Research

Ann Allergy Asthma Immunol. 2025 May 29:S1081-1206(25)00266-2. doi: 10.1016/j.anai.2025.05.024. Online ahead of print.

ABSTRACT

BACKGROUND: Food allergies and inborn errors of immunity (IEIs) were once viewed as distinct disorders-hypersensitivity versus infection susceptibility. However, IEIs are now recognized to include immune dysregulation, with autoimmunity, autoinflammation, lymphoproliferation, and severe atopy. Understanding the overlap between food allergies and IEIs is critical, as allergic inflammation often complicates immune deficiencies.

OBJECTIVE: To examine the shared immunologic mechanisms linking food allergies and IEIs, with a focus on immune dysregulation, barrier defects, microbial dysbiosis, and impaired regulatory T cell (Treg) function.

METHODS: A comprehensive literature review was conducted using PubMed applying search terms including food allergy, primary immunodeficiency, inborn errors of immunity (IEIs), Treg cells, immune dysregulation, autoimmunity, autoinflammation, epithelial barrier dysfunction, and microbiome. Particular focus was placed on identifying studies describing monogenic IEIs characterized by severe allergic phenotypes and elevated IgE levels. Articles were selected based on relevance to the themes of the review, quality of study design, and their contribution to advancing understanding in the field. Priority was given to original research articles, systematic reviews, meta-analyses, and key historical studies.

RESULTS: Allergic symptoms, including food allergy and atopic dermatitis, frequently present early in IEIs and may precede infection susceptibility. Common features include Treg dysfunction, cytokine signaling defects, epithelial barrier compromise, and microbiome alterations. Recognition of these pathways has enhanced diagnosis and led to targeted therapies such as biologics and gene therapy.

CONCLUSION: Regulatory T cells are central to maintaining immune tolerance across allergic, autoimmune, and immunodeficient states. Advances in understanding dysregulated immunity and barrier defects are driving personalized treatment strategies for patients with both food allergy and IEIs.

PMID:40449791 | DOI:10.1016/j.anai.2025.05.024

Front Immunol. 2025 May 15;16:1589052. doi: 10.3389/fimmu.2025.1589052. eCollection 2025.

ABSTRACT

BACKGROUND: Common variable immune deficiency (CVID) is the most prevalent inborn error of immunity (IEI), marked by diverse clinical-immunological phenotypes and significant immune-dysregulation, including granulomatous lymphocytic interstitial lung disease (GLILD). GLILD is a severe manifestation of CVID, contributing to reduced life expectancy and a challenging diagnosis due to its insidious and non-specific clinical course. Current management strategies for GLILD rely on expert opinion due to a lack of randomized controlled trials (RCTs).

OBJECTIVES: This study aims to provide a comprehensive immunophenotypical characterization of CVID patients with and without GLILD, investigate predictive biomarkers for GLILD development, and explore therapeutic strategies, particularly during concomitant SARS-CoV-2 and chronic cytomegalovirus (CMV) infections.

SOURCES: Primary data were collected from a cohort of 25 patients with CVID who underwent high-resolution computed tomography (HRCT), immunophenotyping, and serum immunoglobulin analysis at diagnosis and after immunoglobulin replacement therapy. Existing literature on CVID and GLILD biomarkers, immunological profiles, and therapeutic interventions informed comparative analyses.

CONTENT: Patients with GLILD exhibited distinct immunophenotypical features, including reduced regulatory T-cells, CD8+ naïve, central memory T-cells, and B-cell subsets (memory and switched memory), alongside increased CD21low B-cells and naïve B-cells, indicative of chronic inflammation-driven immune activation. IgA and IgG4 concentrations were significantly lower in patients with GLILD at diagnosis. Immunosuppressive therapy, predominantly mycophenolate mofetil (MMF), demonstrated favorable clinical and functional outcomes, though radiological progression persisted in some cases. CMV infection in patients with GLILD on immunosuppressants resulted in favorable outcomes, underscoring the importance of personalized treatment strategies.

IMPLICATIONS: This study highlights novel immunological markers and clinical-radiological patterns as potential predictors for GLILD, advocating for their integration into diagnostic and monitoring frameworks to reduce reliance on invasive histopathology. Future research should focus on validating biomarkers and conducting RCTs to establish evidence-based guidelines for GLILD management.

PMID:40443662 | PMC:PMC12119541 | DOI:10.3389/fimmu.2025.1589052

J Manag Care Spec Pharm. 2025 Jun;31(6):578-589. doi: 10.18553/jmcp.2025.31.6.578.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by unpredictable recurrent, debilitating, and potentially fatal attacks of subcutaneous and submucosal tissue swelling.

OBJECTIVE: To evaluate all-cause, angioedema-related, and HAE attack-related medical visits and hospitalizations before and after initiation of berotralstat long-term prophylaxis (LTP) for patients with HAE in the United States.

METHODS: This retrospective pre-post analysis used Komodo’s Healthcare Map claims data to identify patients who initiated berotralstat (December 2020 to December 2022). The first entry for berotralstat dispensing was defined as the index date. Inclusion criteria comprised patients aged at least 12 years at index with at least 6 months of continuous insurance eligibility pre-index and evidence consistent with HAE pre-index (International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes D84.1, D68.2, or T78.3x; medication use [on-demand or LTP]; or presence of diagnostic HAE laboratory tests). Rates of all-cause, angioedema-related, and HAE attack-related medical visits per person-year were compared post-index vs pre-index using rate ratios with 95% CIs and P values from generalized estimating equation Poisson regression models with robust SEs. Study limitations included the inability to distinguish HAE types and the uncertainty of whether a dispensed medication was consumed or taken as prescribed.

RESULTS: The study population included 260 patients treated with berotralstat (mean age = 39.7 years; 74.2% female). After berotralstat initiation, there were significant decreases in the rates of all-cause health care resource utilization (HRU): all-cause inpatient (IP) visits decreased by 34% (P = 0.037) and all-cause outpatient/emergency department (OP/ED) visits decreased by 14% (P = 0.005). There were also significant decreases in rates of angioedema-related HRU (IP visits: 52%, P = 0.001; OP/ED visits: 44%, P < 0.001) as well as HAE attack-related HRU (IP visits: 60%, P < 0.001; OP/ED visits: 50%, P < 0.001). Use of on-demand medications decreased significantly after berotralstat initiation (32%, P = 0.002). Results were similar among subgroups of patients defined by HAE treatment history, including patients who were LTP-experienced (n = 126) and LTP-naive but on-demand treatment-experienced (n = 67).

CONCLUSIONS: Prophylactic treatment of HAE with berotralstat was associated with significant reductions in all-cause HRU, including decreases to angioedema-related and HAE attack-related medical visits, hospitalizations, and administration of on-demand treatment.

PMID:40443005 | DOI:10.18553/jmcp.2025.31.6.578

Front Immunol. 2025 May 14;16:1536128. doi: 10.3389/fimmu.2025.1536128. eCollection 2025.

ABSTRACT

BACKGROUND: In this study we included patients with hereditary angioedema (HAE) caused by decreased levels of C1 inhibitor (HAE-C1INH). An increased risk of autoimmune disorders, particularly systemic lupus erythematosus (SLE), has been reported in HAE-C1INH. This suggests that complement consumption affects adaptive immunity.

OBJECTIVE: To investigate lymphocyte subpopulations in relation to disease activity and complement activation in HAE-C1INH patients and matched controls.

METHODS: Flow cytometry of peripheral blood lymphocyte populations, measurements of complement and complement fragments, and collection of clinical data.

RESULTS: NK cell counts were lower in HAE-C1INH patients, and their frequencies were related to disease activity. The T helper (Th) cell balance was skewed towards more Th2 cells and less Th1 cells in HAE-C1INH patients compared to controls. There were also lower frequencies of class-switched B cells and plasmablasts in patients. Levels of C4 and the complement activation fragment C3d were related to disease activity.

CONCLUSIONS: Blood lymphocyte populations are altered in HAE-C1INH, a finding which may be of pathophysiological importance considering the increased risks of both autoimmunity and allergy associated with HAE-C1INH.

PMID:40438097 | PMC:PMC12116338 | DOI:10.3389/fimmu.2025.1536128

Front Immunol. 2025 May 14;16:1576235. doi: 10.3389/fimmu.2025.1576235. eCollection 2025.

ABSTRACT

Hereditary angioedema (HAE) types 1/2 are rare genetic disorders leading to C1 inhibitor (C1INH) deficiency/dysfunction. Guidelines recommend long-term prophylaxis (LTP) to prevent HAE attacks. Subcutaneous (SC) C1INH replacement therapy is approved for LTP in patients with HAE (age indication varies between countries). There is little real-world data on the outcomes of patients who switch to C1INH SC in Europe, particularly those who switch from C1INH IV. This retrospective patient chart analysis captured real-world evidence of the effectiveness of C1INH SC LTP in patients with HAE in Germany (n=69) and Spain (n=37). The primary endpoint was change in annualized attack rate (AAR) in patients who used C1INH IV LTP during a 6-month baseline period and switched to C1INH SC LTP for ≥6 months. Switching to C1INH SC LTP from C1INH IV LTP was associated with a 73.2% reduction in AAR (n=48; P<0.001) compared to baseline. Emergency Room (ER) visits and rescue medication use were also significantly reduced after switching to C1INH SC LTP from C1INH IV LTP. A similar reduction in AAR (68.9%), ER visits (49.8%), and rescue medication use (61.9%) was observed in the overall population (n=105), regardless of treatment at baseline. Similar changes from baseline were seen in patients from Germany and Spain.

PMID:40438099 | PMC:PMC12116583 | DOI:10.3389/fimmu.2025.1576235

World J Gastrointest Endosc. 2025 May 16;17(5):101618. doi: 10.4253/wjge.v17.i5.101618.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is a primary antibody immunodeficiency disorder characterized by diminished IgG levels. Despite ongoing research, the precise pathogenesis of CVID remains unclear. Genetic factors account for only 10%-20% of cases, with an estimated incidence of 1 in 10000 to 1 in 100000, affecting individuals across all age groups.

CASE SUMMARY: We report the case of a 32-year-old man with CVID who presented with a chief complaint of “recurrent diarrhea and significant weight loss over the past 2 years”. Laboratory tests on admission showed fat droplets in stool, while other parameters were within normal ranges. Gastroscopy revealed a smooth gastric mucosa without bile retention or signs of Helicobacter pylori infection; however, the mucosa of the descending segment of the duodenum appeared rough. Further evaluation of the small intestine using computed tomography indicated no abnormalities. Finally, the whole-small bowel double-balloon enteroscopy (DBE) was performed, which revealed various phenotypic changes in the small intestinal mucosa. The patient was diagnosed with CVID, which improved after immunoglobulin therapy, with favorable follow-up outcomes.

CONCLUSION: Non-infectious enteropathy in CVID is rare. Therefore, DBE is essential for diagnosing small intestinal involvement in such cases.

PMID:40438712 | PMC:PMC12110145 | DOI:10.4253/wjge.v17.i5.101618

Clin Exp Immunol. 2025 May 28:uxaf036. doi: 10.1093/cei/uxaf036. Online ahead of print.

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by an aberrant immune response against host tissues. It can arise from diverse triggers like infection, inflammation, malignancy, genetic defects, or therapy-related factors. Cytokine storm, capillary leak syndrome, cytokine release syndrome, and macrophage activation syndrome are the different faces of this chimera, and each of them displays significant clinical variability associated with high mortality. The pathogenesis of both primary and secondary HLH generally follows a similar pattern, involving excessive activation of macrophages and uncontrolled destruction of reticuloendothelial tissues. Environmental triggers cause exaggerated activation of innate immune cells in genetically predisposed individuals. This process is further driven by the release of multiple cytokines and soluble mediators that sustain ongoing inflammation and cause subsequent target organ damage. Biomarkers, including cytokines and inflammatory mediators, are crucial for early detection and monitoring treatment response. Persistent immune activation and inadequate resolution mechanisms result in a destructive inflammatory cascade or “immunological massacre”. Animal models of HLH and MAS elucidate the roles of impaired cytotoxicity, IFN-γ, TLR signaling, and inflammatory cytokines in disease pathogenesis. Trigger-specific differences highlight the involvement of CD8+ T cells, NK cells, macrophages, and cytokines. Therapeutic strategies include cytokine neutralization, adoptive T-cell transfer, and mTOR inhibition. Timely diagnosis and prompt initiation of therapy are essential to mitigate the serious consequences of HLH and improve long-term outcomes.

PMID:40435290 | DOI:10.1093/cei/uxaf036

BMC Med Genomics. 2025 May 27;18(1):95. doi: 10.1186/s12920-025-02145-0.

ABSTRACT

BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking.

OBJECTIVE: This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient’s clinical presentation.

METHODS: A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient’s blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations.

RESULTS: The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein’s C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking.

CONCLUSION: The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.

PMID:40426172 | DOI:10.1186/s12920-025-02145-0

J Res Pharm Pract. 2025 Apr 24;13(4):111-118. doi: 10.4103/jrpp.jrpp_2_25. eCollection 2024 Oct-Dec.

ABSTRACT

OBJECTIVE: In severe cases, COVID-19 can lead to a hyperinflammatory state, resulting in devastating outcomes. Immune modulation using steroids or other immune modulators can regulate the intensity of the inflammatory response; however, this theory has not been adequately assessed in practice. The current study aims to investigate the use of corticosteroids alone or in combination with tocilizumab to treat patients with severe COVID-19.

METHODS: This cross-sectional study was conducted on 166 Iranian patients with severe COVID-19 infection at Al-Zahra Hospital, who were treated with the standard treatment for severe COVID-19 infection, as per the 11^th version of the Iranian guideline for COVID-19 treatment. Patients were categorized into three treatment groups based on the dose of corticosteroid treatment and tocilizumab therapy: (a) high-dose methylprednisolone (>1 mg/kg) alone, (b) low-dose methylprednisolone (<1 mg/kg) followed by one dose of tocilizumab (8 mg/kg); and (c) high-dose methylprednisolone (>1 mg/kg) followed by one dose of tocilizumab (8 mg/kg). Mortality of patients as our primary outcome, laboratory parameters, length of hospitalization, intensive care unit (ICU) admission requirement, and drug-related adverse events were compared between groups.

FINDINGS: The second group showed significantly better outcomes, including shorter ICU stays, lower C-reactive protein and lactate dehydrogenase levels, and higher oxygen saturation and platelet counts than the other groups. Logistic regression revealed increased risks of mortality, nosocomial infection, and adverse effects, including hepatic and renal dysfunction and gastrointestinal bleeding, in Groups B and C compared with Group A.

CONCLUSION: In all evaluated parameters, a low-dose steroid followed by tocilizumab was superior to a high-dose steroid alone or combined with tocilizumab. Although this combination treatment has been assessed worldwide, few studies have focused on its application in Iranian patients with severe COVID-19.

PMID:40432839 | PMC:PMC12105767 | DOI:10.4103/jrpp.jrpp_2_25

Orphanet J Rare Dis. 2025 May 26;20(1):251. doi: 10.1186/s13023-025-03776-3.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a rare inherited disease characterized by recurrent, potentially life-threatening angioedema. The vascular endothelium dysfunction is reported to play a role in angioedema episodes. Here, we conducted a case-control study to explore the correlation between vascular endothelium growth factor (VEGF), a representative indicator for endothelium dysfunction, and HAE as well as its attack frequency, disease control and disease severity.

METHODS: Patients with HAE and non-hereditary angioedema in their attack-free period were prospectively recruited. Demographic and disease information were collected through questionnaires. Disease control of HAE was assessed with the angioedema control test (AECT) with a recall period of three months. The current severity of HAE was comprehensively assessed through frequency of angioedema episodes, occurrence of life-threatening angioedema, necessity for hospitalization or emergency department visits. The plasma VEGF level was measured by chemiluminescence microparticle immunoassay. We compared clinical characteristics between HAE and non-hereditary angioedema patients, as well as among HAE patients with different attack frequency, disease control and disease severity. We further performed several generalized linear models (GLMs) to examine the correlation between VEGF levels and the attack frequency, disease control and disease severity of HAE.

RESULTS: We enrolled 74 patients with HAE and 55 patients with non-hereditary angioedema. HAE patients exhibited higher VEGF levels in remission than controls (112 vs. 60 ng/ml, P < 0.001). VEGF levels further increased in HAE patients with more frequent angioedema attacks, poorer disease control and greater disease severity. Results of GLMs confirmed significant correlations between plasma VEGF concentrations and the attack frequency of angioedema, disease control status and disease severity of HAE.

CONCLUSION: Circulating VEGF level elevated in patients with HAE during attack-free periods, particularly among those with greater disease burden, suggesting the involvement of vascular endothelial dysfunction in the pathogenesis of HAE. VEGF may serve as a predictive biomarker for risk stratification and disease monitoring in HAE.

PMID:40420190 | DOI:10.1186/s13023-025-03776-3