The NF-κB transcription factor is the master regulator of the inflammatory response and is essential for the homeostasis of the immune system. NF-κB regulates the transcription of genes that control inflammation, immune cell development, cell cycle, proliferation, and cell death. The fundamental role that NF-κB plays in key physiological processes makes it an important factor in determining health and disease. The importance of NF-κB in tissue homeostasis and immunity has frustrated therapeutic approaches aimed at inhibiting NF-κB activation. However, significant research efforts have revealed the crucial contribution of NF-κB phosphorylation to controlling NF-κB directed transactivation. Importantly, NF-κB phosphorylation controls transcription in a gene-specific manner, offering new opportunities to selectively target NF-κB for therapeutic benefit. This review will focus on the phosphorylation of the NF-κB subunits and the impact on NF-κB function.

Colonization of the upper respiratory tract by pneumococcus is important both as a determinant of disease and for transmission into the population. The immunological mechanisms that contain pneumococcus during colonization are well studied in mice but remain unclear in humans. Loss of this control of pneumococcus following infection with influenza virus is associated with secondary bacterial pneumonia. We used a human challenge model with type 6B pneumococcus to show that acquisition of pneumococcus induced early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function was associated with the clearance of pneumococcus. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate immune function and altered genome-wide nasal gene responses to the carriage of pneumococcus. Levels of the cytokine CXCL10, promoted by viral infection, at the time pneumococcus was encountered were positively associated with bacterial load.

BackgroundThe objectives of this study were to explore associations between autistic traits and self-reported clinical symptoms in a population with anorexia nervosa (AN). Experimental and self-report evidence reveals similarities between AN and autism spectrum condition (ASC) populations in socio-emotional and cognitive domains; this includes difficulties with empathy, set-shifting and global processing. Focusing on these similarities may lead to better tailored interventions for both conditions.MethodsA cross-sectional independent-groups design was employed. Participants with AN (n = 66) and typical controls (n = 66) completed self-report questionnaires including the Short (10-Item) Version Autism Spectrum Quotient (AQ-10) questionnaire (the first time this has been implemented in this population), the Eating Disorder Examination Questionnaire, the Hospital Anxiety and Depression Scale and the Work and Social Adjustment Scale. Group differences and the relationship between autistic traits and other questionnaire measures were investigated.ResultsThe AN group had a significantly higher AQ-10 total score and a greater proportion scored above the clinical cut-off than the control group. Seven out of ten AQ-10 items significantly discriminated between groups. In the AN group, levels of autistic traits correlated with a greater self-reported anxiety and depression and a lower ability to maintain close relationships; however, eating disorder symptoms were not associated with autistic traits.ConclusionsWomen with anorexia possess a greater number of autistic traits than typical women. AQ-10 items that discriminated between groups related to ‘bigger picture’ (global) thinking, inflexibility of thinking and problems with social interactions, suggesting that autistic traits may exacerbate factors that maintain the eating disorder rather than cause the eating disorder directly. Using screening instruments may improve understanding of patients’ problems, leading to better tailoring of intervention. We conclude that further investigation of autistic traits in AN could inform new intervention approaches based on joint working between ASC and eating disorder services.

SummaryFOXP3 has been identified as a key regulator of immune homeostasis. Mutations within the FOXP3 gene result in dysregulated CD4 + T-cell function and elevated cytokine production, leading to lymphoproliferative disease. FOXP3 expression in CD4 + T cells is primarily detected with the CD4 + CD25 + regulatory T-cell population. In humans the protein is detected as a doublet following immunoblot analysis. The lower band of the doublet has been identified as a splice isoform lacking a region corresponding to exon 2. The aim of this study was to investigate whether the splice variant form lacking exon 2 and a new novel splice variant lacking both exons 2 and 7, were functional inhibitors of CD4 + T-cell activation. The data generated showed that full-length FOXP3 and both splice variant forms of the protein were functional repressors of CD4 + T-cell activation.

All pairwise combinations of three cloned stocks of Trypanosoma brucei (STIB 247L, STIB 386AA and TREU 927/4) were co-transmitted through tsetse flies (Glossina morsitans) and screened for the production of hybrid trypanosomes. Clones of metacyclic and bloodstream trypanosomes from flies harbouring mature infections containing hybrid trypanosomes were established and screened for several isoenzyme and restriction fragment length polymorphisms. For each of the three combinations of parents, some progeny clones were observed to be of a phenotype and genotype indicating that genetic exchange had occurred during development of the trypanosomes in flies. These hybrid clones shared three salient features: (1) where the parents were homozygous variants the progeny were heterozygous, (2) where one of the parents was heterozygous, allelic segregation was observed and (3) the progeny clones were shown to be recombinant when two or more markers for which one of the parents was heterozygous were examined. These results are consistent with the progeny being an F1 in a diploid mendelian genetic system involving meiosis and syngamy. Our observations show that all possible combinations of the three stocks may undergo genetic exchange. A marker analysis of a series of clones each derived from single metacyclic trypanosomes showed that individual flies transmit a mixture of trypanosome genotypes corresponding to F1 progeny and to parental types, indicating that genetic exchange was a non-obligatory event in the life-cycle of the trypanosome. In addition, a preliminary analysis of the phenotype of procyclic stage trypanosomes derived from flies infected with two stocks, indicates that genetic exchange is unlikely to occur at this stage.

Autoimmune and allergic diseases occur when an individual mounts an inappropriate immune response to a self-antigen or an innocuous environmental antigen. This triggers a pathogenic T-cell response resulting in damage to specific tissues and organs. In type 1 diabetes (T1D), this manifests as destruction of the insulin-secreting β cells, resulting in a life-long dependency on recombinant insulin. Modulation of the pathogenic T-cell response with antigen-specific peptide immunotherapy offers the potential to restore the immune homeostasis and prevent further tissue destruction. Recent clinical advances with peptide therapy approaches in both T1D and other diseases are beginning to show encouraging results. New technologies targeting the peptides to specific cell types are also moving from pre-clinical development to the clinic. While many challenges remain in clinical development, not least selection of the optimal dose and dosing frequency, this is clearly becoming a very active field of drug development.

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Impaired awareness of hypoglycemia (IAH) and recurrent severe hypoglycemia (RSH) remain problematic for people with type 1 diabetes (T1D), despite major therapeutic advances. We explored beliefs around hypo-and hyperglycemia in adults with T1D with, and without, IAH and RSH. RESEARCH DESIGN AND METHODS A cross-sectional U.S. multicenter survey included Attitudes to Awareness of Hypoglycemia (A2A; a 19-item questionnaire concerning beliefs about hypoglycemia), the Gold score (single item: awareness of hypoglycemia), and a question about severe hypoglycemia over the preceding year. The survey was emailed to 6,200 adult participants of the annual T1D Exchange clinic registry data collection. A2A data were subjected to principal component analysis with varimax rotation. RESULTS Among 1,978 respondents (response rate 32%), 61.7% were women, mean 6 SD age was 39.6 6 16.3 years, and T1D duration was 23.1 6 13.8 years. Thirty-seven percent reported IAH, 16% RSH, and 9% both. A2A items segregated into three factors, differently distributed by hypoglycemia experience. Respondents with IAH or RSH expressed appropriate concern about hypoglycemia, but those with IAH were more likely to prioritize hyperglycemia concerns than those with intact awareness (P = 0.002). Those with RSH showed greater normalization of asymptomatic hypoglycemia than those without (P = 0.019) and trended toward prioritizing hyperglycemia concerns (P = 0.097), driven by those with both IAH and RSH. CONCLUSIONS Adults with T1D with IAH and RSH report specific cognitions about hypoglycemia and hyperglycemia, which may act as barriers to hypoglycemia avoidance and recovery of awareness. These may be modifiable and present a target for enhancing engagement of vulnerable people with strategies to avoid future hypoglycemia. Severe hypoglycemia (SH) is a serious complication of insulin treatment for type 1 diabetes (T1D). It is associated with cognitive impairment and can lead to confusion, unusual behavior, coma, seizure, cardiac arrhythmia, and impaired quality of life (1,2). SH accounts for between 4 and 10% of deaths in people with T1D under 40 years of age