Oscar De La Calle-martín | Universitat Autònoma de Barcelona (original) (raw)

Papers by Oscar De La Calle-martín

Research paper thumbnail of Non-myeloablative hematopoietic stem cell transplantation in the treatment of severe idiopathic CD4+ lymphocytopenia

European Journal of Haematology, May 25, 2011

A 40-year-old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunis... more A 40-year-old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunistic infections was successfully treated with non-myeloablative allogeneic hematopoietic stem cell transplantation. After conditioning with fludarabine plus low dose of total-body irradiation, CD34+ peripheral blood stem cells obtained by leukapheresis from his HLA-identical sister were infused. T cell and myeloid complete chimerism was achieved at day +28 and remained stable during the follow-up period. The patient did not develop infectious complications during the procedure. At 35 months of follow-up, his CD4+ T cell count was 1019 cells per microliter. Non-myeloablative allogeneic hematopoietic stem cell transplantation should be considered a treatment option for patients with severe forms of idiopathic CD4+ lymphocytopenia.

Research paper thumbnail of Mspl polymorphism of the human p53 gene

Nucleic Acids Research, 1990

Here we report a rapid and simple method to analyze an AccH polymorphism within the human p53 gen... more Here we report a rapid and simple method to analyze an AccH polymorphism within the human p53 gene using the polymerase chain reaction. PCR Primers: The primer sequences corresponded to the 4th exon of the human p53 gene as described by Lamb (1). Sense oligo 5'-AATGGATGATTTGATGCTGTCCC-3' Antisense oligo 5'-CGTGCAAGTCACAGACTTGGC-3' Polymorphism: AccH (CGCG) digest of the amplified fragment identifies two alleles; Al = 259 bp and A2 = 160 bp + 99 bp. Frequency: Allele frequencies were calculated from 90 unrelated Caucasians. Al = 0.32 A2 = 0.68 Chromosomal Localization: The polymorphic AccH recognition site occurs within the 4th exon of the human p53 locus (17ql3) (2). Mendelian Inheritance: Co-dominant segregation demonstrated in 6 two-generation families. PCR Conditions: PCRs were carried out in a total volume of 50 ,ul containing: 500 ng of genomic DNA, 50 pmoles of each prii.ler, 2 mM MgCl2, 200 AM dNTPs, 50 mM KCl, 20 mM Tris-pH 8.3 and 0.1 % gelatine. The amplification is performed for 35 cycles with an annealing temperature of 62°C. The amplified DNA is digested overnight with a tenfold excess of AccH. DNA fragments are resolved by electrophoresis through a 2% agarose gel or a 7% polyacrylamide gel. Acknowledgements: This work was supported by a CAICYT Grant # PB 86-0046 del Ministerio de Educaci6n y Ciencia. 0. de la Calle-Martin was supported by a Hospital Clinic grant.

Research paper thumbnail of Induction of interleukin 2 (IL2) and interferon-γ and enhancement of IL2 receptor expression by a CD26 monoclonal antibody

European Journal of Immunology, 1991

Induction of interleukin 2 (IL 2) and interferon-y and enhancement of IL2 receptor expression by ... more Induction of interleukin 2 (IL 2) and interferon-y and enhancement of IL2 receptor expression by a CD26 monoclonal antibody" The ability of the 134-2C2 monoclonal antibody (mAb; CD26) to transmit an activation signal and to affect Tcell proliferation has been studied. The 134-2C2 mAb, although not being mitogenic by itself, is able to increase the proliferation of purified Tcells in the presence of exogenous interleukin 2 (IL2) or phorbol 12-myristate 13-acetate (PMA). No effect of our mAb was observed on the proliferation of T cells induced by other stimuli such as Sepharose-bound CD3 mAb, phytohemagglutinin or calcium ionophore. Since the co-stimulatory effect of 134-2C2 mAb on PMA-induced Tcell proliferation was strongly inhibited by an anti-Tac antibody, its involvement on the IL2/IL2 receptor pathway was investigated. An increased IL2 secretion in T cells cultured with PMA plus 134-2C2 mAb was observed and Northern blot analysis showed that the mAb 134-2C2 acts synergistically with PMA favoring the induction of both IL2 and interferon-y mRNA synthesis, as well as the enhancement of IL2 receptor and transferrin receptor mRNA expression. Studies on mechanisms implicated in signal transduction showed that 134-2C2 mAb modifies neither intracellular calcium levels nor phosphoinositide breakdown. Additionally, no effect was exerted on protein kinase C translocation. These data suggest that the CD26 antigen is involved in T cell activation in an IL2/IL2 receptor-dependent pathway.

Research paper thumbnail of CPT-A

Encyclopedia of Molecular Mechanisms of Disease, 2009

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (OMIM ... more Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (OMIM 125310); Hereditary multi-infarct dementia; Chronic familial vascular encephalopathy Definition and Characteristics Autosomal dominantly inherited microangiopathy associated with migraine (with aura), recurrent ischemic strokes and progressive cognitive deficits, frequently leading to subcortical ischemic vascular dementia [1]. Additional, less frequent manifestations include psychiatric abnormalities and epileptic seizures. Magnetic resonance images (MRI) of the brain show characteristic subcortical ischemic white matter lesions and lacunar strokes. The lesion pattern is comparable to that seen in sporadic cerebral small vessel disease, with particular temporo-polar involvement (Fig. 1). MRI lesions are known to occur prior to the clinical manifestation and there is a high inter-and intrafamilial clinical variability of the disorder. Sporadic cases without a positive family history (caused by neomutations) have been reported.

Research paper thumbnail of Inherited human ezrin deficiency impairs adaptive immunity

Journal of Allergy and Clinical Immunology

Research paper thumbnail of Unexpected Relevant Role of Gene Mosaicism in Primary Immunodeficiency Diseases

The Journal of allergy and clinical immunology, Jan 28, 2018

Post-zygotic de novo mutations lead to the phenomenon of gene mosaicism. The three main types are... more Post-zygotic de novo mutations lead to the phenomenon of gene mosaicism. The three main types are called somatic, gonadal and gonosomal mosaicism, which differ on the body distribution of post-zygotic mutations. Mosaicism has been occasionally reported in primary immunodeficiency diseases (PID) since early 90s, but its real involvement has not been systematically addressed. To investigate the incidence of gene mosaicism in PID. The amplicon-based deep sequencing method was employed in the three parts of the study that establish the allele frequency of germline variants (n:100), the incidence of parental gonosomal mosaicism in PID families with de novo mutations (n:92) and the incidence of mosaicism in PID families with moderate-to-high suspicious (n:36), respectively. Additional investigations evaluated body distribution of post-zygotic mutations, their stability over time and their characteristics. The range of allele frequency 44.1-55.6% was established for germline variants. Thos...

Research paper thumbnail of A novel gain-of-function STAT1 mutation resulting in basal phosphorylation of STAT1 and increased distal IFN-γ-mediated responses in chronic mucocutaneous candidiasis

Molecular Immunology, 2015

Gain-of-function STAT1 mutations have recently been associated with autosomal dominant chronic mu... more Gain-of-function STAT1 mutations have recently been associated with autosomal dominant chronic mucocutaneous candidiasis (CMC). The purpose of this study was to characterize the three members of a non-consanguineous family, the father and his two sons, who presented with recurrent oral thrush and ocular candidiasis since early childhood. The three patients had reduced levels of IL-17-producing T cells. This reduction affected specifically IL-17(+)IFN-γ(-) T cells, because the levels of IL-17(+)IFN-γ(+) T cells were similar to controls. We found that PBMC (peripheral blood mononuclear cells) from the patients did not respond to Candida albicans ex vivo. Moreover, after polyclonal activation, patients' PBMC produced lower levels of IL-17 and IL-6 and higher levels of IL-4 than healthy controls. Genetic analyses showed that the three patients were heterozygous for a new mutation in STAT1 (c.894A>C, p.K298N) that affects a highly conserved residue of the coiled-coil domain of STAT1. STAT1 phosphorylation levels were significantly higher in patients' cells than in healthy controls, both in basal conditions and after IFN-γ stimulation, suggesting a permanent activation of STAT1. Cells from the patients also presented increased IFN-γ-mediated responses measured as MIG and IP-10 production. In conclusion, we report a novel gain-of-function mutation in the coiled-coil domain of STAT1, which increases STAT1 phosphorylation and impairs IL-17-mediated immunity. The mutation is responsible for CMC in this family with autosomal dominant inheritance of the disease.

Research paper thumbnail of A novel HLA-Cw*07 variant, HLA-Cw*0760, identified by sequence-based typing in a bone marrow donor

Tissue Antigens, 2009

We report the identification of the novel allele HLA-Cw*0760 that was found during confirmatory h... more We report the identification of the novel allele HLA-Cw*0760 that was found during confirmatory highresolution sequence-based typing of a bone marrow donor. The Cw*0760 allele has two nucleotide changes from Cw*070101 at positions 341 and 343 in exon 2, resulting in two amino acid changes from Asp to Ala (codon 90: GAC/GCC) and Gly to Arg (codon 91: GGG/AGG). Figure 1 Alignment of the nucleotide sequences of partial exon 2 and 3 of the novel Cw*0760 allele compared with Cw*070101, Cw*0716, Cw*0756 and Cw*030301 (A). Sequence alignment of intron 2 from Cw*0760, Cw*070101, Cw*020202 and Cw*0716 (B).

Research paper thumbnail of A novel HLA-B*35 variant, HLA-B* 35:02:03, identified by sequence-based typing in a bone marrow donor

Tissue Antigens, 2010

We report the identification of the novel allele human leukocyte antigen-B*35:02:03 that was foun... more We report the identification of the novel allele human leukocyte antigen-B*35:02:03 that was found during confirmatory high-resolution sequence-based typing of a bone marrow donor. The B*35:02:03 allele has one nucleotide change from B*35:02:01 at position 318 in exon 2 which does not result in an amino acid change (codon 82: CGC → CGG).

Research paper thumbnail of From Severe Combined Immunodeficiency to Omenn syndrome after hematopoietic stem cell transplantation in a RAG1 deficient family

Pediatric Allergy and Immunology, 2012

Background: Mutations in RAG genes cause a spectrum of severe immunodeficiencies ranging from Se... more Background: Mutations in RAG genes cause a spectrum of severe immunodeficiencies ranging from Severe Combined Immunodeficiency (SCID) T‐B‐NK+ to Omenn syndrome (OS) through intermediate phenotypes, even for the same alteration. Nowadays, hematopoietic stem cell transplantation (HSCT) is the unique curative treatment available.Methods: We describe three related patients from a Moroccan consanguineous family. Patient 1 developed at 1 month of age moderate eczematous dermatitis with eosinophilia, followed by infections and enteritis. He was transplanted and received reduced intensity conditioning regimen previous to HSCT. His brother, patient 2, was born preterm with a severe neonatal erythroderma, hepatosplenomegaly and lymphadenopathy. Patient 3, cousin of the two siblings, was also born preterm and fulfilled all criteria for classical OS. Immunological evaluation was performed and RAG genes were sequenced.Results: Immunological data from all three patients were very diversed, fro...

Research paper thumbnail of Mutations in the Fas gene found in Spanish ALPS (autoimmune lymphoproliferative syndrome) patients

Journal of Translational Medicine, 2010

Research paper thumbnail of The polymorphism p.G219R of CD40L does not cause immunological alterations in vivo: Conclusions from a X-linked hyper IgM syndrome kindred

Molecular Immunology, 2012

Hyper-IgM syndromes (HIGM) are characterized by low levels of IgG, IgA and IgE and normal to high... more Hyper-IgM syndromes (HIGM) are characterized by low levels of IgG, IgA and IgE and normal to high levels of IgM. Patients with these syndromes present recurrent infections due to an impaired immunoglobulin maturation. The most prevalent form of HIGM, X-linked hyper IgM syndrome (XHIM), is caused by mutations in the gene encoding the CD40 ligand (CD40LG). We present two siblings with XHIM caused by a large CD40LG deletion affecting more than half of the gene, and extended from the end of intron 3 to far upstream of the promoter regions. Genetic analysis in the maternal family discovered the CD40L G219R polymorphism in several members. Segregation of this polymorphism in the kindred indicated that the deletion of CD40LG was a de novo mutation in the mother. Although half of her CD4+ T cells did not express CD40L and the other half expressed the CD40L G219R variant, the mother was healthy. This suggests that this polymorphism is not pathogenic by itself although it has been recently related to X-linked lymphoproliferative syndrome.

Research paper thumbnail of Gene polymorphisms associated with the presence of HALS in d4T-exposed patients

<p>HALS = HIV/HAART-associated lipodystrophy syndrome, TS = thymidylate synthase, MTHFR = m... more <p>HALS = HIV/HAART-associated lipodystrophy syndrome, TS = thymidylate synthase, MTHFR = methylene-tetrahydrofolate reductase,</p>*<p>Heterozygous and wild-type patients,</p>†<p>Homozygous 677T, homozygous 1298C and compound heterozygous patients.</p

Research paper thumbnail of Hipogammaglobulinemia crónica postrasplante de precursores hematopoyéticos y su tratamiento con gammaglobulina subcutánea en pacientes pediátricos

Anales de Pediatría, 2022

Research paper thumbnail of Caso de púrpura trombocitopénica por deficiencia de C2 asociada a dos nuevos haplotipos de HLA

Research paper thumbnail of ¿Hacia dónde va la Sociedad Española de Inmunología?

Research paper thumbnail of Identification of a novel HLA-DRB1 allele, DRB1*0108, by sequence-based DRB typing in two siblings

Research paper thumbnail of B cells and monocytes are not developmentally affected in a case of reticular dysgenesis

Clinical & Experimental Immunology, 1997

SUMMARY We report a patient with reticular dysgenesis (RD) who received an HLA-identical marrow g... more SUMMARY We report a patient with reticular dysgenesis (RD) who received an HLA-identical marrow graft and remained free of infection in spite of incomplete haematological recovery. Mixed chimerism was achieved and resulted from the presence of autologous B cells and monocytes and grafting of donor T cells. Granulocyte recovery was impaired. The B cells were CD5+ (B1 cells) and appeared to be functional, since serum immunoglobulin levels became normal after the graft. The findings described here suggest that in some cases the defect selectively affects different cell types, including the more abundant leucocyte populations, granulocytes and T lymphocytes. However, B cells and monocytes appear to be relatively spared in this case of RD. Furthermore, the present case may provide insight into the mechanism involved in the expansion of distinct B cell subpopulations (B1 and B2 cells).

Research paper thumbnail of Papel de la p53 en la activación linfocitaria y la transformación neoplásica

LA P53, DESCRITA EN 1979, HA SIDO CONSIDERADA DURANTE UNA DECADA COMO UN ONCOGEN. RECIENTEMENTE S... more LA P53, DESCRITA EN 1979, HA SIDO CONSIDERADA DURANTE UNA DECADA COMO UN ONCOGEN. RECIENTEMENTE SE HA DEMOSTRADO QUE ES UN ANTIONCOGEN O FACTOR DE SUPRESION TUMORAL. EN LA PRESENTE TESIS SE ANALIZAN DIVERSOS ASPECTOS RELACIONADOS CON ESTA MOLECULA. EN PRIMER LUGAR SE DEMUESTRA QUE LA P53 SE INDUCE EN LINFOCITOS T HUMANOS EN RESPUESTA A ESTIMULOS PROLIFERATIVOS Y NO PROLIFERATIVOS. EL ANALISIS DE LA EXPRESION DE P53 (ARN Y PROTEINA) EN LINEAS CELULARES HUMANAS DEMUESTRA QUE EXISTEN UNA SERIE DE LINEAS NEGATIVAS (HPB-ALL, JURKAT, NUT-78, U-937, K-562 Y HL-60), EN LAS CUALES NO SE PUEDE INDUCIR LA EXPRESION DE P53 POR NINGUN MEDIO. EL ESTUDIO DEL GEN DE LA P53 NO PERMITE DESCUBRIR UNA ALTERACION EN LAS LINEAS ESTUDIADAS, SALVO EL CASO YA CONOCIDO DE LA HL-60. SIN EMBARGO, HA PERMITIDO DESCUBRIR TRES NUEVOS POLIMORFISMOS GENETICOS (RFLPS) DEFINIDOS POR LOS ENZIMAS DE RESTRICCION ACC II, BGLII Y MSPI. EL EMPLEO CONJUNTO DE LAS TECNICAS DE SOUTHERN, WESTERN Y PCR PERMITE AFIRMAR QUE NO EX...

Research paper thumbnail of Cost-effectiveness analysis of HLA-B* 5701 typing in the prevention of hypersensitivity to abacavir in HIV+ patients in Spain

… y Microbiología Clínica, 2010

Introduction: Approximately 4% to 8% of patients with HIV-1 treated with abacavir present a hyper... more Introduction: Approximately 4% to 8% of patients with HIV-1 treated with abacavir present a hypersensitivity reaction (HSR). Various studies have shown a direct association between human leukocyte antigen (HLA)-B*5701 and HSR to abacavir. The objective of this study was to analyze whether systematic HLA-B*5701 testing to prevent HSR in patients treated with abacavir is a cost-effective option for the Spanish National Health System. Methods: An analytical decision-making model was constructed as a decision tree model for a simulated cohort of 1000 HIV patients to evaluate whether HLA-B*5701 testing to prevent HSR to abacavir was cost effective compared with not performing the test. The parameters included in the model and the use of healthcare resources should the patient develop HSR were taken from the PREDICT-1 study and the opinion of clinical experts. The principal result obtained was the incremental cost per HSR avoided. The time horizon of the analysis was 6 months. All costs were expressed in 2008 Euros. Results: The analysis showed that the total direct healthcare costs per patient were h1344 and h1322 with and without HLA-B*5701 testing respectively, and that 36 cases of HSR were prevented per 1000 screened patients. These results yielded a cost per HSR avoided of h630. The sensitivity analysis showed that the results were sensitive to the cost of the test, with an economic saving of h102 or a cost-effectiveness ratio of h4234. Conclusions: The model predicts that generalized use of the HLA-B*5701 test before prescribing abacavir in HIV + patients could represent an economic saving or a limited additional cost for the National Health System which may be counterbalanced by the benefits in terms of a lower incidence of HSR.

Research paper thumbnail of Non-myeloablative hematopoietic stem cell transplantation in the treatment of severe idiopathic CD4+ lymphocytopenia

European Journal of Haematology, May 25, 2011

A 40-year-old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunis... more A 40-year-old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunistic infections was successfully treated with non-myeloablative allogeneic hematopoietic stem cell transplantation. After conditioning with fludarabine plus low dose of total-body irradiation, CD34+ peripheral blood stem cells obtained by leukapheresis from his HLA-identical sister were infused. T cell and myeloid complete chimerism was achieved at day +28 and remained stable during the follow-up period. The patient did not develop infectious complications during the procedure. At 35 months of follow-up, his CD4+ T cell count was 1019 cells per microliter. Non-myeloablative allogeneic hematopoietic stem cell transplantation should be considered a treatment option for patients with severe forms of idiopathic CD4+ lymphocytopenia.

Research paper thumbnail of Mspl polymorphism of the human p53 gene

Nucleic Acids Research, 1990

Here we report a rapid and simple method to analyze an AccH polymorphism within the human p53 gen... more Here we report a rapid and simple method to analyze an AccH polymorphism within the human p53 gene using the polymerase chain reaction. PCR Primers: The primer sequences corresponded to the 4th exon of the human p53 gene as described by Lamb (1). Sense oligo 5'-AATGGATGATTTGATGCTGTCCC-3' Antisense oligo 5'-CGTGCAAGTCACAGACTTGGC-3' Polymorphism: AccH (CGCG) digest of the amplified fragment identifies two alleles; Al = 259 bp and A2 = 160 bp + 99 bp. Frequency: Allele frequencies were calculated from 90 unrelated Caucasians. Al = 0.32 A2 = 0.68 Chromosomal Localization: The polymorphic AccH recognition site occurs within the 4th exon of the human p53 locus (17ql3) (2). Mendelian Inheritance: Co-dominant segregation demonstrated in 6 two-generation families. PCR Conditions: PCRs were carried out in a total volume of 50 ,ul containing: 500 ng of genomic DNA, 50 pmoles of each prii.ler, 2 mM MgCl2, 200 AM dNTPs, 50 mM KCl, 20 mM Tris-pH 8.3 and 0.1 % gelatine. The amplification is performed for 35 cycles with an annealing temperature of 62°C. The amplified DNA is digested overnight with a tenfold excess of AccH. DNA fragments are resolved by electrophoresis through a 2% agarose gel or a 7% polyacrylamide gel. Acknowledgements: This work was supported by a CAICYT Grant # PB 86-0046 del Ministerio de Educaci6n y Ciencia. 0. de la Calle-Martin was supported by a Hospital Clinic grant.

Research paper thumbnail of Induction of interleukin 2 (IL2) and interferon-γ and enhancement of IL2 receptor expression by a CD26 monoclonal antibody

European Journal of Immunology, 1991

Induction of interleukin 2 (IL 2) and interferon-y and enhancement of IL2 receptor expression by ... more Induction of interleukin 2 (IL 2) and interferon-y and enhancement of IL2 receptor expression by a CD26 monoclonal antibody" The ability of the 134-2C2 monoclonal antibody (mAb; CD26) to transmit an activation signal and to affect Tcell proliferation has been studied. The 134-2C2 mAb, although not being mitogenic by itself, is able to increase the proliferation of purified Tcells in the presence of exogenous interleukin 2 (IL2) or phorbol 12-myristate 13-acetate (PMA). No effect of our mAb was observed on the proliferation of T cells induced by other stimuli such as Sepharose-bound CD3 mAb, phytohemagglutinin or calcium ionophore. Since the co-stimulatory effect of 134-2C2 mAb on PMA-induced Tcell proliferation was strongly inhibited by an anti-Tac antibody, its involvement on the IL2/IL2 receptor pathway was investigated. An increased IL2 secretion in T cells cultured with PMA plus 134-2C2 mAb was observed and Northern blot analysis showed that the mAb 134-2C2 acts synergistically with PMA favoring the induction of both IL2 and interferon-y mRNA synthesis, as well as the enhancement of IL2 receptor and transferrin receptor mRNA expression. Studies on mechanisms implicated in signal transduction showed that 134-2C2 mAb modifies neither intracellular calcium levels nor phosphoinositide breakdown. Additionally, no effect was exerted on protein kinase C translocation. These data suggest that the CD26 antigen is involved in T cell activation in an IL2/IL2 receptor-dependent pathway.

Research paper thumbnail of CPT-A

Encyclopedia of Molecular Mechanisms of Disease, 2009

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (OMIM ... more Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (OMIM 125310); Hereditary multi-infarct dementia; Chronic familial vascular encephalopathy Definition and Characteristics Autosomal dominantly inherited microangiopathy associated with migraine (with aura), recurrent ischemic strokes and progressive cognitive deficits, frequently leading to subcortical ischemic vascular dementia [1]. Additional, less frequent manifestations include psychiatric abnormalities and epileptic seizures. Magnetic resonance images (MRI) of the brain show characteristic subcortical ischemic white matter lesions and lacunar strokes. The lesion pattern is comparable to that seen in sporadic cerebral small vessel disease, with particular temporo-polar involvement (Fig. 1). MRI lesions are known to occur prior to the clinical manifestation and there is a high inter-and intrafamilial clinical variability of the disorder. Sporadic cases without a positive family history (caused by neomutations) have been reported.

Research paper thumbnail of Inherited human ezrin deficiency impairs adaptive immunity

Journal of Allergy and Clinical Immunology

Research paper thumbnail of Unexpected Relevant Role of Gene Mosaicism in Primary Immunodeficiency Diseases

The Journal of allergy and clinical immunology, Jan 28, 2018

Post-zygotic de novo mutations lead to the phenomenon of gene mosaicism. The three main types are... more Post-zygotic de novo mutations lead to the phenomenon of gene mosaicism. The three main types are called somatic, gonadal and gonosomal mosaicism, which differ on the body distribution of post-zygotic mutations. Mosaicism has been occasionally reported in primary immunodeficiency diseases (PID) since early 90s, but its real involvement has not been systematically addressed. To investigate the incidence of gene mosaicism in PID. The amplicon-based deep sequencing method was employed in the three parts of the study that establish the allele frequency of germline variants (n:100), the incidence of parental gonosomal mosaicism in PID families with de novo mutations (n:92) and the incidence of mosaicism in PID families with moderate-to-high suspicious (n:36), respectively. Additional investigations evaluated body distribution of post-zygotic mutations, their stability over time and their characteristics. The range of allele frequency 44.1-55.6% was established for germline variants. Thos...

Research paper thumbnail of A novel gain-of-function STAT1 mutation resulting in basal phosphorylation of STAT1 and increased distal IFN-γ-mediated responses in chronic mucocutaneous candidiasis

Molecular Immunology, 2015

Gain-of-function STAT1 mutations have recently been associated with autosomal dominant chronic mu... more Gain-of-function STAT1 mutations have recently been associated with autosomal dominant chronic mucocutaneous candidiasis (CMC). The purpose of this study was to characterize the three members of a non-consanguineous family, the father and his two sons, who presented with recurrent oral thrush and ocular candidiasis since early childhood. The three patients had reduced levels of IL-17-producing T cells. This reduction affected specifically IL-17(+)IFN-γ(-) T cells, because the levels of IL-17(+)IFN-γ(+) T cells were similar to controls. We found that PBMC (peripheral blood mononuclear cells) from the patients did not respond to Candida albicans ex vivo. Moreover, after polyclonal activation, patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; PBMC produced lower levels of IL-17 and IL-6 and higher levels of IL-4 than healthy controls. Genetic analyses showed that the three patients were heterozygous for a new mutation in STAT1 (c.894A&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;C, p.K298N) that affects a highly conserved residue of the coiled-coil domain of STAT1. STAT1 phosphorylation levels were significantly higher in patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; cells than in healthy controls, both in basal conditions and after IFN-γ stimulation, suggesting a permanent activation of STAT1. Cells from the patients also presented increased IFN-γ-mediated responses measured as MIG and IP-10 production. In conclusion, we report a novel gain-of-function mutation in the coiled-coil domain of STAT1, which increases STAT1 phosphorylation and impairs IL-17-mediated immunity. The mutation is responsible for CMC in this family with autosomal dominant inheritance of the disease.

Research paper thumbnail of A novel HLA-Cw*07 variant, HLA-Cw*0760, identified by sequence-based typing in a bone marrow donor

Tissue Antigens, 2009

We report the identification of the novel allele HLA-Cw*0760 that was found during confirmatory h... more We report the identification of the novel allele HLA-Cw*0760 that was found during confirmatory highresolution sequence-based typing of a bone marrow donor. The Cw*0760 allele has two nucleotide changes from Cw*070101 at positions 341 and 343 in exon 2, resulting in two amino acid changes from Asp to Ala (codon 90: GAC/GCC) and Gly to Arg (codon 91: GGG/AGG). Figure 1 Alignment of the nucleotide sequences of partial exon 2 and 3 of the novel Cw*0760 allele compared with Cw*070101, Cw*0716, Cw*0756 and Cw*030301 (A). Sequence alignment of intron 2 from Cw*0760, Cw*070101, Cw*020202 and Cw*0716 (B).

Research paper thumbnail of A novel HLA-B*35 variant, HLA-B* 35:02:03, identified by sequence-based typing in a bone marrow donor

Tissue Antigens, 2010

We report the identification of the novel allele human leukocyte antigen-B*35:02:03 that was foun... more We report the identification of the novel allele human leukocyte antigen-B*35:02:03 that was found during confirmatory high-resolution sequence-based typing of a bone marrow donor. The B*35:02:03 allele has one nucleotide change from B*35:02:01 at position 318 in exon 2 which does not result in an amino acid change (codon 82: CGC → CGG).

Research paper thumbnail of From Severe Combined Immunodeficiency to Omenn syndrome after hematopoietic stem cell transplantation in a RAG1 deficient family

Pediatric Allergy and Immunology, 2012

Background: Mutations in RAG genes cause a spectrum of severe immunodeficiencies ranging from Se... more Background: Mutations in RAG genes cause a spectrum of severe immunodeficiencies ranging from Severe Combined Immunodeficiency (SCID) T‐B‐NK+ to Omenn syndrome (OS) through intermediate phenotypes, even for the same alteration. Nowadays, hematopoietic stem cell transplantation (HSCT) is the unique curative treatment available.Methods: We describe three related patients from a Moroccan consanguineous family. Patient 1 developed at 1 month of age moderate eczematous dermatitis with eosinophilia, followed by infections and enteritis. He was transplanted and received reduced intensity conditioning regimen previous to HSCT. His brother, patient 2, was born preterm with a severe neonatal erythroderma, hepatosplenomegaly and lymphadenopathy. Patient 3, cousin of the two siblings, was also born preterm and fulfilled all criteria for classical OS. Immunological evaluation was performed and RAG genes were sequenced.Results: Immunological data from all three patients were very diversed, fro...

Research paper thumbnail of Mutations in the Fas gene found in Spanish ALPS (autoimmune lymphoproliferative syndrome) patients

Journal of Translational Medicine, 2010

Research paper thumbnail of The polymorphism p.G219R of CD40L does not cause immunological alterations in vivo: Conclusions from a X-linked hyper IgM syndrome kindred

Molecular Immunology, 2012

Hyper-IgM syndromes (HIGM) are characterized by low levels of IgG, IgA and IgE and normal to high... more Hyper-IgM syndromes (HIGM) are characterized by low levels of IgG, IgA and IgE and normal to high levels of IgM. Patients with these syndromes present recurrent infections due to an impaired immunoglobulin maturation. The most prevalent form of HIGM, X-linked hyper IgM syndrome (XHIM), is caused by mutations in the gene encoding the CD40 ligand (CD40LG). We present two siblings with XHIM caused by a large CD40LG deletion affecting more than half of the gene, and extended from the end of intron 3 to far upstream of the promoter regions. Genetic analysis in the maternal family discovered the CD40L G219R polymorphism in several members. Segregation of this polymorphism in the kindred indicated that the deletion of CD40LG was a de novo mutation in the mother. Although half of her CD4+ T cells did not express CD40L and the other half expressed the CD40L G219R variant, the mother was healthy. This suggests that this polymorphism is not pathogenic by itself although it has been recently related to X-linked lymphoproliferative syndrome.

Research paper thumbnail of Gene polymorphisms associated with the presence of HALS in d4T-exposed patients

<p>HALS = HIV/HAART-associated lipodystrophy syndrome, TS = thymidylate synthase, MTHFR = m... more <p>HALS = HIV/HAART-associated lipodystrophy syndrome, TS = thymidylate synthase, MTHFR = methylene-tetrahydrofolate reductase,</p>*<p>Heterozygous and wild-type patients,</p>†<p>Homozygous 677T, homozygous 1298C and compound heterozygous patients.</p

Research paper thumbnail of Hipogammaglobulinemia crónica postrasplante de precursores hematopoyéticos y su tratamiento con gammaglobulina subcutánea en pacientes pediátricos

Anales de Pediatría, 2022

Research paper thumbnail of Caso de púrpura trombocitopénica por deficiencia de C2 asociada a dos nuevos haplotipos de HLA

Research paper thumbnail of ¿Hacia dónde va la Sociedad Española de Inmunología?

Research paper thumbnail of Identification of a novel HLA-DRB1 allele, DRB1*0108, by sequence-based DRB typing in two siblings

Research paper thumbnail of B cells and monocytes are not developmentally affected in a case of reticular dysgenesis

Clinical & Experimental Immunology, 1997

SUMMARY We report a patient with reticular dysgenesis (RD) who received an HLA-identical marrow g... more SUMMARY We report a patient with reticular dysgenesis (RD) who received an HLA-identical marrow graft and remained free of infection in spite of incomplete haematological recovery. Mixed chimerism was achieved and resulted from the presence of autologous B cells and monocytes and grafting of donor T cells. Granulocyte recovery was impaired. The B cells were CD5+ (B1 cells) and appeared to be functional, since serum immunoglobulin levels became normal after the graft. The findings described here suggest that in some cases the defect selectively affects different cell types, including the more abundant leucocyte populations, granulocytes and T lymphocytes. However, B cells and monocytes appear to be relatively spared in this case of RD. Furthermore, the present case may provide insight into the mechanism involved in the expansion of distinct B cell subpopulations (B1 and B2 cells).

Research paper thumbnail of Papel de la p53 en la activación linfocitaria y la transformación neoplásica

LA P53, DESCRITA EN 1979, HA SIDO CONSIDERADA DURANTE UNA DECADA COMO UN ONCOGEN. RECIENTEMENTE S... more LA P53, DESCRITA EN 1979, HA SIDO CONSIDERADA DURANTE UNA DECADA COMO UN ONCOGEN. RECIENTEMENTE SE HA DEMOSTRADO QUE ES UN ANTIONCOGEN O FACTOR DE SUPRESION TUMORAL. EN LA PRESENTE TESIS SE ANALIZAN DIVERSOS ASPECTOS RELACIONADOS CON ESTA MOLECULA. EN PRIMER LUGAR SE DEMUESTRA QUE LA P53 SE INDUCE EN LINFOCITOS T HUMANOS EN RESPUESTA A ESTIMULOS PROLIFERATIVOS Y NO PROLIFERATIVOS. EL ANALISIS DE LA EXPRESION DE P53 (ARN Y PROTEINA) EN LINEAS CELULARES HUMANAS DEMUESTRA QUE EXISTEN UNA SERIE DE LINEAS NEGATIVAS (HPB-ALL, JURKAT, NUT-78, U-937, K-562 Y HL-60), EN LAS CUALES NO SE PUEDE INDUCIR LA EXPRESION DE P53 POR NINGUN MEDIO. EL ESTUDIO DEL GEN DE LA P53 NO PERMITE DESCUBRIR UNA ALTERACION EN LAS LINEAS ESTUDIADAS, SALVO EL CASO YA CONOCIDO DE LA HL-60. SIN EMBARGO, HA PERMITIDO DESCUBRIR TRES NUEVOS POLIMORFISMOS GENETICOS (RFLPS) DEFINIDOS POR LOS ENZIMAS DE RESTRICCION ACC II, BGLII Y MSPI. EL EMPLEO CONJUNTO DE LAS TECNICAS DE SOUTHERN, WESTERN Y PCR PERMITE AFIRMAR QUE NO EX...

Research paper thumbnail of Cost-effectiveness analysis of HLA-B* 5701 typing in the prevention of hypersensitivity to abacavir in HIV+ patients in Spain

… y Microbiología Clínica, 2010

Introduction: Approximately 4% to 8% of patients with HIV-1 treated with abacavir present a hyper... more Introduction: Approximately 4% to 8% of patients with HIV-1 treated with abacavir present a hypersensitivity reaction (HSR). Various studies have shown a direct association between human leukocyte antigen (HLA)-B*5701 and HSR to abacavir. The objective of this study was to analyze whether systematic HLA-B*5701 testing to prevent HSR in patients treated with abacavir is a cost-effective option for the Spanish National Health System. Methods: An analytical decision-making model was constructed as a decision tree model for a simulated cohort of 1000 HIV patients to evaluate whether HLA-B*5701 testing to prevent HSR to abacavir was cost effective compared with not performing the test. The parameters included in the model and the use of healthcare resources should the patient develop HSR were taken from the PREDICT-1 study and the opinion of clinical experts. The principal result obtained was the incremental cost per HSR avoided. The time horizon of the analysis was 6 months. All costs were expressed in 2008 Euros. Results: The analysis showed that the total direct healthcare costs per patient were h1344 and h1322 with and without HLA-B*5701 testing respectively, and that 36 cases of HSR were prevented per 1000 screened patients. These results yielded a cost per HSR avoided of h630. The sensitivity analysis showed that the results were sensitive to the cost of the test, with an economic saving of h102 or a cost-effectiveness ratio of h4234. Conclusions: The model predicts that generalized use of the HLA-B*5701 test before prescribing abacavir in HIV + patients could represent an economic saving or a limited additional cost for the National Health System which may be counterbalanced by the benefits in terms of a lower incidence of HSR.