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Lancet. 2024 Jan 23:S0140-6736(23)02358-9. doi: 10.1016/S0140-6736(23)02358-9. Online ahead of print.

ABSTRACT

BACKGROUND: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5.

METHODS: This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting.

FINDINGS: 11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab.

INTERPRETATION: Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab.

FUNDING: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

PMID:38278170 | DOI:10.1016/S0140-6736(23)02358-9

Microbiol Spectr. 2024 Jan 26:e0324423. doi: 10.1128/spectrum.03244-23. Online ahead of print.

ABSTRACT

This study aims to summarize the clinical characteristics and prognosis of Listeria monocytogenes (LM) meningitis in children in Chongqing, China. A retrospective analysis of the clinical data and follow-up results of 20 LM meningitis patients admitted to the Children’s Hospital of Chongqing Medical University (CHCMU) from January 2012 to December 2022 was performed. The LM meningitis incidence rate was between 0 and 14.3 per 100,000 persons. The median age at onset was 8.98 months. There were five neonate cases, which all had perinatal abnormalities. Seven non-neonatal cases (7/15, 46.7%) had a documented history of contaminated food intake. One case had primary immunodeficiency. The most common symptoms were fever (20/20), altered consciousness (19/20), and vomiting (15/20). Seven cases had seizures, eight cases had cranial nerve involvement, eight cases had positive Babinski sign, and 10 cases had positive meningeal signs. The most common complications were hyponatremia (6/20), hypokalemia (6/20), respiratory failure (5/20), subdural effusion (3/20), and hydrocephalus (2/20). Treatment primarily involved monotherapy or combination therapy with meropenem (15/20) and ampicillin (10/20). Fifteen cases were treated with monotherapy or combination therapy using vancomycin. Twelve cases were successfully followed up from 10 months to 9 years and 6 months, and all had favorable long-term outcomes. LM meningitis incidence in children is low and with nonspecific clinical manifestations. Strengthening food hygiene and safety education, and avoiding infections during pregnancy are important to prevent LM infection in neonates and high-risk individuals. Meropenem and ampicillin are the preferred treatments. Early diagnosis and treatment can improve prognosis.IMPORTANCEThe incidence of LM meningitis is extremely low, and there is currently no standardized treatment. We conducted a retrospective analysis of ten years of data from CHCMU regarding diagnosed LM meningitis cases, aiming to provide clinical evidence for the diagnosis and treatment.

PMID:38275295 | DOI:10.1128/spectrum.03244-23

Rev Mal Respir. 2024 Jan 24:S0761-8425(24)00002-0. doi: 10.1016/j.rmr.2024.01.002. Online ahead of print.

ABSTRACT

Chronic Granulomatosis Disease (CGD) is an inherited immune deficiency due to a mutation in the genes coding for the subunits of the NADPH oxidase enzyme that affects the oxidative capacity of phagocytic cells. It is characterized by increased susceptibility to bacterial and fungal infections, particularly Aspergillus, as well as complications associated with hyperinflammation and granulomatous tissue infiltration. There exist two types of frequently encountered pulmonary manifestations: (1) due to their being initially pauci-symptomatic, possibly life-threatening infectious complications are often discovered at a late stage. Though their incidence has decreased through systematic anti-bacterial and anti-fungal prophylaxis, they remain a major cause of morbidity and mortality; (2) inflammatory complications consist in persistent granulomatous mass or interstitial pneumoniae, eventually requiring immunosuppressive treatment. Pulmonary complications recurring since infancy generate parenchymal and bronchial sequelae that impact functional prognosis. Hematopoietic stem cell allograft is a curative treatment; it is arguably life-sustaining and may limit the morbidity of the disease. As a result of improved pediatric management, life expectancy has increased dramatically. That said, new challenges have appeared with regard to adults: difficulties of compliance, increased inflammatory manifestations, acquired resistance to anti-infectious therapies. These different developments underscore the importance of the transition period and the need for multidisciplinary management.

PMID:38272769 | DOI:10.1016/j.rmr.2024.01.002

J Clin Immunol. 2024 Jan 25;44(2):55. doi: 10.1007/s10875-024-01658-0.

ABSTRACT

A homozygous missense mutation in the transferrin receptor 1 (TfR1), also known as CD71, leads to a rare inborn error of immunity (IEI) characterized by the impaired lymphocyte activation and proliferation due to defective iron uptake of cells. However, only one causative mutation (c.58T > C, p.Y20H) in the TFRC gene coding for TfR1 has been reported so far. We herein identified a new disease-causing homozygous germline mutation in the TFRC gene (c.64C > T, p.R22W) (referred to as TfR1^R22W from now on) in a Turkish patient with combined immunodeficiency (CID). TfR1^R22W results in impaired TfR1 internalization similar to previously defined TfR1^Y20H mutation. We found that TfR1^R22W is associated with severely restricted B and T lymphocyte clonal diversity and impaired T cell activation and cytokine production as well as defective mitochondrial oxidative phosphorylation in helper T cells. In addition, circulating NK, Treg, and MAIT cell populations were significantly decreased in the patient. Using whole transcriptome analysis, we found dysregulated immune homeostasis and novel biological processes associated with TfR1^R22W. We also identified a considerable expansion of circulating low-density neutrophils (LDNs) in patient’s PBMCs. Overall, TfR1^R22W mutation expands the current understanding of the IEI associated with TfR1 dysfunction and provides new insights underlying impaired immune function, lymphocyte diversity, and granulocyte homeostasis.

PMID:38270687 | PMC:PMC10811203 | DOI:10.1007/s10875-024-01658-0

Genes Immun. 2024 Jan 24. doi: 10.1038/s41435-024-00255-w. Online ahead of print.

ABSTRACT

Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti β2 glycoprotein1 autoantibodies. We performed whole exome sequencing. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.

PMID:38267542 | DOI:10.1038/s41435-024-00255-w

J Clin Immunol. 2024 Jan 24;44(2):54. doi: 10.1007/s10875-024-01659-z.

ABSTRACT

The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.

PMID:38265673 | DOI:10.1007/s10875-024-01659-z

Front Immunol. 2024 Jan 8;14:1278759. doi: 10.3389/fimmu.2023.1278759. eCollection 2023.

ABSTRACT

Regulatory T cells (Treg) are essential for immune balance, preventing overreactive responses and autoimmunity. Although traditionally characterized as CD4+CD25+CD127^lowFoxP3^hi, recent research has revealed diverse Treg subsets such as Tr1, Tr1-like, and CD8 Treg. Treg dysfunction leads to severe autoimmune diseases and immune-mediated inflammatory disorders. Inborn errors of immunity (IEI) are a group of disorders that affect correct functioning of the immune system. IEI include Tregopathies caused by genetic mutations affecting Treg development or function. In addition, Treg dysfunction is also observed in other IEIs, whose underlying mechanisms are largely unknown, thus requiring further research. This review provides a comprehensive overview and discussion of Treg in IEI focused on: A) advances and controversies in the evaluation of Treg extended subphenotypes and function; B) current knowledge and gaps in Treg disturbances in Tregopathies and other IEI including Treg subpopulation changes, genotype-phenotype correlation, Treg changes with disease activity, and available therapies, and C) the potential of Treg cell-based therapies for IEI with immune dysregulation. The aim is to improve both the diagnostic and the therapeutic approaches to IEI when there is involvement of Treg. We performed a non-systematic targeted literature review with a knowledgeable selection of current, high-quality original and review articles on Treg and IEI available since 2003 (with 58% of the articles within the last 6 years) in the PubMed database.

PMID:38259469 | PMC:PMC10800401 | DOI:10.3389/fimmu.2023.1278759

Front Immunol. 2024 Jan 8;14:1286097. doi: 10.3389/fimmu.2023.1286097. eCollection 2023.

ABSTRACT

Ovarian carcinomas have the highest lethality amongst gynecological tumors. A problem after primary resection is the recurrence of epithelial ovarian carcinomas which is often associated with chemotherapy resistance. To improve the clinical outcome, it is of high interest to consider alternative therapy strategies. Due to their pronounced plasticity, γδ T cells are attractive for T-cell-based immunotherapy. However, tumors might escape by the release of lectin galectin-3, which impairs γδ T-cell function. Hence, we tested the effect of galectin-3 on the different γδ T-cell subsets. After coculture between ovarian tumor cells and Vδ1 or Vδ2 T cells enhanced levels of galectin-3 were released. This protein did not affect the cytotoxicity of both γδ T-cell subsets, but differentially influenced the proliferation of the two γδ T-cell subsets. While increased galectin-3 levels and recombinant galectin-3 inhibited the proliferation of Vδ2 T cells, Vδ1 T cells were unaffected. In contrast to Vδ1 T cells, the Vδ2 T cells strongly upregulated the galectin-3 binding partner α3β1-integrin after their activation correlating with the immunosuppressive properties of galectin-3. In addition, galectin-3 reduced the effector memory compartment of zoledronate-activated Vδ2 T cells. Therefore, our data suggest that an activation of Vδ1 T-cell proliferation as part of a T-cell-based immunotherapy can be of advantage.

PMID:38259448 | PMC:PMC10800970 | DOI:10.3389/fimmu.2023.1286097

Eur Ann Allergy Clin Immunol. 2024 Jan 23. doi: 10.23822/EurAnnACI.1764-1489.326. Online ahead of print.

ABSTRACT

Background. Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by B-cell dysfunction and immunoglobulin production deficiency. Dysregulation of interleukin-17 (IL-17) and its receptor IL-17RA have been reported in various immune disorders. This study aimed to investigate the expression of IL-17RA in innate immune cells of CVID patients and its correlation with clinical manifestations. Methods. A cross-sectional study included 22 CVID patients and 14 age- and sex-matched healthy controls. IL-17RA expression was assessed in various immune cell subsets using flow cytometry. Demographic and clinical data were collected, and statistical analysis was performed. Results. CVID patients had elevated IL-17RA expression in neutrophils, non-classical monocytes, and dendritic cells compared to healthy controls. Patients with a history of intestinal microbial colonization, particularly with Campylobacter jejuni and Giardia intestinalis, showed significantly higher IL-17RA expression in innate cells. Elevated IL-17RA expression in monocytes and dendritic cells also correlated with higher fecal calprotectin levels in CVID patients, regardless of microbial colonization. Conclusions. The study suggests that despite previous reports of reduced circulating Th17 cells and IL-17 levels in CVID patients, IL-17RA expression in innate cells may be elevated, potentially indicating altered IL-17 signaling. This heightened IL-17RA expression could contribute to a persistent pro-inflammatory state, possibly due to microbial translocation or other inflammatory factors. The association of IL-17RA expression with gastrointestinal microbial colonization and its correlation with fecal calprotectin underscores the complexity of IL-17RA’s role in CVID pathophysiology. Further research in larger cohorts could elucidate the implications of IL-17RA expression in both infectious and non-infectious inflammatory aspects of CVID.

PMID:38259136 | DOI:10.23822/EurAnnACI.1764-1489.326

Int Urol Nephrol. 2024 Jan 10. doi: 10.1007/s11255-023-03907-4. Online ahead of print.

ABSTRACT

Human inborn errors of immunity (IEIs), previously referred to as primary immunodeficiency disorders (PIDs), are a heterogeneous spectrum of inherited abnormalities of the immune system with different organ involvement. The number of identified IEIs is rapidly increasing, highlighting the non-negligible role of an interdisciplinary approach in clinical diagnosis. Kidney disorders are one of the important comorbidities in some of the affected patients and play a significant role in the diagnosis and course of disease. According to recent studies, 22 types of human IEI with renal manifestations have been identified so far, including immunodeficiency with congenital thrombocytopenia, thymic defects with additional congenital anomalies, complement deficiencies, type 1 interferonopathies, immunity related to non-hematopoietic tissues, congenital neutropenia’s, common variable immunodeficiency disorder (CVID) phenotype and immuno-osseous dysplasia. Based on this classification, we herein review IEIs with renal features and explain the genetic defect, inheritance, and type of renal manifestations.

PMID:38198013 | DOI:10.1007/s11255-023-03907-4