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© 2015, The Author(s).We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous ve

Purpose: To develop an assay to quantify serum immunoglobulin (IgG, IgM, IgA) levels using dried blood spots (DBS) obtained on collection cards to be used as a tool for targeted screening for hypogammaglobulinemia. Methods: DBS samples, along with simultaneous serum samples, were collected from 107 healthy individuals (11 months to 57 years of age). After eluting proteins from DBS, IgG, IgM, and IgA were quantified by an enzyme-linked immunosorbent assay (ELISA). The Ig-DBS assay was validated through calibration curve performance, intra- and inter-assay precision, accuracy, specificity, selectivity, and linearity. The ELISA measurements were compared with serum Ig levels obtained using a standard nephelometry assay on serum samples collected simultaneously with the DBS samples and the results of the two assays were correlated. The stability of IgG, IgM, and IgA in the DBS was tested at room temperature, 36° to 38 °C, 2 to 8 °C, and −25 to −40 °C, from 4 to 14 days. Results: The Ig-DBS assay demonstrated precision, accuracy, specificity, selectivity, and linearity. Using the identified correlation coefficients of 0.834 for IgG, 0.789 for IgM, and 0.918 for IgA, the standard nephelometry-based normal reference ranges for all 3 serum Ig isotypes could be used with the Ig-DBS assay in individuals ≥16 years of age. The DBS samples were stable for 14 days at room temperature in a closed polyethylene bag. Conclusions: The Ig-DBS assay is both sensitive and accurate for quantification of serum immunoglobulins. Samples are sufficiently stable at ambient temperature to allow for convenient shipping and analysis at a centralized laboratory. This assay therefore presents a new option for screening patients ≥16 years of age for hypogammaglobulinemia in any setting.

Background: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells.Methods: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates.Results: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients.Conclusions: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.). [ABSTRACT FROM AUTHOR]

The McMaster Immune Thrombocytopenia (ITP) Summit was an educational seminar from leading experts in immune thrombocytopenia and related disorders geared towards hematologists, internists, immunologists, and clinical and translational scientists. The focus of the Summit was to review the mechanisms, diagnosis and treatment of primary versus secondary ITP. Specific objectives were to describe the unique features of secondary ITP, and to review its mechanisms in the context of autoimmune disease and infection. The key messages in this Summit were: (1) ITP is a heterogeneous disease, and genetic and immunologic insights may help classify patient subtypes; (2) Exploring the autoimmune mechanisms and their association with hypogammaglobulinemia in patients with secondary ITP could improve our understanding of ITP and its subtypes; (3) Investigating the mechanisms of ITP in the context of infections caused by viruses such as CMV, HIV, dengue, and hepatitis C, or bacteria such as H. pylori, or vaccinations could provide insight into the causes of ITP. A better understanding of secondary ITP could help elucidate the pathogenesis of ITP., Competing Interests: D.M, S.R.C., S.M, H.M., V.R.B., and I.N. declare that they have no conflicts of interest. D.C. reports consulting fees from Novartis and Sanofi. D.C. also serves on a Data Safety Monitoring Board or Advisory Board for Novartis and Sanofi. C.N. has received author royalties from UpToDate. Consulting fees were received from ArgenX, Novartis, Sobi, Sanofi, and Genzyme, while an ongoing consultancy exists with Janssen. Honoraria were received from Sanofi. Payments for expert testimony were received from the U.S. Department of Defense Vaccine Program and Stein Mitchell Beato & Missner LLP. Travel support was received from Sanofi for ISTH 2024. Unpaid roles include being a medical advisor for ITP Australia and The UK ITP Support Association, and a committee member with ASH Committee on Quality, ISTH Meeting Planning Committee 2025, and a chair on the ASPHO review course. H.A. received grants or contracts from Agios, Amgen, Novartis, Vaderis, and Sobi to their institution. Consulting payments were received from Amgen, Novartis, Alnylam, Agios, Argenx, Alpine, Sobi, and Pharmacosmos. N.C. disclosed participation on a data safety monitoring board or advisory board, and payment for honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from Amgen, Novartis, Griffols, and Sobi. G.M. disclosed support from McMaster University related to the present manuscript. G.M. has received grants or contracts from Amgen, Argenx, Grifols, Novartis, and Sanofi, and consulting fees from Argenx, Grifols, Novartis, Sanofi, Alpine, and Amgen, along with payments from Amgen, Grifols, and Novartis. Support for attending meetings was provided by Amgen, Grifols, and Novartis. C.C.R. disclosed a consultancy role with Pharming, award committee role with Grifols, and data safety monitoring board role with Otsuka since the initial planning of this manuscript. C.C.R. has received grants or contracts from X4 and NIH USIDNET, and serves on a steering committee for NIH USIDNET. Consulting fees were received from Pharming and X4. C.C.R. also attended meetings and events sponsored by the CIS Summer School 2024, CIS National Meeting 2024, and the California Allergy Immunology Society 2024. Patents are planned, issued, or pending for the use of BTK in inflammatory diseases in CVID. C.C.R. holds a leadership role in the Royal PID group in New York City. H.A.L. has received grants or contracts from Sanofi, and consulting fees from Sanofi, Novartis, and Alpine Immune Sciences. J.B.B. has received consulting fees from Amgen, Novartis, SOBI, UCB, Argenx, Janssen, and RallyBio. D.M.A. declares receiving grants or contract support from the Canadian Institutes of Health Research, Rigel, and Alpine Immune Sciences (all related to ITP), royalties or licenses from UpToDate, and consulting fees from Novartis, Rigel, Amgen, Medison, Sobi, and Argenx (all related to ITP). D.M.A. also serves as an unpaid medical advisor for the Platelet Disorders Support Association., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: NFKB1 encodes p105, which is processed to p50 to mediate canonical nuclear factor-κB (NF-κB) signaling. Although NF-κB is a central driver of inflammation and heterozygous NFKB1 variants are considered the most common monogenic etiologies of common variable immunodeficiency (CVID), few studies have explored how NFKB1 variants shape clinical course or inflammation in CVID., Objective: We leveraged a regional cohort of patients with CVID with and without heterozygous NFKB1 variants to assess how clinical and inflammatory features of CVID are shaped by the presence of these variants., Methods: We compared clinical complications, immunologic features, and plasma cytokine levels of 15 patients with CVID with heterozygous NFKB1 variants and 77 genetically undefined patients with CVID from the same referral base. We also assessed differences between patients with CVID with frameshift or nonsense NFKB1 variants compared with those with missense NFKB1 variants., Results: We found patients with CVID with heterozygous NFKB1 variants to have increased autoimmune disease, bronchiectasis, gastrointestinal infections, inflammatory bowel disease, and plasma cytokines. These findings were more pronounced and included elevation of monocytes in patients with CVID with frameshift or nonsense NFKB1 variants relative to those with missense NFKB1 variants., Conclusions: In a regional cohort, heterozygous NFKB1 variants were associated with worsened CVID clinical course and increased evidence of inflammation in the blood. Patients with CVID with frameshift or nonsense NFKB1 variants had more significant increases in noninfectious complications and peripheral monocytes than those with missense NFKB1 variants. Presence of pathogenic NFKB1 variants in patients with CVID may worsen the disease course and warrant closer monitoring., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Common variable immunodeficiency (CVID) is one of the most common groups of human inborn errors of immunity. In addition to infections resulting from insufficient levels of immunoglobulins and antibodies, a significant proportion of patients develop autoimmune cytopenias, especially immune thrombocytopenia, hemolytic anemia, or neutropenia. They may be the initial manifestation of CVID in a patient who has not had significant infections, and similar episodes may recur at intervals over time. Treatment of these hematologic complications includes the use of corticosteroids or other medications, often including rituximab; splenectomy is discouraged. Here we outline the overall occurrence of these blood cytopenias in a cohort of 408 patients, as well as the clinical and genetic associations noted in these individuals., (Copyright © 2024 by The American Society of Hematology.)

Underrepresentation in clinical genomics research limits the generalizability of findings and the benefits of scientific discoveries. We describe the impact of patient-centered, data-driven recruitment and retention strategies in a pediatric genome sequencing study. We collaborated with a stakeholder board, conducted formative research with adults whose children had undergone genomic testing, and piloted and revised study approaches and materials. Our approaches included racially, ethnically, and linguistically congruent study staff, relational interactions, study visit flexibility, and data-informed quality improvement. Of 1,656 eligible children, only 6.5% declined. Their parents/legal guardians were 76.9% non-White, 65.6% had public health insurance for the child, 49.9% lived below the federal poverty level, and 52.8% resided in a medically underserved area. Among those enrolled, 87.3% completed all study procedures. There were no sociodemographic differences between those who enrolled and declined or between those retained and lost to follow-up. We outline stakeholder-engaged approaches that may have led to the successful enrollment and retention of diverse families. These approaches may inform future research initiatives aiming to engage and retain underrepresented populations in genomics medicine research., Competing Interests: Declaration of interests N.S.A.-H. is an employee and equity holder of 23andMe and serves as a scientific advisory board member for Allelica. E.E.K. received personal fees from Illumina, 23andMe, Allelica, and Regeneron Pharmaceuticals, received research funding from Allelica, and serves as a scientific advisory board member for Encompass, Bio, Overtone, and Galateo Bio. K.B. is an employee and stockholder of Illumina, Inc. M.P.W. receives consulting fees from Sanofi Genzyme and research funding from Abeona, Alexion, Ara Parseghian Medical Research Foundation, BioMarin Pharmaceutical, Cure Sanfilippo Foundation, Dana’s Angels Research Trust, Firefly Fund, Mirium Pharma, Noah’s Hope/Hope4Bridget, Orchard Therapeutics, PassageBio, Sanofi Genzyme, Sio Gene Therapies, Takeda Pharmaceutical, Travere Therapeutics, and Ultragenyx Pharmaceutical., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Human DNA ligase 1 (LIG1) performs the final step in DNA repair and recombination pathways by sealing DNA breaks, and it functions as the main replicative ligase. Hypomorphic LIG1 variants R771W and R641L cause immune deficiencies in LIG1 Syndrome patients. In vitro these LIG1 variants have decreased catalytic efficiency and increased abortive ligation and it is not known if either biochemical defect is sufficient on its own to cause immune deficiency. We investigated the enzymatic activity of several new candidate LIG1 Syndrome variants chosen based on their structural proximity to known clinical variants, low minor allele frequency (MAF), high level of conservation, and concurrence in patients with similar symptoms as LIG1 Syndrome patients. The R305Q substitution is in the DNA binding domain, R768W is in the OB-fold domain, and R641S is in the nucleotidyltransferase domain. Biochemical characterization confirmed deficiencies in ligase activity for all three variants, but also revealed marked differences in comparison to the known LIG1 Syndrome variants. Both the R305Q and R768W substitutions increase the K M for DNA and decrease the catalytic efficiency, however, neither exhibit elevated levels of abortive ligation. In contrast, the R641S variant exhibits a greater impairment of activity as well as a more pronounced level of abortive ligation compared to the known LIG1 Syndrome variant, R641L. This work expands the number of LIG1 alleles that are likely candidates for LIG1 Syndrome, and it raises the question of whether distinct enzymatic deficiencies in LIG1 cause unique clinical impacts in patients harboring these alleles., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Prevention and treatment of infections are primary goals of treatment of children and adults with primary immune deficiencies due to decreased antibody production. Approaches to these goals include immunoglobulin replacement therapy, vaccination, and prophylactic treatment with antimicrobials. In this review, the infectious and non-infectious complications of antibody deficiencies will be discussed along with the limited number of studies that support the effective use of the available therapies and to drive the development of new therapies. Some illustrative case studies will be presented and the outlook for additional controlled clinical trials and potential for therapies driven by the underlying disease genetics will be considered., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)