Nicole Schmitz

Influenza A Vaccine Based on the Extracellular Domain of M2: Weak Protection Mediated via Antibody-Dependent NK Cell Activity

Vaccination of mice with a peptide corresponding to the extracellular part of M2 protein coupled to the immunodominant domain of hepatitis B core can protect mice from a lethal challenge with influenza A virus. As the extracellular part of M2 protein is highly conserved in all known human influenza A strains, such a vaccine may protect against all human influenza A strains, which would represent a major advantage over current vaccine strategies. The present study demonstrates that protection is mediated exclusively by Abs, a very important feature of a successful preventive vaccine. However, these Abs neither bind efficiently to the free virus nor neutralize virus infection, but bind to M2 protein expressed on the surface of virus-infected cells. The presence of NK cells is important for protection, whereas complement is not, supposing that protection is mediated via Ab-dependent, cell-mediated cytotoxicity. The absence of neutralizing Abs results in much weaker protection than that achieved by vaccination with UV-inactivated influenza virus. Specifically, whereas neutralizing Abs completely eliminate signs of disease even at high viral challenge doses, M2-specific Abs cannot prevent infection, but merely reduce disease at low challenge doses. M2-specific Abs fail to protect from high challenge doses, as vaccinated mice undergo lethal infection under these conditions. In conclusion, protection mediated by M2-hepatitis B core vaccine would be insufficient during the yearly epidemics, for which full protection is desirable, and overall is clearly inferior to protection achieved by immunization with classical inactivated viral preparations.

OX40-deficient mice are defective in Th cell proliferation but are competent in generating B cell and CTL Responses after virus infection.

OX40, a member of the TNF receptor superfamily, is expressed on activated T cells and implicated in stimulation of T cells and T-dependent humoral responses. We generated OX40-/- mice and found that the formation of extrafollicular plasma cells, germinal centers, and antibody responses was independent of OX40. After infection with LCMV and influenza virus, OX40-/- mice retain primary and memory cytotoxic T cell responses with normal expansion and decline of specific CTL. In contrast, CD4+ T cell proliferation and the number of IFN-gamma-producing CD4+ T cells were reduced in OX40-/- mice. Moreover, the number of CD4+ T cells infiltrating the lungs of influenza virus-infected OX40-/- mice was reduced. These results define a unique role of OX40 in the generation of optimal CD4+ T cell responses in vivo.

Neural Correlates of Executive Function in Autistic Spectrum Disorders

BACKGROUND Some clinical characteristics of high-functioning individuals with autistic spectrum disorder (ASD) such as repetitive stereotyped behaviors, perseveration, and obsessionality have been related to executive function (EF) deficits, more specifically to deficits in inhibitory control and set shifting and mediating frontostriatal neural pathways. However, to date, no functional imaging study on ASD has investigated inhibition and cognitive flexibility and no one has related EF brain activation to brain structure. METHODS We compared brain activation (using functional magnetic resonance imaging) in 10 normal intelligence adults with ASD and 12 healthy control subjects during three different EF tasks: 1) motor-inhibition (GO/NO-GO); 2) cognitive interference-inhibition (spatial STROOP); and 3) set shifting (SWITCH). Using voxel-based morphometry, we investigated if cortical areas which were functionally different in people with ASD were also anatomically abnormal. RESULTS Compared with control subjects, ASD individuals showed significantly increased brain activation in 1) left inferior and orbital frontal gyrus (motor-inhibition); 2) left insula (interference-inhibition); and 3) parietal lobes (set shifting). Moreover, in individuals with ASD, increased frontal gray matter density and increased functional activation shared the same anatomical location. CONCLUSIONS Our findings suggest an association between successful completion of EF tasks and increased brain activation in people with ASD, which partially may be explained by differences in brain anatomy.

Interleukin-1 Is Responsible for Acute Lung Immunopathology but Increases Survival of Respiratory Influenza Virus Infection

ABSTRACT Interleukin-1α (IL-1α) and IL-1β are proinflammatory cytokines, which induce a plethora of genes and activities by binding to the type 1 IL-1 receptor (IL-1R1). We have investigated the role of IL-1 during pulmonary antiviral immune responses in IL-1R1−/− mice infected with influenza virus. IL-1R1−/− mice showed markedly reduced inflammatory pathology in the lung, primarily due to impaired neutrophil recruitment. Activation of CD4+ T cells in secondary lymphoid organs and subsequent migration to the lung were impaired in the absence of IL-1R1. In contrast, activation of virus-specific cytotoxic T lymphocytes and killing of virus-infected cells in the lung were intact. Influenza virus-specific immunoglobulin G (IgG) and IgA antibody responses were intact, while the IgM response was markedly reduced in both serum and mucosal sites in IL-1R1−/− mice. We found significantly increased mortality in the absence of IL-1R1; however, lung viral titers were only moderately increased. Our results demonstrate that IL-1α/β mediate acute pulmonary inflammatory pathology while enhancing survival during influenza virus infection. IL-1α/β appear not to influence killing of virus-infected cells but to enhance IgM antibody responses and recruitment of CD4+ T cells to the site of infection.

GM-CSF mediates autoimmunity by enhancing IL-6–dependent Th17 cell development and survival

Granulocyte macrophage–colony stimulating factor (GM-CSF) is critically involved in development of organ-related autoimmune inflammatory diseases including experimental allergic encephalitis and collagen-induced arthritis. Roles of GM-CSF in the initiation and in the effector phase of the autoimmune response have been proposed. Our study was designed to investigate the mechanisms of GM-CSF in autoimmunity using a model of autoimmune heart inflammatory disease (myocarditis). The pathological sequel after immunization with heart myosin has been shown previously to depend on IL-1, IL-6, IL-23, and IL-17. We found that innate GM-CSF was critical for IL-6 and IL-23 responses by dendritic cells and generation of pathological Th17 cells in vivo. Moreover, GM-CSF promoted autoimmunity by enhancing IL-6–dependent survival of antigen specific CD4+ T cells. These results suggest a novel role for GM-CSF in promoting generation and maintenance of Th17 cells by regulation of IL-6 and IL-23 in vivo.

Attack Frequency and Disease Duration as Indicators for Brain Damage in Migraine

Objective.— The aim of this study was to pinpoint predilection sites of brain damage in migraine by quantitatively identifying morphometric and diffusion differences in migraineurs, compared with control subjects, and to assess whether migraine attack frequency and attack history are indicators for brain abnormalities in migraineurs.

CD40–CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells

IL-17-producing CD4+ T cells have been recognized as key players in organ-related autoimmune disease; however, the parameters that govern their development are yet to be elucidated fully. By using both in vivo and in vitro systems, we have investigated the role of antigen dose, pathogen-associated molecular patterns, and CD40–CD40 ligand (CD40L) cross-talk in Th17 differentiation. We found that the strength of antigenic stimulation critically influenced the extent of Th17 differentiation, because high, but not low or intermediate, antigen concentrations led to IL-17 production. Strong antigenic stimulation of T cells up-regulated CD40L expression, which in concert with certain microbial stimuli (i.e., cytosine phosphate guanine, curdlan, and zymosan) synergistically increased dendritic cell (DC) IL-6 production and Th17 polarization. CD40-deficient DCs exhibited reduced cytokine release and failed to drive Th17 development in vitro. These results were confirmed in vivo where the absence of CD40–CD40L cross-talk was found to prevent the expansion of IL-17-producing cells and accordingly the development of experimental autoimmune encephalitis. Our data demonstrate that CD40–CD40L cross-talk is important for Th17 development by translating strong T cell receptor and microbial stimuli into IL-6 production.

In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism.

OBJECTIVE The neural basis for autistic spectrum disorders is unclear, but abnormalities in the development of limbic areas and of glutamate have been suggested. Proton magnetic resonance spectroscopy ((1)H-MRS) can be used to measure the concentration of brain metabolites. However, the concentration of glutamate/glutamine in brain regions implicated in autistic spectrum disorders has not yet been examined in vivo. METHOD The authors used (1)H-MRS to investigate the neuronal integrity of the amygdala-hippocampal complex and a parietal control region in adults with autistic spectrum disorders and healthy subjects. RESULTS People with autistic spectrum disorders had a significantly higher concentration of glutamate/glutamine and creatine/phosphocreatine in the amygdala-hippocampal region but not in the parietal region. CONCLUSIONS Abnormalities in glutamate/glutamine may partially underpin the pathophysiology of autistic spectrum disorders, and the authors confirm earlier reports that limbic areas are metabolically aberrant in these disorders.

VSIG4, a B7 family–related protein, is a negative regulator of T cell activation

T cell activation by APCs is positively and negatively regulated by members of the B7 family. We have identified a previously unknown function for B7 family-related protein V-set and Ig domain-containing 4 (VSIG4). In vitro experiments using VSIG4-Ig fusion molecules showed that VSIG4 is a strong negative regulator of murine and human T cell proliferation and IL-2 production. Administration to mice of soluble VSIG4-Ig fusion molecules reduced the induction of T cell responses in vivo and inhibited the production of Th cell-dependent IgG responses. Unlike that of B7 family members, surface expression of VSIG4 was restricted to resting tissue macrophages and absent upon activation by LPS or in autoimmune inflammatory foci. The specific expression of VSIG4 on resting macrophages in tissue suggests that this inhibitory ligand may be important for the maintenance of T cell unresponsiveness in healthy tissues.

Neural correlates of reward in autism

BACKGROUND Lack of social interaction, which is characteristically seen in people with autistic-spectrum disorder, may be caused by malfunctioning of the frontostriatal reward systems. However, no reported in vivo brain imaging studies have investigated reward mechanisms in autistic-spectrum disorder. AIMS To investigate functional brain activation during reward feedback in people with autistic-spectrum disorder and control individuals. METHOD We used event-related functional magnetic resonance imaging to examine the neural substrates of monetary reward in individuals with autistic-spectrum disorder and matched controls. RESULTS When rewarded, individuals with autism compared with control individuals showed significantly greater brain activation in the left anterior cingulate gyrus. In addition, activation of this region was negatively correlated with social interaction as measured by the Autism Diagnostic Interview. CONCLUSIONS In people with autistic-spectrum disorder, achieving reward is associated with significant differences in the activation of areas known to be responsible for attention and arousal, and this may partially underpin some deficits in social behaviour.