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Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD., Alborz University of Medical Sciences, This work was supported by the vice chancellor for research, Alborz University of Medical Sciences.

LL-37 contributes to maintaining the balance between health and disease. Smoking is a risk factor for periodontitis that impairs neutrophil functions. The aim of the present study was to comparatively evaluate gingival crevicular fluid (GCF) LL-37 levels in smoker and non-smoker chronic periodontitis (CP) patients and controls, as well as the effect of non-surgical periodontal treatment on GCF LL-37 levels.Thirty-one CP patients (16 smokers, 15 non-smokers) and thirty-one controls (16 smokers, 15 non-smokers) were included in the study. CP patients received non-surgical treatment. GCF LL-37 levels and periodontal parameters were assessed at baseline, 1 and 3 months after completion of non-surgical periodontal treatment. GCF LL-37 levels were analyzed by ELISA.No significant difference was observed in GCF LL-37 levels between smoker and non-smoker controls (p0.05). Smoker CP group had significantly lower GCF LL-37 level than non-smoker CP group at baseline (p0.05). GCF LL-37 levels significantly decreased in non-smoker CP group at first week, 1 and 3 months after completion of non-surgical periodontal treatment (p0.05) although no significant decrease in GCF LL-37 levels was observed in smoker CP group (p0.05). Periodontal parameters were correlated with GCF LL-37 levels in non-smoker CP group (p0.05), but not in smoker CP group (p0.05).GCF LL-37 levels do not seem to be affected from smoking in periodontal health. However, smoking might have a suppressive effect on GCF LL-37 levels in CP. Non-surgical treatment is effective in decreasing GCF LL-37 levels in non-smoker CP patients but not in smokers with CP.

The aim of the present study was to investigate the effect of cyclosporine-A (CsA) medication on gingival crevicular fluid (GCF) LL-37, human neutrophil peptide (HNP)1-3 and adrenomedullin (ADM) levels.CsA-treated renal transplant recipients with GO (CsA GO+) and without GO (CsA GO-), tacrolimus-medicated renal transplant recipients (n = 20/group), systemically healthy subjects with gingivitis (n = 21) and individuals free of periodontal and systemic diseases (n = 20) were included in the present study. Periodontal parameters were recorded and GCF samples were obtained from the study participants. GCF LL-37, HNP1-3 and ADM levels were analyzed by enzyme-linked immunosorbent assay.GCF LL-37 total amount was higher at GO+ sites than the other study sites (p0.05). Total amount of GCF HNP1-3 was higher in immunosuppressive treatment groups than healthy and gingivitis groups, regardless of GO presence (p0.05). GCF ADM total amount was similar in all study groups. GCF volume, papillary bleeding index and hyperplastic index (p0.05) were significantly correlated with GCF LL-37 total amounts (p0.05), but not with GCF HNP1-3 and ADM total amount at GO+ sites (p0.05).Neutrophil infiltration due to extended inflammation might have increased GCF LL-37 levels at GO+ sites and contributed to the pathogenesis of CsA-induced GO.

Background IgA deficiency (IgAD) is the most common primary antibody deficiency. Although two-third of the cases are reported to be asymptomatic, some IgAD children may have frequent infections that urge the clinicians to search for prophylactic measures. OM-85 BV is one of these agents that is known to stimulate mucosa associated lymphoid tissue, and upregulate Th-1 response. This study was performed to determine a possible role of OM-85 BV in triggering autoimmunity in IgAD children within a four-year-follow up period. Methods Sixty-three children (34 males (54%), 29 females (46%)) with sporadic IgAD and recurrent febrile infections were included. Patients were carefully screened for autoimmunity both on admission and in follow-up: Those with autoimmune features or under immunosuppressant treatment were excluded. Patients were randomly divided into two groups: Group I received bacterial lysate propylaxis (OM-85 BV) (n:37), and Group 2 received no prophylactic regimen (n:26). Development of clinical autoimmune findings or autoantibodies (anti-nuclear antibody (ANA), ANA profile (14 antigens), anti-cytoplasmic antibodies (ANCA), anti-cardiolipin antibodies IgG and IgM (aCL), rheumatoid factor (RF), direct Coombs test, anti-thyroglobulin (anti-T) and anti-thyroid microsomal antigen (anti-M)) were evaluated. Results Mean age of the study group, age at the onset of infectious symptoms and at admission were 102.9 ± 42.2, 27.1 ± 24.9, and 55.2 ± 25.1 months, respectively. Follow-up duration of the whole study group was 48.3 ± 23.1 months. Number of infections was 6.2 ± 2.7 per year in the whole study group. Sixteen patients (25.4%) of the whole study group showed ANA positivity in different patterns and titers. Frequency of ANA, ANCA and RF positivity was 24.3%, 5.4%, 2.7% in Group 1, and 26.9%, 11.5%, 3.8% in Group 2, respectively. Statistical comparisons revealed no significant difference between the two groups. Conclusion Significant clinical or laboratory markers for autoimmunity in follow-up were not observed between receivers or non-receivers of OM-85 BV. Frequency of ANA positivity was comparable to the previously reported values in IgAD children which was not affected by OM-85 BV usage. Possible effect of triggering autoimmunity with repeated cures of bacterial lysates needs to be further clarified. Side effects requiring the cessation of treatment were not recorded.

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. WAS is caused by mutations in the WASP gene which encodes WASP, a 502-amino acid protein. WASP plays a critical role in actin cytoskeleton organization and signalling, and functions of immune cells. We present here the results of genetic analysis of patients with WAS from eleven Eastern and Central European (ECE) countries and Turkey. Clinical and haematological information of 87 affected males and 48 carrier females from 77 WAS families were collected. The WASP gene was sequenced from genomic DNA of patients with WAS, as well as their family members to identify carriers. In this large cohort, we identified 62 unique mutations including 17 novel sequence variants. The mutations were scattered throughout the WASP gene and included single base pair changes (17 missense and 11 nonsense mutations), 7 small insertions, 18 deletions, and 9 splice site defects. Genetic counselling and prenatal diagnosis were applied in four affected families. This study was part of the J Project aimed at identifying genetic basis of primary immunodeficiency disease in ECE countries. This report provides the first comprehensive overview of the molecular genetic and demographic features of WAS in ECE. (C) 2010 Elsevier Ltd. All rights reserved.

To evaluate if type 2 diabetes mellitus increase gingival crevicular fluid (GCF) levels of prostaglandin E(2) (PGE(2)), interleukin-1beta (IL-1beta), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-2 (PAI-2).Seventeen type 2 diabetic patients with periodontal disease (DM), 17 otherwise healthy periodontally diseased patients (PD) and 17 systemically and periodontally healthy control subjects (H) were enrolled. Clinical periodontal measurements were recorded at six sites/tooth. GCF samples were analyzed by ELISA. Data were tested by statistical tests.DM group revealed lower IL-1beta levels than PD group (p0.01). PGE(2), t-PA and PAI-2 levels were similar in DM and PD groups (p0.05). PGE(2), t-PA levels were higher in DM and PD groups than H group (p0.05). PAI-2 level was higher in DM group than H group (p0.05). GCF total amount of PGE(2) in DM group exhibited significant correlations with all clinical periodontal measurements (p0.05).Type 2 diabetes in this study seems not to increase GCF levels of the evaluated inflammatory mediators.

To evaluate in vitro T lymphocyte proliferation and specific antibody response to hepatitis B vaccination in two groups of rats fed with normal and marginal zinc content.Twenty-two Wistar-Albino rats were randomly assigned into two groups and were fed with constant diet. Zinc was suplemented 10mg/kg dry weight in group I (marginal zinc content) (n=14) and 30mg/kg dry weight in group II (n=8). Hepatitis B vaccine (Engerix B, 4mug) was administered intramuscularly after 8 weeks on feeding and a booster dose was applied 4 weeks after the first injection. Rats were killed 3 weeks after the second injection. Peripheral blood mononuclear cells were stimulated in vitro by PHA (2.5mug/ml) and hepatitis B surface antigen (2.5, 5, 10mug/ml). Proliferation was evaluated by ELISA (celltiter-96 aqueous one solution cell proliferation assay). Serum zinc, anti-HBs titer and zinc per dry liver weight were also measured. Two groups were compared with respect to antigen specific antibody and lymphocyte proliferation responses. Proliferation response to HbsAg were expressed as net percent increase (pci) in lymphocyte proliferation from the baseline activity.Rats' mean body weight and weight gain per month were similar. Median serum zinc was 39 (23-75) and 76(64-115)mug/dl of groups I and II rats, respectively (p0.05), while there was no difference in liver zinc content between the two groups (37mug/g dry weight versus 32mug/g dry weight). Median anti-HBs levels of groups I and II were 741 (0-10,000)IU/l, 5791 (558-10,000)IU/l, respectively (p0.05). In lymphocyte proliferation assays, mean net pci with HbsAg of 5 and 10mug/ml were 9.4% and 11.3% in group I rats; while they were 25.3% and 26.1% in group II rats (p0.01 and p0.01, respectively).In vitro cell-mediated immune response and in vivo specific antibody response to hepatitis B vaccine was decreased in rats fed a diet with marginal zinc content. These observations have shown that marginal Zn deficiency might influence the efficacy of hepatitis B vaccination in humans.

The effects of vitamin A and vitamin E supplementation on the IgG response to tetanus toxoid after primary immunization were evaluated in a prospective, randomized controlled clinical trial involving 89 healthy infants with normal serum vitamin A and E levels at 2 months of age. Before the first dose of DPT vaccine, the infants were randomly enrolled into four different study groups [Group I ( n =24): 30,000 IU vitamin A for 3 days just after each three doses of primary vaccination, Group II ( n =21): 150 mg oral vitamin E for only 1 day after the injections for primary immunization, Group III ( n =21): vitamins A and E together in the same order, Group IV ( n =23) no vitamin after DPT vaccines]. Serum tetanus antitoxin (IgG) titres were measured three times; initially at 2 months of age before the first dose of DPT, secondly at 5 months of age 1 month after primary immunization and thirdly at 16–18 months of age before the booster dose of DPT. Before the first dose of the DPT vaccine, 1 month after the third DPT injection and at 16–18 months before the booster dose of DPT, there was no significant difference in serum tetanus antitoxin levels between these four groups. A significant increase was observed in all the groups when serum tetanus antitoxin levels before (2 months) and after (5 months) primary immunization were compared. In addition, serum antibody levels against tetanus significantly decreased in the four groups before booster vaccination. Before the beginning of primary immunization, 15 infants (16.8%) had serum tetanus antitoxins (IgG) below protective level. After three doses of DPT, all the infants had protective antitoxin levels. At 16–18 months of age before booster dose, four infants (10%) also had serum tetanus antitoxins (IgG) below the protective level. No side-effects were observed except bulging fontanelle in two infants in Group I.

We report a patient with complete interleukin-12 receptor beta-1 deficiency associated with cutaneous leukocytoclastic vasculitis. The patient experienced Bacille Calmette Guérin, Mycobacterium chelonae, and Salmonella enteritidis infection. Vasculitis affecting both small arteries and postcapillary venules due to deposition of immune complexes was probably caused by S. enteritidis and/or M. chelonae infection.

The aim of this prospective study is to define the prognostic significance of lymphocyte subset analysis in children with Bell's palsy. Lymphocyte subgroup analysis in peripheral blood was performed in 17 children with Bell's palsy by using flow cytometry. Before a standard protocol of corticosteroid treatment, patients were categorized into two groups for facial nerve impairment on the basis of the clinical findings: Group 1 (mild to moderate impairment), 7 patients; and Group 2 (severe impairment), 10 patients. Outcome of the patients was evaluated at the end of 3 months follow-up and categorized as satisfactory recovery (n = 12) or unsatisfactory recovery (n = 5). Decreased percentages of B cells (CD19) and T helper/inducer (CD4) subsets were measured in patients with Bell's palsy compared with age-matched healthy control patients. Patients with severe impairment had significantly lower percentages of CD4 and CD19 subsets, whereas patients with mild to moderate impairment had only decreased percentage of CD19 subsets. There was no statistically significant difference in the percentage of lymphocyte subsets between the patients with satisfactory and unsatisfactory recovery. These results provide additional support for cell-mediated immunopathogenesis in patients with Bell's palsy, without any prognostic significance for the outcome.

WOS: 000389542700018, PubMed ID: 27350570, Background: The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of T(H)17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear. Objective: We sought to elucidate common mechanisms operating in the different forms of HIES. Methods: We analyzed the differentiation of CD4(+) T-H cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. T-H cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and T-H cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis. Results: There was a profound block in the differentiation of DOCK8-deficient naive CD4(+) T cells into T(H)17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired T(H)17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression. Conclusion: DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES., National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01AI065617]; Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [1059B191300622], Supported by the National Institutes of Health (5R01AI065617, to T.A.C.) and a grant from the Scientific and Technological Research Council of Turkey (1059B191300622 to S.K.).

WOS: 000396606301476

S A T U R D A Y 36 Differences in Clinical Outcome in Patients with Common Variable Immunodeficiency Treated with Ig Replacement Therapy: Results from the ESID Database G. Kindle, K.Warnatz, O. Paschenko, D. Kumararatne, S. S. Kilic, V. Thon, T. Witte, M. Helbert, T. W. Kuijpers, A. Exley, N. Mahlaoui, G. Notheis, H. Longhurst, U. Baumann, A. Jones, N. K€ut€ukc€uler, M. Borte, P. Wagstr€om, C. Feighery, A. Szaflarska, H. Ritterbusch, S. Reda, T. Kononova, Z. Panahloo, B. Grimbacher; Centre of Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, GERMANY, Russian Children’s Clinical Hospital, Moscow, RUSSIAN FEDERATION, Cambridge University Hospital NHS Trust (Addenbrooke’s), Cambridge, UNITED KINGDOM, Uludag University Medical Faculty, Bursa, TURKEY, Masaryk University Medical Faculty, St Anne University Hospital, Brno, CZECH REPUBLIC, Department of Clinical Immunology, Hannover Medical School, Hannover, GERMANY, University of Manchester, Manchester, UNITED KINGDOM, Emma Children’s Hospital, Academic Medical Center (AMC), Amsterdam, NETHERLANDS, Cambridge University Health Partners, Papworth Hospital NHS Foundation Trust, Cambridge, UNITED KINGDOM, CEREDIH: The French PID study group, Unit e d’Immuno-H ematologie & Rhumatologie p ediatriques, Hopital Necker-Enfants Malades, Paris, FRANCE, Dr v. Haunersches Kinderspital, Ludwig Maximilians University, Munich, GERMANY, Barts and the London NHS Trust, London, UNITED KINGDOM, Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, GERMANY, Institute of Child Health/Great Ormond Street Hospital, London, UNITED KINGDOM, Ege University, Faculty of Medicine, Dept of Pediatric Immunology, Bornova, Izmir, TURKEY, Children’s Hospital, Municipal Hospital ’St Georg’, Academic Teaching Hospital of the University of Leipzig, Leipzig, GERMANY, Ryhov County Hospital, Jonkoping, SWEDEN, Department of Immunology,Trinity College Dublin & St. James’ Hospital, Dublin, IRELAND, Department of Clinical Immunology, PolishAmerican Institute of Paediatrics, Medical College, Jagiellonian University, Cracow, POLAND, Department of Pediatric Allergy and Immunology, Children’s Hospital, Faculty of Medicine, Ain Shams University, Cairo, EGYPT, Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, RUSSIAN FEDERATION, Medical Science Department, CSL Behring, Haywards Heath, UNITED KINGDOM, Royal Free Hospital & University College London, London, UNITED KINGDOM. RATIONALE:Themost frequent primary immunodeficiency diagnosis in the ESID Database is common variable immunodeficiency (CVID; n52401). The primary treatment is immunoglobulin (Ig) replacement therapy by intravenous (IV) or subcutaneous (SC) administration. We retrospectively assessed the clinical outcome with Ig therapy in patients with CVID by country and route of administration. METHODS:Datawere provided for patients with CVIDwhowere treated with Ig therapy. Four health parameters were evaluated by country and by route of administration. The number of patients with available data varied from 417 to 645 between the four parameters. RESULTS: There was a highly significant variation between countries in the four outcomes (median occurrence per year, p