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    • The authors of the present study speculate

    2018-11-07

    The authors of the present study speculate that early control of viral replication mediated by CD8+ cytotoxic T ARCA in HLA-B*57+ EC could lead to better CD4+ Tfh cell preservation and that this may be the mechanism behind better preservation of HIV-specific memory B cells. Direct measurement of Tfh and CD8+ T cell subsets in this or other EC cohorts in future studies could help to support this model. In view of the study linking HLA-B*57− EC to ADCC () it would also be interesting to assess ADCC in the cohort used here. The current study is by necessity a snapshot of the subject\'s immune system after many years of HIV infection. Earlier events prior to treatment or natural control may shape the development of the immune response, and it would be of great interest to analyze EC and cART recipients at time points closer to the initial infection event where possible. If HIV-specific memory B cell and neutralizing antibody responses contribute to viral control in HLA-B*57+ individuals as suggested by the authors then it would be desirable to measure neutralizing activity against autologous virus. However given the very low viral titers in EC, isolating such virus from samples used in this study would be technically challenging.
    Crohn\'s disease (CD) is a common form of chronic inflammatory bowel disease (IBD) affecting 21–294 per 100,000 in European populations (). It arises most likely from an interaction between genetic and environmental factors leading to an aberrant immune response to the gut microbiota. Previous genome-wide association studies have described more than 200 genetic loci that are associated with IBD (). (nucleotide-binding oligomerisation domain containing 2), an intracellular sensor of bacteria-derived muramyl dipeptide, was the first genetic association discovered in CD and remains one of the strongest associations (). The mechanisms whereby mutations result in intestinal inflammation in CD remain incompletely understood. Evidence suggests that NOD2 mutations are associated with a loss of innate immune protective mechanisms in both circulating antigen presenting cells and in the intestine (). The three main reported disease-associated polymorphisms (R702W, G908R, and 1007fs) all contribute to disease pathogenesis through interference with bacterial recognition (). Several environmental factors have been postulated in CD, but the most consistent epidemiological evidence points to a clear risk associated with cigarette smoking. Two meta-analyses reveal that current smokers are up to twice as likely to develop CD as non-smokers (OR=1.8–2.0) (). Cigarette smoking can impair both innate and adaptive immune responses, thereby increasing susceptibility to microbial infections which would support its role in the pathogenesis of CD (). The role of genetics and environmental contribution to the aetiology of CD has been the subject of much research over the past decade. It has been reported that cigarette smoke extract can delay mRNA expression leading to the impairment of NOD2 functioning in intestinal epithelial cells (). Given the established roles of NOD2 and cigarette smoking on innate immunity, it is conceivable that cigarette smoking might modulate the functional consequences of CD-associated polymorphism in (). ) describe a study of the interaction of smoking and one of three loss-of-function risk variants in the gene (1007fs). This is the first comprehensive systematic review and meta-analysis of the interaction between and cigarette smoking in CD. Whilst it is clear that smoking and variants increase the risk of CD independently, there is conflicting evidence for their interaction with some studies suggesting a positive interaction, a negative interaction or no interaction. The discordant findings could be explained by the fact that the majority of previous /smoking studies were underpowered to detect an interaction. Based on a large literature review and meta-analysis, the authors conclude that only one of the three known CD risk variants in (1007fs) shows an interaction with smoking exposure and more importantly, this interaction is negative. They subsequently explore this relationship in more detail in a case series of 627 patients which confirms the negative interaction. They suggest this is due to the inverse relationship between prevalence (increased in younger patients with CD) and smoking exposure (increased in older patients with CD) with increasing age of onset. It is important to point out that the authors could not restrict their analysis to individual age groups and hence, they were not able to adjust age as a confounder. However, a similar significant negative interaction between smoking and NOD2 was demonstrated in a previous study by even after adjusting for age at diagnosis. They concluded that the risk increase for CD conferred simultaneously by cigarette smoking and the 1007fs polymorphism is smaller than expected under a multiplicative model.