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Current Immunology Reviews (v.2, #4)

Hepatitis C Virus and Dendritic Cells by Babita Agrawal (pp. 305-312).
A majority of hepatitis C virus (HCV) infected individuals become chronically infected. There are approximately 175 million patients chronically infected with HCV worldwide. Multispecific and vigorous cellular immune responses against HCV antigens have been suggested to play a significant role in viral clearance. Patients with chronic HCV are unable to prime and/or maintain vigorous T cell responses which are required to clear the body of the viral infection. Dendritic cells (DCs) are the professional antigen presenting cells which likely play a dominant role in priming and maintaining vigorous T cell responses in HCV infection. Furthermore, inefficient DCs function may play an important role in progression to chronicity in HCV infection. A number of reports have been published examining the functional and phenotypic impairment of dendritic cells in chronic HCV infection. However, these reports are difficult to reconcile. In this article, studies examining the role and modulation/regulation of dendritic cells in HCV infection will be discussed. These elucidations are extremely important for the rational design of vaccine and/or immunotherapy strategies for chronic HCV infection.

Immune Mechanisms of Sublingual Immunotherapy and Mycobacterial Adjuvants in the Treatment of Allergic Disease by Nerin Bahceciler, Isil Barlan (pp. 313-318).
While safety and efficacy of specific immunotherapy (SIT) by the sublingual route in patients with allergic asthma/rhinitis have now been largely documented, the immunological mechanisms have only started to be investigated. Most likely, the allergen captured within the oral mucosa by Langerhans-like dendritic cells (DCs), subsequently mature and migrate to proximal draining lymph nodes, which then induce T lymphocytes with regulatory function. Animal experiments point to enhanced expansion of TGF-β, IL-10 and Fox p3 mRNA in CD4+ T cells, indicators of tolerance, induced by mucosal vaccination. Meanwhile, although there is still no firm proof in human, data on increase in allergeninduced IL-10 and allergen-specific IgA secretion supports the possible role of T regulatory cells in sublingual immunotherapy. Furthermore, detection of high amounts of lipopolysacharide receptor CD14 on oral DCs support the idea of using adjuvants such as mycobacteria along with allergen within the oral cavity, which may further potentiate the immunomodulatory effect. Adjuvants that induce the generation of allergen-specific T regulatory cells have been suggested to increase the success of SIT. Supporting this concept, Mycobacterium vaccae was demonstrated to induce CD4+CD45RBlow T regs that secrete IL-10 and TGF-β.

The Long Pentraxin PTX3, a Soluble Pattern Recognition Receptor Involved in Innate Immunity,Inflammation and Female Fertility by Cecilia Garlanda, Virginia Maina, Federica Moalli, Alessia Cotena, Livija Deban, Andrea Doni, Alessandro Montanelli, Alberto Mantovani, Barbara Bottazzi (pp. 319-329).
Pentraxins are a family of evolutionarily conserved multifunctional pattern-recognition proteins characterized by a cyclic multimeric structure. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP) and serum amyloid P-component (SAP) are the two short pentraxins. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). CRP and SAP are produced primarily in the liver in response to IL-6, while PTX3 is produced by a variety of tissues and cells and in particular, by innate immunity cells in response to proinflammatory signals and Toll-like receptor (TLR) engagement. PTX3 interacts with several ligands, including growth factors, extracellular matrix components and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes, acting as a predecessor of antibodies. In addition, PTX3 is essential in female fertility by acting as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor acting as a nonredundant component of the humoral arm of innate immunity and involved in tuning inflammation, in matrix deposition and female fertility.

Chemokines and Malaria Infection by Jenny Miu, Andrew Mitchell, Helen Ball, Nicholas Hunt (pp. 331-344).
Malaria is a devastating disease of the tropics, with an estimated 3.2 billion people exposed to the threat of malaria. There are 1-3 million deaths annually, mostly of children in sub-Saharan Africa. Deaths due to malaria often arise from complications of Plasmodium falciparum infection, particularly cerebral malaria, but difficulties during pregnancy also contribute to the high incidence of morbidity and mortality. Cytokines are known to play a major role in the pathogenesis of severe malaria, which is generally considered to be an immunopathological process. Chemokines are a family of chemotactic cytokines, with diverse roles that include cellular trafficking and neuronal signaling. Studies on chemokines in malaria infection indicate that they may be important mediators of the immune response to malaria. There is also evidence to suggest that chemokines are involved in the recruitment of leukocytes to the placenta during pregnancyassociated malaria, and also to the brain during cerebral malaria. Chemokines and infiltrating leukocytes can contribute to the severe manifestations of malaria through the actions of cytokines and other inflammatory mediators, for example, low birth weight in placental malaria, and neurological symptoms in cerebral malaria.

Role of Vitamin A in T Cell Homing to the Gut by Makoto Iwata (pp. 345-355).
Vitamin A supplementation significantly reduces infant mortality in developing countries, largely by reducing persistent diarrhea that is often aggravated by malnutrition. Vitamin A contributes to maintaining the integrity of mucosal epithelia and enhancing IgA responses in the gut. Recently, we found that vitamin A is essential for the homing of T cells to gut tissues. Retinoic acid (RA), an oxidative metabolite of retinol, even at 0.1 to 1 nM, enhances the expression of the gut-homing receptors, the integrin α4β7 and the chemokine receptor CCR9, on T cells upon activation in vitro, and grants them the capacity of migrating to the small intestine. The RA receptors RARα and/or β are involved in this effect. Dendritic cells of the gut-associated lymphoid organs, Peyer's patches and mesenteric lymph nodes, express the RAproducing enzymes, and can produce RA from retinol (vitamin A). Antigenic stimulation of T cells with these dendritic cells enhances α4β7 expression on T cells, depending on the production of RA by dendritic cells and its binding to RAR in T cells. Therefore, vitamin A-derived RA imprints T cells with the gut-homing specificity. Possible roles of this effect in the development of diseases and possible future treatments for them are discussed.

NF-κB Activation by FcεRI-Mediated Signal Transduction by Stefanie Klemm, Jurgen Ruland (pp. 357-360).
NF-κB is a master transcription factor in immunity and inflammation. It can be activated by a large variety of distinct cell surface receptors in response to multiple stimuli. NF-κB activation by the high affinity IgE receptor FcεRI is critical for proinflammatory cytokine production during mast cell activation and is crucial for allergic inflammatory diseases. Recent studies have identified two adaptor proteins, Bcl10 and Malt1, as essential regulators of FcεRI-mediated NF-κB activation. Bcl10 and Malt1 form a signaling complex that operates downstream of PKC enzymes and regulates the production of proinflammatory cytokines in response to FcεRI signaling. Other PKC-dependent mast cell effector functions like degranulation or leukotriene production are not controlled by Bcl10 and Malt1. Thus, the Bcl10/Malt1 complex specifically uncouples the pathway for transcription-dependent cytokine production from degranulation events. This review will summarize our current knowledge of the specific NF-κB activation pathway that is selectively engaged by FcεRI ligation in mast cells.

Regulation of Adaptive Immunity by the Neurotransmitter Norepinephrine by Ian Fisher, Nicholas Kin, Jaclyn McAlees, Virginia Sanders (pp. 361-370).
Endogenous physiological mechanisms are in place to regulate cell activity in organ systems to maintain host homeostasis when challenged. Antigenic exposure is an example of a challenge that disrupts host homeostasis. During this challenge, activated immune cells secrete cytokines that influence central nervous system activity, which in turn activates the peripheral sympathetic nervous system to release the neurotransmitter norepinephrine from nerve terminals located within lymphoid tissues. Norepinephrine binds to the beta2-adrenergic receptor expressed on immune cells to regulate the level of gene expression and the magnitude of an immune response. In this review, we will discuss both in vitro and in vivo findings that indicate the cellular and molecular mechanisms by which norepinephrine stimulation of the beta2- adrenergic receptor on CD4+ T cells and B cells regulates the level of cellular activity to maintain host homeostasis.

Immunological Impediments to Developing a Blood Stage Malaria Vaccine by Michelle Wykes, Alberto Pinzon-Charry, Michael Good (pp. 371-376).
There are 300-500 million cases of malaria each year and of the more than one million people that die each year from malaria, most are children under 5 years of age. The cloning of malaria antigens in 1983 offered great hope of developing a viable subunit vaccine. While some subunit vaccines have shown great promise in model systems, an efficacious human vaccine is still not available. Immunological studies have shown that numerous factors such as parasite's antigenic variation and polymorphism, immunological non-responsiveness to individual vaccine antigens, parasite-induced apoptosis of immune effector and memory cells, immune deviation as a result of maternal immunity and alterations of dendritic cell function can impede the development of vaccines. These findings indicate that alternative novel approaches are required to tackle the disease and induce protection against malaria.
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