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Turk J Pediatr. 2023;65(1):73-80. doi: 10.24953/turkjped.2021.5190.

ABSTRACT

BACKGROUND: Early diagnosis and effective treatment serve as life-saving procedures for primary immunodeficiencies (PIDs) which are very common and a major public health problem in Turkey. Severe combined immunodeficiency (SCID) is constitutively a T-cell defect in which naïve T-cell development is defective due to the mutations in genes responsible for the T cell differentiation and insufficient thymopoiesis. So, assessment of thymopoiesis is very important in the diagnosis of SCID and several combined immune deficiencies (CIDs).

METHODS: The purpose of this study is to examine thymopoiesis in healthy children via measurement of recent thymic emigrants (RTE); T lymphocytes that express CD4, CD45RA and CD31 to establish the RTE reference values in Turkish children. RTE were measured in the peripheral blood (PB) of 120 healthy infants and children between 0-6 years including cord blood samples, by flow cytometry.

RESULTS: The absolute count of RTE cells and their relative ratios were found to be higher during the first year of life, being highest at the 6th month and tending to decrease significantly by age following birth (p=0.001). In the cord blood group, both values were lower than those in the 6-month-old group. The absolute lymphocyte count (ALC) varying by age, was found to reduce to 1850/mm³ in 4-years and after.

CONCLUSIONS: Here we evaluated normal thymopoiesis and established the normal reference levels of RTE cells in the peripheral blood of healthy children aged between 0-6 years. We believe that the collected data will contribute to early diagnosis and monitoring of immune reconstitution; serving as an additional fast and reliable marker for many PID patients especially for SCID including many other CIDs, especially in nations where newborn screening (NBS) via T cell receptor excision circles (TREC) has not yet become available.

PMID:36866987 | DOI:10.24953/turkjped.2021.5190

J Investig Allergol Clin Immunol. 2023 Mar 3:0. doi: 10.18176/jiaci.0900. Online ahead of print.

NO ABSTRACT

PMID:36866971 | DOI:10.18176/jiaci.0900

Semin Immunol. 2023 Feb 28;66:101731. doi: 10.1016/j.smim.2023.101731. Online ahead of print.

ABSTRACT

Allogeneic hematopoietic stem cell transplantation is an effective treatment to cure inborn errors of immunity. Remarkable progress has been achieved thanks to the development and optimization of effective combination of advanced conditioning regimens and use of immunoablative/suppressive agents preventing rejection as well as graft versus host disease. Despite these tremendous advances, autologous hematopoietic stem/progenitor cell therapy based on ex vivo gene addition exploiting integrating γ-retro- or lenti-viral vectors, has demonstrated to be an innovative and safe therapeutic strategy providing proof of correction without the complications of the allogeneic approach. The recent advent of targeted gene editing able to precisely correct genomic variants in an intended locus of the genome, by introducing deletions, insertions, nucleotide substitutions or introducing a corrective cassette, is emerging in the clinical setting, further extending the therapeutic armamentarium and offering a cure to inherited immune defects not approachable by conventional gene addition. In this review, we will analyze the current state-of-the art of conventional gene therapy and innovative protocols of genome editing in various primary immunodeficiencies, describing preclinical models and clinical data obtained from different trials, highlighting potential advantages and limits of gene correction.

PMID:36863140 | DOI:10.1016/j.smim.2023.101731

Front Immunol. 2023 Feb 13;14:1078976. doi: 10.3389/fimmu.2023.1078976. eCollection 2023.

ABSTRACT

Children with complete DiGeorge anomaly (cDGA) have congenital athymia, resulting in severe T cell immunodeficiency and susceptibility to a broad range of infections. We report the clinical course, immunologic phenotypes, treatment, and outcomes of three cases of disseminated nontuberculous mycobacterial infections (NTM) in patients with cDGA who underwent cultured thymus tissue implantation (CTTI). Two patients were diagnosed with Mycobacterium avium complex (MAC) and one patient with Mycobacterium kansasii. All three patients required protracted therapy with multiple antimycobacterial agents. One patient, who was treated with steroids due to concern for immune reconstitution inflammatory syndrome (IRIS), died due to MAC infection. Two patients have completed therapy and are alive and well. T cell counts and cultured thymus tissue biopsies demonstrated good thymic function and thymopoiesis despite NTM infection. Based on our experience with these three patients, we recommend that providers strongly consider macrolide prophylaxis upon diagnosis of cDGA. We obtain mycobacterial blood cultures when cDGA patients have fevers without a localizing source. In cDGA patients with disseminated NTM, treatment should consist of at least two antimycobacterial medications and be provided in close consultation with an infectious diseases subspecialist. Therapy should be continued until T cell reconstitution is achieved.

PMID:36860874 | PMC:PMC9969526 | DOI:10.3389/fimmu.2023.1078976

Front Immunol. 2023 Feb 13;14:1089243. doi: 10.3389/fimmu.2023.1089243. eCollection 2023.

ABSTRACT

BACKGROUND: Humoral immunity depends on the differentiation of B cells into antibody secreting cells (ASCs). Excess or inappropriate ASC differentiation can lead to antibody-mediated autoimmune diseases, while impaired differentiation results in immunodeficiency.

METHODS: We have used CRISPR/Cas9 technology in primary B cells to screen for regulators of terminal differentiation and antibody production.

RESULTS: We identified several new positive (Sec61a1, Hspa5) and negative (Arhgef18, Pold1, Pax5, Ets1) regulators that impacted on the differentiation process. Other genes limited the proliferative capacity of activated B cells (Sumo2, Vcp, Selk). The largest number of genes identified in this screen (35) were required for antibody secretion. These included genes involved in endoplasmic reticulum-associated degradation and the unfolded protein response, as well as post-translational protein modifications.

DISCUSSION: The genes identified in this study represent weak links in the antibody-secretion pathway that are potential drug targets for antibody-mediated diseases, as well as candidates for genes whose mutation results in primary immune deficiency.

PMID:36860866 | PMC:PMC9969136 | DOI:10.3389/fimmu.2023.1089243

Vaccines (Basel). 2023 Feb 3;11(2):354. doi: 10.3390/vaccines11020354.

ABSTRACT

Some studies have found increased coronavirus disease-19 (COVID-19)-related morbidity and mortality in patients with primary antibody deficiencies. Immunization against COVID-19 may, therefore, be particularly important in these patients. However, the durability of the immune response remains unclear in such patients. In this study, we evaluated the cellular and humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in a cross-sectional study of 32 patients with primary antibody deficiency (n = 17 with common variable immunodeficiency (CVID) and n = 15 with selective IgA deficiency) and 15 healthy controls. Serological and cellular responses were determined using enzyme-linked immunosorbent assay and interferon-gamma release assays. The subsets of B and T lymphocytes were measured using flow cytometry. Of the 32 patients, 28 had completed the vaccination regimen with a median time after vaccination of 173 days (IQR = 142): 27 patients showed a positive spike-peptide-specific antibody response, and 26 patients showed a positive spike-peptide-specific T-cell response. The median level of antibody response in CVID patients (5.47 ratio (IQR = 4.08)) was lower compared to healthy controls (9.43 ratio (IQR = 2.13)). No difference in anti-spike T-cell response was found between the groups. The results of this study indicate that markers of the sustained SARS-CoV-2 spike-specific immune response are detectable several months after vaccination in patients with primary antibody deficiencies comparable to controls.

PMID:36851231 | DOI:10.3390/vaccines11020354

Sci Rep. 2023 Feb 27;13(1):3358. doi: 10.1038/s41598-023-30020-4.

ABSTRACT

Kidney renal clear cell carcinoma (KIRC) is one of the common malignant tumors of the urinary system. Patients with different risk levels are other in terms of disease progression patterns and disease regression. The poorer prognosis for high-risk patients compared to low-risk patients. Therefore, it is essential to accurately high-risk screen patients and gives accurate and timely treatment. Differential gene analysis, weighted correlation network analysis, Protein-protein interaction network, and univariate Cox analysis were performed sequentially on the train set. Next, the KIRC prognostic model was constructed using the least absolute shrinkage and selection operator (LASSO), and the Cancer Genome Atlas (TCGA) test set and the Gene Expression Omnibus dataset verified the model’s validity. Finally, the constructed models were analyzed; including gene set enrichment analysis (GSEA) and immune analysis. The differences in pathways and immune functions between the high-risk and low-risk groups were observed to provide a reference for clinical treatment and diagnosis. A four-step key gene screen resulted in 17 key factors associated with disease prognosis, including 14 genes and 3 clinical features. The LASSO regression algorithm selected the seven most critical key factors to construct the model: age, grade, stage, GDF3, CASR, CLDN10, and COL9A2. In the training set, the accuracy of the model in predicting 1-, 2- and 3-year survival rates was 0.883, 0.819, and 0.830, respectively. The accuracy of the TCGA dataset was 0.831, 0.801, and 0.791, and the accuracy of the GSE29609 dataset was 0.812, 0.809, and 0.851 in the test set. Model scoring divided the sample into a high-risk group and a low-risk group. There were significant differences in disease progression and risk scores between the two groups. GSEA analysis revealed that the enriched pathways in the high-risk group mainly included proteasome and primary immunodeficiency. Immunological analysis showed that CD8 (+) T cells, M1 macrophages, PDCD1, and CTLA4 were upregulated in the high-risk group. In contrast, antigen-presenting cell stimulation and T-cell co-suppression were more active in the high-risk group. This study added clinical characteristics to constructing the KIRC prognostic model to improve prediction accuracy. It provides help to assess the risk of patients more accurately. The differences in pathways and immunity between high and low-risk groups were also analyzed to provide ideas for treating KIRC patients.

PMID:36849551 | DOI:10.1038/s41598-023-30020-4

Front Oncol. 2023 Feb 8;13:1107171. doi: 10.3389/fonc.2023.1107171. eCollection 2023.

ABSTRACT

Clonality assessment using the unique rearrangements of immunoglobulin (IG) and T-cell receptor (TR) genes in lymphocytes is a widely applied supplementary test for the diagnosis of B-cell and T-cell lymphoma. To enable a more sensitive detection and a more precise comparison of clones compared with conventional clonality analysis based on fragment analysis, the EuroClonality NGS Working Group developed and validated a next-generation sequencing (NGS)-based clonality assay for detection of the IG heavy and kappa light chain and TR gene rearrangements for formalin-fixed and paraffin-embedded tissues. We outline the features and advantages of NGS-based clonality detection and discuss potential applications for NGS-based clonality testing in pathology, including site specific lymphoproliferations, immunodeficiency and autoimmune disease and primary and relapsed lymphomas. Also, we briefly discuss the role of T-cell repertoire of reactive lymphocytic infiltrations in solid tumors and B-lymphoma.

PMID:36845702 | PMC:PMC9945094 | DOI:10.3389/fonc.2023.1107171

Infect Drug Resist. 2023 Feb 20;16:1049-1059. doi: 10.2147/IDR.S395658. eCollection 2023.

ABSTRACT

BACKGROUND: Respiratory failure in acquired immunodeficiency syndrome (AIDS) patients was the leading cause of intensive care unit (ICU) admission in our center. We aimed to describe the pulmonary infections and outcomes for respiratory failure in AIDS patients.

METHODS: A retrospective study was conducted on AIDS adult patients with respiratory failure who were admitted to the ICU in Beijing Ditan hospital, China, from January 2012 to December 2021. We investigated pulmonary infections complicated by respiratory failure in AIDS patients. The primary outcome was ICU mortality, and a comparison between survivors and nonsurvivors was performed. Multiple logistic regression analysis was used to identify predictors of ICU mortality. The Kaplan-Meier curve and Log rank test were used for survival analysis.

RESULTS: A total of 231 AIDS patients were admitted to ICU with respiratory failure over a 10-year period with a male predominance (95.7%). Pneumocystis jirovecii pneumonia was the main etiology of pulmonary infections (80.1%). The ICU mortality was 32.9%. In multivariate analysis, ICU mortality was independently associated with invasive mechanical ventilation (IMV) [odds ratio (OR), 27.910; 95% confidence interval (CI, 8.392-92.818; p = 0.000) and the time before ICU admission (OR, 0.959; 95% CI, 0.920-0.999; p = 0.046). In the survival analysis, patients with IMV and later admission to ICU had a higher probability of mortality.

CONCLUSION: Pneumocystis jirovecii pneumonia was the primary etiology for respiratory failure in AIDS patients admitted to the ICU. Respiratory failure remains a severe illness with high mortality, and ICU mortality was negatively associated with IMV and later admission to ICU.

PMID:36845022 | PMC:PMC9951600 | DOI:10.2147/IDR.S395658

J Clin Immunol. 2023 Feb 27. doi: 10.1007/s10875-023-01450-6. Online ahead of print.

ABSTRACT

BACKGR OUND: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019.

METHODS: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years.

RESULTS: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result.

CONCLUSION: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.

PMID:36843153 | DOI:10.1007/s10875-023-01450-6