrations of cell culture supernatant of PBMCs with ELISA. RESULTS: There was a significant negative correlation between gene expression of TNFα and LVEF(r = 0.4, p < 0.05). Patients with CHF had increased gene expression of TNFα and IL-6 in PBMCs (p < 0.05). They also had elevated the supernatant levels of these cytokines in cultured PBMCs (p < 0.001). Levels of TNFα and IL-6 were increased in ischemic heart disease compared to non-ischemic heart disease. There was a positive correlation between TNFα and IL-6 levels in CHF patients and severity of CHF in patients. Levels of these cytokines were higher in patients with NYHA III-IV than in NYHA I-II and normal subjects. CONCLUSIONS: Results of this study indicate that peripheral expression of proinflammatory cytokines, TNF-α and IL-6, is important indicators of severity and prognosis in patients with chronic heart disease.

FOXP3, RORγt and IL-10 cytokine profile in chronic heart failure.

BACKGROUND: Distinct subsets of T cells play crucial regulatory roles in inflammatory processes of chronic heart failure (CHF). Retinoic acid receptor-related orphan receptor-γt (Ror-γt) and Forkhead box P3 (Foxp3) have been defined as the "master regulators" of Th17 cells and Treg cells, respectively. At the same time, anti-inflammatory cytokines such as IL-10 may neutralize inflammation in CHF. The current study was designed to compare FOXP3, RORγt and IL-10 protein expression in the blood and IL-10 in supernatant PBMCs in CHF patients versus normal subjects. PATIENTS AND METHODS: Our study population consisted of 42 patients with CHF in four different function classes and 42 healthy subjects who served as controls. RNA extraction and cDNA synthesis was performed and mRNA expression for genes FOXP3, RORγt, IL-10 was determined by RT-PCR. The amount of IL-10 protein in supernatant of PBMCs was measured by ELISA technique. RESULTS: There was no significant difference in FOXP3, RORγt, IL-10 protein expression and supernatant PBMCs IL-10 in CHF patients as compared to control. The level of Foxp3 was significantly lower in CHF patients with ischemic vs non-ischemic cause (p = 0.04). DISCUSSION: Although inflammation plays a central role in the pathophysiology of CHF, the roles of FOXp3, RORγt, and IL-10 remain to be determined (Tab. 3, Ref. 33).

Single nucleotide polymorphisms of IL-2, but not IL-12 and IFN-γ, are associated with increased susceptibility to chronic spontaneous urticaria.

BACKGROUND: A clear picture of interaction of Th1/Th2 cytokines in pathogenesis of chronic spontaneous urticaria (CSU), remains elusive. Impaired IFN-γ production and decreased levels of IL-2 have been reported. The aim of this study was to evaluate the association of Th1 cytokines; IL-2, IL-12 and IFN-γ polymorphisms with CSU. METHODS: 90 patients with CSU and 140 age-sex matched subjects were included in this study. DNA samples were evaluated through PCR-SSP assay in order to detect single nucleotide polymorphisms of IL-12 (A/C -1188) or (rs3212227), IFN-γ (A/T UTR5644) or (rs2069717) and IL-2 (G/T -330 and G/T +166) or (rs2069762 and rs2069763). RESULTS: G allele at -330 at promoter region of IL-2 gene was overrepresented in CSU. Heterozygotes (GT) at this locus and heterozygotes at +166 of IL-2 gene (GT) were more prevalent in CSU group. Additionally, the haplotype GT for loci -330 and +166 of IL-2 gene was powerfully associated with CSU (OR (95%CI)=57.29 (8.43-112.7)). CONCLUSIONS: SNP at position -330 and +166 of IL-2 gene are differently expressed in CSU. The haplotype GT of IL-2 at -330 and +166 might confer vulnerability to a number of immunological disorders in Iranian region.

Association of interleukin 1 gene cluster and interleukin 1 receptor gene polymorphisms with ischemic heart failure.

BACKGROUND: Proinflammatory cytokines have been known to play a considerable part in the pathomechanisms of chronic heart failure (CHF). Given the importance of proinflammatory cytokines in the context of the failing heart, we assessed whether the polymorphisms of interleukin (IL)-1 gene cluster, including IL-1α, IL-1ß, and IL-1 receptor antagonist (IL-1RA) and IL-1R gene are predictors of CHF due to ischemic heart disease. METHODS: Forty- three patients with ischemic heart failure were recruited in this study as patients group and compared with 140 healthy unrelated control subjects. Using polymerase chain reaction with sequence-specific primers method, the allele and genotype frequency of 5 single nucleotide polymorphisms (SNPs) within the IL-1α (-889), IL-1ß (-511, +3962), IL-1R (psti 1970), and IL-1RA (mspa1 11100) genes were determined. RESULTS: The frequency of the IL-1ß -511/C allele was significantly higher in the patient group compared to that in the control group (p = 0.031). The IL-1ß (-511) C/C genotype was significantly overrepresented in patients compared to controls (p = 0.022). CONCLUSIONS: Particular allele and genotype in IL-1ß gene were overrepresented in patients with ischemic heart failure, possibly affecting the individual susceptibility to this disease (Tab. 1, Ref. 27).

Gene polymorphisms of interleukin-10 and transforming growth factor beta in allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a polygenic inflammatory disorder of the upper respiratory airway with an increasing prevalence worldwide. Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-ß), as two cytokines with pleiotropic effects on both innate and adaptive immunity, play important roles in allergic responses. Therefore, this study was performed to evaluate the associations of five polymorphisms of IL-10 and TGF-ß genes with AR. MATERIALS AND METHODS: Ninety-eight patients with AR along with 140 healthy volunteers with no history of AR and with the same ethnicity of the patients were recruited in this study. Genotyping was done for three polymorphisms in promoter region of IL-10 gene (rs1800896, rs1800871, rs1800872), and two polymorphisms in the exonic region of TGF-ß1 gene (rs1982037, rs1800471) using PCR sequence-specific-primers method. RESULTS: A allele and AA genotype in rs1800896 of IL-10 and TT genotype in rs1982037 in TGF-ß were significantly less frequent in the patients than in controls. While the C allele and the CG genotype in rs1800471 in TGF-ß1 were associated with a higher susceptibility to AR. C/C and T/C haplotypes (rs1982037, rs1800471) in TGF-ß1 gene and A/C/A, A/T/C and G/C/A haplotypes (rs1800896, rs1800871, rs1800872) in IL-10 gene were found with higher frequencies in patients than controls. Patients with CC genotype in rs1800871 in Il-10 had significantly lower levels of IgE. CONCLUSION: We found that certain genetic variants in IL-10 and TGF-ß polymorphisms were associated with susceptibility to AR as well as some clinical parameters in the patients with AR.

IL-1A rs1800587, IL-1B rs1143634 and IL-1R1 rs2234650 polymorphisms in Iranian patients with systemic sclerosis.

Systemic Sclerosis (SSc) is a systemic autoimmune disorder, with ambiguous pathogenesis. Genetic and environmental factors were proved to be correlated with SSc aetiology. Single nucleotide polymorphisms (SNPs) in cytokine genes can alter the structure and function of the cytokines and consequently may increase the susceptibility to a specific disease. In this study, we investigated SNPs of the IL-1 gene cluster in Iranian SSc patients. We obtained blood samples from 170 SSc patients and 213 healthy individuals. Cytokine genotyping results were obtained by polymerase chain reaction with sequence-specific primers (PCR-SSP). IL-1A rs1800587, IL-1B rs1143634 and IL-1R1 rs2234650 were evaluated for SNP study. The frequency of the IL-1B rs1143634 CT genotype was significantly lower in SSc patients compared to the controls (OR = 0.584; 95% CI = 0.385-0.886; P-value = 0.023), so we propose that CT genotype of this allele might be protective. According to our haplotype analysis, CCC haplotype frequency is higher in the control group compared to SSc patients (OR = 1.575; 95% CI = 1.176-2.111; P-value = 0.008) and in contrast, CTC haplotype frequency is lower in the control group compared to SSc patients (OR = 0.152; 95% CI = 0.047-0.484; P-value = 0.002), so they might decrease and increase the susceptibility of having SSc, respectively. In addition, we reported two significant diplotypes frequency differences among SSc patients and healthy individuals. It is highly important that there is not much resemblance between the IL-1 gene cluster polymorphism in different populations, so we can indicate that SNPs may play critical roles when they are combined with other genetic and environmental factors.

Association study of interleukin-1 family and interleukin-6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) is a common painful, ulcerative oral inflammatory disorder with unknown aetiology. Immune system and aberrant cytokine cascade deemed to be critical in outbreaks of RAS ulcers. Interleukin-1 (IL-1) and IL-6 are the most potent pro-inflammatory cytokines. Single nucleotide polymorphisms (SNPs) of IL-1 and IL-6 genes can affect the secretion of these cytokines. The aim of this study was to investigate the association between RAS and IL-6 and IL-1 in Iranian subjects with minor RAS. Genomic DNA was obtained from 64 Iranian patients with RAS. IL-1α C -889 T, IL-1ß C -511 T, IL-1ß C +3962 T, IL-1R C pst-I 1970 T, IL-1Ra C Mspa-I11100 T, IL-6 C -174 G and IL-6 A nt +565 G polymorphisms were determined using polymerase chain reaction with sequence-specific primers (PCR-SSP). The frequency of C -174 C genotype in the patients group was significantly different from the healthy control. No other significant differences were found in genotype and alleles frequencies between the two groups. These results indicate that certain SNPs of IL-6 gene at position -174 which located in promoter have association with predisposition of individuals to RAS.

AICDA single nucleotide polymorphism in common variable immunodeficiency and selective IgA deficiency.

BACKGROUND: Primary antibody deficiencies (PADs) are a heterogeneous group of disorders, characterised by increased susceptibility to recurrent bacterial infections. Common variable immunodeficiency (CVID) is the most important PAD from the clinical point of view and selective IgA deficiency (IgAD) is the most common PAD. However, the underlying gene defect in both is still unknown. As a recent study in Europe showed an association between a single nucleotide polymorphism (SNP) of AICDA gene with PADs, this study was performed to evaluate such an association in Iranian patients. METHODS: Fifty-eight patients with PAD, including 39 CVID and 19 IgAD, as well as 34 healthy volunteers, were enrolled in this study. Genotyping was done in all groups for an intronic SNP in AICDA (rs2580874), using real-time PCR genotyping assay. RESULTS: The less frequent genotype of AICDA in IgAD patients was AA, seen in 10.5% of the patients, which was much lower than the 30.8% in CVID patients and 38.2% in the controls. However, these differences were not significant. Indeed the GG genotype in the patients with PADs was seen in 20.7%, compared to 8.8% in the controls without any significant difference. CONCLUSIONS: There was no significant association between the previously reported genetic variant of AICDA gene and the development of CVID or IgAD, but further multi-center studies are also needed.

Interleukin-6 and tumor necrosis factor-alpha gene polymorphisms in chronic idiopathic urticaria.

BACKGROUND: This study was performed to evaluate association of gene polymorphisms among proinflammatory cytokines and susceptibility to chronic idiopathic urticaria (CIU). METHODS: Ninety patients with prolonged urticaria more than 6 weeks were included as case group. Single nucleotide polymorphisms (SNPs) of IL-6 (G/C -174, G/A nt565) and TNF-α (G/A -308, G/A -238) were evaluated, using polymerase chain reaction (PCR); and the results were compared to the control group. RESULTS: G allele was significantly higher in the patients at locus of -238 of promoter of TNF-α gene (p<0.001). Frequency of following genotypes were significantly lower in patients with CIU, compared to controls: AG at -308 and GA at -238 of TNF-α gene (p<0.05 and p<0.001, respectively), CG at -174 and GG at +565 of IL-6 gene (p<0.05). Additionally, following genotypes were more common among patients with CIU: GG at -308 and -238 of TNF-α gene (p<0.05 and p<0.001, respectively), GG at -174 and GA at +565 of IL-6 gene (p<0.05). CONCLUSIONS: Pro-inflammatory cytokine gene polymorphisms can affect susceptibility to CIU. TNF-α promoter polymorphisms as well as IL-6 gene polymorphisms are associated with CIU.

Association of single nucleotide polymorphisms of interleukin-1 family with atopic dermatitis.

BACKGROUND: Interleukin-1 (IL-1) seems to have an important role in early reactions towards microbes, while its genetic variability could affect this role in atopic patients who have a distressed immunity towards dermatological infections. METHODS: Eighty-nine patients with atopic dermatitis (AD), who were referred to a main referral paediatric hospital, were enrolled in this study. Single nucleotide polymorphisms (SNP) of the following IL-1 cluster genes were assessed in this group of patients: IL-1α -889, IL-1ß -511, IL-1ß +3962, IL-1R Pst-I 1970, and IL-1RA Mspa-I 11100. The results were compared with a group of 140 healthy subjects from the same region. RESULTS: Fourteen percent of the controls had TT homozygous genotype in IL-1R at position Pst-I 1970, while only 2% of the patients with AD had this genotype (p=0.005, OR: 0.14, 95%CI: 0.02-0.64). The CC homozygous genotype was the most common genotype in IL-1α position -889 and IL-1ß at position +3962 in both groups of patients with AD and the controls, while the TC heterozygous genotype was the most common genotype in IL-1ß at position -511 and IL-1R at position Pst-I 1970, with no significant difference between the two groups. CONCLUSIONS: This study showed a significant negative association in the IL-1R Mspa-I 11100 TT homozygous genotype in the patients with AD.

Association between the interleukin 6 genotype at position -174 and atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic skin disorder of unknown origin that usually manifests for the first time in early infancy. Different types of genetic predisposition and environmental factors seem to be associated with the disease. METHODS: This study was performed to evaluate the frequency of alleles, genotypes, and haplotypes of interleukin (IL) 6 single-nucleotide polymorphisms (SNPs) at positions -174 and nt565 in 89 Iranian children with AD and 139 healthy controls. RESULTS: The G allele was significantly more frequent at position -174 in IL6 in atopic patients than in the healthy controls (P < .001; OR, 2.82). Genotype GG was found at the same position in 71% of the patients; this frequency was significantly higher than the frequency of 30% recorded in the controls (P < .001; OR, 5.60). The GG haplotype of IL6 (-174, nt565) was significantly more frequent in the atopic patients than in the healthy controls (P < .001; OR, 2.99). CONCLUSIONS: A significant increase in the frequency of the G allele and GG genotype at position -174 of IL6 was found in patients with AD, thus suggesting that production of this cytokine is greater in atopic patients.

Association Between the Interleukin 6 Genotype at Position –174 and Atopic Dermatitis

Antecedentes: La dermatitis atópica (DA) es una alteración crónica de la piel de origen desconocido, que habitualmente comienza en la infancia. Diferentes predisposiciones y factores ambientales se asocian a esta enfermedad. Métodos: Este estudio se realizó en 89 niños iraníes con DA para evaluar la frecuencia de alelos, genotipos y haplotipos de polimorfismos genéticos simples (SNPs) de la IL6 en las posiciones 174 y nt565 en comparación con 139 controles sanos. Resultados: Observamos un incremento significativo del alelo G de la IL6 en la posición –174 en los pacientes con DA comparado con el grupo control (p<0.001, OR=2.82). El genotipo GG de la misma posición se encontró en el 71% de los pacientes frente al 30% en los controles (p<0.001, OR=5.60). También se observa un incremento significativo en el haplotipo GG de la IL6 (-174, nt565) en los pacientes con DA comparados con los controles sanos (p<0.001, OR=2.99). Conclusiones: En conclusión observamos un aumento significativo del alelo Gallele y del genotipo GG en la posición -174 de la IL6 en pacientes con DA, lo que podría sugerir un aumento de la producción de esta citocina en los pacientes con DA (AU)

Background: Atopic dermatitis (AD) is a chronic skin disorder of unknown origin that usually manifests for the first time in early infancy. Different types of genetic predisposition and environmental factors seem to be associated with the disease. Methods: This study was performed to evaluate the frequency of alleles, genotypes, and haplotypes of interleukin (IL) 6 single-nucleotide polymorphisms (SNPs) at positions –174 and nt565 in 89 Iranian children with AD and 139 healthy controls. Results: The G allele was significantly more frequent at position –174 in IL6 in atopic patients than in the healthy controls (P<.001; OR, 2.82). Genotype GG was found at the same position in 71% of the patients; this frequency was significantly higher than the frequency of 30% recorded in the controls (P<.001; OR, 5.60). The GG haplotype of IL6 (–174, nt565) was significantly more frequent in the atopic patients than in the healthy controls (P<.001; OR, 2.99). Conclusions: A significant increase in the frequency of the G allele and GG genotype at position –174 of IL6 was found in patients with AD, thus suggesting that production of this cytokine is greater in atopic patients (AU)

HLA-DRB and HLA-DQA/HLA-DQB allele and haplotype frequencies in Iranian patients with aggressive periodontitis.

BACKGROUND AND OBJECTIVE: Genetic backgrounds play a key role in susceptibility to and protection against a spectrum of periodontal diseases. Like other infectious diseases, the human leukocyte antigen (HLA) have been found to be associated with periodontitis. This study aimed to investigate differences in allele and haplotype frequencies of HLA class II antigens in a sample of Iranian patients with aggressive periodontitis compared with a healthy control group. MATERIAL AND METHODS: Fifty unrelated patients with aggressive periodontitis and 130 healthy volunteers were enrolled in this study. HLA genotyping for HLA-DRB, HLA-DQA1 and HLA-DQB1 was performed using the PCR with sequence-specific primers. Allele and haplotype frequencies were compared across groups. RESULTS: The frequencies of HLA-DQA1*03:01, HLA-DQB1*03:02 and HLA-DQB1*03:05 alleles, as well as that of the HLA-DRB1*04:01 allele, were significantly higher in patients with aggressive periodontitis compared with control subjects (p = 0.01, p = 0.04, p = 0.05 and p = 0.04, respectively). In contrast, the frequency of the HLA-DQB1*0603 allele was significantly lower in patients with aggressive periodontitis compared with control subjects (p = 0.006; odds ratio = 0.20). With regard to haplotype association, a significantly higher frequency of two haplotypes - HLA-DRB1*04:01/HLA-DQA1*03:01/HLA-DQB1*03:02 and HLA-DRB1*16:01/HLA-DQA1*01:03/HLA-DQB1*05:01 - was observed in patients with aggressive periodontitis compared with healthy controls (p = 0.01, odds ratio = 2.56 and p = 0.05, odds ratio = 5.38, respectively). CONCLUSION: These results provide additional evidence that class II HLA polymorphisms, particularly in the DQ locus, are associated with protection against and susceptibility to aggressive periodontitis.

The influence of systemic therapy on the serum levels of IL-6 and IL-8 in pemphigus vulgaris.

BACKGROUND: The place of cell-mediated immunity and cytokines in the immunopathogenesis of pemphigus vulgaris (PV) has not been fully established. OBJECTIVE: To assess the serum levels of pro-inflammatory cytokines, Interleukine-6 (IL-6) and Interleukine-8 (IL-8), in PV patients before and after therapy, to evaluate the influence of therapy on the serum cytokine levels. METHODS: Sixty-six newly diagnosed PV patients enrolled into the study. The serum levels of IL-8 and IL-6 were measured in 66 and 64 patients, respectively. According to the extent of skin and mucosal involvement, the patients were divided into two groups namely mild and severe. The serum levels of cytokines were measured using enzyme-linked immunosorbent assay (ELISA) method before and after 4 weeks of prednisolone plus azathioprine therapy. RESULTS: In 64 patients studied for the serum level of IL-6, the median IL-6 level was significantly decreased from 1.6 to 0.9 pg/mL by therapy (P-value = 0.001). Segregating the patients according to the severity of the disease, the serum level of IL-6 did not differ significantly by therapy in patients with a mild disease. However, in patients with a severe disease the median serum level of IL-6 decreased significantly from 1.8 to 0.9 pg/mL after therapy (P-value = 0.001). No significant changes were found in the IL-8 level by treatment. CONCLUSION: The significant decrease in the IL-6 level after therapy suggests that blocking of IL-6 could have therapeutic benefits for the treatment of PV, particularly in severe forms.

Dynamic Changes of IFN-γ-producing Cells, TGF-ß and Their Preidctive Value in Early Outcomees of Renal Transplantation.

BACKGROUND: A growing body of evidence demonstrated an immune etiology as well as nonimmune mechanisms for episodes of clinical acute rejection and long-term allograft dysfunction. OBJECTIVE: To investigate the correlation of IFN-γ-producing cells and TGF-ß with incidence of clinical acute rejection in living-related and unrelated kidney allogarft recipients during the first post-transplant year. METHODS: This multi-center study was performed on 57 kidney allograft recipients from living-related (n=20) and unrelated (n=37) donors between April 2011 and September 2012 and who were followed prospectively for a mean period of one year. Peripheral blood samples were collected from all patients pre-transplantation and at days 14, 30 and 90 after transplantation; PBMCs were used as responding cells in enzyme-linked immunosorbent spot (ELISPOT) assay to measure the frequency of IFN-γ-producing cells after stimulation with donor lymphocytes. Additionally, TGF-ß levels were measured in cell culture supernatants of ELISPOT assay. RESULTS: During the follow-up period, 45 (79%) patients were diagnosed with stable graft function (group A); 12 (21%) experienced clinical acute rejection episodes (group B). The frequency of IFN-γ-producing cells was significantly (p<0.001) higher in the rejection group in all three times after transplantation. Also, post-transplantation comparison for TGF-ß showed a significantly (p<0.001) higher contents in group A vs. group B. Comparing the post-transplantation levels of TGF-ß and mean numbers of IFN-γ- producing cells between groups A and B demonstrated a continuous increment in TGF-ß and decreasing frequencies of IFN-γ-producing cells in group A vs. group B. CONCLUSION: Serial post-transplantation monitoring of IFN-γ-producing donor reactive cells during the first months is a clinically feasible approach for identification of kidney allogarft recipients at risk for ongoing immune-mediated graft damage and later graft loss.

Serum levels of interleukin (IL)-10, IL-17, transforming growth factor (TGF)-ß1, and interferon-γ cytokines and expression levels of IL-10 and TGF-ß1 genes in renal allograft recipients after donor bone marrow cell infusion.

BACKGROUND: Cytokine storm generated by an alloimmune response after transplantation can lead to either graft survival or rejection. The aim of this study was to evaluate the serum levels of interleukin (IL)-10, IL-17, transforming growth factor (TGF)-ß1, and interferon (IFN)-γ and expression levels of IL-10 and TGF-ß1 in renal allograft recipients with or without donor bone marrow cell infusion (DBMI). METHODS: We retrospectively followed 28 living unrelated kidney recipients, including 14 with and 14 without DBMI infusion for 2 years. Also, 14 healthy subjects were included as a normal control group. PBMC gene expression analysis for mRNA levels of IL-10 and TGF-ß1 cytokines relative to ß-actin as a reference gene was performed using quantitative fluorescence real-time polymerase chain reaction at the end of 2 years posttransplantation. Also, serum levels of IL-10, TGF-ß1, IFN-γ, and IL-17 in the 3 groups were measured by enzyme-linked immunosorbent assay at the same time. RESULTS: Both patient groups showed increased gene expression and serum content of IL-10 compared with normal controls. The expression levels were only significant between control patients and normal subjects (P=.02). Serum levels of IFN-γ and IL-17 were higher in untreated patients compared with normal controls (P=.03 and P=.07, respectively). DBMI patients showed significantly lower levels of serum TGF-ß1 and IL-17 compared with normal subjects (P=.05 and P=.06, respectively). Also, infused patients showed a positive correlation between circulating levels of IL-17 and IL-10 (r=0.692; P=.006), and an inverse correlation between serum creatinine and TGF-ß1 levels (r=-0.580; P=.03). CONCLUSION: The decreased levels of inflammatory cytokines besides IL-10 with increased TGF-ß1 levels and better allograft function with improved clinical outcomes were observed among infused patients, possibly indicating immunomodulatory effects of this approach in kidney allograft patients.

Association of IL1R polymorphism with HLA-B27 positive in Iranian patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is one of the most common causes of inflammatory arthritis, with an estimated prevalence of 0.1-0.9%. Genetic factors have been strongly implicated in its aetiology, and heritability as assessed by twin studies has been estimated to be >90%. HLA- B27 is almost essential for inheritance of AS; it is not merely sufficient for explaining the pattern of familial recurrence of the disease. This study's purpose is to investigate the association of ankylosing spondylitis with single-nucleotide polymorphisms (SNPs) in the IL-1 family: IL-1a (-889C/T) rs1800587, IL-1b (-511C/T) rs16944, IL-1b (+3962C/T) rs1143634, IL-1R (Pst-1 1970C/T) rs2234650 and IL-1RA (Mspa-1 11100C/T) rs315952. 99 unrelated Iranian AS patients and 217 healthy control subjects were selected. Cytokine typing was performed by the polymerase chain reaction with sequence-specific primers assay. The allele and genotype frequencies of the polymorphisms were determined: The IL1α rs1800587, IL1ß rs16944 and IL1ß rs1143634 were not significantly associated with AS. Genotype frequencies at IL1R rs2234650 differed between cases and controls (χ(2)=8.85; p=0.01); the IL1R rs2234650 C/T and T/T genotypes were less common in AS patients than controls. The IL1R rs2234650 C/T genotype was inversely associated with AS comparing with the IL1R rs2234650 C/C genotype (OR=0.48; p=0.005). IL1R rs2234650 C/T genotype was less common in patients than controls (OR=0.37; p=0.02).Furthermore IL1R rs2234650 T allele was strongly associated with HLA-B2702 patients rather than HLA-B2705 but was not associated with HLA-B27 negative patients (OR=0.33; p=0.01). Polymorphisms of IL1α rs1800587, IL1ß rs16944 and IL1ß rs1143634 were not significantly associated with ankylosing spondylitis but inversely in this study IL1R rs2234650 was significantly associated and carriage of T allele in IL1R rs2234650 seems to be protective, while carriage of C allele result in two fold higher risk of developing AS.

Genetic susceptibility to Graves' ophthalmopathy: the role of polymorphisms in proinflammatory cytokine genes.

PURPOSE: In order to investigate the underlying genetic mechanisms of Graves' ophthalmopathy (GO), we examined the association between single-nucleotide polymorphisms in five important proinflammatory cytokines, namely IL-12, TNF-alpha, IFN-gamma, IL-2, and IL-6, with GO in a sample of Iranian adults. METHODS: A total of 57 patients with Graves' disease without GO, 50 patients with GO, and 140 healthy controls were enrolled. Patients were recruited consecutively from the outpatient endocrine clinic of a large university general hospital. Genotype and allele frequencies of the following proinflammatory cytokines were compared between the groups: IL-12 (-1188A/C), TNF-alpha (-308A/G, -238A/G), INF-gamma (UTR 5644A/T), IL-2 (-330T/G, 166G/T), and IL-6 (-174C/G, nt565A/G). A corrected (for multiple testing) P-value (Pc) less than 0.05 was considered statistically significant. RESULTS: The IL-12 -1188C allele (odds ratio (OR)=2.65, Pc<0.01) and CC genotype (OR=7.58, Pc<0.01) were significantly more common in patients with GO than in patients without GO. The TNF-alpha-238A allele was more frequent in patients with GO than in patients without GO (OR=2.99, Pc<0.05). The frequency of the IFN-gamma UTR 5644T allele (OR=2.67, Pc<0.05), AT genotype (OR=13.33, Pc<0.05), and TT genotype (OR=18.46, Pc<0.01) was significantly higher among patients with GO than patients without GO. No significant association was found for other polymorphisms. CONCLUSIONS: We demonstrated that specific polymorphisms in IL-12, IFN- gamma, and TNF-alpha genes are associated with susceptibility to GO in the Iranian population. Our results open a new perspective to genetic correlates of GO.