Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells.

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.

Strategies for choosing a biologic for your patient with allergy or asthma.

OBJECTIVE: To summarize the therapeutic effects and safety of biologics either approved or in clinical development for asthma, chronic obstructive pulmonary disease, urticaria, nasal polyps, atopic dermatitis, and eosinophilic esophagitis. This review attempts to provide some guidance when choosing among agents. DATA SOURCES: Recently published articles obtained through PubMed database searches including research articles, review articles, and case reports. STUDY SELECTIONS: PubMed database searches were conducted using the following keywords: biologics, asthma, COPD, urticaria, atopic dermatitis, food allergy, nasal polyps, and eosinophilic esophagitis. RESULTS: The approval of omalizumab by the Food and Drug Administration in 2003 for patients with asthma paved the way for the development of multiple biologics for a variety of respiratory and allergic diseases. Agents approved by the Food and Drug Administration include mepolizumab, reslizumab, benralizumab, and dupilumab, and several more are in the late stages of clinical development. Owing to the overlap in the pathogenesis of respiratory and allergic diseases, many of these biologics target multiple respiratory and allergic diseases simultaneously. CONCLUSION: The numerous biologic options have made the selection of the best biologic for each patient a potential conundrum for clinicians. Adequate point of care biomarkers to facilitate personalized medical therapy are generally lacking. Furthermore, although clinically effective and generally safe, none of the biologics discussed in this review have induced long-standing disease remission. Nevertheless, these agents have given us the opportunity to treat the most severe patients and to better understand the biology of respiratory and allergic diseases. As knowledgeable physicians, we should embrace and be educated on these novel therapies and the pathways they target.

Epigenetics of Mucus Hypersecretion in Chronic Respiratory Diseases.

Asthma, chronic obstructive pulmonary disease, and cystic fibrosis are three chronic pulmonary diseases that affect an estimated 420 million individuals across the globe. A key factor contributing to each of these conditions is mucus hypersecretion. Although management of these diseases is vastly studied, researchers have only begun to scratch the surface of the mechanisms contributing to mucus hypersecretion. Epigenetic regulation of mucus hypersecretion, other than microRNA post-translational modification, is even more scarcely researched. Detailed study of epigenetic mechanisms, such as DNA methylation and histone modification, could not only help to better the understanding of these respiratory conditions but also reveal new treatments for them. Because mucus hypersecretion is such a complex event, there are innumerable genes involved in the process, which are beyond the scope of a single review. Therefore, the purpose of this review is to narrow the focus and summarize specific epigenetic research that has been conducted on a few aspects of mucus hypersecretion in asthma, chronic obstructive pulmonary disease, cystic fibrosis, and some cancers. Specifically, this review emphasizes the contribution of DNA methylation and histone modification of particular genes involved in mucus hypersecretion to identify possible targets for the development of future therapies for these conditions. Elucidating the role of epigenetics in these respiratory diseases may provide a breath of fresh air to millions of affected individuals around the world.

Hepatitis B vaccine nonresponders: Possible mechanisms and solutions.

OBJECTIVE: Hepatitis B (HBV) is a viral illness that chronically infects 240 million people worldwide, leads to liver disease, and increases risk of hepatocellular carcinoma. The HBV vaccine has decreased HBV infection, and it and the human papilloma virus vaccine are the only vaccines that prevent cancer. Despite the effectiveness of the HBV vaccine, some populations do not develop protective responses. The risk groups for poor response include those with immunosuppression or dialysis-dependent, end-stage renal disease. Five percent of normal people do not have a response. These subjects are deemed HBV "nonresponders." Multiple strategies to improve the immunogenicity of the HBV vaccine are currently being pursued, including vaccine adjuvants, recombinant vaccines, and immune enhancement via up-regulation of dendritic cells. DATA SOURCES: PubMed was searched for peer-reviewed publications published from January 1980 to September 2017. STUDY SELECTIONS: Studies retrieved for inclusion summarized potential mechanisms behind HBV vaccine nonresponsiveness and potential solutions. RESULTS: The mechanisms behind HBV vaccine nonresponsiveness vary between each subject population. Many current and future strategies may provide protective immunity against HBV in each of these populations. CONCLUSION: This review provides a background on the immunology of HBV infection, the possible immunologic mechanisms to explain HBV vaccine nonresponsiveness, current research aimed at improving vaccine effectiveness, and possible future approaches for providing nonresponders protection from HBV.

Role of epigenetics in pulmonary hypertension.

A significant amount of research has been conducted to examine the pathologic processes and epigenetic mechanisms contributing to peripheral hypertension. However, few studies have been carried out to understand the vascular remodeling behind pulmonary hypertension (PH), including peripheral artery muscularization, medial hypertrophy and neointima formation in proximal arteries, and plexiform lesion formation. Similarly, research examining some of the epigenetic principles that may contribute to this vascular remodeling, such as DNA methylation and histone modification, is minimal. The understanding of these principles may be the key to developing new and more effective treatments for PH. The purpose of this review is to summarize epigenetic research conducted in the field of hypertension that could possibly be used to understand the epigenetics of PH. Possible future therapies that could be pursued using information from these studies include selective histone deacetylase inhibitors and targeted DNA methyltransferases. Both of these could potentially be used to silence proproliferative or antiapoptotic genes that lead to decreased smooth muscle cell proliferation. Epigenetics may provide a glimmer of hope for the eventual improved treatment of this highly morbid and debilitating disease.

Mismatch between subjective and objective dysautonomia.

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

Benralizumab for the treatment of asthma.

INTRODUCTION: The classification of asthma into phenotypes and endotoypes allows for the use of targeted therapies, including three biologics which target interleukin 5 (IL-5) signaling in eosinophilic asthma. Areas covered: As of December 2016, two monoclonal antibodies, mepolizumab and reslizumab, are approved by U.S. Food and Drug Administration and one, benralizumab, is in clinical development. Two phase 3 trials for benralizumab, SIROCCO and CALIMA, were published in September 2016. Although there are no direct comparisons among these three anti-IL-5 therapies, the goal of this review is to summarize the current data and discuss their potential similarities and differences, with a focus on benralizumab. Expert commentary: Compared to mepolizumab and reslizumab, the possible advantages of benralizumab are less frequent dosing and a potential to reduce exacerbations irrespective of the blood eosinophil count. Some improvements in asthma symptom scores and quality of life occur with all three biologics, but the clinical meaningfulness of these improvements is less clear. A more defined reference range for eosinophil levels is necessary to determine which subjects will best benefit from these medications. Until quality randomized controlled trials directly compare the three, choosing among them for the treatment of eosinophilic asthma remains difficult.