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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., (© 2022. The Author(s).)

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., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)