Mirjana Radosavljevic - Academia.edu (original) (raw)

Papers by Mirjana Radosavljevic

The Journal of Immunology

AIDS-associated primary central nervous system lymphomas are late events that have an extremely p... more AIDS-associated primary central nervous system lymphomas are late events that have an extremely poor prognosis. Despite different hypotheses, the brain localization of these B cell lymphomas remains an enigma. To better define the cell origin of the lymphomas and the possible role of the B cell receptor (BCR) in the brain localization and/or in the oncogenic transformation, we analyzed the V region genes of the Ig heavy chain expressed by lymphoma cells in five randomly selected patients. After amplifying the rearranged VHDJH DNA by PCR, cloning, and sequencing of the amplified products, we observed that: 1) of the five lymphomas analyzed, four were clearly monoclonal; 2) there was no preferential use of one peculiar VH family or one peculiar segment of gene; 3) the mutation analysis showed that an Ag-driven process occurred in at least two cases, probably before the oncogenic event; and 4) there was no intraclonal variability, suggesting that the hypermutation mechanism is no longe...

The etiopathogenesis of severe COVID-19 remains unknown. Indeed given major confounding factors (... more The etiopathogenesis of severe COVID-19 remains unknown. Indeed given major confounding factors (age and co-morbidities), true drivers of this condition have remained elusive. Here, we employ an unprecedented multi-omics analysis, combined with artificial intelligence, in a young patient cohort where major co-morbidities have been excluded at the onset. Here, we established a three-tier cohort of individuals younger than 50 years without major comorbidities. These included 47 “critical” (in the ICU under mechanical ventilation) and 25 “non-critical” (in a noncritical care ward) COVID-19 patients as well as 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing and structural causal modeling led to key findings. Critical patients were characterized by exacerbated inflammat...

Additional file 1. Supplemental information

Durant ces 15 dernieres annees, la liste des genes dits atypiques de classe I du Complexe Majeur ... more Durant ces 15 dernieres annees, la liste des genes dits atypiques de classe I du Complexe Majeur d'Histocompatibilite (CMH-I) s'est considerablement allongee. Ils sont soit localises au sein du CMH, en position 6p21. 3, comme les genes MIC (MHC class I chain-related molecule), soit codes en dehors du CMH comme les genes codant pour les molecules CD1, ZAG, FcRn, EPCR, MR1, HFE et enfin RAET1. Ces molecules CMH-I apparentees exercent, pour certaines d'entre elles des fonctions dans les reponses immunes innee et adaptative, et pour d'autres des fonctions sans implication directe dans la reponse immune, comme par exemple HFE, impliquee dans le metabolisme du fer ou ZAG dans celui des lipides. Durant ma these je me suis particulierement interessee a la biologie et la fonction de 3 d'entre elles : MIC, MR1 et ZAG. L'allele MICA008/5. 1, caracterise par une deletion de 42 acides amines au niveau de la region cytoplasmique, est le plus frequent quelque soit l'ori...

Science Translational Medicine, 2021

The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confoundi... more The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confounding factors such as age and comorbidities, true mediators of this condition have remained elusive. We used a multi-omics analysis combined with artificial intelligence in a young patient cohort where major comorbidities were excluded at the onset. The cohort included 47 “critical” (in the intensive care unit under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cell proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were used. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biolog...

Pediatric Blood & Cancer, 2020

Pediatric cases represent 1-5% of coronavirus disease 2019 (COVID-19) cases worldwide. 1 This is ... more Pediatric cases represent 1-5% of coronavirus disease 2019 (COVID-19) cases worldwide. 1 This is linked to the fact that infected children present asymptomatic or pauci-symptomatic forms and are therefore not tested, or children are less infected perhaps due to the lower expression level of angiotensin-converting enzyme 2 (ACE2) in their nasal mucosa. 2

Journal of Experimental Medicine, 2020

The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (H... more The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage–specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients’ T cells displayed impaired early activation, immune synapse morphology, and leading...

Autoimmunity Reviews, 2021

Critical Care, 2020

Background Neurotropism of SARS-CoV-2 and its neurological manifestations have now been confirmed... more Background Neurotropism of SARS-CoV-2 and its neurological manifestations have now been confirmed. We aimed at describing delirium and neurological symptoms of COVID-19 in ICU patients. Methods We conducted a bicentric cohort study in two French ICUs of Strasbourg University Hospital. All the 150 patients referred for acute respiratory distress syndrome due to SARS-CoV-2 between March 3 and May 5, 2020, were included at their admission. Ten patients (6.7%) were excluded because they remained under neuromuscular blockers during their entire ICU stay. Neurological examination, including CAM-ICU, and cerebrospinal fluid analysis, electroencephalography, and magnetic resonance imaging (MRI) were performed in some of the patients with delirium and/or abnormal neurological examination. The primary endpoint was to describe the incidence of delirium and/or abnormal neurological examination. The secondary endpoints were to describe the characteristics of delirium, to compare the duration of ...

Pediatric cases represent a small part of COVID-19 cases reported worldwide and children seem to ... more Pediatric cases represent a small part of COVID-19 cases reported worldwide and children seem to be mostly asymptomatic. The specific risks for patients in pediatric oncology wards are not well known yet. We describe here a pediatric hematopoietic stem cell transplant recipient infected by SARS-CoV-2. Despite being at high potential risk of a severe form of COVID-19 the patient we report only presented a rhinitis. She developed anti-SARS-CoV-2 IgM at D14 and IgG at D56 only and had a positive RT-PCR after 42 days. So far, it seems that in this fragile population COVID-19 is largely pauci-symptomatic.

Journal of Clinical Microbiology, 1999

We report the first case of fungemia due to Candida catenulata , a contaminant of dairy products.... more We report the first case of fungemia due to Candida catenulata , a contaminant of dairy products. C. catenulata was isolated from three blood cultures of a patient with gastric cancer. The patient failed to respond to fluconazole but recovered after treatment was switched to amphotericin B. In vitro, C. catenulata was susceptible to amphotericin B and itraconazole and was also susceptible to fluconazole in dose-dependent manner. The likely portal of entry was the digestive tract, as the patient often ate cheese and had multiple gastric ulcerations.

Journal of Immunological Methods, 2018

Here we extensively describe a FACS-based protocol for isolating intact non-stained human eosinop... more Here we extensively describe a FACS-based protocol for isolating intact non-stained human eosinophils from peripheral blood; a stop forward from our recently published initial study. This method of purification could be accomplished in less than 3h with only small volumes of whole blood necessary, even in healthy subjects generally exhibiting low levels of circulating eosinophils. Eosinophil activation during the isolation steps appeared to be minimal and this purification procedure yielded high quality RNA. Moreover, these FACS-isolated eosinophils had prolonged viability in culture and were suitable for further activation assays.

The Journal of clinical investigation, Jan 3, 2017

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome ... more Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was...

Human Immunology, 2016

The human Major Histocompatibility Complex, known as the "Human Leukocyte Antigen (HLA)", could b... more The human Major Histocompatibility Complex, known as the "Human Leukocyte Antigen (HLA)", could be defined as a "super locus" (historically called "supergene") governing the adaptive immune system in vertebrates. It also harbors genes involved in innate immunity. HLA is the most genedense, polymorphic and disease-associated region of the human genome. It is of critical medical relevance given its involvement in the fate of the transplanted organs/tissues and its association with more than 100 diseases. However, despite these important roles, comprehensive sequence analysis of the 4 megabase HLA locus has been limited due to technological challenges. Thanks to recent improvements in Next-Generation Sequencing (NGS) technologies however, one is now able to handle the peculiarities of the MHC notably the tight linkage disequilibrium between genes as well as their high degree of polymorphism (and hence heterozygosity). Increased read lengths, throughput, accuracy, as well as development of new bioinformatics tools now enable to efficiently generate complete and accurate full-length HLA haplotypes without phase ambiguities. The present report reviews current NGS approaches to capture, sequence and analyze HLA genes and loci. The impact of these new methodologies on various applications including HLA typing, population genetics and disease association studies are discussed.

Genes & Immunity, 2015

Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% o... more Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim of the present study was to identify genes associated with spontaneous HCV clearance in a population of Iranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59 selected-candidate-genes in a cohort of 107 HCV-infected participants who spontaneously cleared the infection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to be associated with HCV outcome (P-values o0.03). rs11506105 in EGFR (epidermal growth factor receptor gene), and rs11881222 and rs12979860 in IL28B (interferon-λ3 gene). Multivariate logistic regression of the three markers showed that the A/A genotypes in both rs11506105 (EFGR) and rs11881222 (IL28B), and the C/C genotype in rs12979860 (IL28B) are associated with HCV clearance (recessive model: odds ratio (OR) = 2.06, 95% confidence interval (95% CI) = 1.09-3.88, P = 0.025; OR = 2.09, 95% CI = 1.23-3.60, P = 0.007; and OR = 1.95, 95% CI = 1.15-3.35, P = 0.014 for rs11506105, rs12979860 and rs11881222, respectively). In conclusion, EGFR and IL28B SNPs are strong independent predictive markers of spontaneous viral clearance.

We report the first case of fungemia due to Candida catenulata, a contaminant of dairy products. ... more We report the first case of fungemia due to Candida catenulata, a contaminant of dairy products. C. catenulata was isolated from three blood cultures of a patient with gastric cancer. The patient failed to respond to fluconazole but recovered after treatment was switched to amphotericin B. In vitro, C. catenulata was susceptible to amphotericin B and itraconazole and was also susceptible to fluconazole in dose-dependent manner. The likely portal of entry was the digestive tract, as the patient often ate cheese and had multiple gastric ulcerations.

Immunogenetics, 2015

Despite that the association of Behçet's disease (BD) with the HLA-B5 was first established i... more Despite that the association of Behçet's disease (BD) with the HLA-B5 was first established in the 1970s, a number of recent genome-wide association studies have both confirmed and furthered this association-in various populations-to individual SNPs both inside and outside the HLA. The former include HLA-B, MICA, and HLA-A, while the latter encompass IL10 and IL23R-IL12RB2 regions. The present study examined whether some of these SNPs could be replicated in an Iranian population, where the prevalence of disease is amply documented. Eight SNPs were selected and tested in 552 patients and 417 controls. These were rs7539328, rs12119179, rs1495965, rs1518111, and rs1800871 in IL10 and IL23R-IL12RB2 regions and rs114854070, rs12525170, and rs76546355 (formerly rs116799036) in the HLA locus. The well-known BD-associated genes HLA-B and MICA were independently genotyped. Although we were not able to formally replicate the association with IL10 and IL23R-IL12RB2, we do report that BD in...

Immunogenetics, 2003

The major histocompatibility complex (MHC) comprises approximately one thousandth of the genome a... more The major histocompatibility complex (MHC) comprises approximately one thousandth of the genome and encompasses its most polymorphic members. This diversity enables the MHC, at the population level, to counteract the extraordinarily diverse microbiological threats. Reviewed here are two separate sets of MHC class I genes: MIC and RAET1. Whilst the former are encoded within the MHC (6p21.3), the latter are located on the opposite arm of the same chromosome (6q24.2-q25.3). Differing from the prototypical class I genes in structure, transcription, diversity and potential function, they both exemplify the versatility of the MHC fold, despite convergence onto a single ligand, the activatory C-type lectin-like receptor, NKG2D. Why the immune system uses two distinct gene families to interact with a unique ligand remains a fascinating question. To answer this question, the reader will be chronologically exposed to the field whilst following a single thread, i.e. genomics and gene diversity.

The Journal of Immunology

AIDS-associated primary central nervous system lymphomas are late events that have an extremely p... more AIDS-associated primary central nervous system lymphomas are late events that have an extremely poor prognosis. Despite different hypotheses, the brain localization of these B cell lymphomas remains an enigma. To better define the cell origin of the lymphomas and the possible role of the B cell receptor (BCR) in the brain localization and/or in the oncogenic transformation, we analyzed the V region genes of the Ig heavy chain expressed by lymphoma cells in five randomly selected patients. After amplifying the rearranged VHDJH DNA by PCR, cloning, and sequencing of the amplified products, we observed that: 1) of the five lymphomas analyzed, four were clearly monoclonal; 2) there was no preferential use of one peculiar VH family or one peculiar segment of gene; 3) the mutation analysis showed that an Ag-driven process occurred in at least two cases, probably before the oncogenic event; and 4) there was no intraclonal variability, suggesting that the hypermutation mechanism is no longe...

The etiopathogenesis of severe COVID-19 remains unknown. Indeed given major confounding factors (... more The etiopathogenesis of severe COVID-19 remains unknown. Indeed given major confounding factors (age and co-morbidities), true drivers of this condition have remained elusive. Here, we employ an unprecedented multi-omics analysis, combined with artificial intelligence, in a young patient cohort where major co-morbidities have been excluded at the onset. Here, we established a three-tier cohort of individuals younger than 50 years without major comorbidities. These included 47 “critical” (in the ICU under mechanical ventilation) and 25 “non-critical” (in a noncritical care ward) COVID-19 patients as well as 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing and structural causal modeling led to key findings. Critical patients were characterized by exacerbated inflammat...

Additional file 1. Supplemental information

Durant ces 15 dernieres annees, la liste des genes dits atypiques de classe I du Complexe Majeur ... more Durant ces 15 dernieres annees, la liste des genes dits atypiques de classe I du Complexe Majeur d'Histocompatibilite (CMH-I) s'est considerablement allongee. Ils sont soit localises au sein du CMH, en position 6p21. 3, comme les genes MIC (MHC class I chain-related molecule), soit codes en dehors du CMH comme les genes codant pour les molecules CD1, ZAG, FcRn, EPCR, MR1, HFE et enfin RAET1. Ces molecules CMH-I apparentees exercent, pour certaines d'entre elles des fonctions dans les reponses immunes innee et adaptative, et pour d'autres des fonctions sans implication directe dans la reponse immune, comme par exemple HFE, impliquee dans le metabolisme du fer ou ZAG dans celui des lipides. Durant ma these je me suis particulierement interessee a la biologie et la fonction de 3 d'entre elles : MIC, MR1 et ZAG. L'allele MICA008/5. 1, caracterise par une deletion de 42 acides amines au niveau de la region cytoplasmique, est le plus frequent quelque soit l'ori...

Science Translational Medicine, 2021

The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confoundi... more The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confounding factors such as age and comorbidities, true mediators of this condition have remained elusive. We used a multi-omics analysis combined with artificial intelligence in a young patient cohort where major comorbidities were excluded at the onset. The cohort included 47 “critical” (in the intensive care unit under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cell proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were used. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biolog...

Pediatric Blood & Cancer, 2020

Pediatric cases represent 1-5% of coronavirus disease 2019 (COVID-19) cases worldwide. 1 This is ... more Pediatric cases represent 1-5% of coronavirus disease 2019 (COVID-19) cases worldwide. 1 This is linked to the fact that infected children present asymptomatic or pauci-symptomatic forms and are therefore not tested, or children are less infected perhaps due to the lower expression level of angiotensin-converting enzyme 2 (ACE2) in their nasal mucosa. 2

Journal of Experimental Medicine, 2020

The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (H... more The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage–specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients’ T cells displayed impaired early activation, immune synapse morphology, and leading...

Autoimmunity Reviews, 2021

Critical Care, 2020

Background Neurotropism of SARS-CoV-2 and its neurological manifestations have now been confirmed... more Background Neurotropism of SARS-CoV-2 and its neurological manifestations have now been confirmed. We aimed at describing delirium and neurological symptoms of COVID-19 in ICU patients. Methods We conducted a bicentric cohort study in two French ICUs of Strasbourg University Hospital. All the 150 patients referred for acute respiratory distress syndrome due to SARS-CoV-2 between March 3 and May 5, 2020, were included at their admission. Ten patients (6.7%) were excluded because they remained under neuromuscular blockers during their entire ICU stay. Neurological examination, including CAM-ICU, and cerebrospinal fluid analysis, electroencephalography, and magnetic resonance imaging (MRI) were performed in some of the patients with delirium and/or abnormal neurological examination. The primary endpoint was to describe the incidence of delirium and/or abnormal neurological examination. The secondary endpoints were to describe the characteristics of delirium, to compare the duration of ...

Pediatric cases represent a small part of COVID-19 cases reported worldwide and children seem to ... more Pediatric cases represent a small part of COVID-19 cases reported worldwide and children seem to be mostly asymptomatic. The specific risks for patients in pediatric oncology wards are not well known yet. We describe here a pediatric hematopoietic stem cell transplant recipient infected by SARS-CoV-2. Despite being at high potential risk of a severe form of COVID-19 the patient we report only presented a rhinitis. She developed anti-SARS-CoV-2 IgM at D14 and IgG at D56 only and had a positive RT-PCR after 42 days. So far, it seems that in this fragile population COVID-19 is largely pauci-symptomatic.

Journal of Clinical Microbiology, 1999

We report the first case of fungemia due to Candida catenulata , a contaminant of dairy products.... more We report the first case of fungemia due to Candida catenulata , a contaminant of dairy products. C. catenulata was isolated from three blood cultures of a patient with gastric cancer. The patient failed to respond to fluconazole but recovered after treatment was switched to amphotericin B. In vitro, C. catenulata was susceptible to amphotericin B and itraconazole and was also susceptible to fluconazole in dose-dependent manner. The likely portal of entry was the digestive tract, as the patient often ate cheese and had multiple gastric ulcerations.

Journal of Immunological Methods, 2018

Here we extensively describe a FACS-based protocol for isolating intact non-stained human eosinop... more Here we extensively describe a FACS-based protocol for isolating intact non-stained human eosinophils from peripheral blood; a stop forward from our recently published initial study. This method of purification could be accomplished in less than 3h with only small volumes of whole blood necessary, even in healthy subjects generally exhibiting low levels of circulating eosinophils. Eosinophil activation during the isolation steps appeared to be minimal and this purification procedure yielded high quality RNA. Moreover, these FACS-isolated eosinophils had prolonged viability in culture and were suitable for further activation assays.

The Journal of clinical investigation, Jan 3, 2017

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome ... more Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was...

Human Immunology, 2016

The human Major Histocompatibility Complex, known as the "Human Leukocyte Antigen (HLA)", could b... more The human Major Histocompatibility Complex, known as the "Human Leukocyte Antigen (HLA)", could be defined as a "super locus" (historically called "supergene") governing the adaptive immune system in vertebrates. It also harbors genes involved in innate immunity. HLA is the most genedense, polymorphic and disease-associated region of the human genome. It is of critical medical relevance given its involvement in the fate of the transplanted organs/tissues and its association with more than 100 diseases. However, despite these important roles, comprehensive sequence analysis of the 4 megabase HLA locus has been limited due to technological challenges. Thanks to recent improvements in Next-Generation Sequencing (NGS) technologies however, one is now able to handle the peculiarities of the MHC notably the tight linkage disequilibrium between genes as well as their high degree of polymorphism (and hence heterozygosity). Increased read lengths, throughput, accuracy, as well as development of new bioinformatics tools now enable to efficiently generate complete and accurate full-length HLA haplotypes without phase ambiguities. The present report reviews current NGS approaches to capture, sequence and analyze HLA genes and loci. The impact of these new methodologies on various applications including HLA typing, population genetics and disease association studies are discussed.

Genes & Immunity, 2015

Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% o... more Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim of the present study was to identify genes associated with spontaneous HCV clearance in a population of Iranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59 selected-candidate-genes in a cohort of 107 HCV-infected participants who spontaneously cleared the infection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to be associated with HCV outcome (P-values o0.03). rs11506105 in EGFR (epidermal growth factor receptor gene), and rs11881222 and rs12979860 in IL28B (interferon-λ3 gene). Multivariate logistic regression of the three markers showed that the A/A genotypes in both rs11506105 (EFGR) and rs11881222 (IL28B), and the C/C genotype in rs12979860 (IL28B) are associated with HCV clearance (recessive model: odds ratio (OR) = 2.06, 95% confidence interval (95% CI) = 1.09-3.88, P = 0.025; OR = 2.09, 95% CI = 1.23-3.60, P = 0.007; and OR = 1.95, 95% CI = 1.15-3.35, P = 0.014 for rs11506105, rs12979860 and rs11881222, respectively). In conclusion, EGFR and IL28B SNPs are strong independent predictive markers of spontaneous viral clearance.

We report the first case of fungemia due to Candida catenulata, a contaminant of dairy products. ... more We report the first case of fungemia due to Candida catenulata, a contaminant of dairy products. C. catenulata was isolated from three blood cultures of a patient with gastric cancer. The patient failed to respond to fluconazole but recovered after treatment was switched to amphotericin B. In vitro, C. catenulata was susceptible to amphotericin B and itraconazole and was also susceptible to fluconazole in dose-dependent manner. The likely portal of entry was the digestive tract, as the patient often ate cheese and had multiple gastric ulcerations.

Immunogenetics, 2015

Despite that the association of Behçet's disease (BD) with the HLA-B5 was first established i... more Despite that the association of Behçet's disease (BD) with the HLA-B5 was first established in the 1970s, a number of recent genome-wide association studies have both confirmed and furthered this association-in various populations-to individual SNPs both inside and outside the HLA. The former include HLA-B, MICA, and HLA-A, while the latter encompass IL10 and IL23R-IL12RB2 regions. The present study examined whether some of these SNPs could be replicated in an Iranian population, where the prevalence of disease is amply documented. Eight SNPs were selected and tested in 552 patients and 417 controls. These were rs7539328, rs12119179, rs1495965, rs1518111, and rs1800871 in IL10 and IL23R-IL12RB2 regions and rs114854070, rs12525170, and rs76546355 (formerly rs116799036) in the HLA locus. The well-known BD-associated genes HLA-B and MICA were independently genotyped. Although we were not able to formally replicate the association with IL10 and IL23R-IL12RB2, we do report that BD in...

Immunogenetics, 2003

The major histocompatibility complex (MHC) comprises approximately one thousandth of the genome a... more The major histocompatibility complex (MHC) comprises approximately one thousandth of the genome and encompasses its most polymorphic members. This diversity enables the MHC, at the population level, to counteract the extraordinarily diverse microbiological threats. Reviewed here are two separate sets of MHC class I genes: MIC and RAET1. Whilst the former are encoded within the MHC (6p21.3), the latter are located on the opposite arm of the same chromosome (6q24.2-q25.3). Differing from the prototypical class I genes in structure, transcription, diversity and potential function, they both exemplify the versatility of the MHC fold, despite convergence onto a single ligand, the activatory C-type lectin-like receptor, NKG2D. Why the immune system uses two distinct gene families to interact with a unique ligand remains a fascinating question. To answer this question, the reader will be chronologically exposed to the field whilst following a single thread, i.e. genomics and gene diversity.