Human Cd40 Ligand Deficiency Dysregulates The Macrophage Transcriptome Causing Functional Defects That Are Improved By Exogenous Ifn-gamma

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. Objectives: We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. Methods: After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-gamma (rhIFN-gamma) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-g and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-gamma treatment was studied. Results: Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-gamma but not sCD40L. In contrast, rhIFN-gamma and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-gamma reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-gamma. Additionally, rhIFN-gamma increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin in macrophages from both control subjects and patients. Conclusion: Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-gamma suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.1393900+Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2012/50515-4, 2012/51745-3]Jeffrey Modell FoundationFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

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.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Jeffrey Modell FoundationLatin American Advisory Board on Primary Immunodeficiencies initiativeUniv São Paulo, Inst Biomed Sci, Dept Immunol, BR-05508000 São Paulo, BrazilCtr Invest & Estudios, Dept Biomed Mol, Mexico City, DF, MexicoDr Ricardo Gutierrez Childrens Hosp, Buenos Aires, DF, ArgentinaHosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa RicaPediat Allergy & Immunol Clin, Caxias Do Sul, RS, BrazilAlbert Sabin Hosp, Fortaleza, Ceara, BrazilHosp Base Dist Fed, Brasilia, DF, BrazilIntegrated Ctr Pediat Specialties, Curitiba, PR, BrazilHosp Ninos VJ Vilela, Rosario, ArgentinaHosp Ninos Luis Calvo Mackenna, Santiago, ChileUniv Fed Parana, Dept Pediat, BR-80060000 Curitiba, Parana, BrazilUniv Estadual Campinas, Sch Med, Dept Pediat, Campinas, SP, BrazilConceicao Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Porto Alegre, RS, BrazilChildrens Hosp Lucidio Portela, Teresina, PI, BrazilPontificia Univ Catolica Chile, Div Pediat, Santiago, ChileUniv Estadual Campinas, Sch Med, Dept Med, Campinas, SP, BrazilUniv São Paulo, Ribeirao Preto Med Sch, BR-14049 Ribeirao Preto, SP, BrazilHosp Nacl Edgardo Rebagliati Martins Alergia & In, Lima, PeruUniv Fed Rio de Janeiro, Sch Med, Dept Pediat, Rio de Janeiro, BrazilInst Nacl Pediat, Unidad Invest Inmunodeficiencias, Mexico City, DF, MexicoIMSS, Unidad Med Alta Especialidad 25, Monterrey, Nuevo Leon, MexicoClin Montefiori, Unidad Inmunol, Lima, PeruUNAL, Univ Hosp, Monterrey, Nuevo Leon, MexicoFac Med ABC, Santo Andre, SP, BrazilChildrens Hosp, Dept Pediat, New Orleans, LA USAHop Necker Enfants Malad, INSERM, Unite U768, Paris, FranceUniv Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USASeattle Childrens Res Inst, Seattle, WA USAUniversidade Federal de São Paulo, Dept Pediat, Div Allergy Immunol & Rheumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pediat, Div Allergy Immunol & Rheumatol, São Paulo, BrazilFAPESP: 2012/50515-4FAPESP: 2006/57643-7FAPESP: 2012/51745-3Web of Scienc