Isil B. Barlan

DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation

The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27+ memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src–kinase Syk–transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

Intranasal budesonide spray as an adjunct to oral antibiotic therapy for acute sinusitis in children.

BACKGROUND The role of topical corticosteroids in the treatment of acute sinusitis has not been established in children. OBJECTIVE An attempt was made to determine the impact of topical corticosteroids as an adjunct to antibiotic treatment in the management of childhood sinusitis. METHODS In a double-blind, placebo-controlled study, 151 children with sinusitis were recruited from a general pediatric outpatient clinic and 89 completed a 3-week trial. Treatment consisted of amoxicillin-clavulanate potassium, 40 mg/kg/d tid, combined with bid nasal spray of either budesonide, 50 micrograms, to each nostril (n = 43) or placebo )n = 46_ for 3 weeks. Patients maintained daily symptom cards throughout the study and were examined by the same physician each week. RESULTS Clinical symptoms and signs decreased significantly in both treatment groups in comparison to baseline (P < .01). We detected a significant improvement in the scores of the cough and nasal discharge at the end of second week in the budesonide group when compared with placebo (P < .05). Friedman nonparametric repeated measures ANOVA test revealed a significant decrease in the total weekly scores of cough during the second week of budesonide treatment (P < .001) in contrast to continuous decline during the second and third weeks in the placebo group (P < .001 and P < .05, respectively). While the nasal discharge score decreased significantly during the second week in the budesonide group (P < .01), no significant effect on the nasal discharge score was observed in the placebo group. CONCLUSION These data suggest that topical corticosteroids may be a useful ancillary treatment to antibiotics in childhood sinusitis and effective in reducing the cough and nasal discharge earlier in the course of acute sinusitis.

Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: an open randomized controlled trial

Background In children, the clinical efficacy and immunological mechanisms of sublingual immunotherapy (SLIT) compared with subcutaneous immunotherapy (SCIT) is still to be elucidated.

Impact of Sublingual Immunotherapy on Specific Antibody Levels in Asthmatic Children Allergic to House Dust Mites

Objective: To evaluate the clinical outcome and changes in allergen-specific antibodies during sublingual immunotherapy (SLIT) in house dust mite (HDM)-allergic asthma patients and to compare levels of allergen-specific antibodies in HDM-allergic patients before and after treatment with that of healthy controls. Method: Thirty-one asthma patients allergic to HDM were studied. Patients in groups I (n = 17) and II (n = 14) received SLIT with a standardized Dermatophagoides pteronyssinus plus Dermatophagoides farinae 50/50 extract for 6 and 12 months, respectively. A group of healthy children (n = 8) were enrolled as controls. Patients in both groups were evaluated at the start and at the end of treatment according to daily symptom and medication scores, lung function and skin prick tests, PC20, blood eosinophil count, and Der-p-1-specific IgE, IgA, IgG1 and IgG4 levels. Results: Drug consumption decreased significantly in both groups. Furthermore, PC20 and forced expiratory flow between 25 and 75% of vital capacity of patients in group II improved significantly. Although specific IgA, IgG1 and IgG4 levels did not change throughout the treatment period, total eosinophil count and specific IgE decreased significantly in both groups. According to baseline measurements, specific IgA levels of patients in groups I and II were significantly lower than that of controls. This difference disappeared at the end of the treatment period in both groups. Conclusion: SLIT seems to be effective in ameliorating clinical symptoms, drug consumption and bronchial hyperreactivity, and results in downregulation of Der-p-1-specific IgE production. Furthermore, at the end of SLIT, specific IgA levels, which were decreased compared to healthy controls initially, did no longer differ between patients and controls.

Anaphylaxis to multiple pollen allergen sublingual immunotherapy

prolactin and DHEA-S concentrations was a recognized tendency (3, 6) we investigated correlations within CU subjects for the hormones. There are however some controversies concerning the effect of prolactin on modulation of DHEA-S secretion. No significant correlation between serum DHEA-S and prolactin concentration in our CU patients might indicate that lower DHEA-S serum concentration could not be accounted for by changes in prolactin secretion. In conclusion, it seems that hyperprolactinemia does not accompany the immune-inflammatory processes associated with CU, also in the presence of positive ASST result, which suggests the autoimmune origin of the disease. We did not find any causal relationship between the reduced serum DHEA-S concentration and basal prolactin secretion. The lack of abnormalities in peripherally detectable hormones does not exclude the possibility of prolactin exerting immunomodulatory effects upon the urticarial inflammation. Verification of such hypothesis requires however further studies to be performed.

International Consensus Document (ICON): Common Variable Immunodeficiency Disorders

The International Collaboration in Asthma, Allergy and Immunology initiated an international coalition among the American Academy of Allergy, Asthma & Immunology; the European Academy of Allergy and Clinical Immunology; the World Allergy Organization; and the American College of Allergy, Asthma & Immunology on common variable immunodeficiency. An author group was formed and then divided into individual committees. Within the committee, teams of authors were subgrouped to generate content for specific sections of the document. Content was derived from literature searches, relevant published guidelines, and clinical experience. After a draft of the document was assembled, it was collectively reviewed and revised by the authors. Where evidence was lacking or conflicting, the information presented represents the consensus expert opinion of the group. The full document was then independently reviewed by 5 international experts in the field, none of whom was among the authors of the original. The comments of these reviewers were incorporated before submission for publication.

Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K

Lucas et al. identify humans with a gain-of-function mutation in PIK3R1, encoding the p85α subunit of PI3K. The splice site mutation causes in-frame skipping of exon 11, resulting in altered p85α association with p110δ that stabilizes the catalytic subunit but fails to properly inhibit catalytic activity. The patients have immunodeficiency and lymphoproliferation with skewing of CD8+ T cells toward terminally differentiated and senescent effector cells that have shortened telomeres.

Increased activation-induced cell death of high IFN-γ–producing TH1 cells as a mechanism of TH2 predominance in atopic diseases

BACKGROUND A dysregulated and T(H)2-biased immune response appears to be a key pathogenetic factor in atopic diseases. Increased activation and massive infiltration of T cells in the dermis without any evidence for the expansion of their numbers in peripheral blood characterize atopic dermatitis. OBJECTIVE To investigate differences and mechanisms of T(H)1 and T(H)2 cell activation-induced cell death (AICD) in atopic disease. METHODS Naive (CD4(+)CD45(+)RA) and memory (CD4(+)CD45(+)RO) T cells were isolated from healthy and atopic individuals. T(H)1 and T(H)2 subsets were in vitro differentiated. High IFN-gamma-producing T cells and CXCR3(+) T cells were purified, and AICD of isolated cells was determined in addition to expression of apoptosis receptors and caspase activation. RESULTS T(H)1 cells, particularly their high IFN-gamma-producing fraction, and CXCR3(+) T cells showed significantly increased apoptosis in atopic individuals. During their in vitro differentiation, both T(H)1 and T(H)2 cells of atopic individuals showed increased apoptosis compared with the healthy control group, with a significantly high apoptosis in T(H)1 cells. Increased expression of Fas, Fas-ligand, tumor necrosis factor receptor-II, and caspase activation was detected on T(H)1 cells that underwent apoptosis. Neutralization experiments demonstrated a dominant role of IFN-gamma and Fas-Fas-ligand interaction-mediated suicide in T(H)1 cell AICD. CONCLUSION Predominant T(H)2 profile in atopic diseases might be a result of the increased tendency to activation and apoptosis of high IFN-gamma-producing T(H)1 cells.

Immunological mechanisms of sublingual immunotherapy.

Administration of allergen‐specific immunotherapy by the oral route, sublingual immunotherapy (SLIT), has been shown to be effective, with an improved safety profile compared with subcutaneous administration. However, the precise mechanisms underlying the induction of immune tolerance by SLIT remain unclear. Contact of the allergen with the antigen‐presenting cells in oral mucosa is likely to be critical. Mucosal Langerhans cells can capture the allergen and transport it to local lymph nodes, which may favour the induction of T lymphocytes that suppress the allergic response. In addition, the production of blocking IgG4 antibodies and the involvement of mucosal B cells appear to play a role. There is a growing evidence to support the role of regulatory T cells in controlling the development of asthma and allergic disease. Nevertheless, there remains a lack of firm evidence that SLIT induces regulatory T cells, although preliminary in vitro data suggest that SLIT may increase interleukin‐10, which has a clear role in suppressing the allergic immune response. Further studies are required to determine the involvement of regulatory T cells, the role of different dendritic cell subsets, mucosal B cells as well as the potential use of adjuvants during SLIT.

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.