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1.  Post-traumatic stress disorder: revisiting adrenergics, glucocorticoids, immune system effects and homeostasis. 
This review focuses on post-traumatic stress disorder (PTSD). Several sequelae of PTSD are partially attributed to glucocorticoid-induced neuronal loss in the hippocampus and amygdala. Glucocorticoids and adrenergic agents cause both immediate and late sequelae and are considered from the perspective of their actions on the expression of cytokines as well as some of their physiological and psychological effects. A shift in immune system balance from Th1 to Th2 dominance is thought to result from the actions of both molecular groups. The secretion of glucocorticoids and adrenergic agents is commonly induced by trauma or stress, and synergy between these two parallel but separate pathways can produce long- and short-term sequelae in individuals with PTSD. Potential therapies are suggested, and older therapies that involve the early effects of adrenergics or glucocorticoids are reviewed for their control of acute symptoms. These therapies may also be useful for acute flashback therapy. Timely and more precise glucocorticoid and adrenergic control is recommended for maintaining these molecular groups within acceptable homeostatic limits and thus managing immune and brain sequelae. Psychotherapy should supplement the above therapeutic measures; however, psychotherapy is not the focus of this paper. Instead, this review focuses on the probable molecular basis of PTSD. Integrating historical findings regarding glucocorticoids and adrenergic agents into current research and clinical applications returns the focus to potentially life-changing treatments. Autologous adoptive immune therapy may also offer utility. This paper reports clinical and translational research that connects and challenges separate fields of study, current and classical, in an attempt to better understand and ameliorate the effects of PTSD.
PMCID: PMC4255796  PMID: 25505957
2.  Allogenicity & immunogenicity in regenerative stem cell therapy 
The development of regenerative medicine relies in part on the capacity of stem cells to differentiate into specialized cell types and reconstitute tissues and organs. The origin of the stem cells matters. While autologous cells were initially the preferred ones the need for “off the shelf” cells is becoming prevalent. These cells will be immediately available and they originate from young non diseased individuals. However their allogenicity can be viewed as a limitation to their use. Recent works including our own show that allogenicity of stem cell can be viewed as on one hand detrimental leading to their elimination and on the other hand beneficial through a paracrine effect that can induce a local tissue regenerative effect from endogenous stem cells. Also their immune modulatory capacity can be harnessed to favor regeneration. Therefore the immune phenotype of stem cells is an important criteria to be considered before their clinical use. Immuno monitoring of the consequences of their in vivo injection needs to be taken into account. Transplantation immunology knowledge will be instrumental to enable the development of safe personalized regenerative stem cell therapy.
PMCID: PMC3928705  PMID: 24434327
Allogenicity; embryonic stem cells; HLA; immunogenicity; major histocompatibility complex; SC therapeutics
3.  Mass Spectrometry Reveals Changes in MHC I Antigen Presentation After Lentivector Expression of a Gene Regulation System 
The rapamycin-inducible gene regulation system was designed to minimize immune reactions in man and may thus be suited for gene therapy. We assessed whether this system indeed induces no immune responses. The protein components of the regulation system were produced in the human cell lines HEK 293T, D407, and HER 911 following lentiviral transfer of the corresponding genes. Stable cell lines were established, and the peptides presented by major histocompatibility complex class I (MHC I) molecules on transduced and wild-type (wt) cells were compared by differential mass spectrometry. In all cell lines examined, expression of the transgenes resulted in prominent changes in the repertoire of MHC I-presented self-peptides. No MHC I ligands originating from the transgenic proteins were detected. In vitro analysis of immunogenicity revealed that transduced D407 cells displayed slightly higher capacity than wt controls to promote proliferation of cytotoxic T cells. These results indicate that therapeutic manipulations within the genome of target cells may affect pathways involved in the processing of peptide antigens and their presentation by MHC I. This makes the genomic modifications visible to the immune system which may recognize these events and respond. Ultimately, the findings call attention to a possible immune risk.
PMCID: PMC3586803  PMID: 23403517
gene therapy; genotoxicity; HLA antigens; immune responses
4.  Human Monocytes Differentiate into Dendritic Cells Subsets that Induce Anergic and Regulatory T Cells in Sepsis 
PLoS ONE  2012;7(10):e47209.
Sepsis is a multifactorial pathology with high susceptibility to secondary infections. Innate and adaptive immunity are affected in sepsis, including monocyte deactivation.
Methodology/Principal Findings
To better understand the effects of alterations in monocytes on the regulation of immune responses during sepsis, we analyzed their differentiation in dendritic cell (DC). Cells from septic patients differentiated overwhelmingly into CD1a−negative DC, a population that was only a minor subset in controls and that is so far poorly characterized. Analysis of T cell responses induced with purified CD1a−negative and CD1a+ DC indicated that (i) CD1a−negative DC from both healthy individuals and septic patients fail to induce T cell proliferation, (ii) TGFβ and IL-4 were strongly produced in mixed leukocyte reaction (MLR) with control CD1a−negative DC; reduced levels were produced with patients DC together with a slight induction of IFNγ, (iii) compared to controls, CD1a+ DC derived from septic patients induced 3-fold more Foxp3+ T cells.
Our results indicate a strong shift in DC populations derived from septic patients’ monocytes with expanded cell subsets that induce either T cell anergy or proliferation of T cells with regulatory potential. Lower regulatory cytokines induction on a per cell basis by CD1a−negative dendritic cells from patients points however to a down regulation of immune suppressive abilities in these cells.
PMCID: PMC3468528  PMID: 23071758
5.  A Multicentre Study of Acute Kidney Injury in Severe Sepsis and Septic Shock: Association with Inflammatory Phenotype and HLA Genotype 
PLoS ONE  2012;7(6):e35838.
To investigate the association between severity of acute kidney injury (AKI) and outcome, systemic inflammatory phenotype and HLA genotype in severe sepsis.
Methodology/Principal Findings
Prospective multicenter observational study done in 4 intensive care units in two university hospitals. Severe sepsis and septic shock patients with at least 2 organ failures based on the SOFA score were classified: 1) "no AKI", 2) "mild AKI" (grouping stage 1 and 2 of AKIN score) and 3) "severe AKI" (stage 3 of AKIN score). Sequential measurements: The vasopressor dependency index (VDI; dose and types of drugs) to evaluate the association between hemodynamic status and the development of early AKI; plasma levels of IL-10, macrophage migration inhibitory factor (MIF), IL-6 and HLA-DR monocyte expression. Genotyping of the 13 HLA-DRB1 alleles with deduction of presence of HLA-DRB3, -DRB4 and -DRB5 genes. We used multivariate analysis with competitive risk model to study associations. Overall, 176 study patients (146 with septic shock) were classified from AKIN score as "no AKI" (n = 43), "mild AKI" (n = 74) or "severe AKI" (n = 59). The VDI did not differ between groups of AKI. After adjustment, "mild and severe AKI" were an independent risk factor for mortality (HR 2.42 95%CI[1.01-5.83], p = 0.048 and HR 1.99 95%CI[1.30-3.03], p = 0.001 respectively). "Severe AKI" had higher levels of plasma IL-10, MIF and IL-6 compared to “no AKI” and mild AKI (p<0.05 for each), with no difference in mHLA-DR at day 0. HLA-DRB genotyping showed a significantly lower proportion of 4 HLA-DRB alleles among patients requiring renal replacement therapy (RRT) (58%) than in patients with severe AKI who did not receive RRT (84%) (p = 0.004).
AKI severity is independently associated with mortality and plasma IL-10, MIF or IL-6 levels. Presence of 4 alleles of HLA-DRB in severe AKI patients seems associated with a lower need of RRT.
PMCID: PMC3368929  PMID: 22701553
6.  Predictive, preventive, personalized and participatory medicine: back to the future 
Genome Medicine  2010;2(8):57.
The pioneering work of Jean Dausset on the HLA system established several principles that were later reflected in the Human Genome Project and contributed to the foundations of predictive, preventive, personalized and participatory (P4) medicine. To effectively develop systems medicine, we should take advantage of the lessons of the HLA saga, emphasizing the importance of exploring a fascinating but mysterious biology, now using systems principles, pioneering new technology developments and creating shared biological and information resources.
PMCID: PMC2945014  PMID: 20804580
7.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
PMCID: PMC3221551  PMID: 21745417
8.  Melanoma Spheroids Grown Under Neural Crest Cell Conditions Are Highly Plastic Migratory/Invasive Tumor Cells Endowed with Immunomodulator Function 
PLoS ONE  2011;6(4):e18784.
The aggressiveness of melanoma tumors is likely to rely on their well-recognized heterogeneity and plasticity. Melanoma comprises multi-subpopulations of cancer cells some of which may possess stem cell-like properties. Although useful, the sphere-formation assay to identify stem cell-like or tumor initiating cell subpopulations in melanoma has been challenged, and it is unclear if this model can predict a functional phenotype associated with aggressive tumor cells.
Methodology/Principal Findings
We analyzed the molecular and functional phenotypes of melanoma spheroids formed in neural crest cell medium. Whether from metastatic or advanced primary tumors, spheroid cells expressed melanoma-associated markers. They displayed higher capacity to differentiate along mesenchymal lineages and enhanced expression of SOX2, NANOG, KLF4, and/or OCT4 transcription factors, but not enhanced self-renewal or tumorigenicity when compared to their adherent counterparts. Gene expression profiling attributed a neural crest cell signature to these spheroids and indicated that a migratory/invasive and immune-function modulating program could be associated with these cells. In vitro assays confirmed that spheroids display enhanced migratory/invasive capacities. In immune activation assays, spheroid cells elicited a poorer allogenic response from immune cells and inhibited mitogen-dependent T cells activation and proliferation more efficiently than their adherent counterparts. Our findings reveal a novel immune-modulator function of melanoma spheroids and suggest specific roles for spheroids in invasion and in evasion of antitumor immunity.
The association of a more plastic, invasive and evasive, thus a more aggressive tumor phenotype with melanoma spheroids reveals a previously unrecognized aspect of tumor cells expanded as spheroid cultures. While of limited efficiency for melanoma initiating cell identification, our melanoma spheroid model predicted aggressive phenotype and suggested that aggressiveness and heterogeneity of melanoma tumors can be supported by subpopulations other than cancer stem cells. Therefore, it could be constructive to investigate melanoma aggressiveness, relevant to patients and clinical transferability.
PMCID: PMC3078142  PMID: 21526207
9.  Association of HLA-G Low Expressor Genotype with Severe Acute Graft-Versus-Host Disease after Sibling Bone Marrow Transplantation 
Background: Human leukocyte antigen-G (HLA-G) molecules play a prominent role in immune tolerance. Structurally similar to their classical HLA homologs, they are distinct by having high rate of polymorphism in the non-coding regions including a functionally relevant 14-base pair (bp) insertion/deletion (Ins/Del) allele in the 3′ untranslated region (3′UTR), rarely examined in a hematopoietic stem cell transplantation (HSCT) setting. Here, we analyzed the potential impact of HLA-G Ins/Del dimorphism on the incidence of acute graft-versus-host disease (aGvHD), transplant-related mortality (TRM), overall survival (OS), and incidence of relapse after HSCT using bone marrow (BM) as stem cell source from HLA-matched donors. Methods: One hundred fifty-seven sibling pairs, who had undergone HSCT, were studied for the distribution of the HLA-G 14 bp Ins/Del polymorphism using a polymerase chain reaction (PCR)-based technique. Potential genetic association with the incidence of aGvHD, TRM, and OS was analyzed by monovariate and multivariate analyses. Results: Monovariate analysis showed that the homozygous state for the 14-bp Ins allele is a risk factor for severe aGvHD (grade III and IV; P = 0.008), confirmed subsequently by multivariate analysis [hazard ratio (HR) = 3.5; 95% confidence interval (95%CI) = 1.3–9.5; P = 0.012]. We did not find any association between HLA-G polymorphism and the other studied complications. Conclusion: Our data suggest that the HLA-G low expressor 14 bp Ins allele constitutes a risk factor for the incidence of severe aGvHD in patients who received BM as stem cell source.
PMCID: PMC3342264  PMID: 22566863
hematopoietic stem cell transplantation; HLA-G polymorphism; acute GvHD
10.  A single tumour necrosis factor haplotype influences the response to adalimumab in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;67(4):478-484.
To determine whether tumor necrosis factor (TNF) gene polymorphisms and/or the shared epitope are genetic predictors of response to adalimumab (ADA) in rheumatoid arthritis (RA).
This ancillary study to the Research in Active Rheumatoid Arthritis (ReAct) Phase IIIb study included a large cohort of Caucasian patients with RA from France (N=380) treated with ADA plus methotrexate (MTX) (n=182), ADA plus any other DMARD (N=96) or ADA alone (N=102). The primary outcome was ACR50 at 12 weeks. Patients underwent genotyping for HLA-DRB1 and 3 TNFα gene polymorphisms (-238A/G, -308A/G and -857C/T). Extended haplotypes involving HLA-DRB1 and TNFα loci were reconstructed by use of the PHASE program.
A total of 152 patients (40%) had an ACR50 response at week 12. Neither the number of HLA-DRB1 SE copies nor presence of the 3 TNFα polymorphisms tested separately was significantly associated with ACR50 response at week 12. However, haplotype reconstruction of the TNFα locus revealed the GGC haplotype (-238G/-308G/–857C) in a homozygous form, present in more than half of the patients, significantly associated with a lower ACR50 response at 12 weeks (34% vs. 50% in patients without the haplotype) on treatment with ADA concomitant with MTX (P=0.0041; Pc=0.02). This effect was restricted to the subgroup of patients concomitantly treated with MTX.
This large pharmacogenetic study provides robust data indicating that a single TNFα locus haplotype (-238G/-308G/-857C), present on both chromosomes is associated with a lower response to ADA and MTX therapy in RA patients homozygous for this haplotype.
PMCID: PMC2750008  PMID: 17673491
Adult; Aged; Antibodies, Monoclonal; therapeutic use; Antirheumatic Agents; therapeutic use; Arthritis, Rheumatoid; drug therapy; genetics; Drug Therapy, Combination; Female; Genotype; HLA-DR Antigens; genetics; Haplotypes; Humans; Male; Methotrexate; therapeutic use; Middle Aged; Polymorphism, Single Nucleotide; Treatment Outcome; Tumor Necrosis Factor-alpha; genetics; TNF-alpha; adalimumab; rheumatoid arthritis; genetic polymorphism; haplotype
11.  Dendritic Cells Differentiated in the Presence of a Single-Stranded Viral RNA Sequence Conserve Their Ability To Activate CD4 T Lymphocytes but Lose Their Capacity for Th1 Polarization ▿  
Monocyte-derived dendritic cells (DCs) differentiate in the presence of Toll-like-receptor (TLR) ligands in the course of ongoing infections. A single-stranded RNA (ssRNA) sequence, corresponding to the sequence of the U5 region of human immunodeficiency virus type 1 RNA, was used to mimic viral activation of TLR7 in human DCs. We determined the effector potential of DCs differentiated in the presence of this ssRNA molecule (ssRNA-DCs). ssRNA-DCs phenotypically resembled mature DCs. In contrast, their capacity to allostimulate naive CD4+ T cells resembled that of conventional immature DCs and could be increased by TLR4 stimulation. Th1 polarization of CD4+ T cells and production of interleukin 12p70 (IL-12p70) by ssRNA-DCs were selectively abrogated in response to a late TLR4, but not in response to a CD40, maturation signal. Inhibition of p38 mitogen-activated protein kinase partially restored IL-12p70 secretion but did not restore Th1 polarization, whereas addition of exogenous IL-12 led to recovery of Th1 polarization. In contrast to lipopolysaccharide, ssRNA induced IL-12p70 production at the very earliest stages of DC differentiation, indicating a particular role for TLR7 in monocyte-derived DCs recently engaged in differentiation. These data demonstrate generation of phenotypically mature DCs with the ability to expand CD4+ T lymphocytes lacking Th1/2-polarizing capacity.
PMCID: PMC2446623  PMID: 18400975
12.  Risk maps for range expansion of the Lyme disease vector, Ixodes scapularis, in Canada now and with climate change 
Lyme disease is the commonest vector-borne zoonosis in the temperate world, and an emerging infectious disease in Canada due to expansion of the geographic range of the tick vector Ixodes scapularis. Studies suggest that climate change will accelerate Lyme disease emergence by enhancing climatic suitability for I. scapularis. Risk maps will help to meet the public health challenge of Lyme disease by allowing targeting of surveillance and intervention activities.
A risk map for possible Lyme endemicity was created using a simple risk algorithm for occurrence of I. scapularis populations. The algorithm was calculated for each census sub-division in central and eastern Canada from interpolated output of a temperature-driven simulation model of I. scapularis populations and an index of tick immigration. The latter was calculated from estimates of tick dispersion distances by migratory birds and recent knowledge of the current geographic range of endemic I. scapularis populations. The index of tick immigration closely predicted passive surveillance data on I. scapularis occurrence, and the risk algorithm was a significant predictor of the occurrence of I. scapularis populations in a prospective field study. Risk maps for I. scapularis occurrence in Canada under future projected climate (in the 2020s, 2050s and 2080s) were produced using temperature output from the Canadian Coupled Global Climate Model 2 with greenhouse gas emission scenario enforcing 'A2' of the Intergovernmental Panel on Climate Change.
We have prepared risk maps for the occurrence of I. scapularis in eastern and central Canada under current and future projected climate. Validation of the risk maps provides some confidence that they provide a useful first step in predicting the occurrence of I. scapularis populations, and directing public health objectives in minimizing risk from Lyme disease. Further field studies are needed, however, to continue validation and refinement of the risk maps.
PMCID: PMC2412857  PMID: 18498647
13.  CTLA-4 +49A/G and CT60 gene polymorphisms in primary Sjögren syndrome 
CTLA-4 encodes cytotoxic T lymphocyte-associated antigen-4, a cell-surface molecule providing a negative signal for T-cell activation. CTLA-4 gene polymorphisms have been widely studied in connection with genetic susceptibility to various autoimmune diseases, but studies have led to contradictory results in different populations. This case-control study sought to investigate whether CTLA-4 CT60 and/or +49A/G polymorphisms were involved in the genetic predisposition to primary Sjögren syndrome (pSS). We analysed CTLA-4 CT60 and +49A/G polymorphisms in a first cohort of 142 patients with pSS (cohort 1) and 241 controls, all of Caucasian origin. A replication study was performed on a second cohort of 139 patients with pSS (cohort 2). In cohort 1, the CTLA-4 +49A/G*A allele was found on 73% of chromosomes in patients with pSS, compared with 66% in controls (p = 0.036; odds ratio (OR) 1.41, 95% confidence interval (CI) 1.02 to 1.95). No difference in CTLA-4 CT60 allelic or genotypic distribution was observed between patients (n = 142) and controls (n = 241). In the replication cohort, the CTLA-4 +49A/G*A allele was found on 62% of chromosomes in patients with pSS, compared with 66% in controls (p = 0.30; OR 0.85, 95% CI 0.63 to 1.16). Thus, the CTLA-4 +49A/G*A allele excess among patients from cohort 1 was counterbalanced by its under-representation in cohort 2. When the results from the patients in both cohorts were pooled (n = 281), there was no difference in CTLA-4 +49A/G allelic or genotypic distribution in comparison with controls. Our results demonstrate a lack of association between CTLA-4 CT60 or +49A/G polymorphisms and pSS. Premature conclusions might have been made if a replication study had not been performed. These results illustrate the importance of case-control studies performed on a large number of patients. In fact, sampling bias may account for some contradictory results previously reported for CTLA-4 association studies in autoimmune diseases.
PMCID: PMC1906800  PMID: 17341301
14.  Alteration of HLA-B27 Peptide Presentation after Infection of Transfected Murine L Cells by Shigella flexneri 
Infection and Immunity  1998;66(9):4484-4490.
Shigella flexneri is a triggering agent for reactive arthritis in HLA-B27-susceptible individuals. Considering the intracellular multiplication of bacteria, it seems likely that bacterial peptides may be presented by the major histocompatibility complex (MHC) class I pathway. To examine this hypothesis, we infected HLA-B*2705- and/or human β2-microglobulin-transfected murine L-cell lines with M90T, an invasive strain of S. flexneri. Bacterial infection induced no detectable modifications in the biosynthesis and expression level of HLA-B27, as assessed by immunoprecipitation, Northern blot analysis, and flow cytometry. Using confocal microscopy, we observed that bacterial infection induced a clustering of HLA-B27 molecules during macropinocytosis and before bacterial dissemination from cell to cell. Peptides naturally bound to HLA-B27 molecules were acid eluted from infected cells and separated by high-performance liquid chromatography. Major differences were observed in high-performance liquid chromatography profiles and in the nature of peptides presented following bacterial infection. Although most of the antigens presented were not accessed by Edman degradation, we obtained two sequences partially homologous to bacterial proteins. These peptides lacked the major HLA-B27 peptide anchor (Arg) at position 2, and one had an unusual length of 14 amino acids. These data suggest that alterations in the peptide presentation by HLA-B27 occur during infection, which could be relevant to the pathogenesis of HLA-B27-related arthritis.
PMCID: PMC108542  PMID: 9712804
15.  Measles Virus Nucleocapsid Protein Binds to FcγRII and Inhibits Human B Cell Antibody Production 
Despite the development of an efficient specific immune response during measles virus (MV) infection, an immunosuppression occurs contributing to secondary infections. To study the role of nucleocapsid protein (NP) in MV-induced immunosuppression, we produced recombinant MV NP. Purified recombinant NP exhibited biochemical, antigenic, and tridimensional structure similar to viral NP. By flow cytometry, we showed that viral or recombinant NP bound to human and murine B lymphocytes, but not to T lymphocytes. This binding was specific, independent of MHC class II expression, and dependent of the B lymphocyte activation state. The murine IIA1.6 B cell line, deficient in the Fc receptor for IgG (FcγRII) expression, did not bind NP efficiently. Transfected IIA1.6 cells expressing either murine FcγRIIb1 or b2, or human FcγRIIa, b1*, or b2 isoforms efficiently bound NP. Furthermore, this binding was inhibited up to 90% by monoclonal antibodies 2.4G2 or KB61 specific for murine and human FcγRII, respectively. Finally, the in vitro Ig synthesis of CD40- or Ig-activated human B lymphocytes in the presence of interleukin (IL)-2 and IL-10 was reduced by 50% in the presence of recombinant NP. These data demonstrate that MV NP binds to human and murine FcγRII and inhibits in vitro antibody production, and therefore suggests a role for NP in MV-induced immunosuppression.
PMCID: PMC2198985  PMID: 9221756

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