Ahmed Aziz Bousfiha

Heterozygous gain-of-function (GOF) variants in STAT1 are the most frequent genetic cause of chronic mucocutaneous candidiasis (CMC). Data from Africa remain scarce. We conducted a cross-sectional study at Ibn Rochd University Hospital, Casablanca (2016–2021), enrolling patients with persistent or recurrent mucocutaneous and/or invasive fungal disease. Whole-exome and/or Sanger sequencing were performed, with pathogenicity assessed using ACMG/AMP criteria. We identified 12 patients from 11 kindreds carrying 10 distinct heterozygous STAT1 GOF variants. CMC was the dominant manifestation (11/12, 91%). Mycobacterial infections were documented in 42% of patients and bacterial infections in 50%; one patient presented with cryptococcal meningitis. Autoimmunity was observed in three patients. Two patients died. The c.194A>G (p.D65G) variant, found in a father–son pair, may represent the first clinical description of this substitution as a STAT1 GOF variant. This first dedicated Moroccan cohort demonstrates substantial allelic heterogeneity and a clinical phenotype dominated by infections, particularly tuberculosis, with less frequent autoimmune manifestations than in Western cohorts.

Acute bronchiolitis is the leading cause of infant hospitalization worldwide, with respiratory syncytial virus (RSV) historically predominating. Prospective virological data for the 2025–2026 epidemic season in Morocco were lacking. A prospective observational cohort study was conducted at the Department of Pediatric Infectious Diseases and Clinical Immunology, Casablanca Mother-Child Hospital, from August 2025 through March 2026. Consecutive infants aged 1–24 months hospitalized with acute viral bronchiolitis underwent nasopharyngeal sampling and multiplex rapid antigen testing for RSV, influenza A, influenza B, and SARS-CoV-2. A total of 131 infants were enrolled (median age 4.8 months; male-to-female ratio 0.84:1). At least one virus was identified in 63 patients (48.1%; 95% CI 39.1–57.3%). RSV predominated: 49 sole infections and 2 co-infections with influenza A, totaling 51 positives (80.9% of virus-positive cases; 38.9% of the cohort). Influenza A totaled 8 cases (12.7%), including the 2 co-infections; influenza B accounted for 2 further cases (3.2%). SARS-CoV-2 was not detected. Epidemic activity peaked in January 2026 (65 admissions), declining through February (34) and March (12). All detected pathogens have licensed preventive options, supporting the introduction of nirsevimab, maternal RSV vaccination, and seasonal influenza vaccination as public health priorities in Morocco.

Al-Tamemi et al. describe that autosomal recessive CGD represents a significant disease in the MENA region associated with significant morbidity and mortality. Regional challenges are related to universal newborn BCG vaccine, lack of newborn screening programs, and limitation of curative interventions such as hematopoietic stem cell transplantation and gene therapy.

Invasive bacterial infections caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis remain a major public health concern. This study aimed to perform the molecular characterization of bacterial strains responsible for meningitis in patients of all ages who met the World Health Organization case definition for meningitis and had cerebrospinal fluid samples collected between January 2021 and December 2022 at the Clinical Bacteriology Laboratory of the National Public Health Institute of Mali. We conducted a surveillance-based observational study using national surveillance data collected between January 2021 and December 2022. Data were collected continuously and in real time throughout the study. The analysis was cross-sectional and descriptive. Data were obtained from samples received at the laboratory, accompanied by individual clinical notification forms. For each sample, demographic data and additional clinical information, including vaccination status, were collected. Infection was diagnosed by isolating invasive strains through culture, confirmed by real-time triplex PCR, and positive cases were further characterized by real-time triplex PCR for serotyping. Overall, 103 infections were confirmed among the 1000 samples received, corresponding to a positivity rate of 10.3%. S. pneumoniae predominated with 62%, followed by H. influenzae type b with 36% and N. meningitidis serogroup X with 2%. The identified serotypes of pneumococcus were predominantly not covered by existing vaccines, particularly serotype 23A (38.30%), while others, including serotypes 1 (17.02%) and 3 (10.63%), are included in the PCV13 vaccine. The distribution of cases by age and gender shows a predominance of males, accounting for 60.2% of cases (62/103). The 0–5 age group is by far the largest, accounting for 76.7% of cases (79/103), with males representing 58. 22% (46 cases). These findings highlight the importance and the need for continuous monitoring surveillance of circulating strains and strengthening vaccination efforts to improve prevention.

Patients with STAT2 p.R148Q variant present with life-threatening neuroinflammation, respiratory failure, and high mortality rate. Early genetic recognition and treatment with high-dose JAK inhibitors may improve outcomes in this devastating but potentially treatable interferonopathy.

Fulminant viral hepatitis (FVH) is a devastating condition caused by hepatotropic viruses such as hepatitis A virus (HAV), hepatitis B virus (HBV), and HSV-1/2. We studied 149 FVH patients (73 males and 76 females, aged 1–76) for blood autoantibodies (auto-Abs) neutralizing type I interferons (IFNs; IFN-α2, -β, -ω). Six of 16 (37.5%) HSV-triggered FVH patients carried such auto-Abs on admission, including three with a previously known autoimmune disease. These patients contrasted with 133 HAV- (n = 46) or HBV-triggered (n = 87) patients, none of whom had such detectable auto-Abs. Odds ratios for HSV-triggered FVH in individuals with auto-Abs ranged from 35.3 (95% CI: 13.0–96.2; P < 10–7) for those neutralizing only 100 pg/ml IFN-α/ω to 1,895 (CI: 448.5–8,002; P < 10–12) for those neutralizing both IFN-α and IFN-ω at 10 ng/ml. Over one third of HSV-triggered FVH cases in this international cohort were due to preexisting auto-Abs. This finding highlights auto-Abs against type I IFNs as a major determinant of HSV-FVH and paves the way for targeted preventive or therapeutic interventions.

Advances in genomic technologies, including whole exome and genome sequencing, have transformed diagnosis of monogenic disorders such as inborn errors of immunity (IEIs). In high-consanguinity populations like the United Arab Emirates (UAE), where autosomal recessive disorders are prevalent, early genomic screening shifts care from reactive diagnosis to personalized care. UAE national programs remain limited to premarital or neonatal panels, missing disorders with variable onset or incomplete penetrance. We advocate universal genomic screening to integrate disease-causing alleles into clinical care. As proof of concept, we highlight Mendelian susceptibility to mycobacterial disease (MSMD), an IEI defined by impaired interferon-gamma signaling and severe complications following Bacillus Calmette–Guérin (BCG) vaccination and Mycobacterium tuberculosis disease. We propose a tiered approach using MSMD-related genes within exome or genome platforms, enabling scalable, cost-effective implementation and periodic reanalysis as evidence evolves. In the UAE, high consanguinity, genomic infrastructure, and regulatory frameworks position MSMD as an entry point for population genomic screening, advancing precision medicine and prevention.

CD4 ⁺ T cells are indispensable for optimal immunity to Mycobacterium tuberculosis ( M.tb ), a pathogen that triggers tuberculosis (TB) in humans. M.tb -specific human CD4 ⁺ T cells are known to polarize toward an interferon-γ (IFN-γ)–producing, CCR4 ⁻ CCR6 ⁺ CXCR3 ⁺ T-bet ⁺ RORγT ⁺ T helper 1* cell (T _H 1*cell) memory phenotype. We report that autosomal recessive deficiency of the human lymphocytic surface receptor LY9 (SLAMF3 and CD229), which is found in less than 10 ⁻⁵ individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by T _H 1* cells. T _H 1* cells express higher levels of LY9 than other CD4 ⁺ T cells. Mechanistically, LY9 polarizes naïve CD4 ⁺ T cells toward memory T _H 1* cells by inducing T-bet via signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) and RORγT (thymus-specific retinoid-related orphan receptor γ) without SAP. LY9 costimulation enhances TCR-driven IFN-γ production of memory T _H 1*, but not T _H 1, cells in a T cell–intrinsic manner via NFAT1 (nuclear factor of activated T cells 1) and RORγT. LY9 is likely to govern an optimal T _H 1* cell– and IFN-γ–dependent protective immunity to M.tb in humans.

This report provides an updated classification of inborn errors of immunity (IEIs) involving 508 different genes and 17 phenocopies. Of these, we report 67 novel monogenic defects and 2 phenocopies due to neutralizing anti-cytokine autoantibodies or somatic mutations, which either have been discovered since the previous update (published June 2022) or were reported earlier but have been recently confirmed and/or expanded. The new additions were made after rigorous review of new genetic descriptions of IEIs by the International Union of Immunological Societies (IUIS) Expert Committee using criteria established to define IEI. Although similar pathogenic variants in one gene, in terms of both classes of mutation (missense, nonsense, etc.) and impact on protein function, can result in a spectrum of phenotypic manifestations, they are herein classified according to the most consistently reported phenotype. In addition, because different variants in a single gene can result in recognizable diseases due to gain or loss of function, such cases are classified according to their clinical manifestations as a distinct entry in the same or a different table depending on the associated phenotype. This report will serve as a valuable resource for clinical immunologists and geneticists involved in the molecular diagnosis of individuals with heritable and acquired immunological disorders. Moreover, we expect this report to also serve as a valuable resource for all disciplines of medicine, since patients with IEIs may be first seen by rheumatologists, hematologists, allergists, dermatologists, neurologists, gastroenterologists, and pulmonologists, depending upon their spectrum of presenting clinical features. Finally, expanding the known monogenic and related causes of human immune diseases requires dissection of underlying cellular and molecular mechanisms, which reveals fundamental requirements for specific genes, pathways, processes, and even cell types. Such knowledge may not only contribute to improved patient diagnosis and management but also pave the way to the development and implementation of therapies that target the cause—rather than the symptoms—of these conditions.

Here, we report the 2024 update of the phenotypic classification by the International Union of Immunological Societies (IUIS) expert committee (EC) on inborn errors of immunity (IEI), which accompanies and complements the 2024 genotypic classification. The aim of this classification is to help diagnosis for clinicians at the bedside and focuses on clinical features and basic laboratory phenotypes of specific IEI. In this update, 559 IEI are described, including 67 novel monogenic defects and 2 new phenocopies. This phenotypic classification is presented in the form of decision trees when possible, with essential clinical or immunological phenotype entries.