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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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Cabral-Marques, Otavio [1, 2] ; Franca, Tabata Takahashi [1] ; Al-Sbiei, Ashraf [3] ; Schimke, Lena Friederike [1, 2] ; Khan, Taj Ali [1, 4] ; Feriotti, Claudia [1] ; da Costa, Tania Alves [1] ; Reis Junior, Osvaldo [5] ; Weber, Cristina Worm [6] ; Ferreira, Janaira Fernandes [7] ; Tavares, Fabiola Scancetti [8] ; Valente, Claudia [8] ; Watanabe Di Gesu, Regina Sumiko [9] ; Lqbal, Asif [10] ; Riemekasten, Gabriela [2] ; Amarante-Mendes, Gustavo Pessini [11] ; Marzagio Barbuto, Jose Alexandre [1, 12] ; Costa-Carvalho, Beatriz Tavares [13] ; Soeiro Pereira, Paulo Vitor [1, 14] ; Fernandez-Cabezudo, Maria J. [15] ; Garcia Calich, Vera Lucia [1] ; Notarangelo, Luigi D. [16] ; Torgerson, Troy R. [17, 18] ; al-Ramadi, Basel K. [3] ; Ochs, Hans D. [17, 18] ; Condino-Neto, Antonio [1]
Total Authors: 26
Affiliation:
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[1] Univ Sao Paulo, Dept Immunol, Inst Biomed Sci, 1730 Linen Prestes Ave, BR-05508000 Sao Paulo - Brazil
[2] Univ Lubeck, Dept Rheumatol, Lubeck - Germany
[3] UAE Univ, Dept Med Microbiol & Immunol, Coll Med & Hlth Sci, Al Ain - U Arab Emirates
[4] Kohat Univ Sci & Technol, Dept Microbiol, Kohat - Pakistan
[5] Univ Estadual Campinas, Cent Lab High Performance Technol LaCTAD, Campinas, SP - Brazil
[6] Pediat Allergy & Immunol Clin, Caxias Do Sul - Brazil
[7] Albert Sabin Hosp, Fortaleza, Ceara - Brazil
[8] Hosp Base Dist Fed, Unit Pediat, Pediat Immunol Clin, Asa Sul - Brazil
[9] Conceicao Children Hosp, Div Allergy & Immunol, Dept Pediat, Porto Alegre, RS - Brazil
[10] Univ Sao Paulo, Dept Biochem, Inst Chem, Sao Paulo - Brazil
[11] Univ Sao Paulo, Dept Parasitol, Inst Biomed Sci, Sao Paulo - Brazil
[12] Univ Sao Paulo, NETCEM, Cell & Mol Therapy Ctr, Sao Paulo - Brazil
[13] Univ Fed Sao Paulo, Div Allergy & Immunol, Dept Pediat, Sao Paulo - Brazil
[14] Univ Fed Maranhao, Dept Pathol, Sao Luis - Brazil
[15] UAE Univ, Dept Biochem, Coll Med & Hlth Sci, Al Ain - U Arab Emirates
[16] NIAID, Lab Clin Immunol & Microbiol, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA
[17] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 - USA
[18] Seattle Childrens Res Inst, Seattle, WA - USA
Total Affiliations: 18
Document type: Journal article
Source: Journal of Allergy and Clinical Immunology; v. 142, n. 5, p. 1571+, NOV 2018.
Web of Science Citations: 5
Abstract

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-gamma (rhIFN-gamma) 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-gamma 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-gamma, indicating a potential novel therapeutic application for this cytokine. (AU)

FAPESP's process: 12/51745-3 - The role of CD40L-CD40 interaction in the antifungal immune response mediated by neutrophils and macrophages in humans
Grantee:Antonio Condino Neto
Support type: Regular Research Grants
FAPESP's process: 12/50515-4 - Role of CD40L-CD40 interaction in neutrophil and macrophage-mediated antifungal immune response in humans
Grantee:Otávio Cabral Marques
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 16/22158-3 - Molecular genetic mechanisms of primary immunodeficiencies
Grantee:Antonio Condino Neto
Support type: Research Projects - Thematic Grants