Search

BACKGROUND. Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder with impaired immunity against intracellular pathogens, such as mycobacteria, attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains, and environmental mycobacteria, in otherwise healthy individuals. In Mexico, the estimated incidence of tuberculosis in 2019 was 23 cases/100,000 people. BCG vaccination is mandatory in Mexico. PURPOSE. To review the clinical, immunological, and genetic characteristics of MSMD patients followed in ten hospitals across Mexico. METHODS. This retrospective study describes the clinical, immunological, and genetic characteristics of patients in Mexico diagnosed with MSMD from 2006 to 2021. RESULTS. Twenty-two patients from 17 kindreds were diagnosed with MSMD. Fourteen were male (64%) and eight were female. After BCG vaccination, 12 patients (70%) developed BCG infections. Six (22%) developed infections caused by Salmonella, and 11 (50%) developed infections caused by fungi, particularly Histoplasma. Thirteen different pathogenic variants were identified in IL12RB1 (n = 13), IFNGR1 (n = 3), and IFNGR2 (n = 1). Seven of the 22 patients died; the main cause was disseminated BCG infection. CONCLUSION. Interleukin-12Rβ1 deficiency was the main cause of MSMD in the Mexican cohort. The main etiologic agent responsible for morbidity and mortality was BCG.

Autosomal recessive (AR) DOCK8 deficiency is a well-known actinopathy, a combined primary immune deficiency with impaired actin polymerization that results in altered cell mobility and immune synapse. DOCK8-deficient patients present early in life with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial pneumonia, and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before its genetic etiology was known, patients were described as having a form of Hyper-IgE syndrome, a name now deprecated in favor of genetic defects. We describe a school-age male patient with a clinical picture suggestive of DOCK8 deficiency, except for high serum IgE or a family history: early onset, failure to thrive, eczema, warts, condyloma, bronchiolitis, pneumonia, recurrent otitis media, bronchiectasis, candidiasis, leukocytosis, eosinophilia, high IgA, low IgG, and low CD4+ T cells. We were able to confirm the diagnosis through protein expression and whole-exome sequencing. We review the clinical, laboratory, and genetic features of 200 DOCK8-deficient patients; at least 4 other patients have had no elevated IgE, and about 40% do not have Hyper-IgE (above 1,000 IU/mL). Despite this, the constellation of signs, symptoms, and findings allow the suspicion of DOCK8 deficiency and other actinopathies.

Mutations in Recombinase Activating Genes 1 and 2 (RAG1/2) results in human severe combined immunodeficiency (SCID). The products of these genes, are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Nonsense mutations in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with missense mutations may develop leaky SCID or Omenn syndrome (OS). A group of non-previously recognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two previously unidentified variants as causative of pathological manifestations associated to immunodeficiency. This study represents the first case series of RAG1 or RAG2 deficient patients from Mexico and Latin America.

Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 "agreed" and 38 "nonagreed" statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.

Background: X-linked agammaglobulinemia (XLA) is characterized by the absence of immunoglobulin and B cells. Patients suffer from recurrent bacterial infections from early childhood, and require lifelong immunoglobulin replacement therapy. Mutations in BTK (Bruton’s Tyrosine Kinase) are associated with this phenotype. Some patients that present XLA do not show typical clinical symptoms, resulting in delayed diagnosis due to the lack of a severe phenotype. This study presents a report of five XLA patients from four different families and attempts to determine a relationship between delayed diagnosis and the occurrence of BTK mutations. Methods: Samples from patients with antibody deficiency were analyzed to determine BTK expression, immunophenotyping and mutation analysis. Clinical and laboratory data was analyzed and presented for each patient. Results: Most patients presented here showed atypical clinical and laboratory data for XLA, including normal IgM, IgG, or IgA levels. Most patients expressed detectable BTK protein. Sequencing of BTK showed that these patients harbored missense mutations in the pleckstrin homology and Src-homology-2 domains. When it was compared to public databases, BTK sequencing exhibited a new change, along with three other previously reported changes. Conclusions: Delayed diagnosis and atypical manifestations in XLA might be related to mutation type and BTK expression.

Btk is the protein affected in XLA, a disease identified as a B cell differentiation defect. Btk is crucial for B cell differentiation and activation, but its role in other cells is not fully understood. This review focuses on the function of Btk in monocytes, neutrophils, and platelets and the receptors and signaling cascades in such cells with which Btk is associated.

Background X-linked agammaglobulinemia (XLA) is characterized by impaired B-cell differentiation caused by mutations in Bruton's tyrosine kinase (Btk) gen. Btk is expressed in myeloid cells and recent evidence support that it participates in Toll like receptor signaling, but results regarding its rol in XLA patients are contradictories. Objective To evaluate lipopolysaccharide (LPS)-induced pro-inflammatory cytokine response in peripheral blood mononuclear cells (PBMC) from XLA patients. Methods Thirteen patients with XLA were included in the study. PBMC LPS-induced TNF-α, IL-1β, IL-6, and IL-10 production was determined by ELISA and compared with that obtained from matched healthy controls. Cytokine production was correlated with the severity of the mutation, affected domain and clinical characteristics. Results In response to LPS, PBMC from XLA patients produced significantly higher amounts of pro-inflammatory cytokines and IL-10 compared with controls and this production is not influenced by the neither severity of mutation or the affected domain. PBMC from patients with a history of more hospital admissions before diagnosis and patients with lower expression of Btk in monocytes produced higher levels of TNF-α and IL-1β, respectively. PBMC from patients with lower IgA levels showed a higher production of TNF-α and IL-1β. Less severe (punctual) mutations in Btk gene were associated with higher IgG levels at diagnosis. Conclusions Our results demonstrated a predominantly inflammatory response in XLA patients after LPS stimuli and suggest a TLR signaling dysregulation in absence of Btk. This response may be influenced by environmental factors.