Publications by authors named "Alejandro Nieto-Patlán"

9 Publications

  • Page 1 of 1

A purely quantitative form of partial recessive IFN-γR2 deficiency caused by mutations of the initiation or second codon.

Hum Mol Genet 2018 11;27(22):3919-3935

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France.

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-γ immunity. Germline bi-allelic mutations of IFNGR2 can underlie partial or complete forms of IFN-γ receptor 2 (IFN-γR2) deficiency. Patients with partial IFN-γR2 deficiency express a dysfunctional molecule on the cell surface. We studied three patients with MSMD from two unrelated kindreds from Turkey (P1, P2) and India (P3), by whole-exome sequencing. P1 and P2 are homozygous for a mutation of the initiation codon(c.1A>G) of IFNGR2, whereas P3 is homozygous for a mutation of the second codon (c.4delC). Overexpressed mutant alleles produce small amounts of full-length IFN-γR2 resulting in an impaired, but not abolished, response to IFN-γ. Moreover, SV40-fibroblasts of P1 and P2 responded weakly to IFN-γ, and Epstein Barr virus-transformed B cells had a barely detectable response to IFN-γ. Studies in patients' primary T cells and monocyte-derived macrophages yielded similar results. The residual expression of IFN-γR2 protein of normal molecular weight and function is due to the initiation of translation between the second and ninth non-AUG codons. We thus describe mutations of the first and second codons of IFNGR2, which define a new form of partial recessive IFN-γR2 deficiency. Residual levels of IFN-γ signaling were very low, accounting for the more severe clinical phenotype of these patients with residual expression levels of normally functional surface receptors than of patients with partial recessive IFN-γR2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN-γ signaling were higher.
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http://dx.doi.org/10.1093/hmg/ddy275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216222PMC
November 2018

Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction.

J Clin Immunol 2019 04 5;39(3):298-308. Epub 2019 Mar 5.

Laboratory for Inborn Errors of Immunity, Department of Immunology and Microbiology, KU Leuven, Leuven, EU, Belgium.

DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.
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http://dx.doi.org/10.1007/s10875-019-00603-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647034PMC
April 2019

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23.

Sci Immunol 2018 12;3(30)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4 T cells, including, in particular, mycobacterium-specific T1* cells (CD45RACCR6), is dependent on both IL-12 and IL-23. Last, we show that , , and have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rβ2-deficient than IL-12Rβ1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.
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http://dx.doi.org/10.1126/sciimmunol.aau6759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380365PMC
December 2018

A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency.

J Clin Immunol 2018 07 11;38(5):617-627. Epub 2018 Jul 11.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France.

Purpose: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs.

Methods: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS).

Results: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n = 1) or in trans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%).

Conclusion: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.
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http://dx.doi.org/10.1007/s10875-018-0527-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329663PMC
July 2018

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

J Clin Invest 2018 08 6;128(9):3957-3975. Epub 2018 Aug 6.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.
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http://dx.doi.org/10.1172/JCI97116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118590PMC
August 2018

Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia.

J Clin Immunol 2018 04 27;38(3):278-282. Epub 2018 Mar 27.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France.

Purpose: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30).

Methods: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain.

Results: Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect.

Conclusions: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.
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http://dx.doi.org/10.1007/s10875-018-0490-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934323PMC
April 2018

Recognition of Candida albicans by Dectin-1 induces mast cell activation.

Immunobiology 2015 Sep 11;220(9):1093-100. Epub 2015 May 11.

Department of Immunology, National School of Biological Sciences-National Polytechnic Institute, ENCB-IPN, Mexico. Electronic address:

Mast cells are crucial elements of the innate immune response. They reside in tissues that are commonly exposed to the external environment, such as the skin and mucosae, where they can rapidly detect the presence of pathogens and mount a potent inflammatory response that recruits other cellular effectors of the immune response. The contribution of mast cells to the immune response to viruses, bacteria, protozoa and multicellular parasites is well established, but there is scarce information about the role of these cells in fungal infections. In this study, we analyzed if mast cells are activated by Candida albicans and if the C-type lectin receptor Dectin-1 is involved in its recognition. We found that both yeasts and hyphae of C. albicans-induced mast cell degranulation and production of TNF-α, IL-6, IL-10, CCL3 and CCL4, while only yeasts were able to induce IL-1β. Mast cells also produced ROS after stimulation with both dimorphic phases of C. albicans. When mast cells were activated with yeasts and hyphae, they showed decreased expression of IκBα and increased presence of phosphorylated Syk. Blockade of the receptor Dectin-1, but not Toll-like receptor 2, decreased TNF-α production by mast cell in response to C. albicans. These results indicate that mast cells are capable of sensing the two phases of C. albicans, and suggest that mast cells participate as an early inductor of inflammation during the early innate immune response to this fungus.
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http://dx.doi.org/10.1016/j.imbio.2015.05.005DOI Listing
September 2015

Differential activation of dendritic cells by Mycobacterium tuberculosis Beijing genotype.

Immunol Invest 2014 21;43(5):436-46. Epub 2014 Mar 21.

Department of Immunology, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional , ENCB-IPN , México .

Mycobacterium tuberculosis (Mtb) inhibits dendritric cells (DC) function in order to delay T cell response. Furthermore, there is increasing evidence that genetic diversity of Mtb strains can affect their interaction with the immune system. Beijing genotype has attracted attention because of its high prevalence and multi-drug resistance. Although it is known that this genotype is hypervirulent and differentially activates macrophages when compared to other genotypes, little is known about its interaction with DC. In order to address this issue, murine bone marrow derived DC (BMDC) were stimulated with soluble extracts (SE) from BCG, H37Rv, Canetti and Beijing genotypes. We observed that unlike other mycobacteria strains, SE-Beijing was unable to induce maturation of DC as assessed by cell surface MHC-II expression. DC stimulated with SE-Beijing failed to produce IL-12 and TNF-α, but did secrete IL-10. Interestingly, SE-Beijing induced CCR7 and PDL-1 on BMDC, but did not induce the expression of CD86. When BMDC stimulated with SE-Beijing were used to activate CD4+ cells they were unable to induce a Th1 response when compared with less virulent genotypes. These results indicate that Beijing is able to modulate DC activation and function, which may be related to the pathogenesis induced by this genotype.
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http://dx.doi.org/10.3109/08820139.2014.880120DOI Listing
January 2015