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Iran J Allergy Asthma Immunol. 2023 Oct 29;22(5):504-509. doi: 10.18502/ijaai.v22i5.13999.

ABSTRACT

Most patients with X-linked agammaglobulinemia are susceptible to infections, while some cases also suffer from inflammatory or autoimmune complications. We describe a patient with progressive encephalitis who improved after the use of immunomodulatory treatment with corticosteroids, fluoxetine, and nitazoxanide. In most of the cases the evolution of the progressive encephalitis is complicated and catastrophic. Based on our experience and the review of the literature, we propose the use of this combined treatment to control this devastating complication.

PMID:38085151 | DOI:10.18502/ijaai.v22i5.13999

BMC Med Genomics. 2023 Dec 11;16(1):323. doi: 10.1186/s12920-023-01765-8.

ABSTRACT

BACKGROUND: Severe combined immunodeficiency (SCID) is a group of fatal primary immunodeficiencies characterized by the severe impairment of T-cell differentiation. IL7R deficiency is a rare form of SCID that usually presents in the first months of life with severe and opportunistic infections, failure to thrive, and a high risk of mortality unless treated. Although recent improvements in early diagnosis have been achieved through newborn screening, few IL7R-related SCID patients had been reported in the Chinese population.

CASE PRESENTATION: Here, we retrospectively analyzed a case of SCID in a 5-month-old girl with symptoms, including severe T-cell depletion, recurrent fever, oral ulcers, pneumonia, hepatosplenomegaly, bone marrow hemophagocytosis, and bacterial and viral infections. Whole-exome sequencing (WES), quantitative PCR (qPCR), and chromosome microarray analysis (CMA) were performed to identify the patient’s genetic etiology. We identified a 268 kb deletion and a splicing variant, c.221 + 1G > A, in the proband. These two variants of IL7R were inherited from the father and mother.

CONCLUSIONS: To our knowledge, this is the first report of whole IL7R gene deletion in combination with a pathogenic splicing variant in a patient with SCID. This deletion also expands the pathogenic variation spectrum of SCID caused by IL7R. The incorporation of exome-based copy number variant analysis makes WES a powerful molecular diagnostic technique for the clinical diagnosis of pediatric patients.

PMID:38082310 | DOI:10.1186/s12920-023-01765-8

Front Immunol. 2023 Nov 23;14:1271324. doi: 10.3389/fimmu.2023.1271324. eCollection 2023.

ABSTRACT

Germline HAVCR2 mutation has been reported to be associated with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) leading to Hemophagocytic lymphohistiocytosis (HLH). Several studies have indicated that HAVCR2 mutation can cause HLH even in the absence of lymphoma, though the exact mechanism remains unclear. In this article, we reported five cases of HAVCR2 mutation-associated HLH. Our analysis revealed an elevated level of IL-1RA in the serum of these patients. Furthermore, we investigated the potential mechanisms underlying HLH associated with HAVCR2 mutation based on changes in cytokine levels. Our findings suggest that HAVCR2 mutation may represent a distinct genetic defect underlying HLH, differing from traditional primary HLH.

PMID:38077348 | PMC:PMC10701531 | DOI:10.3389/fimmu.2023.1271324

J Allergy Clin Immunol. 2023 Dec 8:S0091-6749(23)02411-9. doi: 10.1016/j.jaci.2023.11.914. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) often lack specific disease models and personalized management. Signal transducer and activator of transcription (STAT)-1 gain-of-function (GoF) is such example of an IEI with diverse clinical phenotype with unclear pathomechanisms and unpredictable response to therapy. Limitations in obtaining fresh samples for functional testing and research further highlights the need for patient-specific ex-vivo platforms.

OBJECTIVE: Using STAT1-GoF as an example IEI, we investigated the potential of patient-derived expanded potential stem cells (EPSC) as an ex-vivo platform for disease modelling and personalized treatment.

METHODS: We generated EPSC derived from individual STAT1-GoF patients. STAT1 mutations were confirmed with Sanger sequencing. Functional testing including STAT1 phosphorylation/dephosphorylation and gene expression with or without Janus-kinase inhibitors (JAKi) were performed. Functional tests were repeated on EPSC lines with GoF mutations repaired by CRISPR/Cas9 editing.

RESULTS: EPSC were successfully reprogrammed from STAT1-GoF patients and expressed the same pluripotent makers as controls, with distinct morphological differences. Patient-derived EPSC recapitulated the functional abnormalities of index STAT1-GoF patients with STAT1 hyperphosphorylation and increased expression of STAT1 and its downstream genes (IRF1, APOL6, and OAS1) following IFNγ stimulation. Addition of ruxolitinib and baricitinib inhibited STAT1 hyperactivation in STAT1-GoF EPSC in a dose-dependent manner, which was not observed with tofacitinib. Corrected STAT1 phosphorylation and downstream gene expression were observed among repaired STAT1-GoF EPSC cell lines.

CONCLUSION: This proof-of-concept study demonstrates the potential of our patient-derived EPSC platform toward modelling STAT1-GoF. We propose this platform toward researching, recapitulating and repairing other IEI in the future.

PMID:38072195 | DOI:10.1016/j.jaci.2023.11.914

J Autoimmun. 2023 Dec 9;142:103152. doi: 10.1016/j.jaut.2023.103152. Online ahead of print.

ABSTRACT

Anti-nuclear antibodies are the hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma. However, the molecular mechanisms of B cell tolerance breakdown in these pathological contexts are poorly known. The study of rare familial forms of autoimmune diseases could therefore help to better describe common biological mechanisms leading to B cell tolerance breakdown. By Whole-Exome Sequencing, we identified a new heterozygous mutation (p.R594C) in ERN1 gene, encoding IRE1α (Inositol-Requiring Enzyme 1α), in a multiplex family with several members presenting autoantibody-mediated autoimmunity. Using human cell lines and a knock-in (KI) transgenic mouse model, we showed that this mutation led to a profound defect of IRE1α ribonuclease activity on X-Box Binding Protein 1 (XBP1) splicing. The KI mice developed a broad panel of autoantibodies, however in a subclinical manner. These results suggest that a decrease of spliced form of XBP1 (XBP1s) production could contribute to B cell tolerance breakdown and give new insights into the function of IRE1α which are important to consider for the development of IRE1α targeting strategies.

PMID:38071801 | DOI:10.1016/j.jaut.2023.103152

Immunol Rev. 2023 Dec 8. doi: 10.1111/imr.13295. Online ahead of print.

ABSTRACT

Fungi are opportunists: They particularly require a defect of immunity to cause severe or disseminated disease. While often secondary to an apparent iatrogenic cause, fungal diseases do occur in the absence of one, albeit infrequently. These rare cases may be due to an underlying genetic immunodeficiency that can present variably in age of onset, severity, or other infections, and in the absence of a family history of disease. They may also be due to anti-cytokine autoantibodies. This review provides a background on how human genetics or autoantibodies underlie cases of susceptibility to severe or disseminated fungal disease. Subsequently, the lessons learned from these inborn errors of immunity marked by fungal disease (IEI-FD) provide a framework to begin to mechanistically decipher fungal syndromes, potentially paving the way for precision therapy of the mycoses.

PMID:38069482 | DOI:10.1111/imr.13295

J Clin Med. 2023 Dec 3;12(23):7480. doi: 10.3390/jcm12237480.

ABSTRACT

Inborn errors of immunity (IEIs) are a heterogeneous group of diverse clinical and genetic phenotypes that have an estimated combined prevalence as high as 1/1000. Increased risk of frequent, severe, or opportunistic infections is a common feature of IEIs, but there are also diverse immune-mediated, non-infective complications that are associated with significant morbidity and mortality. As patient survival increases, these are becoming more apparent within the liver. Hepatic involvement of IEIs may not only manifest as infections, but also nodular regenerative hyperplasia, granulomatous disease, autoimmune hepatitis and malignancy. As therapeutic options for patients are expanding, with both pharmaceutical treatments as well as haematopoietic stem cell transplant (HSCT), iatrogenic liver injury is increasingly common and important to identify. This review article summarises the spectrum of hepatic complications seen in IEIs, and highlights the challenges of management within this patient cohort, where immunosuppression is poorly tolerated. Early recognition and prompt diagnosis of potential hepatic complications is therefore crucial in ensuring potentially reversible causes are treated, but significant uncertainty remains regarding best practice for many features of immune dysregulation with limited high-quality evidence.

PMID:38068532 | DOI:10.3390/jcm12237480

Cureus. 2023 Nov 3;15(11):e48222. doi: 10.7759/cureus.48222. eCollection 2023 Nov.

ABSTRACT

Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic syndrome characterized by new-onset refractory status epilepticus preceded by a febrile illness. Limited literature exists regarding the relationship between primary immunodeficiencies and immune-mediated epilepsy, and the relationship between new-onset refractory status epilepticus and common variable immunodeficiency (CVID) is not well-understood. We present a case of a 21-year-old female with a history of recurrent sinus infections, asthma, thrombocytopenia, atrioventricular nodal reentrant tachycardia, and neonatal seizures who presented with fever and new-onset status epilepticus. She was ultimately diagnosed with a heterozygous variant in TNFRSF13B c.311G>A (p.Cys104Tyr), which encodes for a tumor necrosis factor receptor implicated in CVID.

PMID:38054159 | PMC:PMC10694393 | DOI:10.7759/cureus.48222

Clin Immunol. 2023 Dec 3:109858. doi: 10.1016/j.clim.2023.109858. Online ahead of print.

ABSTRACT

BACKGROUND: We investigated two brothers who presented with repeated lung infections after 6 months of age. Lymphocytes and neutrophils were significantly decreased, and both had bronchiectasis and emphysema.

OBJECTIVE: We sought to characterize the complete picture of lung injury in some types of primary immunodeficiency disease, followed by verification and analysis.

METHODS: We performed immune function determination, a complete examination of the respiratory system, genetic analysis, and literature research.

RESULTS: The levels of lymphocytes, neutrophils, monocytes, and natural killer cells in the brothers were significantly decreased. The IgM and IgG levels of the older brother were decreased, while the IgM and IgA levels of the younger brother were decreased. Both brothers had bronchial wall erosion with a worm-eaten appearance and decreased lung function. Genetic testing revealed a hemizygous missense mutation (c.511C > T:p.R171W) in exon 5 of the MSN gene, which was inherited from the mother. A literature review showed that the primary immunodeficiency caused by MSN gene mutations is an X-linked recessive genetic disease with four known gene mutation sites, including nonsense and missense mutations. Nonsense mutations result in a higher incidence of autoimmune diseases and a lower degree of immune function impairment. Nonsense mutations closer to the front of the MSN gene may cause more severe disease. Neonatal disease screening can improve the early diagnosis rate, but hematopoietic stem cell transplantation (HSCT) treatment is controversial.

CONCLUSION: The primary immunodeficiency disease caused by MSN gene mutation is an X-linked recessive genetic disease that involves structural and functional damage to the respiratory system, and the worm-eaten appearance of the bronchial wall under endoscopy may be a relatively specific sign. The general manifestations of this disease are recurrent infections from 1 month to 6 months after birth, significantly reduced counts of lymphocytes and neutrophils, and decreased cellular and humoral immune function. Different types of MSN gene mutations and nonsense mutations at different sites have different clinical phenotypes. This study enriches the known spectrum of this disease.

PMID:38052292 | DOI:10.1016/j.clim.2023.109858

Vox Sang. 2023 Dec 5. doi: 10.1111/vox.13555. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Plasma-derived medicinal products (PDMPs) are essential to treat many chronic conditions such as haemophilia and primary immunodeficiency. Patients living in low middle-income and low-income countries (LMICs and LICs, respectively) have limited access to PDMPs. The aim of this article is to explore the challenges of accessing PDMPs in LMICs and LICs.

MATERIALS AND METHODS: A review of the literature and reports on blood safety, plasma production and its utilization to produce PDMPs in LMICs and LICs was carried out.

RESULTS: There is huge wastage of recovered plasma in LMICs and LICs as a result of a lack of good manufacturing practice (GMP) in the production of plasma for fractionation. Together with the high cost of imported PDMP procurement, patients have limited access to such products.

CONCLUSION: There is a need to improve the situation by using domestically sourced plasma through the initiation of local plasma programmes through a stepwise approach to improve access to PDMPs in LMICs and LICs.

PMID:38050721 | DOI:10.1111/vox.13555