Primary immune regulatory disorders (PIRDs) constitute a subset of inborn errors of immunity and are characterized by lymphoproliferation, autoimmunity, malignancy, and infection. Unlike classical p

Non-IgE immune-mediated gastrointestinal disorders constitute a heterogeneous group of enigmatic conditions that are on the rise. This category encompasses entities like food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). These are immune-mediated reactions to certain foods without the involvement of allergen-specific IgE in their pathogenesis. Eosinophilic esophagitis (EoE) is also included in this group, acknowledged for its mixed IgE and non-IgE-mediated characteristics. The diagnostic landscape is fraught with challenges, given the poorly understood nature of these disorders and their propensity to manifest with varying and overlapping clinical presentations, typically emerging in infancy with common potential triggers such as cow’s milk and soy. Presently, confirmatory testing for most of these conditions is limited and invasive, emphasizing the pivotal role of a thorough history and physical examination in reaching a diagnosis. Notably, there are limited guidelines for diagnosis and management for most of these disorders. This article elucidates the key distinctions among these disorders, provides an overview of existing diagnostic and therapeutic approaches, and addresses existing knowledge and research gaps. The considerable impact on the quality of life of non-IgE immune-mediated allergic disorders of the gastrointestinal tract, which can result in debilitating complications such as nutritional deficiencies, mental health disorders, and eating disorders, underscores the urgency for comprehensive exploration and management strategies.

Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of genetic disorders affecting the development and function of the immune system. While IEIs traditionally present with recurrent infections, an increasing number of cases manifest with early-onset severe atopy, including atopic dermatitis, food allergies, asthma, and allergic rhinitis—features that are often overlooked. This can lead to delayed diagnosis and treatment, which is crucial for IEI patients due to the risk of severe infections. We conducted a literature search and reviewed all IEIs that can present with early-onset severe atopy. The hallmark features of these disorders often include early-onset, persistent, and severe atopic dermatitis, food allergies, and recurrent episodes of asthma, which may be refractory to treatments. Additionally, we discuss the importance of recognizing such severe atopy as a potential indicator of an underlying immune deficiency, particularly when accompanied by unusual infections, growth failure, or autoimmunity. This review aims to raise awareness of this association and emphasize the need for early diagnosis and genetic testing in patients with atypical or treatment-resistant allergic diseases, allowing for more timely diagnosis of underlying immunodeficiencies and appropriate treatments.

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.

Peanut allergy presents a significant and growing public health concern, marked by its increasing prevalence and potential for severe allergic reactions. Traditional diagnostic methods, such as skin prick testing and serum IgE assays, serve as cornerstone approaches but often fall short in specificity, sensitivity, and risk stratification. This has driven the development of innovative diagnostic technologies, including component-resolved diagnostics, basophil activation tests, bead-based epitope assays, molecular diagnostics, and artificial intelligence applications. These advancements promise greater diagnostic precision, improved patient stratification, and tailored management strategies. However, challenges such as high costs, accessibility issues, and the need for standardized protocols hinder their widespread clinical adoption. This review explores the evolution of peanut allergy diagnostics, comparing traditional and emerging methodologies, and discusses their clinical implications, limitations, and future directions. The integration of advanced technologies with established approaches holds the potential to revolutionize peanut allergy diagnosis and management, ultimately enhancing patient care and outcomes.

Inborn errors of immunity (IEIs) are a group of more than 485 disorders that impair immune development and function with variable reported incidence, severity, and clinical phenotypes. A subset of IEIs blend increased susceptibility to infection, autoimmunity, and malignancy and are known collectively as primary immune regulatory disorders (PIRDs). Programmed cell death, or apoptosis, is crucial for maintaining the balance of lymphocytes. Genetic-level identification of several human inherited diseases with impaired apoptosis has been achieved, such as autoimmune lymphoproliferative syndrome (ALPS), caspase-8 deficiency state (CEDS), X-linked lymphoproliferative syndrome (XLP), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway disorders. The consequences of this disease are manifested by abnormal lymphocyte accumulation, resulting in clinical features such as lymphadenopathy, hepatomegaly, splenomegaly, and an increased risk of lymphoma. Additionally, these disorders are often associated with autoimmune disease, particularly involving blood cells. Understanding the molecular pathogenesis of these conditions has provided critical insights into the signaling pathways that regulate apoptosis and lymphocyte activation, shedding light on mechanisms of immune dysregulation. This review focuses on the intersection between apoptosis, autoimmunity, and lymphoproliferation, discussing how dysregulation contributes to the development of these immune disorders. These conditions are characterized by excessive lymphocyte accumulation, autoimmunity, and/or immunodeficiency. Understanding their molecular pathogenesis has offered new insights into the signaling mechanisms that regulate apoptosis and lymphocyte activation.