Manish Butte

Sci Rep. 2022 Jun 21;12(1):10416. doi: 10.1038/s41598-022-14522-1.

ABSTRACT

Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders that include primary immunodeficiency’s and other disorders affecting different aspects of the immune system. Next-Generation Sequencing (NGS) is an essential tool to diagnose IEI. We report our 3-year experience in setting up facilities for NGS for diagnosis of IEI in Chandigarh, North India. We used a targeted, customized gene panel of 44 genes known to result in IEI. Variant analysis was done using Ion Reporter software. The in-house NGS has enabled us to offer genetic diagnoses to patients with IEI at minimal costs. Of 121 patients who were included pathogenic variants were identified in 77 patients. These included patients with Chronic Granulomatous Disease, Severe Combined Immune Deficiency, leukocyte adhesion defect, X-linked agammaglobulinemia, Ataxia Telangiectasia, Hyper-IgE syndrome, Wiskott Aldrich syndrome, Mendelian susceptibility to mycobacterial diseases, Hyper-IgM syndrome, autoimmune lymphoproliferative syndrome, and GATA-2 deficiency. This manuscript discusses the challenges encountered while setting up and running targeted NGS for IEI in our unit. Genetic diagnosis has helped our patients with IEI in genetic counselling, prenatal diagnosis, and accessing appropriate therapeutic options.

PMID:35729272 | DOI:10.1038/s41598-022-14522-1

Eur Respir J. 2022 Jun 21:2200176. doi: 10.1183/13993003.00176-2022. Online ahead of print.

ABSTRACT

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing co-morbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex, however PCD genetic testing is rapidly moving from research into clinical diagnostics and would confirm the cause of bronchiectasis.

METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital, Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data was accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK.

RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17/142 (12%) individuals by whole genome sequencing. Similarly in a single centre with access to pathological diagnostic facilities, 5-10% patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4,898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing.

CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

PMID:35728977 | DOI:10.1183/13993003.00176-2022

Clin Chim Acta. 2022 Jun 18:S0009-8981(22)01186-X. doi: 10.1016/j.cca.2022.06.003. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder (PID) due to genetic defects in the NADPH oxidase of phagocytes. Affected patients become susceptible to infections such as pneumonia, diarrhea, and skin ulcer types. The patients require life-long treatment with prophylactic antibiotics, antifungals, or hematopoietic stem cell transplantation (HSCT) therapy. Early, accurate diagnosis will contribute to the life-prolonging of patients with CGD. This study’s aim is to identify the mutation related to the disease. Case presentation Six patients from different Vietnamese families were collected for genetic analysis at Allergy, Immunology, and Rheumatology Department, Vietnam National Hospital Pediatrics. They were diagnosed with CGD by flow cytometry test with the conversion of dihydrorhodamine (DHR) 123 to rhodamine 123.

METHODS: We performed whole exome sequencing (WES) as a tool for detecting novel mutations. The mutations were confirmed by the Sanger sequencing method in patients and their families. The influence of the mutations was predicted with the in silico analysis tools: PROVEAN, SIFT, PolyPhen 2, Mutation Taster, and MaxEntScan.

RESULTS: In this study, five mutations were found in six unrelated patients with CGD from different Vietnamese families. Three novel pathogenic mutations were detected including one mutation (c.45+2T>G) in the CYBB gene and two mutations (c.187_188insA and c.289G>C) in the NCF2 gene.

CONCLUSIONS: Our results of CGD-related mutations contribute to the general understanding of the etiology of the disease and emphasize that WES sequencing can be used as a tool to help to diagnose carriers as well as assist in genetic counseling and prenatal screening.

PMID:35728702 | DOI:10.1016/j.cca.2022.06.003

Front Immunol. 2022 Jun 2;13:912571. doi: 10.3389/fimmu.2022.912571. eCollection 2022.

ABSTRACT

BACKGROUND: Patients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity.

OBJECTIVES: To determine the immunogenicity of the third primary SARS-CoV-2 immunisation in a heterogeneous cohort of patients with antibody deficiency.

METHODS: Participants enrolled in the COV-AD study were sampled before and after their third vaccine dose. Serological and cellular responses were determined using ELISA, live-virus neutralisation and ELISPOT assays.

RESULTS: Following a two-dose schedule, 100% of healthy controls mounted a serological response to SARS-CoV-2 vaccination, however, 38.6% of individuals with antibody deficiency remained seronegative. A third primary SARS-CoV-2 vaccine significantly increased anti-spike glycoprotein antibody seroprevalence from 61.4% to 76.0%, the magnitude of the antibody response, its neutralising capacity and induced seroconversion in individuals who were seronegative after two vaccine doses. Vaccine-induced serological responses were broadly cross-reactive against the SARS-CoV-2 B.1.1.529 variant of concern, however, seroprevalence and antibody levels remained significantly lower than healthy controls. No differences in serological responses were observed between individuals who received AstraZeneca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b2 during their initial two-dose vaccine schedule. SARS-CoV-2 infection-naive participants who had received a heterologous vaccine as a third dose were significantly more likely to have a detectable T cell response following their third vaccine dose (61.5% vs 11.1%).

CONCLUSION: These data support the widespread use of third primary immunisations to enhance humoral immunity against SARS-CoV-2 in individuals with antibody deficiency.

PMID:35720400 | PMC:PMC9201027 | DOI:10.3389/fimmu.2022.912571

Front Immunol. 2022 Jun 2;13:886540. doi: 10.3389/fimmu.2022.886540. eCollection 2022.

ABSTRACT

We report two patients with DNA repair disorders (Artemis deficiency, Ataxia telangiectasia) with destructive skin granulomas, presumably triggered by live-attenuated rubella vaccinations. Both patients showed reduced naïve T cells. Rapid resolution of skin lesions was observed following hematopoietic stem cell transplantation. However, the patient with AT died due to complications of severe hepatic veno-occlusive disease 6 month after HSCT. Dried blood spots obtained after birth were available from this patient and showed absent T-cell receptor excision circles (TRECs). Therefore, newborn screening may help to prevent patients with moderate T-cell deficiency from receiving live-attenuated rubella vaccine potentially causing granulomas.

PMID:35720367 | PMC:PMC9201904 | DOI:10.3389/fimmu.2022.886540

Adv Biomed Res. 2022 Apr 29;11:31. doi: 10.4103/abr.abr_169_21. eCollection 2022.

ABSTRACT

Ataxia-telangiectasia (AT) is a type of primary immunodeficiency characterized by an autosomal recessive mode of inheritance and usually presents with progressive cerebellar ataxia in early life. This complex disease is associated with humoral and cellular immune dysfunction and other features including characteristic oculocutaneous telangiectasia and increased predisposition to cancers, particularly lymphoma and leukemia. An 11-year-old Iranian girl presented with primary immunodeficiency and was diagnosed as having AT according to her clinical manifestations and molecular findings. She had a history of two types of non-Hodgkin’s lymphoma and showed spontaneous regression of her diffuse large B-cell lymphoma without any specific treatment. Gene mutations and dysfunction in patients with AT result in different manifestations including abnormal development of the thymus, immunodeficiency, increased susceptibility to malignancies, and increased radiosensitivity. No standard treatment is available for these patients. The use of immunotherapeutic strategies in patients with primary immune deficiency disease-associated tumors is potentially important.

PMID:35720220 | PMC:PMC9201233 | DOI:10.4103/abr.abr_169_21

Ann Allergy Asthma Immunol. 2022 Jun 16:S1081-1206(22)00529-4. doi: 10.1016/j.anai.2022.06.009. Online ahead of print.

ABSTRACT

OBJECTIVE: To update clinicians on current evidence regarding the immunogenicity and safety of COVID-19 vaccines in patients with Inborn Errors of Immunity (IEI).

DATA SOURCES: Peer reviewed, published studies in Pubmed, clinical trials listed on clinicaltrial.gov, and professional organization and governmental guidelines.

STUDY SELECTIONS: Literature searches on Pubmed and clinicaltrials.gov were performed using a combination of the following keywords: Primary Immunodeficiency, COVID-19, SARS-CoV-2, vaccination RESULTS: Twenty-six studies met criteria and were included in this review. Overall, antibody responses to COVID-19 vaccination were seen in 72% of study subjects, with stronger responses observed following mRNA vaccination. Neutralizing antibodies were detected in IEI patients, though consistently at lower levels than healthy controls. Risk factors for poor antibody responses included diagnosis of common variable immunodeficiency (CVID), presence of autoimmune comorbidities, and use of rituximab. T cells responses were detectable in most patients with IEI, with poorer responses often seen in CVID patients. Safety of COVID-19 vaccines in patients with IEI were acceptable with high rates of reactogenicity but very few serious adverse events, including in patients with immune dysregulation.

CONCLUSION: COVID-19 vaccines are safe in patients with IEI and appear to be immunogenic in most individuals, with stronger responses seen following mRNA vaccinations.

PMID:35718282 | DOI:10.1016/j.anai.2022.06.009

NPJ Genom Med. 2022 Jun 17;7(1):38. doi: 10.1038/s41525-022-00308-x.

ABSTRACT

Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3-8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.

PMID:35715439 | DOI:10.1038/s41525-022-00308-x

Sci Immunol. 2022 Jun 24;7(72):eabn9301. doi: 10.1126/sciimmunol.abn9301. Epub 2022 Jun 17.

ABSTRACT

The strain 68-1 rhesus cytomegalovirus (RhCMV)-based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8⁺ T cells that recognize epitopes presented by major histocompatibility complex (MHC)-II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II- and/or MHC-Ia-restricted CD8⁺ T cells do not protect against SIV, it remains unclear whether MHC-E-restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II-restricted component. Using host microRNA (miR)-mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope-targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142-mediated tropism restriction eliminated MHC-E epitope-targeted CD8⁺ T cell priming, yielding an exclusively MHC-II epitope-targeted response. Inhibition with the endothelial cell-selective miR-126 eliminated MHC-II epitope-targeted CD8⁺ T cell priming, yielding an exclusively MHC-E epitope-targeted response. Dual miR-142 + miR-126-mediated tropism restriction reverted CD8⁺ T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8⁺ T cell responses were generally similar, only the vectors programmed to elicit MHC-E-restricted CD8⁺ T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy.

PMID:35714200 | DOI:10.1126/sciimmunol.abn9301

Acta Biochim Biophys Sin (Shanghai). 2022 Jun 25. doi: 10.3724/abbs.2022071. Online ahead of print.

ABSTRACT

Clinical information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with inborn errors of immunity (IEI) during the current Coronavirus disease 2019 (COVID-19) pandemic is still limited. Proper DNA repair machinery is required for the development of the adaptive immune system, which provides specific and long-term protection against SARS-CoV-2. This review highlights the impact of SARS-CoV-2 infections on IEI patients with DNA repair disorders and summarizes susceptibility risk factors, pathogenic mechanisms, clinical manifestations and management strategies of COVID-19 in this special patient population.

PMID:35713311 | DOI:10.3724/abbs.2022071