Gabriel Gras

Immune Suppression and Th1/Th2 Balance in Pregnancy Revisited: A (Very) Personal Tribute to Tom Wegmann

PROBLEM: The paradigm of local suppression necessary to understand the survival of the fetal allograft is often compared with the host‐tumor relationship.

Modulations of Cytokine Expression in Pregnant Women

PROBLEM: Although the overall anti‐infectious and anti‐parasitic immunity of parous women appears normal, several aspects of maternal cell‐mediated and humoral immunity are altered during pregnancy. This has been suggested to occur via preferential local and systemic secretion of Th‐2 type cytokines, which down‐regulate or prevent secretion/action of Th‐1 type cytokines, in animals as well as in humans.

Expression of excitatory amino acid transporter‐2 (EAAT‐2) and glutamine synthetase (GS) in brain macrophages and microglia of SIVmac251‐infected macaques

Na+‐dependent transporters for glutamate (excitatory amino acid transporters, EAATs) clear extracellular glutamate in the brain and prevent excitotoxic neuronal damage. Glutamine synthetase (GS) provides metabolic support for neurones by producing the neurotrophic amino acid glutamine. EAAT and GS expression has recently been demonstrated in macrophages and microglial cells inu2003vitro, and in two models of acute inflammation inu2003vivo. This observation might modify our current understanding of brain inflammation, which considers activated microglia and brain macrophages as the main neurotoxic cells through their production of a variety of neurotoxins, including glutamate. EAAT and GS expression by these cells would entail neuroprotective and neurotrophic properties, counterbalancing the deleterious consequences of microglial activation.

Regulated Expression of Sodium-dependent Glutamate Transporters and Synthetase: a Neuroprotective Role for Activated Microglia and Macrophages in HIV Infection?

It is now widely accepted that neuronal damage in HIV infection results mainly from microglial activation and involves apoptosis, oxidative stress and glutamate‐mediated neurotoxicity. Glutamate toxicity acts via 2 distinct pathways: an excitotoxic one in which glutamate receptors are hyperactivated, and an oxidative one in which cystine uptake is inhibited, resulting in glutathione depletion and oxidative stress. A number of studies show that astrocytes normally take up glutamate, keeping extracellular glutamate concentration low in the brain and preventing excitotoxicity. This action is inhibited in HIV infection, probably due to the effects of inflammatory mediators and viral proteins. Other in vitro studies as well as in vivo experiments in rodents following mechanical stimulation, show that activated microglia and brain macrophages express high affinity glutamate transporters. These data have been confirmed in chronic inflammation of the brain, particularly in SIV infection, where activated microglia and brain macrophages also express glu‐tamine synthetase. Recent studies in humans with HIV infection show that activated microglia and brain macrophages express the glutamate transporter EAAT‐1 and that expression varies according to the disease stage. This suggests that, besides their recognized neurotoxic properties in HIV infection, these cells also have a neuroprotective function, and may partly make up for the inhibited astrocytic function, at least temporarily. This hypothesis might explain the discrepancy between microglial activation which occurs early in the disease, and neuronal apoptosis and neuronal loss which is a late event. In this review article, we discuss the possible neuro‐protective and neurotrophic roles of activated microglia and macrophages that may be generated by the expression of high affinity glutamate transporters and glutamine synthetase, 2 major effectors of glial glutamate metabolism, and the implications for HIV‐induced neuronal dysfunction, the underlying cause of HIV dementia.

Mechanisms of opsonized HIV entry in normal B lymphocytes

Using our in vitro model of normal B cell infection that functions with low doses of HIV but requires virus opsonization by seropositive patient serum, and complement, we analyzed what receptors allowed virus entry. Here, we show that HIV infection of B cells occurs through 2 major receptors: the CD4 antigen and the CR1/CR2 complex. These 2 pathways work independently since a complete inhibition of virus entry requires both CD4 and CD21/CD35 blockade on CD4dim tonsillar B cells whereas only the latter is critical on CD4‐negative B cells.

Neutralizing Antibodies and Complement-Mediated, Antibody-Dependent Enhancement (C'-ADE) of Human Immunodeficiency Virus Infection in Its Vertical Transmission

PROBLEM: Mother‐to‐child transmission is a major route for the spread of human immunodeficiency virus (HIV) worldwide. Our understanding of its mechanisms and parameters is still limited. Among the factors possibly involved in virus passage determination are the level and quality of antiviral humoral response.