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BMJ Case Rep. 2024 Dec 5;17(12):e258833. doi: 10.1136/bcr-2023-258833.

ABSTRACT

Biotinidase deficiency, a rare metabolic disorder characterised by abnormal biotin metabolism, affects the biotin-dependent carboxylase functions. Primarily characterised by neurological and skin disorder, it may present with myriad features. Early recognition is important for preventing long-term morbidities. Here, we describe a case of a neonate presenting with seizures and a clinical picture suggestive of immunodeficiency. Multiple superficial abscesses along with septic arthritis of the left knee and left hip led to suspicion of primary immunodeficiency disorder. On evaluation, there was severe biotinidase deficiency. The neonate was supplemented with biotin, after which there were no further episodes of severe infection requiring hospitalisation, seizures or skin manifestation. This case report highlights the wide spectrum of clinical picture these disorders may present with and the low threshold for their evaluation and treatment.

PMID:39638577 | DOI:10.1136/bcr-2023-258833

Cell Rep Med. 2024 Nov 26:101846. doi: 10.1016/j.xcrm.2024.101846. Online ahead of print.

ABSTRACT

CRISPR-engineered chimeric antigen receptor (CAR) T cells are at the forefront of novel cancer treatments. However, several reports describe the occurrence of CRISPR-induced chromosomal aberrations. So far, measures to increase the genomic safety of T cell products focused mainly on the components of the CRISPR-Cas9 system and less on T cell-intrinsic features, such as their massive expansion after T cell receptor (TCR) stimulation. Here, we describe driving forces of indel formation in primary human T cells. Increased T cell activation and proliferation speed correlate with larger deletions. Editing of non-activated T cells reduces the risk of large deletions with the downside of reduced knockout efficiencies. Alternatively, the addition of the small-molecule pifithrin-α limits large deletions, chromosomal translocations, and aneuploidy in a p53-independent manner while maintaining the functionality of CRISPR-engineered T cells, including CAR T cells. Controlling T cell activation and pifithrin-α treatment are easily implementable strategies to improve the genomic integrity of CRISPR-engineered T cells.

PMID:39637860 | DOI:10.1016/j.xcrm.2024.101846

Front Immunol. 2024 Nov 20;15:1478411. doi: 10.3389/fimmu.2024.1478411. eCollection 2024.

ABSTRACT

BACKGROUND: Newborn screening (NBS) for severe combined immunodeficiency (SCID) has improved the prognosis of SCID. In Japan, NBS testing (measurement of the T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC)) was launched in 2017 and has expanded nationwide in recent years. In this study, we report a Japanese patient with X-linked SCID with a novel IL2RG variant identified through NBS. The patient underwent cord blood transplantation (CBT).

CASE: The patient had no siblings or family history of inborn errors of immunity. He was born at 38 weeks of gestation and weighed 3,072 g. His NBS results revealed TREC 0 copies/10⁵ cells (normal value: >565 copies/10⁵ cells), which was considered suggestive of SCID. The patient was referred to our hospital. Although his lymphocyte count was 1,402/μL, naïve T cells and CD56⁺ natural killer (NK) cells were decreased to 0% and 0.05% of the total lymphocytes, respectively. Flow cytometric measurement testing revealed a decrease in γc protein expression in the B lymphocytes and NK lymphocytes. We identified a hemizygous novel missense variant (c.256A>C, p.Thr86Pro) of IL2RG. Both in silico and structural analyses revealed that this variant is likely pathogenic. At 3 months of age, he underwent CBT from a human leukocyte antigen-full-matched unrelated donor. The conditioning regimen included fludarabine (180 mg/m²) and targeted busulfan (35 mg×h/L). The patient achieved high-level donor chimerism and immune reconstitution, including B-cell function, at 13 months.

CONCLUSION: Using NBS, the patient was diagnosed as having X-linked SCID with a novel missense variant of IL2RG. Early diagnosis using NBS tests enables safe hematopoietic stem cell transplantation without complications such as infection. We also found that even SCID with novel variants can be accurately diagnosed using the NBS program. In Japan, the test uptake rate is approximately 80% due to the high number of self-funded screening tests, and it is hoped that the uptake rate will increase in the future.

PMID:39635533 | PMC:PMC11614797 | DOI:10.3389/fimmu.2024.1478411

Dermatol Reports. 2023 Sep 13;16(3):9837. doi: 10.4081/dr.2024.9837. eCollection 2024 Sep 2.

NO ABSTRACT

PMID:39635573 | PMC:PMC11616579 | DOI:10.4081/dr.2024.9837

J Res Med Sci. 2024 Sep 30;29:59. doi: 10.4103/jrms.jrms_813_22. eCollection 2024.

ABSTRACT

BACKGROUND: Primary biliary cholangitis (PBC) can impact both the quality of life and the survival of patients. The study aimed to determine the survival rate and associated variables in patients with PBC.

MATERIALS AND METHODS: This cohort research comprised 65 patients diagnosed with PBC who were admitted to the pathology section between January 2010 and December 2019. Survival was determined by reviewing hospital medical data and following up with the patients. The impact of demographic factors, clinical, laboratory, and histopathological aspects on patient survival time was investigated using Kaplan-Meier survival analysis and Cox regression.

RESULTS: The average period of follow-up was 6.25 years with a standard deviation of 3.2 years. In surviving patients, the baseline bilirubin level was 2.83, but in deceased or transplanted patients, it was 8.95 (P = 0.002). The baseline albumin level was 3.99 in surviving patients and 3.66 in deceased or transplanted patients (P = 0.024). The incidence of cirrhosis in those who survived was 1.8%, but in patients who died or underwent a transplant, it was 40%. Out of 65 cases, 3 patients (4.7%) died and 7 (10%) had liver transplants. Survival rates of patients vary based on factors such as jaundice (P = 0.002), weariness (P = 0.03), cirrhosis (P < 0.001), and vitiligo (P = 0.033). There were notable variations in the average Mayo score between the two groups of patients who had liver transplantation and survived, with scores of 7.21 and 5.61, respectively.

CONCLUSION: The study found that aspartate aminotransferase and alanine aminotransferase levels, baseline and final bilirubin, albumin, antinuclear antibody, the presence of cirrhosis, and jaundice significantly influenced patient survival with PBC.

PMID:39629031 | PMC:PMC11613980 | DOI:10.4103/jrms.jrms_813_22

Semin Pediatr Neurol. 2024 Dec;52:101169. doi: 10.1016/j.spen.2024.101169. Epub 2024 Nov 19.

ABSTRACT

Ataxia telangiectasia (AT) is a rare neurocutaneous syndrome that results from biallelic pathogenic variants in the ataxia telangiectasia mutated (ATM) gene, named for its characteristic cerebellar ataxia in the early toddler years and variable oculocutaneous telangiectasias in the school age years. While its name only hints at neurologic and cutaneous manifestations, this multisystemic disorder also has important immunologic, oncologic, respiratory, and endocrinologic implications. This article will review the function of the ATM gene, the neurologic manifestations of AT, non-neurologic complications, mimickers of AT (including other disorders of defective DNA repair), and the realm of therapeutic research for AT.

PMID:39622612 | DOI:10.1016/j.spen.2024.101169

Semin Pediatr Neurol. 2024 Dec;52:101168. doi: 10.1016/j.spen.2024.101168. Epub 2024 Nov 8.

ABSTRACT

Chedíak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the Lysosomal Trafficking Regulator (LYST) gene, leading to defective lysosomal function in immune cells, melanocytes, and neurons. Clinically, CHS is characterized by a spectrum of symptoms, including immunodeficiency, partial oculocutaneous albinism, bleeding tendencies, neurodevelopmental deficits and progressive neurodegenerative symptoms. The severity of CHS correlates with the type of LYST mutation: the classic form, linked to nonsense or frameshift mutations, presents early in childhood with severe immune dysfunction, recurrent infections, and a high risk of hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory state. Without timely treatment, including hematopoietic stem cell transplantation (HSCT), prognosis is poor, with high mortality in early life. Atypical forms, associated with missense mutations, manifest later with milder immunologic symptoms but inevitably progress to neurological impairment, including cognitive decline and motor dysfunction. Diagnosing CHS is complex due to its rarity, phenotypic variability, and overlap with other disorders. A thorough approach, incorporating clinical evaluation, peripheral blood smear for giant granules in leukocytes, and genetic testing for LYST mutations, is crucial for accurate diagnosis. Management of CHS requires a multidisciplinary approach, focusing on HSCT for immunologic and hematologic stabilization and symptomatic and supportive care for neurological symptoms. Even those patients who undergo stabilizing HSCT eventually develop neurological difficulties. This review provides an in-depth exploration of CHS, covering its epidemiology, clinical presentation, molecular genetics, diagnostic challenges, and current management strategies, while emphasizing the necessity of a comprehensive, multidisciplinary approach to improve patient outcomes.

PMID:39622608 | DOI:10.1016/j.spen.2024.101168

J Allergy Clin Immunol. 2024 Nov 30:S0091-6749(24)01282-X. doi: 10.1016/j.jaci.2024.11.030. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEIs) are more than 500 different rare congenital disorders of the immune system characterized by susceptibility to infections and immune dysregulation. The significant overlap of the clinical features among the different forms may lead to diagnostic delay. High throughput sequencing techniques may allow a timely genetic definition. Guidelines for the use and the interpretation of genetic testing produced by the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) do not cover specificities for the application to IEIs.

OBJECTIVE: The aim of this consensus study is to define the best approach to genetic testing for IEIs.

METHODS: A panel of experts in the context of the Italian Primary Immunodeficiency Network (IPINet) composed a list of statements that were evaluated using Delphi method.

RESULTS: The experts recommend that genetic testing for IEIs should be offered to selected patients with warning signs for IEIs and highlight the crucial role of thorough phenotyping and functional tests for the conclusive diagnosis of IEI. Comprehensive educational programs targeted to health care professionals and the public should be developed to increase IEIs awareness and reduce the diagnostic delay. Ethical issues should be pondered over the diagnostic advantages of genetic tests requested for diagnostic purposes.

CONCLUSION: Adherence to the guidelines on the use and interpretation of genetic testing for the diagnosis of IEIs should help limiting the inappropriate use of these techniques and reduce the risk of misdiagnosis and apprehension for inconclusive genetic results.

PMID:39622296 | DOI:10.1016/j.jaci.2024.11.030

J Allergy Clin Immunol. 2024 Nov 30:S0091-6749(24)01283-1. doi: 10.1016/j.jaci.2024.11.031. Online ahead of print.

ABSTRACT

BACKGROUND: CD4⁺ T cells play essential roles in adaptive immunity. Distinct CD4⁺ T cell subsets – Th1, Th2, Th17, Th22, T follicular helper and regulatory T cells – have been identified and their contributions to host defence and immune regulation are increasingly well-defined. IL-9 producing Th9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human Th9 cells remain incompletely defined.

OBJECTIVE: Define signalling pathways that regulate IL-9 production by human CD4⁺ T cells.

METHODS: Human naive and memory CD4⁺ T cells were cultured under different conditions and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4⁺ T cells from a broad range of patients (n=92) with pathogenic variants in key immune genes (n=21) to differentiate into IL-9⁺ cells.

RESULTS: We identified two culture conditions that yielded IL-9-expressing cells from naïve CD4⁺ T cells, and amplified IL-9 production by in vivo-generated memory CD4⁺ T cells: TGFβ plus IL-4 (i.e. Th9 polarising condition), and the combination of IL-21, IL-23, IL-6, IL-1β and TGFβ (i.e. Th17 polarising condition). Combining these conditions had a synergistic effect in generating IL-9⁺CD4⁺ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signalling via the TCR and STAT5. Importantly, IL-9 induction was restrained by IFNγ/STAT1 and IL-10.

CONCLUSIONS: Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4⁺ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.

PMID:39622295 | DOI:10.1016/j.jaci.2024.11.031

Vox Sang. 2024 Dec 1. doi: 10.1111/vox.13769. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Intravenous polyvalent immunoglobulins (IVIG) for prophylaxis in patients with primary immunodeficiency disorders (PIDs) exposes them to life-threatening infections and debilitating diseases. To improve access to IVIG in lower middle-income countries, the WHO recommends a stepwise approach for the local production of purified and virus-inactivated plasma immunoglobulins by national blood transfusion services using new technologies and medical devices. One new technology relies on single-use sterile medical devices for the purification of plasma immunoglobulin G (IgG), as well as lipid-enveloped virus inactivation from mini-pools of recovered plasma separated from whole blood (mini-pool IVIG [MP-IVIG]). This study aimed to compare the safety and efficacy of MP-IVIG to standard IVIG (STD-IVIG).

MATERIALS AND METHODS: In this prospective crossover clinical study, we investigated the safety and efficacy of MP-IVIG for STD-IVIG preparations as a replacement therapy in a cohort of 21 paediatric patients with PID.

RESULTS: Both MP-IVIG and STD-IVIG were effective in reducing the frequency of severe bacterial infections and hospital admissions in patients with PID. Mild side effects have been observed in seven patients (6.2%) with PID who received MP-IVIG and five patients (5.3%) who received STD-IVIG. No moderate or severe side effects or haemolytic transfusion reactions were reported. The mortality rates were also comparable and were not related to the study products.

CONCLUSION: MP-IVIG presented no safety issues and was as effective as STD-IVIG in IgG replacement in patients with PID. Due to the small numbers, the results have to be addressed with caution.

PMID:39617397 | DOI:10.1111/vox.13769