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Sci Immunol. 2022 Mar 25;7(69):eabi7160. doi: 10.1126/sciimmunol.abi7160. Epub 2022 Mar 25.

ABSTRACT

IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline IKZF1 haploinsufficient (IKZF1^HI) and dominant-negative (IKZF1^DN) variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous IKZF1 variants (R183C/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (T_H) skewing toward T_H2, low numbers of regulatory T cells (T_reg), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1^HI and IKZF1^DN, IKZF1^R183H/C proteins showed increased DNA binding associated with increased gene expression of T_H2 and PC differentiation, thus demonstrating that IKZF1^R183H/C behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T_H2 and PC abnormalities caused by IKZF1^R183H/C. These data extend the spectrum of pathological mechanisms associated with IKZF1 deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.

PMID:35333544 | DOI:10.1126/sciimmunol.abi7160

J Clin Immunol. 2022 Mar 23. doi: 10.1007/s10875-022-01209-5. Online ahead of print.

ABSTRACT

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a type I interferonopathy usually characterized by early-onset neurologic regression. Biallelic mutations in LSM11 and RNU7-1, components of the U7 small nuclear ribonucleoprotein (snRNP) complex, have been identified in a limited number of genetically unexplained AGS cases. Impairment of U7 snRNP function results in misprocessing of replication-dependent histone (RDH) pre-mRNA and disturbance of histone occupancy of nuclear DNA, ultimately driving cGAS-dependent type I interferon (IFN-I) release.

OBJECTIVE: We performed a clinical, genetic, and immunological workup of 3 unrelated patients with uncharacterized AGS.

METHODS: Whole exome sequencing (WES) and targeted Sanger sequencing of RNU7-1 were performed. Primary fibroblasts were used for mechanistic studies. IFN-I signature and STAT1/2 phosphorylation were assessed in peripheral blood. Cytokines were profiled on serum and cerebrospinal fluid (CSF). Histopathology was examined on brain and kidney tissue.

RESULTS: Sequencing revealed compound heterozygous RNU7-1 mutations, resulting in impaired RDH pre-mRNA processing. The 3′ stem-loop mutations reduced stability of the secondary U7 snRNA structure. A discrete IFN-I signature in peripheral blood was paralleled by MCP-1 (CCL2) and CXCL10 upregulation in CSF. Histopathological analysis of the kidney showed thrombotic microangiopathy. We observed dysregulated STAT phosphorylation upon cytokine stimulation. Clinical overview of all reported patients with RNU7-1-related disease revealed high mortality and high incidence of organ involvement compared to other AGS genotypes.

CONCLUSIONS: Targeted RNU7-1 sequencing is recommended in genetically unexplained AGS cases. CSF cytokine profiling represents an additional diagnostic tool to identify aberrant IFN-I signaling. Clinical follow-up of RNU7-1-mutated patients should include screening for severe end-organ involvement including liver disease and nephropathy.

PMID:35320431 | DOI:10.1007/s10875-022-01209-5

Front Immunol. 2022 Mar 4;13:827242. doi: 10.3389/fimmu.2022.827242. eCollection 2022.

ABSTRACT

It is critical to protect immunocompromised patients against COVID-19 with effective SARS-CoV-2 vaccination as they have an increased risk of developing severe disease. This is challenging, however, since effective mRNA vaccination requires the successful cooperation of several components of the innate and adaptive immune systems, both of which can be severely affected/deficient in immunocompromised people. In this article, we first review current knowledge on the immunobiology of SARS-COV-2 mRNA vaccination in animal models and in healthy humans. Next, we summarize data from early trials of SARS-COV-2 mRNA vaccination in patients with secondary or primary immunodeficiency. These early clinical trials identified common predictors of lower response to the vaccine such as anti-CD19, anti-CD20 or anti-CD38 therapies, low (naive) CD4⁺ T-cell counts, genetic or therapeutic Bruton tyrosine kinase deficiency, treatment with antimetabolites, CTLA4 agonists or JAK inhibitors, and vaccination with BNT162b2 versus mRNA1273 vaccine. Finally, we review the first data on third dose mRNA vaccine administration in immunocompromised patients and discuss recent strategies of temporarily holding/pausing immunosuppressive medication during vaccination.

PMID:35309332 | PMC:PMC8931657 | DOI:10.3389/fimmu.2022.827242

Cureus. 2022 Feb 13;14(2):e22183. doi: 10.7759/cureus.22183. eCollection 2022 Feb.

ABSTRACT

Follicular bronchiolitis (FB) associated with immunodeficiency is not commonly reported in peer-reviewed literature. Herein, we present a case of FB associated with IgG2/IgG4 deficiency. The presence of non-specific respiratory symptoms, including cough and dyspnea with exertion, led to a CT scan of the chest, which showed diffuse, peripheral, micronodular tree-in-bud opacities and an isolated area of bronchiectasis. Despite an extensive workup, including a non-diagnostic transbronchial biopsy, no obvious etiology for the patient’s clinical presentation was established, and a surgical lung biopsy was needed to confirm the diagnosis of FB. Further lab testing to evaluate for immunodeficiency confirmed an isolated deficiency in both IgG2 and IgG4. Although treating the underlying cause of FB is the standard of care, there are no established guidelines regarding standard management of FB associated with immunodeficiency, specifically IgG2/IgG4 deficiency. Therefore, a careful evaluation for immunodeficiency should be considered when evaluating for the underlying etiology of FB, as management options differ depending on the underlying diagnosis.

PMID:35308746 | PMC:PMC8923243 | DOI:10.7759/cureus.22183

Hematol Transfus Cell Ther. 2022 Mar 6:S2531-1379(22)00035-9. doi: 10.1016/j.htct.2022.01.014. Online ahead of print.

ABSTRACT

INTRODUCTION: Haploinsufficiency of the hematopoietic transcription factor GATA2 is associated with a broad spectrum of diseases, including infection susceptibility and neoplasms. We aimed to investigate GATA2 variants in patients with non-tuberculous mycobacterial (NTM) and/or fungal infections (FI) without known immunodeficiencies.

METHOD: We performed GATA2 genotyping in patients with NTM and/or FI.

RESULTS: Twenty-two patients were enrolled (seventeen FI, four NTM and one with both infections). The pathogenic variant NG_029334.1:g.16287C>T was found in one patient (4.5%) and two asymptomatic offsprings. We also found the likely-benign variant NG_029334.1:g.12080G>A (rs2335052), the benign variant NG_029334.1:g.16225C>T (rs11708606) and the variant of uncertain significance NG_029334.1:g.16201G>A (rs369850507) in 18.2%, 27.3%, and 4.5% of the cases, respectively. Malignant diseases were additionally diagnosed in six patients.

CONCLUSION: Although detected in 45.4% of the patients, most GATA2 variants were benign or likely benign. Identifying a pathogenic variant was essential for driving both the patient’s treatment and familial counseling. Pathogenic variants carriers should receive genetic counseling, subsequent infection prevention measures and malignancies surveillance. Additionally, case-control genotyping should be carried out in Brazil to investigate whether the observed variants may be associated with susceptibility to opportunistic infections and/or concurrent neoplasms.

PMID:35307305 | DOI:10.1016/j.htct.2022.01.014

Scand J Immunol. 2022 Mar 19:e13164. doi: 10.1111/sji.13164. Online ahead of print.

ABSTRACT

Common variable immunodeficiency (CVID) is accompanied by various lymphocyte abnormalities believed to be mostly responsible for disease features in patients with no diagnosed monogenic defects. Here, we evaluated the association of B and T lymphocyte abnormalities with the incidence of CVID. Twenty-six genetically unsolved CVID patients were examined for B and T lymphocyte subsets by flow cytometry and CD4⁺ T cell proliferation by Carboxyfluorescein succinimidyl ester (CFSE) test. We detected a reduction in total, naive, memory B cells and plasmablasts, and also total, naive, central memory and regulatory CD4⁺ T cells, besides naive CD8⁺ T cells. There were an increase in CD21^low and transitional B cells, effector memory (EM) and terminally differentiated effector memory (T_EMRA ) CD4⁺ T cell subsets as well as total, EM, T_EMRA , activated and cytotoxic CD8⁺ T cells among non-monogenic CVID patients. CD4⁺ T cells proliferation response was reduced regarding both division index and percent divided. In conclusion, regarding the similarity of lymphocyte abnormalities between patients without genetic defects and those with monogenic defects, genetic mutations are not responsible for these specific lymphocyte changes. However, the novel correlations observed between lymphocyte alterations among genetically unsolved CVID patients may serve as a guide to predict the potential of future CVID development for hypogammaglobulinemia children.

PMID:35305035 | DOI:10.1111/sji.13164

Scand J Immunol. 2022 Mar 18:e13163. doi: 10.1111/sji.13163. Online ahead of print.

ABSTRACT

BACKGROUND: Human Inborn Errors of Immunity (IEIs) are clinically and genetically heterogeneous group of diseases, with relatively mild clinical course or severe types that can be life-threatening. Severe combined immunodeficiency (SCID) is the most severe form of IEIs, which is caused by monogenic defects that impair the proliferation and function of T, B, and NK cells. According to the most recent report by the International Union of Immunological Societies (IUIS), SCID caused by mutations in IL2RG, JAK3, FOXN1, CORO1A, PTPRC, CD3D, CD3E, CD247, ADA, AK2, NHEJ1, LIG4, PRKDC, DCLRE1C, RAG1 and RAG2 genes.

METHODS: The targeted next-generation sequencing (TNGS) workflow based on Ion AmpliSeq™ Primary Immune Deficiency Research Panel was designed for sequencing 264 IEI related genes on Ion S5™ Sequencer.

RESULTS: Herein, we present 21 disease-causing variants (12 novel) which were identified in 22 patients in 8 different SCID genes.

CONCLUSION: Next generation sequencing allowed a rapid and an accurate diagnosis SCID patients.

PMID:35303369 | DOI:10.1111/sji.13163

Eur Ann Allergy Clin Immunol. 2022 Mar 18. doi: 10.23822/EurAnnACI.1764-1489.251. Online ahead of print.

NO ABSTRACT

PMID:35301845 | DOI:10.23822/EurAnnACI.1764-1489.251

J Allergy Clin Immunol Pract. 2022 Mar 14:S2213-2198(22)00143-X. doi: 10.1016/j.jaip.2022.01.047. Online ahead of print.

ABSTRACT

Artificial and augmented intelligence (AI) and machine learning (ML) methods are expanding into the health care space. Big data are increasingly used in patient care applications, diagnostics, and treatment decisions in allergy and immunology. How these technologies will be evaluated, approved, and assessed for their impact is an important consideration for researchers and practitioners alike. With the potential of ML, deep learning, natural language processing, and other assistive methods to redefine health care usage, a scaffold for the impact of AI technology on research and patient care in allergy and immunology is needed. An American Academy of Asthma Allergy and Immunology Health Information Technology and Education subcommittee workgroup was convened to perform a scoping review of AI within health care as well as the specialty of allergy and immunology to address impacts on allergy and immunology practice and research as well as potential challenges including education, AI governance, ethical and equity considerations, and potential opportunities for the specialty. There are numerous potential clinical applications of AI in allergy and immunology that range from disease diagnosis to multidimensional data reduction in electronic health records or immunologic datasets. For appropriate application and interpretation of AI, specialists should be involved in the design, validation, and implementation of AI in allergy and immunology. Challenges include incorporation of data science and bioinformatics into training of future allergists-immunologists.

PMID:35300959 | DOI:10.1016/j.jaip.2022.01.047

J Clin Immunol. 2022 Mar 16. doi: 10.1007/s10875-022-01218-4. Online ahead of print.

ABSTRACT

PURPOSE: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a primary immunodeficiency first described in 2013, which is caused by gain-of-function mutations in PIK3CD or PIK3R1, and characterized by recurrent respiratory tract infections, lymphoproliferation, herpesvirus infection, autoimmunity, and enteropathy. We sought to review the clinical phenotypes, immunological characteristics, treatment, and prognosis of APDS in a large genetically defined Chinese pediatric cohort.

METHODS: Clinical records, radiology examinations, and laboratory investigations of 40 APDS patients were reviewed. Patients were contacted via phone call to follow up their current situation.

RESULTS: Sinopulmonary infections and lymphoproliferation were the most common complications in this cohort. Three (10.3%) and five (12.5%) patients suffered localized BCG-induced granulomatous inflammation and tuberculosis infection, respectively. Twenty-seven patients (67.5%) were affected by autoimmunity, while malignancy (7.5%) was relatively rare to be seen. Most patients in our cohort took a combined treatment of anti-infection prophylaxis, immunoglobulin replacement, and immunosuppressive therapy such as glucocorticoid or rapamycin administration. Twelve patients underwent hematopoietic stem cell transplantation (HSCT) and had a satisfying prognosis.

CONCLUSION: Clinical spectrum of APDS is heterogeneous. This cohort’s high incidence of localized BCG-induced granulomatous inflammation and tuberculosis indicates Mycobacterial susceptibility in APDS patients. Rapamycin is effective in improving lymphoproliferation and cytopenia. HSCT is an option for those who have severe complications and poor response to other treatments.

PMID:35296988 | DOI:10.1007/s10875-022-01218-4