Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis - 01/03/12

Doi : 10.1016/j.jaci.2011.10.026

Otavio Cabral Marques, MSc ^a,^g, Christina Arslanian, BSc ^a, Rodrigo Nalio Ramos, MSc ^a, Mariana Morato, MSc ^a, LenaFriederike Schimke, MD ^a,^g, Paulo Vitor Soeiro Pereira, MSc ^a, Sonia Jancar, MD, PhD ^a, Janaíra Fernandes Ferreira, MD ^b, Cristina Worm Weber, MD ^c, Gisele Kuntze, MD ^d, Nelson Augusto Rosario-Filho, MD, PhD ^e, Beatriz Tavares Costa Carvalho, MD ^f, Patricia Cruz Bergami-Santos, PhD ^a, Mary J. Hackett, BSc ^g, Hans D. Ochs, MD ^g, Troy R. Torgerson, MD, PhD ^g, Jose Alexandre Marzagão Barbuto, MD, PhD ^a,^{^{These authors contributed equally to this work.}}, Antonio Condino-Neto, MD, PhD ^a,^{^{These authors contributed equally to this work.}}^⁎
^a Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
^b Albert Sabin Hospital, Fortaleza, Brazil
^c Pediatric Allergy and Immunology Clinic, Caxias do Sul, Brazil
^d Pequeno Principe Hospital, Curitiba, Brazil
^e Department of Pediatrics, Federal University of Paraná Medical School, Curitiba, Brazil
^f Department of Pediatrics, Division of Allergy-Immunology and Rheumatology, Federal University of São Paulo, São Paulo, Brazil
^g Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Hospital, Seattle, Wash

Corresponding author: Antonio Condino-Neto, MD, PhD, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 1730 Lineu Prestes Ave, São Paulo, SP 05508-000, Brazil.

Abstract

Background

Patients with X-linked hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood.

Objective

To determine whether monocyte-derived dendritic cells (DCs) from patients with X-HIGM exhibit normal responses to fungal pathogens.

Methods

DCs from patients and controls were evaluated for the expression of costimulatory (CD80 and CD86) and MHC class II molecules and for their ability to produce IL-12 and IL-10 in response to Candida albicans and Paracoccidioides brasiliensis. We also evaluated the ability of C albicans– and P brasiliensis–pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (T_H) 17 cells, and production of IFN-γ, TGF-β, IL-4, IL-5, and IL-17.

Results

Immature DCs from patients with X-HIGM showed reduced expression of CD80, CD86, and HLA-DR, which could be reversed by exogenous trimeric soluble CD40L. Most important, mature DCs from patients with X-HIGM differentiated by coculturing DCs with fungi secreted minimal amounts of IL-12 but substantial amounts of IL-10 compared with mature DCs from normal individuals. Coculture of mature DCs from X-HIGM patients with autologous T cells led to low IFN-γ production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally, in vitro incubation with soluble CD40L reversed the decreased IL-12 production and the skewed T_H2 pattern response.

Conclusion

Absence of CD40L during monocyte/DC differentiation leads to functional DC abnormalities, which may contribute to the susceptibility to fungal infections in patients with X-HIGM.

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Key words : CD40 ligand deficiency, fungal infections, dendritic cells, X-linked hyper-IgM syndrome, primary immunodeficiency

Abbreviations used : APCs, CD40L, DCs, iDCs, mDCs, PTX3, sCD40L, X-HIGM

Plan

Lymphocyte stimulation assay

Evaluation of T_H17 function

Analysis of cytokine and pentraxin 3 release

Statistical analysis

Results

iDCs from CD40L-deficient patients express normal TLR2, TLR4, and CD14 but reduced CD80, CD86, and HLA-DR that can be reversed by treating iDCs with sCD40L

DCs from CD40L-deficient patients promote normal generation of T_H17 cells

mDCs from CD40L-deficient patients show imbalanced production of IL-12/IL-10

DCs from CD40L-deficient patients induce similar levels of lymphocyte proliferation compared with normal controls

mDCs from CD40L-deficient patients induce a T_H2-skewed T-cell response

The skewed T_H2 pattern response of CD40L-deficient patients can be reversed by exogenous sCD40L

Discussion

	This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo— grant 2008/06635-0 to O.C.M., grant 2008/55700-9 to A.C.N., and grant 2009/54599-5 to J.A.M.B.—and by the Jeffrey Modell Foundation.
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis - 01/03/12

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

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