CTL specific for HIV have been described in lungs of infected patients at early stages of HIV dis... more CTL specific for HIV have been described in lungs of infected patients at early stages of HIV disease. In order to characterize the evolution over time of HIV-specific CTL, we have analyzed the cytotoxic function and the cell surface phenotype of the alveolar lymphocytes from 41 patients at various stages of HIV disease. We demonstrated a progressive decline of alveolar anti-HIV CTL activity and detected Ts cells from the lungs of patients with advanced HIV disease. These alveolar T cells strongly suppressed the effector phase of anti-HIV CTL lysis. They lacked a marked specificity of function because they also block anti-HLA CTL response and were not restricted by the HLA-class-I transplantation Ag. They displayed the CD3, CD8, and HNK1 markers, were CD4 and CD16 negative, and lacked NK activity. The presence of Ts cells at late stages of HIV disease could thus partly explain the inefficiency of host defenses against HIV.
Two lines of mice genetically selected for high and low in vitro responses to PHA were used to ev... more Two lines of mice genetically selected for high and low in vitro responses to PHA were used to evaluate the impact of T cell polyclonal expansion on acquired resistance to Listeria monocytogenes. The selective breeding induced two major consequences in low responder mice: (1) a reduction of the number of L3T4+ cells and (2) a restriction of T cell expansion upon PHA stimulation, predominantly affecting the Lyt-2+ subset, and associated with an abridgment of IL-2 production. In vivo PHA stimulation induced anti-Listeria protection in high responder mice, but was much less effective in low responder mice. Flow cytometer analysis revealed that T cell proliferation was also reduced in low responder mice during the course of Listeria infection, implying both L3T4+ and Lyt-2+ subsets. This defect did not apparently influence the kinetics of bacterial elimination in host tissues, which was similar in both lines during primary Listeria infection. In contrast, the expression of delayed-type ...
In previous studies we demonstrated the triggering of the phospholipase C (PLC) pathway during th... more In previous studies we demonstrated the triggering of the phospholipase C (PLC) pathway during the activation of an Ag-specific human CD4+ T lymphocyte clone by a mitogenic pair of CD2 (X11,D66) mAb. Similar conditions were applied to investigate a possible involvement of a phospholipase A2 (PLA2) acting as an additional alternative pathway during human T cell activation. Our results show that arachidonic acid or its derivatives are released after CD2 triggering. This release is largely independent of PLC activation and is mediated by a PLA2 because: 1) phosphatidylcholine is the preferential source of [3H]arachidonate release; 2) [3H]arachidonic acid release and phosphatidylcholine hydrolysis are blocked by two inhibitors of solubilized PLA2, mepacrine, and 4-p-bromophenacylbromide; and 3) we evidenced a PLA2 activity in cell homogenates. Extracellular calcium appears to play a critical role because the effects of CD2 mAb were inhibited in a Ca2(+)-depleted medium. In contrast, pro...
Proceedings of the National Academy of Sciences of the United States of America, Jan 9, 2015
Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowe... more Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and th...
Natural killer (NK) cells provide defense in the early stages of the immune response against vira... more Natural killer (NK) cells provide defense in the early stages of the immune response against viral infections. Killer cell immunoglobulin-like receptors (KIR) expressed on the surface of NK cells play an important role in regulating NK cell response through recognition of human leukocyte antigen (HLA) class I molecules on target cells. Previous studies have shown that specific KIR/ligand combinations are associated with the outcome of several viral infectious diseases. We investigated the impact of inhibitory and activating KIR and their HLA-class I ligand genotype on the susceptibility to Chikungunya virus (CHIKV) and Dengue virus (DENV2) infections. From April to July 2010 in Gabon, a large outbreak of CHIKV and DENV2 concomitantly occurred in two provinces of Gabon (Ogooué-Lolo and Haut-Ogooué). We performed the genotypic analysis of KIR in the combination with their cognate HLA-class I ligands in 73 CHIKV and 55 DENV2 adult cases, compared with 54 healthy individuals. We found i...
Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ... more Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in healthy populations (5-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 × 0 −8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 × 0 −43) and DRB1*1301-DQB1*0603 (P < 3 × 0 −7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 × 0 −4). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility. Narcolepsy-cataplexy is a sleep disorder characterized by invalidating excessive daytime sleepiness and cataplexy (loss of muscle tone Q4 Q4 triggered by strong emotions) 1. Epidemiologic surveys estimate a disease prevalence ranging from 0.03% to 0.16% depending on ethnicity. However, narcolepsy is still an underdiagnosed condition. Extensive efforts over the past 30 years to gain a better understanding of the genetic basis of the disease have identified a striking association with the HLA region 2. Nearly 100% of individuals of European ancestry affected by narcolepsy with cataplexy carry the HLA haplotype DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 (ref. 2). This association is thought to represent a virtually necessary but not sufficient risk factor, because 15-25% of healthy individuals in the general population carry the associated HLA haplotype. More recently, it has been shown that the best biological marker for narcolepsy is a deficiency in the hypothalamic neuropeptide hypocretin-1 (orexin-A), which has significantly reduced, if not undetectable, levels in the cerebrospinal fluid of almost all HLA-DRB1*1501-positive individuals with narcolepsy and cataplexy 3. This, together with the selective loss of hypocretin neurons in the lateral hypothalamus 4,5 , has led to the hypothesis that narcolepsy is caused by an autoimmune attack targeting hypocretin-producing neurons. Recently, we reported the identification of circulating TRIB2specific antibodies reactive with hypocretin neurons, confirming the autoimmune nature of narcolepsy 6 for the first time.
ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) infection of individuals carrying the two all... more ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) infection of individuals carrying the two alleles of the CCR5Δ32 mutation (CCR5−/−) has rarely been reported, but how the virus overcomes theCCR5Δ32protective effect in these cases has not been delineated. We have investigated this in 6 infected (HIV+) and 25 HIV−CCR5−/−individuals. CD4+T lymphocytes isolated from HIV−CCR5−/−peripheral blood mononuclear cells (PBMCs) showed lower levels of CXCR4 expression that correlated with lower X4 Env-mediated fusion. Endogenous CCR5Δ32 protein was detected in all HIV−CCR5−/−PBMC samples (n= 25) but not in four of six unrelated HIV+CCR5−/−PBMC samples. Low levels were detected in another two HIV+CCR5−/−PBMC samples. The expression of adenovirus 5 (Ad5)-encoded CCR5Δ32 protein restored the protective effect in PBMCs from three HIV+CCR5−/−individuals but failed to restore the protective effect in PBMCs isolated from another three HIV+CCR5−/−individuals. In the latter samples, pulse-chase analyse...
Objective: To determine the influence of heterozygosity for the ∆32 mutant CCR-5 allele on HIV-1 ... more Objective: To determine the influence of heterozygosity for the ∆32 mutant CCR-5 allele on HIV-1 disease progression. Design: HIV-1 disease progression and serum viral load were analysed according to the CC chemokine receptor (CCR)-5 genotype in 412 Caucasian patients (319 men and 93 women) with a known date of seroconversion, who were enrolled in the SEROCO cohort (median follow-up, 74 months). Results: The frequency of heterozygosity for the mutant allele was 17% and did not differ according to sex or risk factor for HIV infection. Heterozygotes were significantly less likely than patients with two functional alleles to have symptomatic primary infection. Their serum viral load was lower during the 6-to 24-month plateau phase after seroconversion. This difference persisted afterwards, although the rate of decline in CD4+ cells was similar. Kaplan-Meier survival curves showed slower progression to clinical AIDS in heterozygotes during the first 7 years following infection (P < 0.02), the two curves tending to join thereafter (overall log-rank test, P = 0.17). However, the interaction term with time did not reach significance in a Cox model. The overall relative risk of progression was 0.67 (95% confidence interval, 0.38-1.18) and was not influenced by adjustment for age at seroconversion or symptomatic primary infection. After adjustment for early viral load the relative risk was 0.83. Pneumocystis carinii pneumonia and toxoplasmosis were less likely to be the first AIDS-defining illness in heterozygotes than in the other patients (0 versus 24.7% of AIDS cases, P = 0.04), despite similar management. Conclusion: Deletion of one CCR-5 gene allele appears to protect against HIV-1 disease progression, mainly during the early years of the infection. Heterozygosity for the deletion leads to persistently lower viral load, and also seems to protect against some opportunistic infections.
Human immunodeficiency virus (HIV)-1–infected long-term nonprogressors (LT-NP) represent less tha... more Human immunodeficiency virus (HIV)-1–infected long-term nonprogressors (LT-NP) represent less than 5% of HIV-1–infected patients. In this work, we tried to understand whether combined genotypes of CCR5-▵32, CCR2-64I, SDF1-3′A and HLA alleles can predict the LT-NP status. Among the chemokine receptor genotypes, only the frequency of the CCR5-▵32 allele was significantly higher in LT-NP compared with the group of standard progressors. The predominant HLA alleles in LT-NP were HLA-A3, HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7. A combination of both HLA and chemokine receptor genotypes integrated in a multivariate logistic regression model showed that if a subject is heterozygous for CCR5-▵32 and homozygous for SDF1 wild type, his odds of being LT-NP are increased by 16-fold, by 47-fold when a HLA-B27 allele is present with HLA-DR6 absent, and by 47-fold also if at least three of the following alleles are present: HLA-A3, HLA-B14, HLA-B17, HLA-DR7. This model allowed a correct cla...
The American Journal of Tropical Medicine and Hygiene, 1999
To define the medical characteristics of intravascular drug users in Ho Chi Minh City, Vietnam, w... more To define the medical characteristics of intravascular drug users in Ho Chi Minh City, Vietnam, we examined 280 men, of whom 235 were infected with human immunodeficiency virus (HIV), being treated in a rehabilitation center. The patients used mainly opium, often in shooting galleries (50%). The prevalence of oral candidiasis (58%) and zoster infection (20%) was high in HIV-seropositive patients, whereas oral hairy leukoplasia and Kaposi's sarcoma were absent. The prevalence of acquired immunodeficiency syndrome was 24%. More than 80% of the patients had infections with hepatitis C virus, hepatitis B virus, cytomegalovirus, or human T cell lymphotropic virus type-1. The CD4ϩ cell counts correlated well with viral load. Only HIV-1 subtype E was detected in the 30 patients tested. A cohort study of HIV-infected subjects in this population seems feasible, and would permit introduction of anti-retroviral therapy The large number of HIV-seronegative subjects sharing the same at-risk practices as the HIV-infected subjects raises the possibility of natural protection in this population.
Cellulaire (SFGM-TC) and the Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI)... more Cellulaire (SFGM-TC) and the Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI) We retrospectively analyzed the impact of HLA-DPB1 mismatches in a large cohort of 1342 French patients who underwent 10/10 HLA-matched unrelated HSCT. A significant impact of HLA-DPB1 allelic mismatches (2 vs 0) was observed in severe acute GVHD (aGVHD III-IV) (risk ratio (RR) = 1.73, confidence interval (CI) 95% 1.09-2.73, P = 0.019) without impact on OS, TRM, relapse and chronic GVHD (cGVHD). According to the T-cell epitope 3 (TCE3)/TCE4 HLA-DPB1 disparity algorithm, 37.6% and 58.4% pairs had nonpermissive HLA-DPB1, respectively. TCE3 and TCE4 disparities had no statistical impact on OS, TRM, relapse, aGVHD and cGVHD. When TCE3/TCE4 disparities were analyzed in the graft-vs-host or host-vs-graft (HVG) direction, only a significant impact of TCE4 nonpermissive disparities in the HVG direction was observed on relapse (RR = 1.34, CI 95% 1.00-1.80, P = 0.048). In conclusion, this French retrospective study shows an adverse prognosis of HLA-DPB1 mismatches (2 vs 0) on severe aGVHD and of nonpermissive TCE4 HVG disparities on relapse after HLA-matched 10/10 unrelated HSCT.
Short paper We have developed a monoclonal antibody (mAb), termed anti-TigammaA, which recognizes... more Short paper We have developed a monoclonal antibody (mAb), termed anti-TigammaA, which recognizes an antigenic determinant carried by a variable segment of the T cell receptor (TcR) y chain. This determinant, encoded by the V,9 gene, is expressed on approximately 3% of peripheral blood lymphocytes. In the present study, we have found that binding of anti-TigammaA mAb to its specific ligand results in the triggering of the phosphatidylinositol (PI) cycle-related metabolic process. Indeed, an increased labeling of both phosphatidic acid and PI, related to an enhanced turnover of PI cycle-dependent phospholipids, was observed following exposure of 32P orthophosphoric acid-labeled cells to anti-TigammaA mAb. In addition, there was a rapid rise in intracellular free calcium concentrations. Similar experiments have been performed previously on CD3' TcRa/P-cells with an anti-CD3 mAB. They predicted that signals produced by the interaction between the second TcR and its ligand(s) would be transmitted via the PI cycle-linked intracellular second messengers. We confirm this hypothesis in an experimental system where stimulation occurs directly through the y/S receptor structure.
Background: Rheumatoid Arthritis (RA) is the most common systemic autoimmune disease, with a resp... more Background: Rheumatoid Arthritis (RA) is the most common systemic autoimmune disease, with a respective expanded genetic research 1. Immunogenetic studies have documented the positive correlation of various gene loci with incidence and/or disease profile. However, the description of gene loci negatively related to the incidence of RA is rarely documented. Apart from an early study involving HLA class II, there has been no reference to any genetic locus associated with a protective role against RA incidence. Objectives: To identify the sequence of the functional areas of the TRAF1 (TNF receptor associated factor 1-a protein involved in the intracellular signaling pathway of TNF) gene. Methods: 172 patients and 95 controls were genetically assessed for the sequence of the seven exons of the gene TRAF1. Results: On the position 9:120905076 of exon 7, the registered polymorphism G/A (rs143265058) was described in the controls group. The same polymorphism was not confirmed in any of the patients. Further functional proteomic study of the polymorphism with computing programs (software), revealed that the presence of this polymorphism leads to a differentiation of the quaternary structure of TRAF1 protein, possibly affecting the cohesion of intracellular TNF signaling pathway 2. Conclusions: The present reference is one of the extremely rare genetic studies describing a protective gene locus against rheumatoid arthritis, and a pioneer of its kind in the use of Applied Informatics in the depiction of the quaternary structure of the encoded protein. At the same time, it is one of the few immunogenetic studies describing the functional proteomics of the encoded protein, plotting on a molecular level specific interaction modifications affecting the intracellular signaling pathway of TNF. References:
To further understand the exceptional HIV-1 control observed in Post-Treatment Controllers (PTCs)... more To further understand the exceptional HIV-1 control observed in Post-Treatment Controllers (PTCs) from the Virological and Immunological Sustained CONtrol after Treatment Interruption study we investigated their HIV-specific T-cell responses. Polyfunctionality of HIV-specific CD4 and CD8 T cells and the ratios of HIV-specific CD4 T cells per infected cells were similar in post-treatment controllers, continuously early-treated patients and long-term non-progressors Overall early treatment appears to preserve robust HIV-specific CD4 T cells, which might contribute to the posttreatment control of HIV.
Open Journal of Rheumatology and Autoimmune Diseases, 2016
The era of whole genome study analysis has introduced a profound research in the genetics of auto... more The era of whole genome study analysis has introduced a profound research in the genetics of autoimmune diseases. Some of the new genetic loci that have been associated with the development or the severity of autoimmune diseases have been thoroughly studied, conferring a more detailed understanding of disease pathophysiology. Furthermore, single nucleotide polymorphisms (SNPs) have been described not only in coding regions of the human genome but also in non-coding areas (introns), the importance of which has not been yet clarified. Over the last years, such an SNP has been associated with the development of rheumatoid arthritis, the most frequent autoimmune disease. This SNP is at the position 122730060 of chromosome 9 in the TRAF1/C5 region and consists of a substitution of the nucleotide base guanine (G)-which is considered the ancestral phenotype-by alanine (A). It has been indicated that G is the aggravating nucleotide, and that G/G is the disease predisposing phenotype, conferring >1.3× risk for RA. On this background, we performed a genome study on a Greek population of northern Greece (Macedonia) in order to identify the association of this SNP with RA in our group.
Patients et méthodes.-Nous avons réalisé une étude phénotypique portant sur 37 patients ayant une... more Patients et méthodes.-Nous avons réalisé une étude phénotypique portant sur 37 patients ayant une MEC histologiquement prouvée, suivis dans notre centre
A 43 year old female patient presented for recurrent bacterial lower respiratory infections. A re... more A 43 year old female patient presented for recurrent bacterial lower respiratory infections. A research for immunodeficiency status revealed total hypogammaglobulinemia, reduced IgG1, IgG2, IgG3 subclass levels, and low number of B lymphocytes (CD19+). Common Variable Immunodeficiency (CVID) 11.2 category was diagnosed according to recent criteria of primary immunodeficiencies (PID). Further immunological study consisting of genetic polymorphism of genes relating to differentiation, activation and function of B cells (ICOS, BAFF receptor BCMA and TACI) was performed, which did not reveal any related mutations. T cell parameters and Th1/Th2 cytokine network did not show any disturbances. It is postulated that probable endstage B cell differentiation defects should be investigated. The patient receives IVIGs replacement thereafter and the rate and severity of infections have significantly improved.
Inadequate reconstitution of CD4+ lymphocyte and interleukin (IL)-2 production defect are observe... more Inadequate reconstitution of CD4+ lymphocyte and interleukin (IL)-2 production defect are observed after bone marrow or peripheral blood stem cell transplantation (SCT). We studied immune reconstitution after SCT in 33 consecutive patients who received allogeneic SCT (17 patients) or autologous SCT (16 patients). The aims were to assess the regeneration of the CD4+ T-cell subset with regard to helper cell differentiation. CD4+ T-cell subset regeneration and expansion of the CD4+CD7- subset were studied by immunofluorescence analysis. CD4+CD7- cell cytokine secretion was analyzed after cell sorting and costimulation of the CD3 and CD28 pathways, in enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction assays. We report a relative expansion of the CD4+CD7- subset within CD4+ T cells, detected as early as 1 month after bone marrow transplantation and decreasing after day 60. CD4+CD7- T cells preferentially expressed CD45RO and activation markers such as ...
CTL specific for HIV have been described in lungs of infected patients at early stages of HIV dis... more CTL specific for HIV have been described in lungs of infected patients at early stages of HIV disease. In order to characterize the evolution over time of HIV-specific CTL, we have analyzed the cytotoxic function and the cell surface phenotype of the alveolar lymphocytes from 41 patients at various stages of HIV disease. We demonstrated a progressive decline of alveolar anti-HIV CTL activity and detected Ts cells from the lungs of patients with advanced HIV disease. These alveolar T cells strongly suppressed the effector phase of anti-HIV CTL lysis. They lacked a marked specificity of function because they also block anti-HLA CTL response and were not restricted by the HLA-class-I transplantation Ag. They displayed the CD3, CD8, and HNK1 markers, were CD4 and CD16 negative, and lacked NK activity. The presence of Ts cells at late stages of HIV disease could thus partly explain the inefficiency of host defenses against HIV.
Two lines of mice genetically selected for high and low in vitro responses to PHA were used to ev... more Two lines of mice genetically selected for high and low in vitro responses to PHA were used to evaluate the impact of T cell polyclonal expansion on acquired resistance to Listeria monocytogenes. The selective breeding induced two major consequences in low responder mice: (1) a reduction of the number of L3T4+ cells and (2) a restriction of T cell expansion upon PHA stimulation, predominantly affecting the Lyt-2+ subset, and associated with an abridgment of IL-2 production. In vivo PHA stimulation induced anti-Listeria protection in high responder mice, but was much less effective in low responder mice. Flow cytometer analysis revealed that T cell proliferation was also reduced in low responder mice during the course of Listeria infection, implying both L3T4+ and Lyt-2+ subsets. This defect did not apparently influence the kinetics of bacterial elimination in host tissues, which was similar in both lines during primary Listeria infection. In contrast, the expression of delayed-type ...
In previous studies we demonstrated the triggering of the phospholipase C (PLC) pathway during th... more In previous studies we demonstrated the triggering of the phospholipase C (PLC) pathway during the activation of an Ag-specific human CD4+ T lymphocyte clone by a mitogenic pair of CD2 (X11,D66) mAb. Similar conditions were applied to investigate a possible involvement of a phospholipase A2 (PLA2) acting as an additional alternative pathway during human T cell activation. Our results show that arachidonic acid or its derivatives are released after CD2 triggering. This release is largely independent of PLC activation and is mediated by a PLA2 because: 1) phosphatidylcholine is the preferential source of [3H]arachidonate release; 2) [3H]arachidonic acid release and phosphatidylcholine hydrolysis are blocked by two inhibitors of solubilized PLA2, mepacrine, and 4-p-bromophenacylbromide; and 3) we evidenced a PLA2 activity in cell homogenates. Extracellular calcium appears to play a critical role because the effects of CD2 mAb were inhibited in a Ca2(+)-depleted medium. In contrast, pro...
Proceedings of the National Academy of Sciences of the United States of America, Jan 9, 2015
Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowe... more Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and th...
Natural killer (NK) cells provide defense in the early stages of the immune response against vira... more Natural killer (NK) cells provide defense in the early stages of the immune response against viral infections. Killer cell immunoglobulin-like receptors (KIR) expressed on the surface of NK cells play an important role in regulating NK cell response through recognition of human leukocyte antigen (HLA) class I molecules on target cells. Previous studies have shown that specific KIR/ligand combinations are associated with the outcome of several viral infectious diseases. We investigated the impact of inhibitory and activating KIR and their HLA-class I ligand genotype on the susceptibility to Chikungunya virus (CHIKV) and Dengue virus (DENV2) infections. From April to July 2010 in Gabon, a large outbreak of CHIKV and DENV2 concomitantly occurred in two provinces of Gabon (Ogooué-Lolo and Haut-Ogooué). We performed the genotypic analysis of KIR in the combination with their cognate HLA-class I ligands in 73 CHIKV and 55 DENV2 adult cases, compared with 54 healthy individuals. We found i...
Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ... more Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in healthy populations (5-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 × 0 −8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 × 0 −43) and DRB1*1301-DQB1*0603 (P < 3 × 0 −7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 × 0 −4). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility. Narcolepsy-cataplexy is a sleep disorder characterized by invalidating excessive daytime sleepiness and cataplexy (loss of muscle tone Q4 Q4 triggered by strong emotions) 1. Epidemiologic surveys estimate a disease prevalence ranging from 0.03% to 0.16% depending on ethnicity. However, narcolepsy is still an underdiagnosed condition. Extensive efforts over the past 30 years to gain a better understanding of the genetic basis of the disease have identified a striking association with the HLA region 2. Nearly 100% of individuals of European ancestry affected by narcolepsy with cataplexy carry the HLA haplotype DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 (ref. 2). This association is thought to represent a virtually necessary but not sufficient risk factor, because 15-25% of healthy individuals in the general population carry the associated HLA haplotype. More recently, it has been shown that the best biological marker for narcolepsy is a deficiency in the hypothalamic neuropeptide hypocretin-1 (orexin-A), which has significantly reduced, if not undetectable, levels in the cerebrospinal fluid of almost all HLA-DRB1*1501-positive individuals with narcolepsy and cataplexy 3. This, together with the selective loss of hypocretin neurons in the lateral hypothalamus 4,5 , has led to the hypothesis that narcolepsy is caused by an autoimmune attack targeting hypocretin-producing neurons. Recently, we reported the identification of circulating TRIB2specific antibodies reactive with hypocretin neurons, confirming the autoimmune nature of narcolepsy 6 for the first time.
ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) infection of individuals carrying the two all... more ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) infection of individuals carrying the two alleles of the CCR5Δ32 mutation (CCR5−/−) has rarely been reported, but how the virus overcomes theCCR5Δ32protective effect in these cases has not been delineated. We have investigated this in 6 infected (HIV+) and 25 HIV−CCR5−/−individuals. CD4+T lymphocytes isolated from HIV−CCR5−/−peripheral blood mononuclear cells (PBMCs) showed lower levels of CXCR4 expression that correlated with lower X4 Env-mediated fusion. Endogenous CCR5Δ32 protein was detected in all HIV−CCR5−/−PBMC samples (n= 25) but not in four of six unrelated HIV+CCR5−/−PBMC samples. Low levels were detected in another two HIV+CCR5−/−PBMC samples. The expression of adenovirus 5 (Ad5)-encoded CCR5Δ32 protein restored the protective effect in PBMCs from three HIV+CCR5−/−individuals but failed to restore the protective effect in PBMCs isolated from another three HIV+CCR5−/−individuals. In the latter samples, pulse-chase analyse...
Objective: To determine the influence of heterozygosity for the ∆32 mutant CCR-5 allele on HIV-1 ... more Objective: To determine the influence of heterozygosity for the ∆32 mutant CCR-5 allele on HIV-1 disease progression. Design: HIV-1 disease progression and serum viral load were analysed according to the CC chemokine receptor (CCR)-5 genotype in 412 Caucasian patients (319 men and 93 women) with a known date of seroconversion, who were enrolled in the SEROCO cohort (median follow-up, 74 months). Results: The frequency of heterozygosity for the mutant allele was 17% and did not differ according to sex or risk factor for HIV infection. Heterozygotes were significantly less likely than patients with two functional alleles to have symptomatic primary infection. Their serum viral load was lower during the 6-to 24-month plateau phase after seroconversion. This difference persisted afterwards, although the rate of decline in CD4+ cells was similar. Kaplan-Meier survival curves showed slower progression to clinical AIDS in heterozygotes during the first 7 years following infection (P < 0.02), the two curves tending to join thereafter (overall log-rank test, P = 0.17). However, the interaction term with time did not reach significance in a Cox model. The overall relative risk of progression was 0.67 (95% confidence interval, 0.38-1.18) and was not influenced by adjustment for age at seroconversion or symptomatic primary infection. After adjustment for early viral load the relative risk was 0.83. Pneumocystis carinii pneumonia and toxoplasmosis were less likely to be the first AIDS-defining illness in heterozygotes than in the other patients (0 versus 24.7% of AIDS cases, P = 0.04), despite similar management. Conclusion: Deletion of one CCR-5 gene allele appears to protect against HIV-1 disease progression, mainly during the early years of the infection. Heterozygosity for the deletion leads to persistently lower viral load, and also seems to protect against some opportunistic infections.
Human immunodeficiency virus (HIV)-1–infected long-term nonprogressors (LT-NP) represent less tha... more Human immunodeficiency virus (HIV)-1–infected long-term nonprogressors (LT-NP) represent less than 5% of HIV-1–infected patients. In this work, we tried to understand whether combined genotypes of CCR5-▵32, CCR2-64I, SDF1-3′A and HLA alleles can predict the LT-NP status. Among the chemokine receptor genotypes, only the frequency of the CCR5-▵32 allele was significantly higher in LT-NP compared with the group of standard progressors. The predominant HLA alleles in LT-NP were HLA-A3, HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7. A combination of both HLA and chemokine receptor genotypes integrated in a multivariate logistic regression model showed that if a subject is heterozygous for CCR5-▵32 and homozygous for SDF1 wild type, his odds of being LT-NP are increased by 16-fold, by 47-fold when a HLA-B27 allele is present with HLA-DR6 absent, and by 47-fold also if at least three of the following alleles are present: HLA-A3, HLA-B14, HLA-B17, HLA-DR7. This model allowed a correct cla...
The American Journal of Tropical Medicine and Hygiene, 1999
To define the medical characteristics of intravascular drug users in Ho Chi Minh City, Vietnam, w... more To define the medical characteristics of intravascular drug users in Ho Chi Minh City, Vietnam, we examined 280 men, of whom 235 were infected with human immunodeficiency virus (HIV), being treated in a rehabilitation center. The patients used mainly opium, often in shooting galleries (50%). The prevalence of oral candidiasis (58%) and zoster infection (20%) was high in HIV-seropositive patients, whereas oral hairy leukoplasia and Kaposi's sarcoma were absent. The prevalence of acquired immunodeficiency syndrome was 24%. More than 80% of the patients had infections with hepatitis C virus, hepatitis B virus, cytomegalovirus, or human T cell lymphotropic virus type-1. The CD4ϩ cell counts correlated well with viral load. Only HIV-1 subtype E was detected in the 30 patients tested. A cohort study of HIV-infected subjects in this population seems feasible, and would permit introduction of anti-retroviral therapy The large number of HIV-seronegative subjects sharing the same at-risk practices as the HIV-infected subjects raises the possibility of natural protection in this population.
Cellulaire (SFGM-TC) and the Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI)... more Cellulaire (SFGM-TC) and the Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI) We retrospectively analyzed the impact of HLA-DPB1 mismatches in a large cohort of 1342 French patients who underwent 10/10 HLA-matched unrelated HSCT. A significant impact of HLA-DPB1 allelic mismatches (2 vs 0) was observed in severe acute GVHD (aGVHD III-IV) (risk ratio (RR) = 1.73, confidence interval (CI) 95% 1.09-2.73, P = 0.019) without impact on OS, TRM, relapse and chronic GVHD (cGVHD). According to the T-cell epitope 3 (TCE3)/TCE4 HLA-DPB1 disparity algorithm, 37.6% and 58.4% pairs had nonpermissive HLA-DPB1, respectively. TCE3 and TCE4 disparities had no statistical impact on OS, TRM, relapse, aGVHD and cGVHD. When TCE3/TCE4 disparities were analyzed in the graft-vs-host or host-vs-graft (HVG) direction, only a significant impact of TCE4 nonpermissive disparities in the HVG direction was observed on relapse (RR = 1.34, CI 95% 1.00-1.80, P = 0.048). In conclusion, this French retrospective study shows an adverse prognosis of HLA-DPB1 mismatches (2 vs 0) on severe aGVHD and of nonpermissive TCE4 HVG disparities on relapse after HLA-matched 10/10 unrelated HSCT.
Short paper We have developed a monoclonal antibody (mAb), termed anti-TigammaA, which recognizes... more Short paper We have developed a monoclonal antibody (mAb), termed anti-TigammaA, which recognizes an antigenic determinant carried by a variable segment of the T cell receptor (TcR) y chain. This determinant, encoded by the V,9 gene, is expressed on approximately 3% of peripheral blood lymphocytes. In the present study, we have found that binding of anti-TigammaA mAb to its specific ligand results in the triggering of the phosphatidylinositol (PI) cycle-related metabolic process. Indeed, an increased labeling of both phosphatidic acid and PI, related to an enhanced turnover of PI cycle-dependent phospholipids, was observed following exposure of 32P orthophosphoric acid-labeled cells to anti-TigammaA mAb. In addition, there was a rapid rise in intracellular free calcium concentrations. Similar experiments have been performed previously on CD3' TcRa/P-cells with an anti-CD3 mAB. They predicted that signals produced by the interaction between the second TcR and its ligand(s) would be transmitted via the PI cycle-linked intracellular second messengers. We confirm this hypothesis in an experimental system where stimulation occurs directly through the y/S receptor structure.
Background: Rheumatoid Arthritis (RA) is the most common systemic autoimmune disease, with a resp... more Background: Rheumatoid Arthritis (RA) is the most common systemic autoimmune disease, with a respective expanded genetic research 1. Immunogenetic studies have documented the positive correlation of various gene loci with incidence and/or disease profile. However, the description of gene loci negatively related to the incidence of RA is rarely documented. Apart from an early study involving HLA class II, there has been no reference to any genetic locus associated with a protective role against RA incidence. Objectives: To identify the sequence of the functional areas of the TRAF1 (TNF receptor associated factor 1-a protein involved in the intracellular signaling pathway of TNF) gene. Methods: 172 patients and 95 controls were genetically assessed for the sequence of the seven exons of the gene TRAF1. Results: On the position 9:120905076 of exon 7, the registered polymorphism G/A (rs143265058) was described in the controls group. The same polymorphism was not confirmed in any of the patients. Further functional proteomic study of the polymorphism with computing programs (software), revealed that the presence of this polymorphism leads to a differentiation of the quaternary structure of TRAF1 protein, possibly affecting the cohesion of intracellular TNF signaling pathway 2. Conclusions: The present reference is one of the extremely rare genetic studies describing a protective gene locus against rheumatoid arthritis, and a pioneer of its kind in the use of Applied Informatics in the depiction of the quaternary structure of the encoded protein. At the same time, it is one of the few immunogenetic studies describing the functional proteomics of the encoded protein, plotting on a molecular level specific interaction modifications affecting the intracellular signaling pathway of TNF. References:
To further understand the exceptional HIV-1 control observed in Post-Treatment Controllers (PTCs)... more To further understand the exceptional HIV-1 control observed in Post-Treatment Controllers (PTCs) from the Virological and Immunological Sustained CONtrol after Treatment Interruption study we investigated their HIV-specific T-cell responses. Polyfunctionality of HIV-specific CD4 and CD8 T cells and the ratios of HIV-specific CD4 T cells per infected cells were similar in post-treatment controllers, continuously early-treated patients and long-term non-progressors Overall early treatment appears to preserve robust HIV-specific CD4 T cells, which might contribute to the posttreatment control of HIV.
Open Journal of Rheumatology and Autoimmune Diseases, 2016
The era of whole genome study analysis has introduced a profound research in the genetics of auto... more The era of whole genome study analysis has introduced a profound research in the genetics of autoimmune diseases. Some of the new genetic loci that have been associated with the development or the severity of autoimmune diseases have been thoroughly studied, conferring a more detailed understanding of disease pathophysiology. Furthermore, single nucleotide polymorphisms (SNPs) have been described not only in coding regions of the human genome but also in non-coding areas (introns), the importance of which has not been yet clarified. Over the last years, such an SNP has been associated with the development of rheumatoid arthritis, the most frequent autoimmune disease. This SNP is at the position 122730060 of chromosome 9 in the TRAF1/C5 region and consists of a substitution of the nucleotide base guanine (G)-which is considered the ancestral phenotype-by alanine (A). It has been indicated that G is the aggravating nucleotide, and that G/G is the disease predisposing phenotype, conferring >1.3× risk for RA. On this background, we performed a genome study on a Greek population of northern Greece (Macedonia) in order to identify the association of this SNP with RA in our group.
Patients et méthodes.-Nous avons réalisé une étude phénotypique portant sur 37 patients ayant une... more Patients et méthodes.-Nous avons réalisé une étude phénotypique portant sur 37 patients ayant une MEC histologiquement prouvée, suivis dans notre centre
A 43 year old female patient presented for recurrent bacterial lower respiratory infections. A re... more A 43 year old female patient presented for recurrent bacterial lower respiratory infections. A research for immunodeficiency status revealed total hypogammaglobulinemia, reduced IgG1, IgG2, IgG3 subclass levels, and low number of B lymphocytes (CD19+). Common Variable Immunodeficiency (CVID) 11.2 category was diagnosed according to recent criteria of primary immunodeficiencies (PID). Further immunological study consisting of genetic polymorphism of genes relating to differentiation, activation and function of B cells (ICOS, BAFF receptor BCMA and TACI) was performed, which did not reveal any related mutations. T cell parameters and Th1/Th2 cytokine network did not show any disturbances. It is postulated that probable endstage B cell differentiation defects should be investigated. The patient receives IVIGs replacement thereafter and the rate and severity of infections have significantly improved.
Inadequate reconstitution of CD4+ lymphocyte and interleukin (IL)-2 production defect are observe... more Inadequate reconstitution of CD4+ lymphocyte and interleukin (IL)-2 production defect are observed after bone marrow or peripheral blood stem cell transplantation (SCT). We studied immune reconstitution after SCT in 33 consecutive patients who received allogeneic SCT (17 patients) or autologous SCT (16 patients). The aims were to assess the regeneration of the CD4+ T-cell subset with regard to helper cell differentiation. CD4+ T-cell subset regeneration and expansion of the CD4+CD7- subset were studied by immunofluorescence analysis. CD4+CD7- cell cytokine secretion was analyzed after cell sorting and costimulation of the CD3 and CD28 pathways, in enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction assays. We report a relative expansion of the CD4+CD7- subset within CD4+ T cells, detected as early as 1 month after bone marrow transplantation and decreasing after day 60. CD4+CD7- T cells preferentially expressed CD45RO and activation markers such as ...
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Papers by I. Theodorou