High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as “age-associated B cells” (ABCs). T-bet–deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21 ^lo CD11c ^hi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS , IL21R , SEC61B , DUSP4 , DAPP1 , SOX5 , CD79B , and CXCR4 . Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11c ^hi CD21 ^lo B cells.

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7–9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2–5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6–35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1–9.6]) of IFN-ω and/or IFN-α2.

Patients with inborn errors of immunity (IEI) are prone to develop infections, either due to a broad spectrum of pathogens or to only one microbe. Since skin is a major barrier tissue, cutaneous infections are among the most prevalent in patients with IEI due to high exposures to many microbes. In the general population, human papillomaviruses (HPVs) cause asymptomatic or self-healing infections, but, in patients with IEI, unusual clinical expression of HPV infection is observed ranging from epidermodysplasia verruciformis (EV) (a rare disease due to β-HPVs) to profuse, persistent, and recalcitrant warts (due to α-, γ-, and μ-HPVs) or even tree man syndrome (due to HPV2). Mutations in EVER1, EVER2, and CIB1 are associated with EV phenotype; GATA2, CXCR4, and DOCK8 mutations are typically associated with extensive HPV infections, but there are several other IEI that are less frequently associated with severe HPV lesions. In this review, we describe clinical, immunological, and genetic patterns of IEI related to severe HPV cutaneous infections and propose an algorithm for diagnosis of IEI with severe warts associated, or not, with lymphopenia.

Background/Objectives: Corona virus disease 2019 (COVID-19) poses a threat to global public health. The early identification of critical cases is crucial to providing timely treatment to patients. Here, we investigated whether the neutrophil levels could predict COVID-19 complications. Methods: We performed a retrospective study of patients with COVID-19, admitted to the Cheikh Khalifa International University Hospital, Casablanca, Morocco. Laboratory test results collected upon admission and during hospitalization were analyzed based on clinical information. Results: Our study revealed that a rise in neutrophil “PNN” levels was associated with respiratory deterioration and intubation. They were positively correlated with the procalcitonin and C-reactive protein levels. Interestingly, PNN (polynuclear neutrophil) levels on day 5 proved to be a better predictor of intubation, acute respiratory distress syndrome (ARDS), and mortality than the initial PNN counts, C-reactive protein, or procalcitonin. Moreover, binary logistic regression with stratified PNN-day 5 data revealed that a PNN level on day 5 > 7.7 (109/L) was an independent risk factor for mortality and ARDS. Finally, the PNN levels on day 5 and proinflammatory cytokine IL-6 were positively correlated. Conclusions: Our data showed that neutrophilia proved to be an excellent predictor of complications and mortality during hospitalization and could be used to improve the management of patients with COVID-19.

Unusual viral skin infections might be the first clinical manifestation in children with an inborn error of immunity (IEI). We performed a prospective study from 1 October 2017 to 30 September 2021, at the Department of Pediatric Infectious Diseases and Clinical Immunity of Ibn Rochd University Hospital-Casablanca. During this period, on 591 patients newly diagnosed with a probable IEI, eight of them (1.3%), from six independent families, had isolated or syndromic unusual viral skin infections, which were either profuse, chronic or recurrent infections, and resistant to any treatment. The median age of disease onset was nine years old and all patients were born from a first-degree consanguineous marriage. By combining clinical, immunological and genetic investigations, we identified GATA2 deficiency in one patient with recalcitrant profuse verrucous lesions and monocytopenia (1/8) and STK4 deficiency in two families with HPV lesions, either flat or common warts, and lymphopenia (2/8), as previously reported. We also identified COPA deficiency in twin sisters with chronic profuse Molluscum contagiosum lesions, pulmonary diseases and microcytic hypochromic anemia (2/8). Finally, we also found one patient with chronic profuse MC lesions and hyper IgE syndrome, (1/8) and two patients with either recalcitrant profuse verrucous lesions or recurrent post-herpetic erythema multiforme and a combined immunodeficiency (2/8) with no genetic defect identified yet. Raising clinicians awareness that infectious skin diseases might be the consequence of an inborn error of immunity would allow for optimized diagnosis, prevention and treatment of patients and their families.

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.