Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

Background: Mycobacteria include ubiquitous species of varying virulence. However, environmental and individual-specific factors, particularly host genetics, play a crucial role in the outcome of exposure to mycobacteria. The first molecular evidence of a monogenic predisposition to mycobacteria came from the study of Mendelian susceptibility to mycobacterial disease (MSMD), a rare inborn error of IFN-γ immunity conferring a selective susceptibility to infections even with low virulent mycobacteria, in patients, mostly children, without recognizable immune defects in routine tests. This article provides a global and updated description of the most important molecular, cellular, and clinical features of all known monogenic defects of MSMD. Results: Over the last 20 years, 19 genes were found to be mutated in MSMD patients (IFNGR1, IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1, TYK2, IRF8, CYBB, JAK1, RORC, NEMO, and SPPL2A), and the allelic heterogeneity at these loci has led to the definition of 35 different genetic defects. Despite the clinical and genetic heterogeneity, almost all genetic etiologies of MSMD alter the interferon gamma (IFN-γ)-mediated immunity, by impairing or abolishing IFN-γ production or the response to this cytokine or both. It was proven that the human IFN-γ level is a quantitative trait that defines the outcome of mycobacterial infection. Conclusion: The study of these monogenic defects contributes to understanding the molecular mechanism of mycobacterial infections in humans and to the development of new diagnostic and therapeutic approaches to improve care and prognosis. These discoveries also bridge the gap between the simple Mendelian inheritance and complex human genetics.

Major histocompatibility complex class (MHC)‐II deficiency is a rare autosomal recessive combined immunodeficiency, accounting for 4.1% of inborn errors of immunity (IEI) cases in North Africa and the Middle East. Most patients do not survive beyond the age of 10 years. The cases described in this study are rare and unusual for MHC‐II deficiency. We report the cases of four unrelated patients of Moroccan origin with MHC‐II deficiency. Immunophenotyping of lymphocyte subpopulations and analysis of human leukocyte antigen‐DR (HLA‐DR) expression were performed using flow cytometry. Genetic analysis was conducted through direct sequencing. The mean age of our patients was 18.75 years (range 16–26 years); the mean age at diagnosis was 14.07 years, and the mean age of onset of symptoms was 5.25 months. The clinical presentation is characterized by recurrent pulmonary infections with predominant bronchial dilatation and hemorrhagic rectocolitis. The diagnosis was confirmed in all patients by absence of HLA‐DR expression and detection of the c.338‐25_338del mutation in RFXANK . Three (75%) of our patients are still alive and are on monthly intravenous immunoglobulin (IVIG) therapy. It is important to consider MHC‐II deficiency in the differential diagnosis of combined immunodeficiencies across all age groups. Further studies are needed to elucidate the various phenotypes associated with this condition.

Community-acquired urinary tract infections (UTIs) represent a significant public health issue, primarily due to the increasing antibiotic resistance among uropathogens. This study assesses the resistance status of uropathogenic community Enterobacterales to various antibiotics, particularly aminoglycosides, and determines the prevalence of aminoglycoside-modifying enzyme (AME) genes, while investigating the coexistence of 16S rRNA methylating enzymes. We analyzed 628 clinical isolates of Enterobacterales obtained from 4282 cytobacteriological urine examinations at the Pasteur Institute Casablanca, Morocco, collected from October 2018 to December 2021. Identification and antibiotic susceptibility testing were conducted using the VITEK 2^® COMPACT system, following CA-SFM guidelines. DNA extraction utilized the heat shock method, and subsequent PCR was performed. Gram-negative bacteria accounted for 85% of isolates, with Enterobacterales representing 91% of this group. E. coli (73%) and Klebsiella pneumoniae (20%) were the most common species among Enterobacterales. Resistance was particularly high for ampicillin (76.7%) and amoxicillin-clavulanate (58%). Among aminoglycosides, gentamicin and tobramycin resistance rates were 33.5% and 35%, respectively, while amikacin resistance was observed in 21.3% of isolates. High frequencies of AME genes were detected, with AAC(3′)-IIa (27.7%) and AAC(6′)-Ib (25.9%) being the most prevalent. Notably, no 16S rRNA methylation genes (rmtA, rmtB, rmtC, rmtD) were found. All tested strains exhibited biofilm-forming capacity, with K. pneumoniae demonstrating intense biofilm production. The study highlights a concerning trend of antibiotic resistance among uropathogenic Enterobacterales in the community setting, correlating genotype with resistance phenotype and emphasizing the need for enhanced surveillance and targeted treatment strategies.