Receptors that recognize conserved pathogen molecules are the first line of cellular innate immunity defense. Toll-like receptors (TLRs) are the best understood of the innate immune receptors that detect infections in mammals. Key features of the fish TLRs and the factors involved in their signaling cascade have high structural similarity to the mammalian TLR system. However, the fish TLRs also exhibit very distinct features and large diversity which is likely derived from their diverse evolutionary history and the distinct environments that they occupy. Six non-mammalian TLRs were identified in fish. TLR14 shares sequence and structural similarity with TLR1 and 2, and the other five (TLR19, 20, 21, 22 and 23) form a cluster of novel TLRs. TLR4 was lost from the genomes of most fishes, and the TLR4 genes found in zebrafish do not recognize the mammalian agonist LPS and are likely paralogous and not orthologous to mammalian TLR4 genes. TLR6 and 10 are also absent from all fish genomes sequenced to date. Of the at least 16 TLR types identified in fish, direct evidence of ligand specificity has only been shown for TLR2, TLR3, TLR5M, TLR5S and TLR22. The common carp TLR2 was shown to recognize the synthetic triacylated lipopeptide Pam(3)CSK(4) and lipopeptides from gram positive bacteria. The membrane-bound TLR5 (TLR5M) signaling in response to flagellin in rainbow trout is amplified through interaction with the soluble form (TLR5S) in a positive loop feedback. In Fugu, TLR3 is localized to the endoplasmic reticulum (ER) and recognizes relatively short dsRNA, while TLR22 has a surveillance function like the human cell-surface TLR3. Genome and gene duplications have been major contributors to the teleost's rich evolutionary history and genomic diversity. Duplicate or multi-copy TLR genes were identified for TLR3 and 7 in common carp, TLR4b, 5, 8 and 20 in zebrafish, TLR8a in rainbow trout and TLR22 in rainbow trout and Atlantic salmon. The main task for current and near-future fish TLRs research is to develop specificity assays to identify the ligands of all fish TLRs, which will advance comparative immunology research and will contribute to our understanding of disease resistance mechanisms in fish and the development of new adjuvants and/or more effective vaccines and therapeutics.

Toll-like receptors in bony fish: from genomics to function.

Early exposure to environmental levels of sulfamethoxazole triggers immune and inflammatory response of healthy zebrafish larvae

We describe a novel extension of the Genomic Matching Technique (GMT) that defines haplotypes of the mannose binding lectin (MBL) region in Zebrafish (D. rerio). Four ancestral haplotypes have been identified to date, with at least one of these demonstrating a significant increase in resistance to L. anguillarum. MBL activates the lectin pathway of the complement system and stimulates the development of the complement cascade and the Membrane Attack Complex. Polymorphisms in humans have been associated with increased susceptibility and severity to a number of pathogenic organisms. As teleosts have a relatively immature acquired immune system, polymorphisms within MBL and other innate defence genes are likely to be critical in defining their susceptibility/resistance to various pathogenic organisms. We report multiple copies of MBL-like genes in D. rerio, with up to three copies tightly linked within a cluster spanning ∼15 kb on chromosome 2. Genomic analysis suggests that duplication, retroviral insertion and possibly gene mutation and/or deletion have been key factors in the evolution of this cluster. Molecular analysis has revealed extensive polymorphism, including at least five distinct amplicons and haplospecific gene copy number variation. This study demonstrates polymorphism within a critical component of the teleost innate immune system. The polymorphisms and the haplotypes encoding the unique variants are likely to be informative in defining susceptibility/resistance to infectious agents commonly encountered within aquatic environments. Future investigations will define other important haplotypes and transfer the knowledge to other finfish species, thereby enabling selection of broodstock for the aquaculture industry.

Mannose binding lectin ( MBL ) copy number polymorphism in Zebrafish ( D. rerio ) and identification of haplotypes resistant to L. anguillarum

Immunology of carbohydrate-based vaccines.

Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance against nuclear and cytoplasmic self-antigens, induction of immunity and tissue inflammation. Lupus nephritis (LN), the most important predictor of morbidity in SLE, develops in almost 30% of SLE patients at disease onset and in up to 50-60% within the first 10 years. Firstly, in this review, we put the pathogenic mechanisms of the disease into a conceptual frame, giving emphasis to the role of the innate immune system in this loss of self-tolerance and the induction of the adaptive immune response. In this aspect, many mechanisms have been described such as dysregulation and acceleration of cell-death pathways, an aberrant clearance and overload of immunogenic acid-nucleic-containing debris and IC, and the involvement of antigen-presenting cells and other innate immune cells in the induction of this adaptive immune response. This result in a clonal expansion of autoreactive lymphocytes with generation of effector T-cells, memory B-cells and plasma cells that produce autoantibodies that will cause kidney damage. Secondly, we review the immunological pathways of damage in the kidney parenchyma, initiated by autoantibody binding and immune complex deposition, and followed by complement-mediated microvascular injury, activation of kidney stromal cells and the recruitment of leukocytes. Finally, we summarize the rationale for the treatment of LN, from conventional to new targeted therapies, focusing on their systemic immunologic effects and the minimization of podocytary damage. 

From systemic lupus erythematosus to lupus nephritis: The evolving road to targeted therapies.

Mechanisms of Lymphocyte Activation and Immune Regulation X

TIR Domain-Containing Adaptors Regulate TLR Signaling Pathways.- Toll-Like Receptors: Linking Innate and Adaptive Immunity.- Activation of Insect and Vertebrate Toll Signaling: From Endogenous Cytokine Ligand to Direct Recognition of Pathogen Patterns.- Genetic Analysis of Innate Immunity: Identification and Function of the TIR Adapter Proteins.- NF-?B, an Evolutionarily Conserved Mediator of Immune and Inflammatory Responses.- Influence of KIR Diversity on Human Immunity.- NKG2D in Innate and Adaptive Immunity.- Specific and Non-Specific Natural Killer Cell Responses to Viral Infection.- Antigen Processing and Presentation by Dendritic Cells: Cell Biological Mechanisms.- Human Thymic Stromal Lymphopoietin Triggers Dendritic Cell-Mediated Allergic Inflammation and CD4+ T Cell Homeostatic Expansion.- Role of TRAF6 in the Immune System.- The Innate Functions of Dendritic Cells in Peripheral Lymphoid Tissues.- The Mannose-Binding Lectin: An Infection Susceptibility Gene.- Immunotherapy Via Dendritic Cells.- Ontogeny of Lagerhans Cells and Graft Versus Host Disease.- Role of the CD19 and CD21/35 Receptor Complex in Innate Immunity, Host Defense and Autoimmunity.- Role of Complement Receptor 2 in the Pathogenesis of Systemic Lupus Erythematosus.- Complement Regulation During Pregnancy.

/pdf/mechanisms-of-lymphocyte-activation-and-immune-regulation-x-cllugmu0rc.pdf

Mechanisms of lymphocyte activation and immune regulation X : innate immunity

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Mechanisms of Lymphocyte Activation and Immune Regulation X

Mechanisms of lymphocyte activation and immune regulation X : innate immunity