Innate immunity in alcoholic liver disease

Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease.     

Innate immunity against viruses

Viruses are obligate parasites which are able to infect cells of all living organisms. Multiple antiviral defense mechanisms have appeared early in evolution of the immune system. Higher vertebrates have the most complex antiviral immunity which is based on both innate and adoptive immune responses. However, majority of living organisms, including plants and invertebrates, rely exclusively on innate immune mechanisms for protection against viral infections. There are some striking similarities in several components of the innate immune recognition between mammals, plants and insects, rendering these signaling cascades as highly conserved in the evolution of the immune system. This review summarizes recent advances in the field of innate immune recognition of viruses, with particular interest on pattern-recognition receptors.     

Innate immunity and adjuvants

Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.     

Innate immunity: unfolding the neuro-immuno connections

The innate immune system maintains health and fitness during infection by eliminating infectious agents and by limiting damage caused by pathogens or immune activation. The nervous system contributes to innate immunity by modulating the expression of antimicrobial peptides and by regulating the unfolded protein response.     

Innate immunity: the worm fights back

Innate immunity is an evolutionarily ancient defense system that enables animals and plants to resist invading microorganisms. Recent studies have demonstrated the existence of innate immune responses in Caenorhabditis elegans.     

Innate immunity to tropical theileriosis

The intracellular protozoan parasite Theileria annulata causes a severe, and often fatal, disease of pure and cross-bred cattle in tropical and subtropical countries. The present review refers to the importance of innate immunity as far as it is known to date in this infectious disease. Specifically, macrophages and the mediators produced by these cells are outlined. In addition, the latest findings concerning cattle breed differences in susceptibility to T. annulata infection in relation to macrophage activation are discussed.     

Innate immunity in early chordates and the appearance of adaptive immunity

In the urochordate Ciona intestinalis some membrane Immunoglobulin superfamily members with ancestral features of antigen receptors are homologs of vertebrate adhesion molecules acting as virus receptors. They include the following: the junction adhesion molecule (reovirus receptor) (JAM), the Cortical thymocyte marker of Xenopus (CTX family) (Coxsackie's virus receptor) and the poliovirus receptor (PVR). In humans these genes belong to the same linkage group, of which 4 paralogous groups exist. This situation is consistent with the notion that the Ciona set of genes would correspond to a preduplication state. In addition, the human region 3q13 and its paralogs, harbour genes remotely related to the nectin family that can be detected in Protostomes (human CRTAM and CD80-86 related to Drosophila Beat). In addition, this linkage group contains several CDs important for the immune system CD166, CD47 and many members of the tetraspanin family. The VC1-like core of the nectin is homologous to the VCI core of the MHC-linked tapasin and to the VC1 segments of, for example, specific antigen receptors of vertebrates, and could be related to a primitive antigen receptor gene. It is suggested that the virus binding property of the members of this family was exploited, and that they were recruited in the vertebrate immune system following the introduction of the somatic rearrangement machinery. In this way the adaptive immune system could have developed from a set of receptors involved in a primitive local innate immunity involving NF-kappaB-mediated apoptosis.     

Innate immunity to Paracoccidioides brasiliensis infection

Innate immunity is based in pre-existing elements of the immune system that directly interact with all types of microbes leading to their destruction or growth inhibition. Several elements of this early defense mechanism act in concert to control initial pathogen growth and have profound effect on the adaptative immune response that further develops. Although most studies in paracoccidioidomycosis have been dedicated to understand cellular and humoral immune responses, innate immunity remains poorly defined. Hence, the main purpose of this review is to present and discuss some mechanisms of innate immunity developed by resistant and susceptible mice to Paracoccidioides brasiliensis infection, trying to understand how this initial host-pathogen interface interferes with the protective or deleterious adaptative immune response that will dictate disease outcome. An analysis of some mechanisms and mediators of innate immunity such as the activation of complement proteins, the microbicidal activity of natural killer cells and phagocytes, the production of inflammatory eicosanoids, cytokines, and chemokines among others, is presented trying to show the important role played by innate immunity in the host response to P. brasiliensis infection.     

Innate immunity: NKT cells in the spotlight

Cells of the innate immune system provide a first line of defense against microbial invaders. Recent studies have revealed how one intriguing member of the innate immune system, the natural killer T cell, is activated during bacterial infections.     

Innate immunity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motor neurons are selectively targeted. Although the underlying cause remains unclear, evidence suggests a role for innate immunity in disease pathogenesis. Neuroinflammation in areas of motor neuron loss is evident in presymptomatic mouse models of ALS and in human patients. Efforts aimed at attenuating the inflammatory response in ALS animal models have delayed symptom onset and extended survival. Seemingly conversely, attempts to sensitize cells of the innate immune system and modulate their phenotype have also shown efficacy. Effectors of innate immunity in the CNS appear to have ambivalent potential to promote either repair or injury. Because ALS is a syndromic disease in which glutamate excitotoxicity, altered cytoskeletal protein metabolism, oxidative injury, mitochondrial dysfunction and neuroinflammation all contribute to motor neuron degeneration, targeting inflammation via modulation of microglial function therefore holds significant potential as one aspect of therapeutic intervention and could provide insight into the exclusive vulnerability of motor neurons.     

Innate immunity and the pathogenicity of inhaled microbial particles

Non-infectious inhaled microbial particles can cause illness by triggering an inappropriate immunological response. From the pathogenic point of view these illnesses can be seen to be related to on one hand autoimmune diseases and on the other infectious diseases.In this review three such illnesses are discussed in some detail. Hypersensitivity pneumonitis (HP) is the best known of these illnesses and it has also been widely studied in animal models and clinically. In contrast to HP Pulmonary mycotoxicosis (PM) is not considered to involve immunological memory, it is an acute self-limiting condition is caused by an immediate "toxic" effect. Damp building related illness (DBRI) is a controversial and from a diagnostic point poorly defined entity that is however causing, or attributed to cause, much more morbidity than the two other diseases.In the recent decade there has been a shift in the focus of immunology from the lymphocyte centered, adaptive immunity towards innate immunity. The archetypal cell in innate immunity is the macrophage although many other cell types participate. Innate immunity relies on a limited number of germline coded receptors for the recognition of pathogens and signs of cellular damage. The focus on innate immunity has opened new paths for the understanding of many chronic inflammatory diseases. The purpose of this review is to discuss the impact of some recent studies, that include aspects concerning innate immunity, on our understanding of the pathogenesis of inflammatory diseases associated with exposure to inhaled microbial matter.