The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

Abstract

Summary Dynamic changes in metabolism have long been understood as critical for both the initiation and maintenance of innate and adaptive immune responses. A number of recent advances have clarified details of how metabolic pathways can specifically affect cellular function in immune cells. Critical to this understanding is ongoing study of the congenital disorders of glycosylation and other genetic disorders of metabolism that lead to altered immune function in humans. While there are a number of immune phenotypes associated with metabolic derangements caused by single gene disorders, several genetic mutations have begun to link discrete alterations in metabolism and growth specifically with allergic disease. This subset of primary atopic disorders is of particular interest as they illuminate how hypomorphic mutations which allow for some residual function of mutated protein products permit the “abnormal” allergic response. This review will highlight how mutations altering sugar metabolism and mTOR activation place similar constraints on T lymphocyte metabolism to engender atopy, and how alterations in JAK/STAT signaling can impair growth and cellular metabolism while concomitantly promoting allergic diseases and reactions in humans.

Exploration of the Molecular Mechanism of FUZI (Aconiti Lateralis Radix Praeparata) in Allergic Rhinitis Treatment Based on Network Pharmacology

“…The JAK/STAT signaling pathway is capable of facilitating the differentiation of different Th subsets. For example, IL-2/STAT5 and IL-4/STAT6 signaling pathways are capable of activating Th2 differentiation, and IL-6-activated STAT3 can enhance mast cell degranulation, leading to allergic reactions [38][39][40]. The JAK/STAT signaling pathway has become a target for treating various immune diseases.…”

Case Report: Eosinophilic Esophagitis in a Patient With a Novel STAT1 Gain-of-Function Pathogenic Variant

“…Atopic presentations reported to date have included eczema, asthma and food allergies ( 12 , 15 , 18 – 21 ). Despite the above, atopy and eosinophilic disorders are still not commonly considered a predominant feature of STAT1 GOF, as opposed to other disorders affecting JAK/STAT signaling such as STAT3 LOF, STAT5B LOF or GOF, and JAK1 GOF ( 22 ). While gastrointestinal eosinophilia has been reported in a few STAT1 GOF patients ( 15 , 23 ), this was typically identified following diagnosis of oropharyngeal/esophageal Candidiasis, and may have represented a secondary tissue reaction to fungal infection.…”

Targeted pharmacologic immunomodulation for inborn errors of immunity

“…12,13 This further complicates matters for patients who are receiving prophylactic antimicrobials, and targeted disease immunomodulators heading into transplantation that generally requires conditioning regimens and prophylaxis for graft-vs-host disease. It is now more apparent that monogenic defects affecting immune function may present with severe and/or recurrent infection, 14 uncontrolled inflammation, 15 allergies and hypersensitivity reactions, 16,17 lymphoproliferation 18 and cancer predisposition. 19 Targeted treatment approaches may help to alleviate disease morbidity and mortality.…”