Geldmacher C.,Immunology Laboratory |
Geldmacher C.,Ludwig Maximilians University of Munich |
Ngwenyama N.,Immunology Laboratory |
Schuetz A.,Referral Hospital |
And 18 more authors.
Journal of Experimental Medicine | Year: 2010
HIV-1 infection results in the progressive loss of CD4 T cells. In this study, we address how different pathogen-specific CD4 T cells are affected by HIV infection and the cellular parameters involved. We found striking differences in the depletion rates between CD4 T cells to two common opportunistic pathogens, cytomegalovirus (CMV) and Mycobacterium tuberculosis (MTB). CMV-specific CD4 T cells persisted after HIV infection, whereas MTBspecific CD4 T cells were depleted rapidly. CMV-specific CD4 T cells expressed a mature phenotype and produced very little IL-2, but large amounts of MIP-1β. In contrast, MTBspecific CD4 T cells were less mature, and most produced IL-2 but not MIP-1β. Staphylococcal enterotoxin B-stimulated IL-2-producing cells were more susceptible to HIV infection in vitro than MIP-1β-producing cells. Moreover, IL-2 production was associated with expression of CD25, and neutralization of IL-2 completely abrogated productive HIV infection in vitro. HIV DNA was found to be most abundant in IL-2-producing cells, and least abundant in MIP-1β-producing MTB-specific CD4 T cells from HIV-infected subjects with active tuberculosis. These data support the hypothesis that differences in function affect the susceptibility of pathogen-specific CD4 T cells to HIV infection and depletion in vivo, providing a potential mechanism to explain the rapid loss of MTB-specific CD4 T cells after HIV infection.
Martino M.,Section of Psychiatry |
Rocchi G.,Section of Psychiatry |
Escelsior A.,Section of Psychiatry |
Contini P.,Immunology Laboratory |
And 6 more authors.
Psychoneuroendocrinology | Year: 2013
Backgrounds: Nerve growth factor (NGF) is involved in the modulation of the neuro-endocrine-immune (NEI) system, whereas alterations in neuroplasticity and NEI homeostasis seem to play a role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate NGF levels variations in MDD patients during antidepressant treatment with duloxetine, a relatively newer SNRI. Methods: 30 MDD patients and 32 healthy controls were assessed using Hamilton depression scale (HAM-D) and monitored for NGF serum levels at baseline, week 6 and week 12 of duloxetine treatment (60. mg/day) and at baseline, respectively. Results: According to early clinical response to duloxetine (defined at week 6 by reduction >50% of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who overall reached clinical response at week 12. Laboratory analysis showed overall significant lower baseline NGF levels among depressed patients compared to healthy controls, not significantly in ER and significantly in ENR. During duloxetine treatment NGF levels further decreased in association with clinical response, reaching significantly lower values in ER at W6 compared to controls, and in ENR at W12 compared to baseline. Conclusions: A decrease in NGF levels during duloxetine treatment in association to clinical response could be indicative of a relative restoring of NEI stress-adaptation system, since stressors, inducing neuronal instability due to neurotrophins activity changes, permits circuitry remodeling as background in the selection of alternative adaptive behaviors. However, the lower baseline NGF levels found in MDD patients that further decrease during the treatment could represent a lower neurotrophin set point, possibly reflecting a functional impairment in stress-adaptive neuroplasticity in depressive disorders. © 2013 Elsevier Ltd.
Toh B.-H.,Monash University |
Toh B.-H.,Monash Institute of Medical Research |
Toh B.-H.,Immunology Laboratory |
Chan J.,Monash University |
And 4 more authors.
Clinical Reviews in Allergy and Immunology | Year: 2012
Autoimmune gastritis is the outcome of a pathological CD4 T cell-mediated autoimmune response directed against the gastric H/K-ATPase. Silent initially, the gastric lesion becomes manifest in humans by the development of megaloblastic pernicious anemia arising from vitamin B12 deficiency. Cutting edge issues in this disease relate to its epidemiology, immunogenetics, a role for Helicobacter pylori as an infective trigger through molecular mimicry, its immunopathogenesis, associated organ-specific autoimmune diseases, laboratory diagnosis, and approaches to curative therapy. © Springer Science+Business Media, LLC 2010.
Venet F.,Immunology Laboratory |
Venet F.,University Claude Bernard Lyon 1 |
Lepape A.,University Claude Bernard Lyon 1 |
Lepape A.,University of Lyon |
And 2 more authors.
Critical Care | Year: 2011
Septic syndromes represent a major healthcare problem worldwide. Clinical and experimental evidence indicates that septic patients rapidly present with numerous compromised immune functions. Although flow cytometry remains a relatively confidential diagnostic tool, it could be useful at every step of ICU patient management. Indeed, neutrophil CD64 expression is a sensitive and specific tool for diagnosis of sepsis in adults, neonates and children. Diminished monocyte HLA-DR expression is a reliable marker for the development of monocyte anergy, prediction of secondary nosocomial infection and death in critically ill patients. Finally, the measurement of an increased CD4+CD25+CD127lowregulatory T-cell percentage may represent a reliable marker for the diagnosis of lymphocyte dysfunctions in these patients. Ideally, these biomarkers should be part of a panel helping to define ICU patients' immune status. The potential of flow cytometry is further illustrated by use of the biomarkers listed above as stratification tools in preliminary clinical studies. Importantly, many other markers of immune dysfunctions are currently under development that could further enable the administration of targeted individualized therapy in ICU patients. The next critical step would be to use these standardized flow cytometry protocols in large multicentric clinical trials testing individualized immunotherapy. © 2011 BioMed Central Ltd.
Fornaro M.,University of Catania |
Rocchi G.,University of Genoa |
Escelsior A.,University of Genoa |
Contini P.,Immunology Laboratory |
Martino M.,University of Genoa
Journal of Affective Disorders | Year: 2013
Background: Correlational studies investigating neurohormonal-cytokine modulation by antidepressants suggest, among others, variations in cytokines balances as state markers of different biological subtypes of major depressive disorder (MDD) and response predictors to specific treatments. Objective of the study was to investigate cytokines modulation by duloxetine, a relatively newer SNRI with clean dual serotonin/norepinephrine mechanism. Methods: 30 MDD patients and 32 healthy controls were assessed using Hamilton Depression Scale (HAM-D) and monitored for levels of IL-1β, IL-2, IL-4, IL-10, IL-12, IFN-γ and TNF-α, at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. Results: Early responders (ER: defined at week 6 by reduction >50% of baseline HAM-D score) and early non-responders (ENR) showed opposite trends in cytokine levels during duloxetine treatment: ENR were characterized by baseline Th2 shift compared to controls (lower IL-1β, IFN-γ and TNF-α) with increase in Th1 cytokines levels during treatment (increase of IL-1β, IL-12, IFN-γ, IL-1β/IL-10 and TNF-α/IL-10, decrease of IL-10), achieving clinical response at week 12; ER were characterized by baseline Th2-to-Th1 relative switch compared to ENR (higher IL-1β, IL-1β/IL-10 and TNF-α/IL-10) with reduction in Th1 cytokines levels during treatment (decrease of TNF-α and TNF-α/IL-10), achieving clinical response at week 6. Limitations: Small sample size. Conclusions: In accordance to early clinical response, duloxetine treatment could divide depressed patients into at least 2 subgroups characterized by clinical and laboratory differentiated behavior, suggesting different neurobiological background within depressive syndrome differentially sensitive to different drug components: pro-serotonergic effect and increase in Th1 cytokines in ENR vs. pro-noradrenergic effect and decrease in Th1 cytokines in ER. © 2012 Elsevier B.V.
Hotchkiss R.S.,University of Washington |
Monneret G.,Immunology Laboratory |
Payen D.,Hopital Lariboisiere
The Lancet Infectious Diseases | Year: 2013
Failures of highly touted trials have caused experts to call for re-evaluation of the current approach toward sepsis. New research has revealed key pathogenic mechanisms; autopsy results have shown that most patients admitted to intensive care units for treatment of sepsis had unresolved septic foci at post mortem, suggesting that patients were unable to eradicate invading pathogens and were more susceptible to nosocomial organisms, or both. These results suggest that therapies that improve host immunity might increase survival. Additional work showed that cytokine production by splenocytes taken post mortem from patients who died of sepsis is profoundly suppressed, possibly because of so-called T-cell exhaustion-a newly recognised immunosuppressive mechanism that occurs with chronic antigenic stimulation. Results from two clinical trials of biomarker-guided therapeutic drugs that boosted immunity showed promising findings in sepsis. Collectively, these studies emphasise the degree of immunosuppression that occurs in sepsis, and explain why many previous sepsis trials which were directed at blocking inflammatory mediators or pathogen recognition signalling pathways failed. Finally, highly encouraging results from use of the new immunomodulatory molecules interleukin 7 and anti-programmed cell death 1 in infectious disease point the way for possible use in sepsis. We hypothesise that immunoadjuvant therapy represents the next major advance in sepsis. © 2013 Elsevier Ltd.
Monneret G.,Immunology Laboratory |
Venet F.,Immunology Laboratory |
Kullberg B.-J.,Radboud University Nijmegen |
Netea M.G.,Radboud University Nijmegen
Medical Mycology | Year: 2011
Sepsis and related infectious syndromes, including nosocomial infections, represent a major but largely under recognized healthcare problem worldwide, accounting for thousands of deaths every year. After a short pro-inflammatory phase, severely injured ICU patients enter a stage of protracted immunosuppression illustrated by reactivation of dormant viruses or infections due to microorganisms, including fungi, which are normally pathogenic solely in immunocompromised hosts. This brief review will focus on immune dysfunctions described so far in ICU patients regarding monocytes and T lymphocytes (as examples for innate and adaptive immune cells) and on their potential use as biomarkers for identification of patients at risk of secondary nosocomial infections and for guidance of immunotherapy. Finally, we will more specifically focus on the risk for fungal infections in ICU patients, and on the potential beneficial effects of adjunctive therapy not only to prevent these infections, but also to reinforce immune responses once they are already diagnosed. © 2011 ISHAM.
Dunphy S.E.,Trinity College Dublin |
Guinan K.J.,BioAtlantis |
Chorcora C.N.,Trinity College Dublin |
Jayaraman J.,University of Cambridge |
And 5 more authors.
Genes and Immunity | Year: 2015
Natural killer (NK) cells are lymphocytes that function as part of the innate immune system. Their activity is controlled by a range of inhibitory and activating receptors, including the important killer-cell immunoglobulin-like receptors (KIR). The KIR are a multi-gene family of receptors that interact with the human leukocyte antigen (HLA) class I family of molecules and are characterised by extensive allelic polymorphism. Their expression on the cell surface of NK cells is highly variable, but the factors responsible for this variability are not yet clearly understood. In the current study, we investigated KIR expression in a healthy human cohort that we had previously characterised in depth at a genetic level, with KIR allele typing and HLA class I ligand genotypes available for all donors (n=198). Allelic polymorphism significantly affected the phenotypic expression of all KIR analysed, whereas HLA ligand background influenced the expression levels of 2DL1 and 2DL3. In particular, we found that although 2DL2 may influence 2DL1 expression, this appears to be owing to variation in 2DL1 copy number. Finally, the inhibitory receptor LILRB1 had higher expression levels in individuals with B/B KIR genotypes, suggesting a possible relationship between KIR and non-KIR receptors, which serves to balance NK cell activation potential. © 2015 Macmillan Publishers Limited All rights reserved.
Venet F.,Immunology Laboratory |
Lukaszewicz A.-C.,University Paris Diderot |
Payen D.,University Paris Diderot |
Hotchkiss R.,University of Washington |
Monneret G.,Immunology Laboratory
Current Opinion in Immunology | Year: 2013
Preliminary studies suggest that a subgroup of septic patients with severe immune alterations is at high risk of death or nosocomial infection and therefore could benefit from adjunctive immune stimulating therapies. There is thus an urgent need for robust biomarkers usable in routine conditions evaluating rapidly evolving immune status in patients. Although functional testing remains a gold standard, its standardization remains challenging. Therefore, surrogate markers such as monocyte HLA-DR expression, are being developed. Such biomarkers of immune functionality will enable a novel approach in the design of clinical trials evaluating immunostimulating therapies in sepsis at the right time and in the right patient. © 2013 Elsevier Ltd.
Sonora C.,Immunology Laboratory |
Calo G.,University of Buenos Aires |
Fraccaroli L.,University of Buenos Aires |
Perez-Leiros C.,University of Buenos Aires |
And 2 more authors.
American Journal of Reproductive Immunology | Year: 2014
Problem: Women with celiac disease (CD) are often affected by atypical presentations of the disease associated with reproductive disorders as a main extra-digestive complaint. Here, we analyzed if autoantibodies against tissue transglutaminase (tTG) in sera from CD patients with reproductive disorders could display direct effects through their interaction with tTG expressed on trophoblast cells and phagocytes inducing tissue damage and interfering in the clearance of trophoblast apoptotic bodies. Method of study: Sera from CD women with reproductive disorders were obtained, and their ability to induce apoptosis of Swan-71 (cytotrophoblast cell line) and to modulate the wound-healing and phagocytes process was tested. Results: Swan-71 cells expressed tTG and CD sera displayed a significant decrease in trophoblast cell migration and a delay in injury healing on trophoblast cells, compared with those observed with control sera. Moreover, CD sera significantly reduced trophoblast cell proliferation and increased apoptosis levels in comparison with those observed in the control sera. Finally, autoantibodies against tTG interfere in the clearance of trophoblast apoptotic bodies through a mechanism involving MFG-E8 (milk fat globulin-EGF factor 8)-tTG binding. Conclusion: The anti-tTG antibodies might contribute to trophoblast damage and disrupt the phagocytosis process of apoptotic bodies that could promote a pro-inflammatory microenvironment. © 2014 John Wiley & Sons A/S.