Paulo Vitor Soeiro Pereira

First Report of the Hyper-IgM Syndrome Registry of the Latin American Society for Immunodeficiencies: Novel Mutations, Unique Infections, and Outcomes

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

Clinical and Genotypic Spectrum of Chronic Granulomatous Disease in 71 Latin American Patients: First Report from the LASID Registry

We analyzed data from 71 patients with chronic granulomatous disease (CGD) with a confirmed genetic diagnosis, registered in the online Latin American Society of Primary Immunodeficiencies (LASID) database.

CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ

Background: Patients with X‐linked hyper‐IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L‐CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L‐deficient patients are susceptible to life‐threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. Objectives: We sought to analyze whether peripheral neutrophils from CD40L‐deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN‐&ggr; (rhIFN‐&ggr;) on neutrophil function. Methods: We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L‐deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. Results: Neutrophils from CD40L‐deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN‐&ggr; but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L‐deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL‐60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L‐deficient patients. Conclusion: Our data suggest a nonredundant role of CD40L‐CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN‐&ggr;, indicating a potential novel therapeutic application for this cytokine.

Leukocytes from wheezing infants release lower amounts of IL-12 and IFN-γ compared to non-wheezing infants.

This study investigated environmental endotoxin exposure during early life, sensitization to aeroallergens, the production of cytokines by LPS‐stimulated leukocytes, and the development of a wheezing phenotype in a prospective cohort of infants with high risk of developing allergic diseases.