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Vaccine. 2021 Apr 22:S0264-410X(21)00450-3. doi: 10.1016/j.vaccine.2021.04.015. Online ahead of print.

ABSTRACT

Antibody responses to pneumococcal polysaccharide vaccination are frequently used as a diagnostic tool for humoral immunodeficiencies, part of the larger collection of inborn errors of immunity. Currently, arbitrary criteria, such as a serotype specific titer of >/= 1.3 µg/mL is most often used as a cut-off for interpretation of pneumococcal antibody responses. The magnitude of the antibody response to each of the 23 serotypes in Pneumovax®, and serotype-specific cut-offs in healthy pneumococcal vaccine-naïve adults has not been previously characterized. IgG antibody concentrations were measured prospectively for 23 pneumococcal serotypes pre and 4-6 weeks post-Pneumovax® vaccination in 100 healthy adults, using a multiplex bead-based assay. Antibodies to 19 of 23 serotypes were informative for distinguishing subjects who responded to vaccination, and the serotype threshold was determined to be 9 of 19 serotypes, which characterized an antibody response to pneumococcal vaccination. While this study may facilitate classification of IgG serotype-specific antibody responses post-pneumococcal vaccination in adult patients undergoing diagnostic immunological evaluation for antibody immunodeficiencies or other relevant contexts, additional studies in healthy children and S. pneumoniae protein-conjugate-vaccinated healthy adults will need to be undertaken in the future.

PMID:33896666 | DOI:10.1016/j.vaccine.2021.04.015

J Allergy Clin Immunol. 2021 Apr 22:S0091-6749(21)00654-0. doi: 10.1016/j.jaci.2021.04.015. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Whilst increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.

OBJECTIVE: To analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.

METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies (ESID) registry. Patients with autoinflammatory diseases were excluded due to the limited number registered.

RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed due to family history only and 0.8% presented with malignancy. Two thirds of IEI patients presented before the age of 6 years, but a quarter of patients only developed initial symptoms as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between 6 and 25 years of age with male predominance until age 10, shifting to female predominance after age 40. Infections were most prevalent as a first manifestation in patients presenting after age 30.

CONCLUSION: An exclusive focus on infection-centered warning signs would have missed around 25% of IEI patients that initially present with other manifestations.

CLINICAL IMPLICATIONS: We provide a data-based rationale to add immune dysregulation and syndromic features to the IEI warning signs, which may significantly improve early IEI diagnosis.

PMID:33895260 | DOI:10.1016/j.jaci.2021.04.015

Eur J Clin Pharmacol. 2021 Apr 24. doi: 10.1007/s00228-021-03141-w. Online ahead of print.

NO ABSTRACT

PMID:33893861 | DOI:10.1007/s00228-021-03141-w

J Crohns Colitis. 2021 Apr 23:jjab077. doi: 10.1093/ecco-jcc/jjab077. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Very early onset inflammatory bowel disease (VEOIBD) is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic etiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation.

METHODS: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss, and, in the majority, recurrent infections. Genetic etiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on PBMCs and functional studies with epithelial cell lines were employed.

RESULTS: In each of the 10 patients, we identified damaging heterozygous or biallelic variants in Syntaxin-Binding Protein 3 gene (STXBP3), a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and led to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity.

CONCLUSION: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

PMID:33891011 | DOI:10.1093/ecco-jcc/jjab077

Ethiop J Health Sci. 2020 Nov;30(6):1051-1054. doi: 10.4314/ejhs.v30i6.26.

ABSTRACT

BACKGROUND: Wiskott Aldrich syndrome is a primary immunodeficiency notable for eczema, recurrent infections, bleeding diathesis and microcytic thrombocytopenia.

CASE: A 4½ year old boy presented with recurrent sinopulmonary infections, repeated treatment for severe eczema since infancy, thrombocytopenia with low platelet volume. His brother and uncles died during childhood due to repeated illnesses. We outline ways to diagnose and manage children in resource limited settings.

CONCLUSION: Wiskott Aldrich syndrome can be diagnosed by its clinical triad of syndromes. Mutation of the WASP gene confirms diagnosis. Increasing reports of primary immune deficiencies in Ethiopia call for improved education and care for clinical immunology.

PMID:33883853 | PMC:PMC8047228 | DOI:10.4314/ejhs.v30i6.26

J Virol. 2021 Apr 21:JVI.02211-20. doi: 10.1128/JVI.02211-20. Online ahead of print.

ABSTRACT

Merkel cell polyomavirus (MCPyV) infects most of the human population asymptomatically, but in rare cases leads to a highly aggressive skin cancer called Merkel cell carcinoma (MCC). MCC incidence is much higher in aging and immunocompromised populations. The epidemiology of MCC suggests that dysbiosis between the host immune response and the MCPyV infectious cycle could contribute to the development of MCPyV-associated MCC. Insufficient restriction of MCPyV by normal cellular processes, for example, could promote the incidental oncogenic MCPyV integration events and/or entry into the original cell of MCC. Progress towards understanding MCPyV biology has been hindered by its narrow cellular tropism. Our discovery that primary human dermal fibroblasts (HDFs) support MCPyV infection has made it possible to closely model cellular responses to different stages of the infectious cycle. The present study reveals that the onset of MCPyV replication and early gene expression induces an inflammatory cytokine and interferon stimulated gene (ISG) response. The cGAS-STING pathway, in coordination with NF-κB, mediates induction of this innate immune gene expression program. Further, silencing of cGAS or NF-κB pathway factors led to elevated MCPyV replication. We also discovered that the PYHIN protein IFI16 localizes to MCPyV replication centers, but does not contribute to the induction of ISGs. Instead, IFI16 upregulates inflammatory cytokines in response to MCPyV infection by an alternative mechanism. The work described herein establishes a foundation for exploring how changes to the skin microenvironment induced by aging or immunodeficiency might alter the fate of MCPyV and its host cell to encourage carcinogenesis.ImportanceMCC has a high rate of mortality and an increasing incidence. Immune-checkpoint therapies have improved the prognosis of patients with metastatic MCC. Still, a significant proportion of the patients fail to respond to immune-checkpoint therapies or have a medical need for iatrogenic immune-suppression. A greater understanding of MCPyV biology could inform targeted therapies for MCPyV-associated MCC. Moreover, cellular events preceding MCC oncogenesis remain largely unknown. The present study aims to explore how MCPyV interfaces with innate immunity during its infectious cycle. We describe how MCPyV replication and/or transcription elicit an innate immune response via cGAS-STING, NF-κB, and IFI16. We also explore the impacts of this response on MCPyV replication. Our findings illustrate how healthy cellular conditions may allow low-level infection that evades immune destruction until highly active replication is restricted by host responses. Conversely, pathologic conditions could result in unbridled MCPyV replication that licenses MCC tumorigenesis.

PMID:33883226 | DOI:10.1128/JVI.02211-20

Arthritis Rheumatol. 2021 Apr 21. doi: 10.1002/art.41767. Online ahead of print.

ABSTRACT

OBJECTIVE: Silica is one of the strongest environmental substances linked with autoimmunity. The aim of this study was to assess the prevalence of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and renal limited vasculitis (RLV) in a French northeast region, and their geospatial association with quarries.

METHODS: Potential ANCA-Associated Vasculitis (AAV) cases were identified using three sources: hospital records, immunology laboratories and the National Health Insurance System. Patients who resided in Alsace on January 1, 2016 and fulfilled ACR AAV criteria or Chapel Hill Consensus Conference 2012 definition were included. Incomplete case ascertainment was corrected using capture-recapture analysis. The spatial association between the number of cases and quarries in each administrative entity was assessed using geographical weighted regression (GWR).

RESULTS: From 910 potential AAV cases, we identified 185 patients meeting inclusion criteria: 120 GPA, 35 MPA, 30 RLV. The number of cases missed by any source was 6.4 (95%CI 3.6-11.5). Accordingly, the 2016 estimated prevalence in Alsace was 65.5 cases per million inhabitants (95%CI 47.3-93.0) for GPA, 19.1 (95%CI 11.3-34.3) for MPA, and 16.8 (95%CI 8.7-35.2) for RLV. The risk of AAV was significantly increased in communes with quarries (OR: 2.51 [95%CI: 1.66-3.80]) and GWR revealed a significant spatial association between quarries and GPA cases (p = 0.039), and, regarding ANCA serotype, between quarries and both PR3-AAV (p = 0.04) and MPO-AAV (p = 0.03).”

CONCLUSION: In a region with a high density of quarries, the spatial association of AAV with quarries supports the role of silica as a specific environmental factor.

PMID:33881225 | DOI:10.1002/art.41767

Case Rep Infect Dis. 2021 Apr 4;2021:6615722. doi: 10.1155/2021/6615722. eCollection 2021.

ABSTRACT

Pulmonary infection due to Mycobacterium abscessus occurs in patients with cystic fibrosis, but rarely in immunocompetent children without underlying lung pathology. Treatment is complicated by frequent resistance to many antibiotics. We present a case report of a 4-month-old female infant with 2 months of cough, difficulty feeding, and failure to thrive, with extensive culture-confirmed M. abscessus pulmonary infection without identified immunodeficiency or underlying lung pathology following multidisciplinary evaluation. We describe our complete evaluation including immunodeficiency evaluation incorporating whole-exome sequencing, describe our antibiotic selection and treatment duration given complicated susceptibility pattern of the M. abscessus isolate, and review literature for nontuberculous mycobacterial pulmonary disease in immunocompetent children. A complete multidisciplinary evaluation for underlying lung disease and primary and acquired immunodeficiency should be undertaken in pediatric patients with M. abscessus pneumonia. Confirming macrolide susceptibility through erm(41) gene evaluation is clinically important for isolates with complicated susceptibility pattern.

PMID:33880194 | PMC:PMC8046554 | DOI:10.1155/2021/6615722

Medicine (Baltimore). 2021 Apr 23;100(16):e25603. doi: 10.1097/MD.0000000000025603.

ABSTRACT

Gliomas have the highest incidence among primary brain tumors, and the extracellular matrix (ECM) plays a vital role in tumor progression. We constructed a risk signature using ECM-related genes to predict the prognosis of patients with gliomas.mRNA and clinical data from glioma patients were downloaded from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed ECM-related genes were screened, and a risk signature was built using least absolute shrinkage and selection operator (LASSO) Cox regression. Cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to assess immune infiltration in different risk groups. Gene set enrichment analysis (GSEA) was performed to explore the molecular mechanisms of the genes employed in the risk score.Differentially expressed ECM-related genes were identified, and their associated regulatory mechanisms were predicted via analysis of protein-protein interaction (PPI), transcription factor (TF) regulatory and TF coexpression networks. The established risk signature considered 17 ECM-related genes. The prognosis of the high-risk group was significantly worse than that of the low-risk group. We used the CGGA database to validate the signature. CIBERSORT indicated that the levels of naive B cells, activated memory CD4 T cells, regulatory T cells, gamma delta T cells, activated NK cells, monocytes, activated dendritic cells and activated mast cells were higher in the high-risk group. The levels of plasma cells, CD8 T cells, naive CD4 T cells, resting memory CD4 T cells, M0 macrophages, M1 macrophages, resting mast cells, and neutrophils were lower in the high-risk group. Ultimately, GSEA showed that the terms intestinal immune network for IgA production, primary immunodeficiency, and ECM receptor interaction were the top 3 terms enriched in the high-risk group. The terms Wnt signaling pathway, ErbB signaling pathway, mTOR signaling pathway, and calcium signaling pathway were enriched in the low-risk group.We built a risk signature to predict glioma prognosis using ECM-related genes. By evaluating immune infiltration and biofunctions, we gained a further understanding of this risk signature. This risk signature could be an effective tool for predicting glioma prognosis.This study did not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.

PMID:33879726 | DOI:10.1097/MD.0000000000025603

Pacing Clin Electrophysiol. 2021 Apr 20. doi: 10.1111/pace.14246. Online ahead of print.

ABSTRACT

Over the past decade, the emergence of the subcutaneous implantable cardioverter defibrillator (S-ICD) has provided cardiologists with an option to provide both primary or secondary prevention treatment of sudden cardiac death (SCD) without the associated risks that come with the use of intracardiac leads. S-ICD may prove to be a useful option in those who are young, have thromboembolic risk, immunodeficiency states, unfavourable anatomy due to adult congenital heart disease (ACHD). This article reviews the existing literature to determine whether S-ICD can prove to be a safe alternative in comparison to Transvenous implantable cardioverter defibrillator (TV-ICD) and in which patient population should S-ICD be considered over TV-ICD. This article is protected by copyright. All rights reserved.

PMID:33878197 | DOI:10.1111/pace.14246