Selma Cecilia Scheffler-Mendoza

Background: Inborn errors of immunity ( IEIs ) affecting thymic cell development or function can result in thymic aplasia or hypoplasia, autoimmunity, and the generation of neutralizing autoantibodies (Auto‐Abs) targeting type I interferons ( IFNs ) ( AAN ‐I‐ IFNs ). FOXN1 is a master transcriptional regulator of thymic epithelial cells and the impact of the FOXN1 variants spans a spectrum from pathogenic to benign. In pediatric patients with heterozygous FOXN1 variants the full spectrum of clinical and immunological determinants remains to be defined. Methods: Using a luminex multiplex immunoassay, we assessed the presence of auto‐Abs against 14 cytokines. We then employed two complementary in vitro cellular assays to test the neutralizing capacity of circulating auto‐Abs against type I IFNs . Results: Here, we present the case of an 11‐year‐old child who presented at 20 days of age with multiple severe infections. Genetic analysis revealed a heterozygous FOXN1 variant: c.1448_1451del. The patient tested positive for auto‐Abs against type I IFNs. Functional assays confirmed the presence of auto‐Abs with neutralizing activity against IFN‐α2 (at both low [10 ng/mL] and high [50 ng/mL] concentrations) and against IFN‐ω (only at 0.1 ng/mL and 10 ng/mL), but not against IFN‐β. Five months later, following four doses of rituximab, circulating autoantibodies levels decreased by about 60%. Conclutions: These findings suggest that heterozygous FOXN1 variants can impair thymic development in a manner that promotes the selective emergence of neutralizing auto‐Abs against type I IFNs, thereby predisposing affected individuals to severe viral infections. Monitoring these auto‐Abs may support personalized therapeutic strategies for affected patients.

Background: Patients with chronic granulomatous disease (CGD) can develop hemophagocytic lymphohistiocytosis (HLH), exacerbating mortality risk. Despite its clinical significance, data on HLH in CGD from international cohorts remain limited. This study aims to describe the occurrence of HLH in a cohort of patients with CGD, providing clinical insight into this association and emphasizing the need for early recognition and effective management. Methods: The records of 60 patients with CGD were reviewed. Those meeting the diagnostic criteria for HLH based on the HScore were included in the analysis. Both descriptive and inferential statistics were employed to evaluate the data. Results: Eleven patients (18.3%) fulfilled the HLH diagnostic criteria. The median interval between CGD genetic diagnosis and HLH onset was 36 months, with a median age at HLH diagnosis of 67 months. Infectious triggers were identified in eight cases, with Salmonella and Aspergillus species being the most common. One case involved an inflammatory trigger—multisystem inflammatory syndrome in children (MIS‐C) following SARS‐CoV‐2 infection. Mortality was high: 72.7% of the patients with HLH died. No significant difference ( p = .338) was observed between those who died after receiving only immunosuppressive therapy ( n = 2) and those who received both intravenous immunoglobulin and immunosuppressive therapy ( n = 6). Conclusion: HLH in CGD is associated with a high mortality rate. Notably, MIS‐C can present as an inflammatory trigger for HLH in this population. Careful evaluation of HLH parameters is recommended for all patients with CGD admitted with infection or inflammation to facilitate early diagnosis and guide management.

Background: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by defective antibody production and impaired differentiation of B cells. B cell proliferation is an essential step for antibody synthesis. Depending on the nature of the stimulus, their response may be either T-cell-dependent or T-cell-independent. Methods: We studied 23 CVID patients and 14 healthy donors (HD). The patients were categorized based on their percentage of memory B cells. In addition to standard immunophenotyping of circulating human B and T cell subsets, an in vitro CFSE dilution assay was used to assess the proliferative capacity of B cells and to compare the activation of the T cell-dependent and T cell-independent response among the patients. Results: Patients with a reduction in memory B cells exhibited an increase in follicular T cells (Tfh) and showed low proliferation in response to PKW, CpG, and SAC stimuli (Condition II) (p= 0.0073). In contrast, patients with a normal percentage of memory B cells showed a high expression of IL-21R and low proliferation in response to CPG (Condition III); IL-21, CD40L, and anti-IgM (Condition IV) stimuli (p= 0.0163 and p = 0.0475, respectively). Conclusion: Defective proliferation in patients depends on the type of stimulus used and the phenotypic characteristics of the patients. Further studies are necessary to understand the disease mechanisms, which may guide us toward identifying genetic defects associated with CVID.

Purpose: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8‐Def) in a tertiary care center for children.Methods: Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8‐Def. Genetic analysis was performed with targeted‐ or whole‐exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan–Meier method.Results: We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1–54 months). The median follow‐up time was 53.4 months (4.8–118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum‐driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis.Conclusion: DOCK8‐Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI‐associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8‐Def. Therefore, an early diagnosis of DOCK8‐Def is essential to facilitate an adequate treatment such as HSCT.

Chronic granulomatous disease (CGD) presents with granuloma formation and lethal infections. It is inherited in an autosomal or X-linked recessive pattern. We describe a 10-month-old patient with a fatal secondary HLH as a CGD primary manifestation. We carried out an autopsy and found noncaseating granulomas, an aspergilloma in the lung, and hemophagocytosis. We performed a DHR assay on the patient’s mother and grandmother, showing a bimodal pattern conclusive of X-linked CGD. Thus, our definitive diagnosis was CGD complicated by macrophage activation syndrome. CGD is caused by phagocytes’ inability to control pathogens, resulting in granulomas. Secondary HLH is a severe complication and could be characterized by the proliferation of macrophages and T lymphocytes and the production of proinflammatory cytokines. The early suspicion of this presentation helps establish a specific treatment, and the study of the carriers helps determine the etiology.

Inborn errors of immunity may present with autoimmunity and autoinflammation as hallmark clinical manifestations. We aimed to identify the potential monogenic causes of autoimmune disorders in 26 patients from a pediatric reference hospital in Mexico through whole-exome sequencing. We specifically selected patients with a family history of autoimmune diseases, early-onset symptoms, and difficult-to-control autoimmune disorders or autoimmunity associated with infection predisposition. We identified the genetic variants that were compatible with the patients' phenotype in 54% of the patients. Autoimmune diseases are often caused by a combination of genetic factors, but cases that appear at a young age are resistant to treatment or occur in clusters, as well as the presence of autoimmune symptoms alongside infectious diseases should raise suspicion for an underlying inborn error of immunity.

El síndrome multisistémico inflamatorio pediátrico, temporalmente asociado a COVID-19 (MIS-C/PIMS), es una nueva condición post-infecciosa secundaria a la infección por SARS-CoV2. Se ha caracterizado por una respuesta inflamatoria con afección multisistémica, con involucro de varios mecanismos de daño inmunológico como el incremento exagerado de citocinas y el daño epitelial. El tratamiento inmunomodulador está dirigido a controlar las manifestaciones de hiperinflamación, para estabilizar y prevenir secuelas a largo plazo. PALABRAS CLAVE: COVID-19, tratamiento inmunomodulador, inmunología, gammaglobulina, Enfermedad de Kawasaki, SARS-CoV-2, síndrome multisistémico inflamatorio pediátrico (MIS-C /PIMS)

Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients’ B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4 ⁺ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.