Issues

This review explores how genetic variation impacts early B cell development, highlighting key genes and pathways involved in lineage commitment, V(D)J recombination, and B cell maturation. It discusses inherited rare variants and more common polymorphisms that predispose to B cell–related immune disorders and malignancies.

Germline variants in IKZF family proteins cause inborn errors of immunity characterized by variable degrees of immunodeficiency, immune dysregulation, and occasional malignancies.

Here, we review IEI that can present with rheumatologic and autoimmune complications and the role of genetic testing for establishing a molecular diagnosis and devising personalized treatment plans to improve patient outcomes.

This article describes the ethical dilemmas encountered by clinical immunologists in the evaluation of an inborn error of immunity. Potential sources of health disparities are reviewed. This article describes several key ethical principles and articulates how immunologists can navigate ethical dilemmas in their practice.

Omenn syndrome is a severe autosomal recessive combined immunodeficiency whose only curative treatment is allogeneic stem cell transplantation. We describe a rare case of infiltrative cardiomyopathy secondary to Omenn syndrome successfully treated by a combination of anti-IL5 antibodies and alemtuzumab, allowing successful HSCT.

A patient with a predominantly neurological phenotype was found to have a mosaic STAT5B gain-of-function variant and was successfully treated with HCT.

We present a case of increased within-host viral diversity linked to impaired type I interferon response during COVID-19.

Autosomal dominant STAT1 deficiency is a monogenic defect that increases susceptibility to coccidioidomycosis in humans.

This is the first reported case of Down syndrome complicated by severe combined immunodeficiency successfully treated with hematopoietic stem cell transplantation. While Down syndrome can lead to low TREC levels in newborn screening, which typically recover spontaneously, careful follow-up is indispensable for potential risk.

We report the case of a patient with complete TYK2 deficiency and virally induced hypereosinophilia and respiratory failure who responded to IL-5 blockade. TYK2 may be involved in regulating the Th1/Th2 balance in favor of Th1 and downregulating eosinophil recruitment in the airway.

Patients with TAP1/TAP2 deficiency develop rubella-associated skin granulomas due to impaired HLA-I antigen presentation. Markedly elevated rubella IgG levels may support diagnosis when PCR is unavailable. These findings also underscore the specific vulnerability of such patients to live-attenuated rubella vaccination.

A large, previously unknown deletion of 12 protein-coding genes in X-linked CGD with MLP was identified. Allogeneic Kx− RBCs were collected from another individual with MLP, and non-cryopreserved RBCs were readily available over several months prior to HSCT to the peritransplant phase.

Authors report a patient with recurrent respiratory infections and bronchiectasis due to an atypical splice-site PIK3R1 variant causing APDS2. Functional studies confirmed PI3Kδ hyperactivation.

Worldwide, most patient registries for IEI are national, with limited geographical/temporal scope. This 30-year ESID registry analysis of 30,628 patients’ longitudinal datasets enables robust epidemiological studies on natural courses, including diagnosis, treatment, and survival, supporting expanded newborn screening and future AI applications in IEI research.

Type I IFN autoantibodies (auto-Abs) impair antiviral immunity and are associated with severe COVID-19. This study reveals a 6.7% prevalence of auto-Abs in critically ill Brazilian patients, predominantly affecting older individuals, and links their presence to worse clinical outcomes.

This study focuses on the clinical and microbiologic description of invasive aspergillosis in Mexican patients with chronic granulomatous disease. It highlights the diagnostic and therapeutic difficulties encountered and suggests the development of strategies to improve the outcome of these patients.

We describe seven intronic pathogenic variants underlying inborn errors of immunity.

STAT1-GOF disease is characterized by infections and autoimmunity. In this article, overall survival after allogeneic HSCT in an international cohort of 36 patients is 72.2%, markedly improved from an earlier report. Pre-treatment with JAK inhibitors is associated with better event-free survival.

We report a case of disseminated gonococcal infection linked to complement factor I (FI) deficiency, with a prior vasculitis-like episode. FI deficiency should be suspected in the setting of complement consumption, characterized by low levels of multiple complement components.

22q11.2 deletion syndrome causes thymic hypoplasia. In an embryonic mouse model, Sox9-expressing chondrocytes expanded in the hypoplastic thymuses. A drug screen identified minoxidil as a therapeutic that restored thymus growth and limited the overproduction of collagens and ECM proteins when administered in pregnant mice.