Publications by authors named "Noe Ramirez-Alejo"

13 Publications

  • Page 1 of 1

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

J Clin Immunol 2021 Apr 8;41(3):639-657. Epub 2021 Jan 8.

Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Paris, France.

Purpose: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown.

Methods: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives.

Results: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic.

Conclusion: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.
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http://dx.doi.org/10.1007/s10875-020-00930-3DOI Listing
April 2021

Homozygosity for P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry.

Proc Natl Acad Sci U S A 2019 05 8;116(21):10430-10434. Epub 2019 May 8.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France.

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, = 2 × 10]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with , as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for P1104A may account for ∼1% of TB cases in Europeans.
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http://dx.doi.org/10.1073/pnas.1903561116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534977PMC
May 2019

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Sci Immunol 2018 12;3(30)

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

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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http://dx.doi.org/10.1126/sciimmunol.aau8714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341984PMC
December 2018

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

Mendelian susceptibility to mycobacterial disease: 2014-2018 update.

Immunol Cell Biol 2019 04 25;97(4):360-367. Epub 2018 Oct 25.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, UMR 1163, Necker Hospital for Sick Children, Paris, France.

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. Since 1996, disease-causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase-like 2 A deficiency, (2) TYK2-deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN-γR2 deficiency, and (4) two forms of syndromic MSMD: RORγ/RORγT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.
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http://dx.doi.org/10.1111/imcb.12210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438774PMC
April 2019

Hemophagocytic Lymphohistiocytosis as a Complication in Patients with MSMD.

J Clin Immunol 2016 07 4;36(5):420-2. Epub 2016 May 4.

Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.

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http://dx.doi.org/10.1007/s10875-016-0292-3DOI Listing
July 2016

Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.

J Exp Med 2015 Sep 24;212(10):1641-62. Epub 2015 Aug 24.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Enfants Malades Hospital, 75015 Paris, France University Paris Descartes, Imagine Institute, 75006 Paris, France

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
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http://dx.doi.org/10.1084/jem.20140280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577846PMC
September 2015

Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura.

Clin Immunol 2015 Oct 24;160(2):163-71. Epub 2015 Jun 24.

Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City 07360, Mexico. Electronic address:

NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916G>A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females.
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http://dx.doi.org/10.1016/j.clim.2015.06.007DOI Listing
October 2015

Successful adjunctive immunoglobulin treatment in patients affected by leukocyte adhesion deficiency type 1 (LAD-1).

Immunol Res 2015 Mar;61(3):260-8

Departamento de Inmunología Clínica, Instituto Nacional de Pediatría, CP 04530, Mexico City, Mexico.

Two patients with a severe leukocyte adhesion deficiency type 1 (LAD-1) phenotype were analyzed by flow cytometry and functional assays to demonstrate the improper adhesive and phagocytic responses of their leukocytes. A single homozygous defect that involves a missense mutation (c.817G>A) that encodes for a G273R substitution in CD18 was identified in both patients. The adhesion and phagocytosis assays demonstrated the inability of patients' leukocytes to perform these functions. Expression of the LFA-1 (CD11a/CD18) on the co-transfected HEK 293 cells with the mutated form of CD18 was not detected. Finally, both patients have been treated with immunoglobulin as an adjunctive therapy with positive results. We propose that intravenous immunoglobulin treatment is safe and efficacious in LAD-1 patients before hematopoietic stem cell transplantation and helpful in controlling severe infections. Subcutaneous immunoglobulin appeared to help wound healing in refractory ulcers in these patients.
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http://dx.doi.org/10.1007/s12026-014-8619-8DOI Listing
March 2015

Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella.

J Interferon Cytokine Res 2014 May 20;34(5):307-17. Epub 2013 Dec 20.

Department of Molecular Biomedicine, CINVESTAV-IPN , Mexico City, Mexico .

Since 1996, several studies characterizing the association between primary immunodeficiencies and susceptibility to infections with environmental and non-pathogenic mycobacteria such as the Bacillus Calmette-Guérin (Mycobacterium bovis Bacillus of Calmette Guérin strain) as well as disseminated infections by Salmonella spp. have been conducted. These conditions, grouped in the so-called Mendelian susceptibility to mycobacterial diseases, include a primary immunodeficiency caused by mutations in 7 autosomal genes (IFNGR1, IFNGR2, IL12B, IL12BR1, STAT1, ISG15, and IRF8) and an X-linked gene (NEMO). This syndrome presents a high degree of allelic heterogeneity and variable penetrance. This review focuses on the analysis of the first reported cases of these diseases, as well as on the molecular findings involved in each of them.
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http://dx.doi.org/10.1089/jir.2013.0050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015507PMC
May 2014

Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation.

Blood 2013 Oct 20;122(14):2390-401. Epub 2013 Aug 20.

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

We report a molecular study of the two known patients with autosomal recessive, partial interferon-γ receptor (IFN-γR)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-γR2 levels on the surface of the three latter patients' cells are slightly lower than those on control cells. The patients' cells also display impaired, but not abolished, response to IFN-γ. Moreover, the R114C, S124F, G141R and G227R IFNGR2 hypomorphic alleles all encode misfolded proteins with abnormal N-glycosylation. The mutants are largely retained in the endoplasmic reticulum, although a small proportion reach and function at the cell surface. Strikingly, the IFN-γ response of the patients' cells is enhanced by chemical modifiers of N-glycosylation, as previously shown for patients with gain-of-glysosylation T168N and misfolding 382-387dup null mutations. All four in-frame IFNGR2 hypomorphic mutant alleles encoding surface-expressed receptors are thus deleterious by a mechanism involving abnormal N-glycosylation and misfolding of the IFN-γR2 protein. The diagnosis of partial IFN-γR2 deficiency is clinically useful, as affected patients should be treated with IFN-γ, [corrected] unlike patients with complete IFN-γR2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-γR2 deficiency due to misfolding or gain-of-glycosylation receptors.
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http://dx.doi.org/10.1182/blood-2013-01-480814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790508PMC
October 2013

IL-12Rβ1 deficiency: mutation update and description of the IL12RB1 variation database.

Hum Mutat 2013 Oct 8;34(10):1329-39. Epub 2013 Aug 8.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rβ1 and molecular genetics of human IL12RB1.
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http://dx.doi.org/10.1002/humu.22380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104692PMC
October 2013

[Disseminated Tuberculosis in an Infant with IFNg-IL-12/IL 23 Axis Defect].

Rev Alerg Mex 2012 Apr-Jun;59(2):86-92

Departamento de Alergia e InmunologÌa ClÌnica Pedi·trica, Hospital Infantil de MÈxico Federico GÛmez, MÈxico, D.F.

BCG vaccine contains low virulence Mycobacterium bovis bacillus. In Mexico it is given at birth with few reported adverse reactions in immunocompetent children; however, in immuno-compromised patients it can cause serious local or systemic adverse reactions. The most frequent related diseases include chronic granulomatous disease (CGD), human immunodeficiency virus infection (HIV), severe combined immunodeficiency (SCID) and mendelian susceptibility to mycobacterial disease (MSMD). At this time, the innate defect of the IFN-?/IL-12/IL-23 axis constitutes the main implied alteration in patients with MSMD. We present the case of an infant with disseminated mycobacterial infection and history of BCG given at birth and documentation of an altered functional study of the IFN-?/IL12/IL-23 axis, specifically at the IL-12 pathway, which is susceptible to improve with exogenous IFN-? administration. Treatment was started with antituberculous drugs plus subcutaneous IFN-?, with a marked clinical improvement. In children with disseminated infection by weakly virulent intracellular microorganisms, such as the species included in BCG vaccine, primary or secondary underlying immunodeficiency should be ruled out.
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April 2016