Olcay Yegin

Cutting Edge: A Common Polymorphism Impairs Cell Surface Trafficking and Functional Responses of TLR1 but Protects against Leprosy

TLRs constitute an essential family of pattern recognition molecules that, through direct recognition of conserved microbial components, initiate inflammatory responses following infection. In this role, TLR1 enables host responses to a variety of bacteria, including pathogenic species of mycobacteria. In this study, we report that I602S, a common single nucleotide polymorphism within TLR1, is associated with aberrant trafficking of the receptor to the cell surface and diminished responses of blood monocytes to bacterial agonists. When expressed in heterologous systems, the TLR1 602S variant, but not the TLR1 602I variant, exhibits the expected deficiencies in trafficking and responsiveness. Among white Europeans, the 602S allele represents the most common single nucleotide polymorphism affecting TLR function identified to date. Surprisingly, the 602S allele is associated with a decreased incidence of leprosy, suggesting that Mycobacterium leprae subverts the TLR system as a mechanism of immune evasion.

Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome

BACKGROUND The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. OBJECTIVE To elucidate mechanisms underlying different forms of HIES. METHODS A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. RESULTS Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. CONCLUSION In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.

TNF-α gene 1031 T/C polymorphism in Turkish patients with Behçet's disease

Background  Genetic factors that predispose individuals to Behçets disease (BD) are considered to play an important role in development of the disease. The tumour necrosis factor (TNF)‐α gene, which is closely linked to the HLA‐B51 gene, is involved in susceptibility for BD. Recently, a polymorphism at position −1031 within the TNF‐α promoter region was demonstrated to be responsible for susceptibility to BD in a British population. However, the functional effects of this polymorphism have not yet been determined.

Interleukin-1β, Tumor Necrosis Factor-α, and Nitrite Levels in Febrile Seizures

Proinflammatory cytokines (such as interleukin-1β, tumor necrosis factor-α) and nitric oxide are known to have both direct and indirect modulating effects on neurons and neurotoxic neurotransmitters released during excitation or inflammation. We measured interleukin-1β, tumor necrosis factor-α, and nitrite levels in the peripheral blood and cerebrospinal fluid of children with febrile seizures and compared our results with those of children with febrile illnesses without seizures. Twenty-nine children with febrile seizure and 15 controls were studied. The mean concentrations of interleukin-1β and nitrite were significantly increased in the cerebrospinal fluid (P < .01) of the children with febrile seizure. There were no significant changes in serum interleukin-1β, tumor necrosis factor-α, nitrite, and cerebrospinal fluid tumor necrosis factorα levels. Our data support the hypothesis that increased production of interleukin-1β in the central nervous system or increased diffusion of interleukin-1β through the blood-brain barrier is involved in the pathogenesis of febrile seizures. (J Child Neurol 2002;17:749—751).

Specific interleukin‐1 gene polymorphisms in Turkish patients with Behçet's disease

Abstract:  Genetic factors that predispose individuals to Behçets disease (BD) are considered to play important roles in the development of the disease. The pro‐inflammatory cytokine interleukin‐1 (IL‐1) has been implicated in the pathogenesis of BD. Our aim was to determine a possible association of specific polymorphisms of IL‐1α, IL‐1β, and IL‐1 receptor antagonist genes with susceptibility for BD. We genotyped 72 patients with BD and 163 healthy controls for IL‐1α−889, IL‐1β−511, and +3953 (nt5887) single‐nucleotide polymorphisms besides IL‐1 receptor antagonist variable number of tandem repeat polymorphism (for five different alleles). Comparison of the IL‐1β+3953 T allele and TT genotype frequencies showed a significant difference between patients with BD and controls (54.2 vs. 40.5%, OR = 1.74, P = 0.024, and 40.3 vs. 19.6%, OR = 2.76, P = 0.009, respectively). However, no difference was observed in the genotype or allele frequencies of IL‐1α−889, IL‐1β−511, and IL‐1 receptor antagonist between the patients with BD and the controls. Our results indicate that susceptibility to BD is increased in individuals carrying the IL‐1β+3953 T allele and TT genotype.

Cytokines in acute rheumatic fever

Abstract Plasma concentrations of inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8 and TNFα) were determined by ELISA in 27 patients with acute rheumatic fever (RF), 12 with only arthritis (RFA) and 15 with rheumatic heart disease (RHD), before, during and after treatment. Altogether, significant increases in TNFα, IL-8 and IL-6 levels were observed in the acute phase as compared to the data found during and after treatment. No significant differences were observed for the other cytokines. Elevations of one or more of the inflammatory cytokines were observed in 9 of 12 patients with RFA, and 12 of 15 with RHD. Increase of TNFα (6/9) and IL-8 (5/9) levels were higher in RHD patients with cardiac failure. These cytokines were below the detection limits on day 7 of treatment in all 22 patients, except in two, and in all 10 days after treatment. Conclusions These findings suggest that inflammatory cytokines, as TNFα, IL-8 and IL-6, may play a patho‐genic role in rheumatic fever.

Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients

BACKGROUND Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A mutation in one of the 4 genes encoding the components p22(phox), p47(phox), p67(phox), and p40(phox) of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A mutation in the CYBB gene encoding gp91(phox) leads to X-linked recessive CGD. OBJECTIVE The aim of this study is to show the correlation between clinical, functional, and genetic data of patients with CGD from Turkey. METHODS We report here the results of 89 patients with CGD from 73 Turkish families in a multicenter study. RESULTS Most of the families (55%) have an AR genotype, and 38% have an X-linked genotype; patients from 5 families with a suspected AR genotype (7%) were not fully characterized. We compared patients with CGD according to the severity of NADPH oxidase deficiency of neutrophils. Patients with A22(0), A67(0) or X91(0) phenotypes with a stimulation index of 1.5 or less have early clinical presentation and younger age at diagnosis (mean, 3.2 years). However, in p47(phox)-deficient cases and in 5 other AR cases with high residual oxidase activity (stimulation index ≥ 3), later and less severe clinical presentation and older age at diagnosis (mean, 7.1 years) were found. Pulmonary involvement was the most common clinical feature, followed by lymphadenitis and abscesses. CONCLUSION Later and less severe clinical presentation and older age at diagnosis are related to the residual NADPH oxidase activity of neutrophils and not to the mode of inheritance. CGD caused by A22(0) and A67(0) subtypes manifests as severe as the X91(0) subtype.

HLA Antigens and Linkage Disequilibrium Patterns in Turkish Behçet's Patients

Behçets disease (BD) is a multisystem disorder featuring mucocutaneous, ocular, articular, vascular, intestinal, pulmonary, and neurologic involvement. Although the pathogenesis of the disease is still unknown, most studies have proposed that immunologic factors may play a major role in its development in genetically predisposed individuals.

Mannose-binding lectin levels in children with asthma.

Mannose‐binding lectin (mbl), one of the important components of innate immunity, can activate the lectin pathway of the complement system. After binding mannose containing carbohydrate structures of foreign antigen, mbl initiates and regulates the inflammatory responses. Asthma is a complex inflammatory disease of the lung involving many components of the immune system. Our objective was to investigate the serum mbl levels of asthmatic children in comparison with healthy controls. Serum mbl levels were determined by nephelometric assay in 72 asthmatic children (5–15 yr old) and 30 healthy age‐matched controls. Mbl levels of asthmatic children were measured both during acute attack and after complete remission. There was no significant difference between the mbl levels during acute attack (median 4.1 mg/l) or quiescence of symptoms (median 3.6 mg/l). Serum mbl levels both during acute attack or quiescence of symptoms was significantly higher in asthmatic children than in the healthy controls (median 2.8 mg/l, p < 0.0001 for each). Furthermore, mbl levels of asthmatic children positively correlated with peripheral blood eosinophils (r = 0.377, p < 0.001), which is a systemic component of airway inflammation in asthma. Our findings indicate that mbl may be implicated in the pathogenesis of asthma by contributing to airway inflammation or by increasing the risk of developing asthma.

Hemoglobinopathies in the District of Antalya, Turkey

A screening program was conducted to ascertain the incidence of hemoglobinopathies in the district of Antalya, Turkey. The survey sample was selected from the household registration forms of health centers by systematic random sampling. Heparinized blood samples were collected from 1,616 subjects from 884 families. The prevalence of beta thalassemia traits with increased Hb A2 was 10.2%. This is higher than that found in previous studies performed in Antalya. The prevalence of abnormal hemoglobins (Hbs) was found to be 0.8%. Four subjects had Hb AS; five had Hb D-Los Angeles (B 121 [GH4] Glu-Gln); one had Hb Ube-2 (68 [E1] Ans-Asp), one had Hb P-Nilotic (fusion between B 22 and) and two had Hb D-like variants.