Activation-Induced Cytidine Deaminase (AID) Deficiency Causes the Autosomal Recessive Form of the Hyper-IgM Syndrome (HIGM2)

AbstractThe activation-induced cytidine deaminase (AID) gene, specifically expressed in germinal center B cells in mice, is a member of the cytidine deaminase family. We herein report mutations in the human counterpart of AID in patients with the autosomal recessive form of hyper-IgM syndrome (HIGM2). Three major abnormalities characterize AID deficiency: (1) the absence of immunoglobulin class switch recombination, (2) the lack of immunoglobulin somatic hypermutations, and (3) lymph node hyperplasia caused by the presence of giant germinal centers. The phenotype observed in HIGM2 patients (and in AID−/− mice) demonstrates the absolute requirement for AID in several crucial steps of B cell terminal differentiation necessary for efficient antibody responses

Use of the internet by Italian pediatricians: habits, impact on clinical practice and expectations

<p>Abstract</p> <p>Background</p> <p>Medical professionals go online for literature searches and communication with families.</p> <p>We administered a questionnaire to members of the Italian Society of Pediatrics to assess determinants of their use of the Internet, of social platforms and of personal health records during clinical practice.</p> <p>Methods</p> <p>All the 9180 members of the Italian Society of Pediatrics were invited to fill in a questionnaire concerning use of the Internet and usefulness of Internet-based tools during clinical practice. The questionnaire was administered through the SurveyMonkey^®web platform. Logistic regression analysis was used to study factors affecting use and influence of the Internet in clinical practice.</p> <p>Results</p> <p>A total of 1335 (14.5%) members returned the questionnaire. Mean age was 49.2 years, 58.6% were female. 32.3% had access to the Internet through a Smartphone. 71.9% of respondents used the Internet during clinical practice, mainly searching for guidelines and drug references. Use of the Internet during clinical practice was more frequent among younger pediatricians (OR 0.964; 95% CI 0.591-0.978), males (OR 1.602; 95% CI 1.209-2.123) and those living in Northern and Central Italy (OR 1.441; 95% CI 1.111-1.869), while it was lower among family pediatricians. 94.6% of respondents were influenced in their clinical practice by information found on the Internet, in particular younger pediatricians (OR 0.96, 95% CI 0.932-0.989), hospital pediatricians (OR 2.929, 95% CI 1.708-5.024), and other pediatric profiles (OR 6.143, 95%CI 1.848-20.423). 15.9% of respondents stated that social networks may be useful in pediatric practice. Slightly more than half (50.5%) of respondents stated that personal health records may be clinically relevant. Registrars and hospital pediatricians were more likely to perceive personal health records as useful tools for clinical practice. Additional resources pediatricians would like to access were free bibliographic databases and tools for interacting with families.</p> <p>Conclusions</p> <p>Italian pediatricians frequently use the Internet during their practice. One-third of them access the Internet through a Smartphone. Interaction with families and their empowerment can be improved by the use of Internet tools, including personal health records, toward which respondents show a significant interest. Though, they show a general resistance to the introduction of social networks in clinical practice.</p

Dysregulated miR-155 and miR-125b Are Related to Impaired B-cell Responses in Down Syndrome

Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS. GC size, numbers of GC B cells and Follicular Helper T cells (TFH) expressing BCL6 cells were severely reduced. The expression of miR-155 and miR-125b was increased in tonsillar memory B cells and miR-125b was also higher than expected in plasma cells (PCs). Activation-induced cytidine deaminase (AID) protein, a miR-155 target, was significantly reduced in MBCs of DS patients. Increased expression of miR-155 was also observed in vitro. MiR-155 was significantly overexpressed in PBMCs activated with CpG, whereas miR-125b was constitutively higher than normal. The increase of miR-155 and its functional consequences were blocked by antagomiRs in vitro. Our data show that the expression of HSA21-encoded miR-155 and miR-125b is altered in B cells of DS individuals both in vivo and in vitro. Because of HSA21-encoded miRs may play a role also in DS-associated dementia and leukemia, our study suggests that antagomiRs may represent pharmacological tools useful for the treatment of DS

Effect of in vitro treatment with reducing drugs on structure and function of human secretory immunoglobulin A.

Samples of unstimulated whole saliva from 15 healthy children with 0.5--6 mg/100 ml of secretory IgA and from 10 healthy adults with 4--18 mg/100 ml of secretory IgA were pooled and treated in vitro with dithiothreitol and alpha-mercaptopropionylglycine. The effect of these reducing drugs on the immunochemical properties of secretory IgA was evaluated. Dithiothreitol induced depolymerization of secretory IgA and splitting of the secretory piece from the IgA molecule; furthermore it strongly reduced the titer of secretory antibodies to Escherichia coli antigens. The drug alpha-mercaptopropionylglycine apparently did not affect either the polymeric structure of secretory IgA or the titer of secretory anti-E. coli antibodies; however it induced splitting of the secretory piece. On the whole it appers that drugs with reducing properties, currently employed for liquifying mucous secretions in clinical practice, should be carefully evaluated for possible depressive side-effects on local immunity

Comparison of the frequency of atopic diseases in children with severe and partial IgA deficiency.

Similar frequencies of atopic diseases and of elevated total serum IgE levels were observed in 40 children with serum IgA levels below 5 mg/dl and absence of salivary IgA (severe selective IgA deficiency, SIgAD) and in 40 children with serum IgA levels above 5 mg/dl but below -2 SD of age-normal mean values and presence of salivary IgA (partial SIgAD). These findings suggest that the absence of secretory IgA, which has been postulated to play a protective role by excluding allergens at the mucosal level, does not appear to play a crucial role in the pathogenesis of atopic diseases

Presentation of Wiskott Aldrich syndrome as isolated thrombocytopenia

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