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Zhonghua Bing Li Xue Za Zhi. 2025 Feb 8;54(2):203-209. doi: 10.3760/cma.j.cn112151-20241209-00838.

ABSTRACT

极早发炎症性肠病是6岁之前儿童发生的具有炎症性肠病样症状的一组疾病，包括真正的炎症性肠病和单基因炎症性肠病（mIBD），后者涉及多种与原发免疫缺陷相关基因。极早发炎症性肠病，包括mIBD，病理组织学表现多样，临床表现及临床治疗反应均存在不同。本文总结了近年认识的常见mIBD和极早发炎症性肠病的病理诊断进展。.

PMID:39863544 | DOI:10.3760/cma.j.cn112151-20241209-00838

J Clin Med. 2025 Jan 14;14(2):497. doi: 10.3390/jcm14020497.

ABSTRACT

Background/Objectives: Gastrointestinal diseases are a major cause of morbidity in common variable immunodeficiency disorder (CVID), clinically often mimicking other conditions including celiac disease and inflammatory bowel disease (IBD). Hence, diagnosis of CVID remains challenging. This study aims to raise awareness and highlight histopathological clues for CVID in intestinal biopsies, emphasizing diagnostic pitfalls for the pathologist/gastroenterologist. Methods: We reviewed 63 (18 duodenal, 23 ileal, 22 colonic) biopsies and case histories from seven CVID patients, obtained over a 31-year period, with attention to active inflammation, intraepithelial lymphocytes, plasma cells, lymphoid hyperplasia, crypt/villous architecture, subepithelial collagen, apoptosis, granulomas, and infections. Clinical information of 41 pathology requests was reviewed. Results: Gastrointestinal symptoms were variable. Histological features included IBD-like (3/7), celiac disease-like (2/7), graft-versus-host disease (GVHD)-like (2/7), lymphocytic sprue/colitis-like (3/7), collagenous colitis-like (2/7), and acute colitis-like (4/7) patterns, often overlapping (2/7) and/or changing over time (3/7). Lymphoid hyperplasia was seen in 3/7 patients; 1/7 had giardiasis; and 5/7 had few plasma cells, usually only in part of the gut (3/5). Clinical information of 12/41 (29%) pathology requests mentioned known/suspected CVID, despite being known in 33/41 (80%). Conclusions: Clinical/histological features of CVID in the gut are diverse, often mimicking IBD, microscopic colitis, celiac disease and/or GVHD, hence the importance of adequate clinical information. Some histological features are atypical of these established entities and may indicate CVID, as may overlapping/changing histological patterns and/or few plasma cells in part of the gut. Awareness of the heterogenous clinical presentation and histopathological indicators of CVID may improve diagnosis.

PMID:39860504 | DOI:10.3390/jcm14020497

J Clin Med. 2025 Jan 9;14(2):363. doi: 10.3390/jcm14020363.

ABSTRACT

Background/Objectives: The nuclear factor (NF)-kB essential modulator (NEMO) has a crucial role in the NFκB pathway. Hypomorphic IKBKG pathogenic variants cause ectodermal dysplasia with immunodeficiency (EDA-ID) in affected males. However, heterozygous amorphic IKBKG variants could be responsible for Incontinentia Pigmenti (IP) in female carriers. Typically, IP patients do not exhibit immunodeficiency, although hypomorphic variants might lead to immunodeficiency in female IP patients. Here, we report the case of an IKBKG female carrier, with no IP but an unexpected picture of immunodeficiency. She had a positive family history for the same genetic condition. Methods: We performed immunological, molecular, and functional analysis to evaluate NEMO contribution. Results: The patient was healthy until the age of 25 when severe asthma and Hashimoto thyroiditis occurred. She had HLAB27-positive ankylosing spondylitis, non-tubercular mycobacteriosis, and pulmonary aspergillosis infections. We found CD19+ B cell lymphopenia and T cell subset alterations. Sanger sequencing revealed a heterozygous IKBKG variant at position +1 of the 5′ UTR of the gene which disrupted the normal pre-mRNA splicing. We observed a decreased NEMO protein expression, a reduced level of mRNA, and a defective NF-κB pathway. Conclusions: These findings suggest a possible correlation between the partial loss of NEMO function and the immunodeficiency observed in this patient. This case could expand our understanding of NEMO deficiency in female carriers.

PMID:39860371 | DOI:10.3390/jcm14020363

Genes (Basel). 2024 Dec 26;16(1):18. doi: 10.3390/genes16010018.

ABSTRACT

Background: The advent of next-generation sequencing (NGS) has revolutionized the analysis of genetic data, enabling rapid identification of pathogenic variants in patients with inborn errors of immunity (IEI). Sometimes, the use of NGS-based technologies is associated with challenges in the evaluation of the clinical significance of novel genetic variants. Methods: In silico prediction tools, such as SpliceAI neural network, are often used as a first-tier approach for the primary examination of genetic variants of uncertain clinical significance. Such tools allow us to parse through genetic data and emphasize potential splice-altering variants. Further variant assessment requires precise RNA assessment by agarose gel electrophoresis and/or cDNA Sanger sequencing. Results: We found two novel heterozygous variants in the coding region of the LYST gene (c.10104G>T, c.10894A>G) in an individual with a typical clinical presentation of Chediak-Higashi syndrome (CHS). The SpliceAI neural network predicted both variants as probably splice-altering. cDNA assessment by agarose gel electrophoresis revealed the presence of abnormally shortened splicing products in each variant’s case, and cDNA Sanger sequencing demonstrated that c.10104G>T and c.10894A>G substitutions resulted in a shortening of the 44 and 49 exons by 41 and 47 bp, respectively. Both mutations probably lead to a frameshift and the formation of a premature termination codon. This, in turn, may disrupt the structure and/or function of the LYST protein. Conclusions: We identified two novel variants in the LYST gene, predicted to be deleterious by the SpliceAI neural network. Agarose gel cDNA electrophoresis and cDNA Sanger sequencing allowed us to verify inappropriate splicing patterns and establish these variants as disease-causing.

PMID:39858566 | DOI:10.3390/genes16010018

J Clin Immunol. 2025 Jan 24;45(1):67. doi: 10.1007/s10875-025-01857-3.

ABSTRACT

BACKGROUND: Ataxia telangiectasia mutated (ATM) kinase plays a critical role in DNA double-strand break (DSB) repair. Ataxia telangiectasia (A-T) patients exhibit abnormalities in immunoglobulin isotype expression and class switch recombination (CSR). This study investigates the role of residual ATM kinase expression and activity in the severity of A-T disease.

METHODS: A-T patients with defined genetic diagnoses were classified based on CSR and based on the severity of their medical complications. Isolated peripheral blood mononuclear cells from any patient were evaluated before and after exposure to 0.5 Gy ionizing radiation for one minute. Western blotting was performed to identify the expression of ATM and phosphorylated ATM (p-ATM) proteins compared to age-sex-matched healthy controls.

RESULTS: In severe A-T patients (n = 6), the majority (66.7%) had frameshift mutations, while 33.3% had nonsense mutations in the ATM gene. The mild group (n = 3) had two cases of splice errors and one missense mutation. All patients with CSR defect had elevated IgM serum levels, whereas all switched immunoglobulins were reduced in them. Expression of ATM and p-ATM proteins was significantly lower (p = 0.01) in all patients compared to healthy controls, both pre-and post- and post-radiation. Additionally, low ATM and p-ATM protein expression levels were linked with the clinical severity of patients but were not correlated with CSR defects.

CONCLUSION: Expression and activation of ATM protein were defective in A-T patients compared to healthy controls. Altered expression of ATM and p-ATM proteins may have potential clinical implications for prognostic evaluation and symptom severity assessment in individuals with A-T.

PMID:39853455 | DOI:10.1007/s10875-025-01857-3

Vet Sci. 2025 Jan 9;12(1):35. doi: 10.3390/vetsci12010035.

ABSTRACT

The primary aim of this study was to determine the accuracy of saliva as a proxy for blood in cats using Anigen Rapid^® FIV point-of-care (PoC) kits and as an easy collection technique applicable for all veterinary clinics and shelters. A secondary aim was to report FIV prevalence in various Australian states/territories and key cat risk factors associated with FIV infection. In total, 382 cats were recruited from patients presenting to private, shelter and teaching hospital veterinary clinics in Australia. Information collected for each cat included age, sex, neuter status, postcode, and health status (‘healthy’ versus ‘sick’). The traditional blood testing technique with Anigen Rapid^® was used to determine the FIV status of cats. Comparative saliva testing found 48/382 (12.5%) cats were FIV-positive. Test sensitivity for Anigen Rapid^® FIV using saliva was 84.2% (48/57; 95% CI 80.6 to 87.9). Test specificity for Anigen Rapid^® FIV using saliva was 100% (325/325). The two significant cat risk factors for FIV infection were sex (male) and health status (sick). In terms of demographic information, prevalence in Tasmania and the Northen Territory was reported for the first time. This study proves the ability to utilise cheap and readily available consumables for less invasive FIV testing purposes by using saliva instead of blood, for example, when screening cat before adoption in shelters and in cats prior to annual FIV re-vaccination.

PMID:39852909 | DOI:10.3390/vetsci12010035

Zool Res. 2025 Jan 18;46(1):249-260. doi: 10.24272/j.issn.2095-8137.2024.195.

ABSTRACT

Severe combined immunodeficiency disease (SCID), characterized by profound immune system dysfunction, can lead to life-threatening infections and death. Animal models play a pivotal role in elucidating biological processes and advancing therapeutic strategies. Recent advances in gene-editing technologies, including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), CRISPR/Cas9, and base editing, have significantly enhanced the generation of SCID models. These models have not only deepened our understanding of disease pathophysiology but have also driven progress in cancer therapy, stem cell transplantation, organ transplantation, and infectious disease management. This review provides a comprehensive overview of current SCID models generated using novel gene-editing approaches, highlighting their potential applications in translational medicine and their role in advancing biomedical research.

PMID:39846200 | DOI:10.24272/j.issn.2095-8137.2024.195

Fetal Pediatr Pathol. 2025 Jan 23:1-7. doi: 10.1080/15513815.2025.2449948. Online ahead of print.

ABSTRACT

Background:Pseudomonas aeruginosa (PA), a gram-negative bacillus, has varied clinical manifestations with septicemia as the most lethal. PA infection is usually regarded as opportunistic and often nosocomial. Case Presentation: We present a case of a “healthy” pediatric patient presenting with upper respiratory symptoms who rapidly deteriorated. Blood cultures grew Pseudomonas aeruginosa shortly after death. The postmortem examination revealed Pseudomonal vasculopathy of the central nervous system and genetic testing detected an autosomal recessive pathogenic variant in IRAK-4. Discussion: Community-acquired Pseudomonal sepsis in previously healthy children is rare. Studies have found that up to 20% of children presenting with sepsis have an underlying immune defect. Deficiency of IRAK-4 predisposes patients to recurrent, life-threatening, microbial infections, notably Streptococcus pneumoniae, Staphylococcus aureus, and PA. Conclusion: A primary immunodeficiency should be suspected in a “healthy” child presenting with sepsis by an unexpected bacterium as the clinical consequences may be severe and the findings may have reproductive implications for the parents.

PMID:39846126 | DOI:10.1080/15513815.2025.2449948

Front Immunol. 2025 Jan 8;15:1475448. doi: 10.3389/fimmu.2024.1475448. eCollection 2024.

ABSTRACT

BACKGROUND: With recent advances in clinical practice, including the use of reduced-toxicity conditioning regimens and innovative approaches such as ex vivo TCRαβ/CD19 depletion of haploidentical donor stem cells or post-transplant cyclophosphamide (PTCY), hematopoietic stem cell transplantation (HSCT) has emerged as a curative treatment option for a growing population of patients with inborn errors of immunity (IEI). However, despite these promising developments, graft failure (GF) remains a significant concern associated with HSCT in these patients. Although a second HSCT is the only established salvage therapy for patients who experience GF, there are no uniform, standardized strategies for performing these second transplants. Furthermore, even less data is available regarding the outcomes and best practices for a third HSCT as a salvage measure when a second HSCT fails to achieve engraftment.

CASE PRESENTATION: A 6-year-old boy with leukocyte adhesion deficiency type I (LAD-I) experienced GF after the first and second HSCT from a matched unrelated donor. As a salvage measure, the patient received a dual in vivo T-cell depleted haploidentical HSCT. The conditioning regimen for this third HSCT included anti-thymocyte globulin (ATG) and PTCY. Complete donor chimerism was assessed using the short tandem repeat (STR) PCR technique. By day +28 after the transplant, the expression of the leukocyte adhesion molecules CD18, CD11b, and CD11c on the patient’s peripheral blood neutrophils had recovered to over 99%. It remained stable throughout the 18-month follow-up period.

CONCLUSION: T-cell replete haploidentical HSCT with ATG and PTCY may be a viable salvage option for LAD patients who have rejected prior HSCT.

PMID:39845947 | PMC:PMC11751042 | DOI:10.3389/fimmu.2024.1475448

Biomedica. 2024 Dec 23;44(Sp. 2):51-62. doi: 10.7705/biomedica.7398.

ABSTRACT

INTRODUCTION: Predominant antibody deficiency is the most frequent group of innate immunity errors, but information about patients’ nutritional status is scarce.

OBJECTIVES: To characterize the nutritional status of Colombian patients with predominant antibody deficiencies.

MATERIAL AND METHODS: Material and methods. We analyzed medical charts of patients with predominant antibody deficiency in a pediatric hospital in Bogotá.

RESULTS: We analyzed 55 medical charts. The most frequent diagnoses were specific deficiencies of polysaccharide antibodies and immunoglobulin A, common variable immunodeficiency, and agammaglobulinemia. More than 70% of the patients had sinopulmonary infections, with pneumonia being the most frequent, followed by otitis and sinusitis. In children under five years, 45% had adequate weight for their height, 18% had a risk of malnutrition, and 18% had moderate acute malnutrition. Four-point-five percent had obesity, 4.5% showed overweight, and 9% had a risk of being overweight. Of those older than five years, 54% had an adequate body mass index, 22.5% showed overweight, 9.6% were at risk of thinness, and 9.6% were thin. We found that the risk of short stature and short stature per se were more frequent than the expected height in these patients. The percentages of patients with short stature were higher than those reported nationally.

CONCLUSIONS: Due to the epidemic of childhood obesity, it will be more frequent to find overweight or obesity in children above five years. Therefore, finding short stature could be a more sensitive alarm sign for predominant antibody deficiency.

PMID:39836854 | DOI:10.7705/biomedica.7398