Clinical Reviews in Allergy & Immunology最新文献

{"title":"Baseline Blood Eosinophil Count for Identifying Superior Responders to Biologics in Chronic Rhinosinusitis with Nasal Polyps: A Systematic Review and Meta-Analysis.","authors":"Yang Zheng, Wei Liu, Yujuan Yang, Haoran Lu, Huikang Wang, Zhen Liu, Congxian Lu, Jianbo Fu, Yingxue Li, Xicheng Song, Yu Zhang","doi":"10.1007/s12016-025-09130-6","DOIUrl":"10.1007/s12016-025-09130-6","url":null,"abstract":"<p><p>Current guidelines recommend the presence of type 2 inflammation as one of the indications for biologic therapy in chronic rhinosinusitis with nasal polyps (CRSwNP). Although blood eosinophil (Eos) levels are commonly used as a biomarker for type 2 inflammation, their value in predicting differential responses to biologic treatment has not been verified by high-quality evidence. We searched the PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (Central) databases, and hand-searched Clinicaltrials.gov for all RCTs that used biologic therapies for CRSwNP. Primary outcomes included the nasal polyp score (NPS), nasal congestion score (NCS), a 22-item sino-nasal outcome test (SNOT-22) score, and loss of smell (Los) score. This study is registered with PROSPERO (CRD420251063136). This meta-analysis included 9 studies comprising 10 RCTs (n = 2,551), all of which were judged to be at a high risk of selection bias. The results showed that when compared with placebo treatment, biologic therapy significantly improved all outcome measures, including the NPS, NCS, SNOT-22 score, and LoS score, —regardless of baseline Eos levels. However, inter-subgroup comparisons clearly showed that both the Eos ≥ 150 cells/µL and Eos ≥ 300 cells/µL groups had significantly greater improvements in their NPS and NCS when compared with the Eos < 150 cells/µL group (p < 0.05). In contrast, improvements in the SNOT-22 scores and LoS scores were comparable across all subgroups, with no statistically significant differences observed. An exploratory analysis suggested that at the Eos ≥ 300 cells/µL threshold, anti-IL-4Rα monoclonal antibodies may be superior to anti-IL-5 monoclonal antibodies for improving the NPS and NCS (p < 0.05). Although biologics demonstrate efficacy in the overall CRSwNP population, a baseline blood eosinophil count ≥ 150 cells/µL pinpoints the patient subgroup with a superior response.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"69 1","pages":"1"},"PeriodicalIF":11.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Efficacy of Combined and Standalone Oral Immunotherapies for Peanut Allergy: a Bayesian Network Meta-Analysis of RCTs.","authors":"Xinyu Tian, Shuang Liu, Lisha Li, Kai Guan","doi":"10.1007/s12016-025-09118-2","DOIUrl":"10.1007/s12016-025-09118-2","url":null,"abstract":"<p><strong>Background: </strong>Peanut allergy is a chronic IgE-mediated disease with potentially life-threatening consequences. While several immunotherapeutic strategies have emerged, including oral immunotherapy (OIT), omalizumab (OMA)-based therapies, and probiotic and peanut oral immunotherapy (PPOIT), the comparative effectiveness of these interventions remains unclear. This study aimed to evaluate the relative efficacy and safety of combined and standalone oral immunotherapies for peanut allergy using a Bayesian network meta-analysis (NMA).</p><p><strong>Methods: </strong>A systematic literature search was conducted in PubMed, EMBASE, and Web of Science up to March 2025. We included randomized controlled trials (RCTs) involving patients with IgE-mediated peanut allergy who received OIT + OMA, OMA monotherapy, OIT alone, or PPOIT. Outcomes included low-dose and high-dose desensitization, sustained unresponsiveness (SU), and safety outcomes (adverse events, AEs). The risk of bias was assessed using RoB 2. Analyses were performed using R software (version 4.4.3) with Bayesian NMA methods.</p><p><strong>Results: </strong>Nineteen RCTs involving 2040 participants were included. Based on Probability Scores (P-scores), OIT + OMA demonstrated the highest efficacy for both low- (P-score: 97.20%) and high-dose desensitization (96.69%), followed by PPOIT (70.15% and 51.16%), OIT third (64.40% and 52.72%), and OMA fourth (75.29% and 71.21%). PPOIT and OIT showed moderate efficacy for SU. OIT was associated with a higher frequency of AEs compared with placebo.</p><p><strong>Conclusions: </strong>Combination and modified immunotherapies may offer improved efficacy and safety profiles, though results should be interpreted in the context of limited data and study heterogeneity.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"113"},"PeriodicalIF":11.3,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12748126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunopathogenesis and Therapeutics of Systemic Lupus Erythematosus: an Integrative Review.","authors":"Qian Lyu, Huan Zou, Shen Hu","doi":"10.1007/s12016-025-09119-1","DOIUrl":"10.1007/s12016-025-09119-1","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disease with a strong female predisposition, characterized by multi-organ inflammation and damage. Its pathogenesis arises from a complex interplay of genetic susceptibility, epigenetic alterations, hormonal influences, and environmental triggers. This confluence drives a sustained loss of self-tolerance and profound immune dysregulation. Innate immune dysfunction, featuring unchecked type I interferon (IFN) production and defective clearance of cellular debris, exposes autoantigens. Concurrent adaptive immune defects include a breakdown of B and T cell tolerance, leading to pathogenic autoantibody production, dysregulated cytokine networks, and aberrant lymphocyte interactions. These processes culminate in tissue injury via immune complex deposition and direct cellular effects. This review synthesizes current understanding of these multifaceted immunological mechanisms in SLE, underscoring how their delineation has informed the development of targeted biologic therapies and highlighting the ongoing need for translational research to improve patient outcomes. Furthermore, emerging insights into the heterogeneity of immune pathways among patients emphasize the potential for personalized treatment approaches tailored to specific molecular profiles.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"112"},"PeriodicalIF":11.5,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between COVID-19 and New-Onset Autoimmune Diseases: Updated Systematic Review and Meta-Analysis of 97 Million Individuals.","authors":"Chih-Chen Tzang, Henry Sheng, Vicky Fu-Hsuan Kuo, Chiao-An Luo, Tzu-An Lin, Yi-Ting Lee, Ewen Shengyao Huang, Pei-Hsun Wu, Bor-Show Tzang, Tsai-Ching Hsu","doi":"10.1007/s12016-025-09124-4","DOIUrl":"10.1007/s12016-025-09124-4","url":null,"abstract":"<p><p>SARS-CoV-2 infection may induce long-term immune dysregulation; however, its contribution to the development of autoimmune disease remains disputed. We aim to quantify the relative risk of new-onset autoimmune diseases following COVID-19 and its modifiers through a systematic review and meta-analysis of population-based cohort studies. MEDLINE, Embase, Cochrane Library, and Web of Science were searched to March 31, 2025, for cohort studies comparing individuals with and without confirmed COVID-19. Random-effects meta-analysis estimated pooled hazard ratios (HRs) with 95% CIs. Subgroup analyses examined the severity of acute COVID-19, vaccination status, and demographics. Risk of bias was evaluated with the Newcastle-Ottawa Scale, certainty of evidence with GRADE, and publication bias with funnel plots and Egger's test. The review protocol was prospectively registered in PROSPERO (CRD42025646186). Seventeen cohort studies, including over 250 million person-years, were included. COVID-19 was associated with a 49% increased risk of new-onset autoimmune-related diseases (AIRD; HR = 1.49, 95% CI: 1.21-1.83; p = 0.0002). Significant associations (p < 0·05) were observed for 17 of 23 outcomes, with the strongest risks in antiphospholipid syndrome (HR = 2·16), ANCA-associated vasculitis (HR = 2·15), mixed connective tissue disease (HR = 2·12), and immune thrombocytopenic purpura (HR = 1·87). Risk was higher after severe infection (HR = 1.70), but was reduced in vaccinated individuals (HR = 0.56, compared to 1.42 in unvaccinated individuals). The certainty of evidence was moderate for conditions with large effect sizes, but low overall, reflecting heterogeneity across studies and the non-randomized design of the included studies. SARS-CoV-2 infection increases the risk of autoimmune diseases, particularly those affecting vascular and connective tissue. Risk is amplified by severe infection and attenuated by vaccination. These findings highlight the necessity of vaccination and targeted follow-up in severe COVID survivors.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"111"},"PeriodicalIF":11.5,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunological Mechanisms and Outcomes of T-cell-Targeted Immunotherapy in Food Allergy: A Systematic Review.","authors":"Svetlana Fesenko, Stella A Nicolaou","doi":"10.1007/s12016-025-09122-6","DOIUrl":"10.1007/s12016-025-09122-6","url":null,"abstract":"<p><p>Food allergy is an increasing public health concern characterized by inappropriate Th2-driven immune responses to otherwise harmless food antigens, leading to IgE-mediated hypersensitivity. Current management strategies rely on allergen avoidance and emergency interventions, which fail to address the root cause of immune dysregulation. Given the central role of helper T cells, particularly Th2 and regulatory T cells (Tregs), this systematic review evaluates the efficacy, safety, and immunological effects of three T cell-targeted allergen-specific immunotherapies: oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT). Thirteen studies, comprising 14 study arms, from four databases were included following PRISMA 2020 guidelines and PICOS-based selection. Based on the study design, RoB 2 and ROBINS-I tools were used to evaluate risk of bias. OIT demonstrated strong clinical and immunological outcomes, with high desensitization and sustained unresponsiveness (SU) rates, increased FOXP3⁺ Tregs, and suppression of Th2 cytokines (IL-4, IL-5, IL-13). SLIT showed moderate immunomodulatory effects with better tolerability, while EPIT provided the safest profile but limited T cell reprogramming. Overall, this review highlights the therapeutic potential of targeting T cells in food allergies and supports the use of OIT as the most effective current strategy, despite a higher risk of adverse events. While SLIT and EPIT remain promising, particularly in pediatric populations, further research is needed to enhance durability, personalize treatments, and combine immunotherapies with adjuncts such as biologics or Treg-promoting agents to achieve lasting immune tolerance. PROSPERO registration ID: CRD420251012358.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"109"},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Mechanisms and Hypotheses for Pathogenic Microorganisms Triggering Kawasaki Disease.","authors":"Jinhan Yu, Linlin Cheng, Haoting Zhan, Yuan Huang, Siyu Wang, Haolong Li, Yongmei Liu, Yingchun Xu, Ye Guo, Yongzhe Li","doi":"10.1007/s12016-025-09120-8","DOIUrl":"10.1007/s12016-025-09120-8","url":null,"abstract":"<p><p>Kawasaki disease (KD) is an acute, self-limiting systemic vasculitis of early childhood and remains the leading cause of acquired heart disease in developed nations. Despite decades of investigation, its etiology and immunopathogenesis are still not fully understood. This review integrates nearly six decades of histopathological, epidemiological, and immunological research to examine infection-driven mechanisms underlying KD. Current evidence indicates that KD may result from a convergence of microbial and host factors: viral infections can trigger mucosal IgA-mediated immune activation; superantigens may induce T-cell receptor (TCR) Vβ-skewed cytokine release; conventional antigens appear to elicit oligoclonal adaptive immune responses consistent with infection-associated vasculitis; and gut microbiota dysbiosis may amplify systemic inflammation through disruption of intestinal barrier integrity and short-chain fatty acid metabolism. Rather than a single-pathogen infection, KD likely reflects infection-triggered immune dysregulation in genetically susceptible children. By contrasting these mechanistic hypotheses, this review highlights the need for longitudinal, multi-omics studies integrating metagenomic, transcriptomic, and serologic analyses to delineate causal microbial signatures, identify diagnostic biomarkers, and guide precision immunomodulatory strategies for this complex pediatric vasculitis.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"110"},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multisectoral Study of Mpox Epidemiology, Resistance Surveillance, and Policy Gaps: Toward a One Health Framework.","authors":"Durjoy Mistry, Mehjabin Hossain, B S Diba, J D Plabon, M A Shams, M T Rahman, A S M Bakibillah","doi":"10.1007/s12016-025-09121-7","DOIUrl":"10.1007/s12016-025-09121-7","url":null,"abstract":"<p><p>Mpox, formerly known as monkeypox, has recently spread beyond its traditional epidemic areas. Several regions of Africa have been affected and have become a health concern globally. This review presents epidemiology, clinical symptoms, diagnostic developments, treatment methods, and policy gaps of Mpox. Methodologically, this review incorporates data from over 70 peer-reviewed journal articles, official epidemiological bulletins, and curated surveillance datasets from WHO, CDC, and PubMed to provide an evidence-based analysis of Mpox. As all data were derived from secondary sources, no sampling method was utilized. Firstly, we examined the primary causes of the virus's resurgence, including zoonotic spillover, human-to-human transmission, and globalization, which contribute to the spread of Mpox disease. Next, we discussed different treatment alternatives for Mpox, such as Tecovirimat and JYNNEOS vaccination, diagnostic techniques including polymerase chain reaction (PCR), serological tests, and new point-of-care diagnostics based on clustered regularly interspaced short palindromic repeats (CRISPR). Then, we highlighted the public health challenges of Mpox, including misdiagnosis, healthcare disparities, and the impact on immunosuppressed populations, particularly HIV-positive individuals. Finally, this study discussed the socioeconomic implications of Mpox outbreaks, emphasizing the need for global collaboration, enhanced surveillance, and robust vaccination programs to minimize future outbreaks.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"108"},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathophysiologic Mechanisms and Targeted Treatments Associated with the Nervous System in Cutaneous Allergic Diseases.","authors":"Hantian Zhang, Weiyi Xiang, Yi Tong, Xian Jiang, Linghong Guo","doi":"10.1007/s12016-025-09115-5","DOIUrl":"10.1007/s12016-025-09115-5","url":null,"abstract":"<p><p>The skin is a highly innervated and immunologically active barrier organ, where neuro-immune interactions critically shape both physiological homeostasis and disease progression. Growing evidence indicates that bidirectional crosstalk between the nervous and immune systems is not only central to the pathogenesis of allergic skin diseases but also represents an emerging frontier for therapeutic innovation. In this review, we systematically examine atopic dermatitis (AD), contact dermatitis (CD), and urticaria, integrating insights into peripheral pathways-mediated by sensory neurons, cytokine networks, and immune cells-and central mechanisms involving the hypothalamic-pituitary-adrenal axis and higher neural circuits. By contrasting shared and disease-specific neuro-immune signatures, we highlight how these mechanisms underlie distinct inflammatory phenotypes and clinical manifestations. We further evaluate current and investigational therapies, including biologics and small molecules that target neuro-immune signaling, and discuss their translational significance. Looking ahead, we identify unresolved questions and propose future directions aimed at leveraging neuro-immune mechanisms to advance precision diagnosis and personalized interventions in allergic skin diseases.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"107"},"PeriodicalIF":11.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the Gap in Secondary Antibody Deficiencies: Current Evidence and Unmet Needs in Diagnosis and Management with Immunoglobulin Replacement.","authors":"Andy Ka Chun Kan, Ben Chun Yin Chan, Chak Sing Lau, Philip H Li","doi":"10.1007/s12016-025-09116-4","DOIUrl":"10.1007/s12016-025-09116-4","url":null,"abstract":"<p><p>Secondary antibody deficiency (SAD) represents a substantial yet under-recognised global healthcare burden. It is more prevalent than primary antibody deficiency, but frequently under-diagnosed and variably managed worldwide. Prompt diagnosis is often hindered by insufficient awareness among clinicians, lack of global consensus on screening/monitoring for SAD among at-risk patients, inadequate clinical immunology services and lack of standardised referral pathways/protocols. Management practices vary widely, with little international agreement, particularly regarding threshold to initiate immunoglobulin replacement, as well as regimen, dosage and frequency of immunoglobulin administration. Subcutaneous immunoglobulin (SCIg) replacement emerged as a promising alternative to traditional intravenous immunoglobulin (IVIg) replacement. IVIg requires monthly infusions in inpatient/day-hospital settings leading to high peak serum IgG and subsequent variations with end-of-cycle 'wear-off effect', causing more systemic side effects and increased risk of breakthrough infections, and disruption of daily life and employment. While previous evidence was largely derived from primary antibody deficiency, recent comparative studies on SAD patients indicate that SCIg replacement, through weekly self-administered infusions, can achieve more stable and higher trough serum IgG, lower infection rates, fewer systemic adverse reactions and enhanced health-related quality-of-life compared to IVIg. There is also potential cost-savings from the use of SCIg replacement. This review emphasises the urgent need for standardised guidelines on screening/diagnosis and treatment of SAD, and large-scale multi-centre trials and real-world studies on IVIg vs SCIg replacement among SAD patients, which will facilitate better identification, management, and health-outcomes for SAD patients, ultimately alleviating a significant global health challenge through coordinated clinical, research, and policy efforts.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"106"},"PeriodicalIF":11.3,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12681477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Common Variable Immunodeficiency Disorders: A perspective from New Zealand.","authors":"Rohan Ameratunga, Hilary J Longhurst, Klaus Lehnert, Euphemia Leung, Richard Steele, See-Tarn Woon","doi":"10.1007/s12016-025-09099-2","DOIUrl":"10.1007/s12016-025-09099-2","url":null,"abstract":"<p><p>Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic Primary Immunodeficiency (PID) in adults and children. Patients with CVID present with predominant antibody deficiency with varying degrees of impaired cellular immunity. CVID was previously a diagnosis of exclusion, which led to considerable uncertainty about which patients would qualify for subcutaneous or intravenous immunoglobulin (SCIG/IVIG) replacement. Over the last twelve years, several sets of diagnostic criteria have been published which identify these disorders with greater precision. These new CVID diagnostic criteria assist with decisions on treatment, particularly SCIG/IVIG replacement. With the advent of massively parallel genome sequencing technologies, it has become apparent that a significant proportion of individuals with a CVID phenotype have an underlying causative genetic defect. If such a pathogenic variant is identified, these individuals are removed from the overarching diagnosis of CVID and are deemed to have a CVID-like disorder caused by a specific Inborn Error of Immunity (IEI). New Zealand has had a long-standing customized PID genetic testing program. Two novel autosomal dominant pathogenic variants causing CVID-like disorders, consequent to haploinsufficiency of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFKB1) and Transcription Factor 3 (TCF3), were identified in New Zealand families. The latter pathogenic variant was shown to have an epistatic interaction with TNFRSF13B (TACI) in a patient with a digenic CVID-like disorder. Epistasis is the synergistic, non-linear interaction between two or more genetic loci, leading to much more severe (or much milder) disease. This perspective reviews the current understanding of these disorders with contributions from three New Zealand-based studies: The Prospective NZ CVID and the NZ hypogammaglobulinemia sub-studies as well as a large retrospective case series of Transient Hypogammaglobulinemia of Infancy (THI). These clinical and genomic studies have offered insights into the complexities of these rare PIDs. This review examines current areas of uncertainty in the diagnosis of of these disorders.</p>","PeriodicalId":10423,"journal":{"name":"Clinical Reviews in Allergy & Immunology","volume":"68 1","pages":"105"},"PeriodicalIF":11.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12669308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}