Ligands For Innate Immune Receptors Research Articles

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis.

The human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

B cell activating factor is induced by toll-like receptor and NOD-like receptor-ligands and plays critical role in IgM synthesis in Labeo rohita.

B-cell activating factor (BAFF), an important member of the tumor necrosis factor superfamily, plays critical roles in the modulation of B-cell functions and enhancement of immune response in the host. Like higher vertebrates, the important role of BAFF in boosting immune response against diverse pathogens was also envisaged in fishes. We therefore, studied BAFF in rohu (Labeo rohita), a freshwater food fish species of highest economic importance in the Indian subcontinent. Full-length rohu-BAFF- cDNA comprised of 804bp nucleotide long ORF, encoding 267 amino acid residues, and shared high structural similarity with human-BAFF. It was expressed in the embryonic developmental stages suggesting its key role in immune response at the early life of fish. In Aeromonas hydrophila infection and rhabdoviral antigen stimulation, BAFF-gene expression in rohu was induced across the organs/tissues. Stimulation of un-treated healthy rohu fish leukocytes, and viral or bacterial or BSA (bovine serum albumin) antigen stimulated rohu fish leukocytes with recombinant-BAFF (r-BAFF) resulted in enhanced expression of immunoglobulin (Ig)M. Both in-vitro and in-vivo treatment with toll-like receptor (TLR)- ligand (poly I:C) or nod-like receptor (NLR)- ligands (iE-DAP and MDP) resulted in TLR and NLR activation and BAFF-gene expression. This is the first report showing BAFF-expression by innate immune receptor-ligands and its critical role in enhancing adaptive immune response in fish.

The Central Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Septic Pathogen Lipid Transport and Clearance.

Microbial cell walls contain pathogenic lipids, including LPS in gram-negative bacteria, lipoteichoic acid in gram-positive bacteria, and phospholipomannan in fungi. These pathogen lipids are major ligands for innate immune receptors and figure prominently in triggering the septic inflammatory response. Alternatively, pathogen lipids can be cleared and inactivated, thus limiting the inflammatory response. Accordingly, biological mechanisms for sequestering and clearing pathogen lipids from the circulation have evolved. Pathogen lipids released into the circulation are initially bound by transfer proteins, notably LPS binding protein and phospholipid transfer protein, and incorporated into high-density lipoprotein particles. Next, LPS binding protein, phospholipid transfer protein, and other transfer proteins transfer these lipids to ApoB-containing lipoproteins, including low-density (LDL) and very-low-density lipoproteins and chylomicrons. Pathogen lipids within these lipoproteins and their remnants are then cleared from the circulation by the liver. Hepatic clearance involves the LDL receptor (LDLR) and possibly other receptors. Once absorbed by the liver, these lipids are then excreted in the bile. Recent evidence suggests pathogen lipid clearance can be modulated. Importantly, reduced proprotein convertase subtilisin/kexin type 9 activity increases recycling of the LDLR and thereby increases LDLR on the surface of hepatocytes, which increases clearance by the liver of pathogen lipids transported in LDL. Increased pathogen lipid clearance, which can be achieved by inhibiting proprotein convertase subtilisin/kexin type 9, may decrease the systemic inflammatory response to sepsis and improve clinical outcomes.

Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant

Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1- and Th-17-balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell-mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses.

Toll‐like receptors 2 and 3 agonists differentially affect oligodendrocyte survival, differentiation, and myelin membrane formation

Toll-like receptors (TLRs) play a key role in controlling innate immune responses to a wide variety of pathogen-associated molecules as well as endogenous signals. In addition, TLR expression within nonimmune cells has been recognized as as modulator of cell behavior. In this study we have addressed the question of whether functional TLRs are expressed on oligodendrocytes, the myelinating cells of the central nervous system. Primary cultures of rat oligodendrocytes at different maturation stages were found to express TLR2 and, to lesser extent, TLR3. Immunocytochemical analysis revealed that both TLRs were localized at the cell body and primary processes and were excluded from myelin-like membranes. Interestingly, innate immune receptor ligands were able to modulate oligodendrocyte survival, differentiation, and myelin-like membrane formation, indicating that TLRs on oligodendrocytes are functional. In highly purified oligodendrocytes cultures, the TLR2 agonist zymosan promoted survival, differentiation, and myelin-like membrane formation, whereas poly-I:C, a TLR3 ligand, was a potent inducer of apoptosis. Together, these data indicate that, in addition to other neural cell types, also oligodendrocytes express functional TLRs, which play a role in regulating various aspects of oligodendrocyte behavior.

The role of hyperglycemia in mechanisms of exacerbated inflammatory responses within the oral cavity

Immune modulating factors are necessary for pathogen clearance, but also contribute to host tissues damage, as those seen in periodontal diseases. Many of these responses can be exacerbated by host conditions including type 2 diabetes [T2D], where toll-like receptor 4 [TLR4] and the receptor for advanced glycated end products [RAGE] play a significant role. Here we investigate causality associated with the increase in inflammatory markers observed in periodontally diseased patients with T2D using multi-variant correlation analysis. Inflammation associated with periodontal diseases, characterized by elevated pro-inflammatory cytokines, innate immune receptor expression, and cellular infiltrate was exacerbated in patients with T2D. In addition, a feed forward loop regulated by poor glycemic control was associated with a loss of mucosal barrier integrity and accumulation of innate immune receptor ligands resulting in an exacerbation of ongoing inflammation, where RAGE and TLR4 cooperated to induce responses in oral epithelial cells, which were exacerbated by hyperglycemia.

Human Neuronal Cells Possess Functional Cytoplasmic and TLR-Mediated Innate Immune Pathways Influenced by Phosphatidylinositol-3 Kinase Signaling

Innate immune pathways are early defense responses important for the immediate control and eventual clearance of many pathogens, where signaling is initiated via pattern recognition receptor (PRR)-mediated events that occur in a ligand- and cell-type specific manner. Within CNS neurons, innate immune pathways are likely crucial to control pathogens that target these essential yet virtually irreplaceable cells. However, relatively little is known about the induction and regulation of neuronal PRR signaling. In this report, we used human neuronal cell lines and primary rat neuronal cultures to examine PRR expression and function. We found that several innate immune receptor ligands, including Sendai virus, the dsRNA mimetic polyinosinic-polycytidylic acid, and LPS all activated differentiation-dependent neuronal innate immune pathways. Functional genetic analyses revealed that IFN regulatory factor 3-mediated pathways that resulted in IFN-beta transcriptional upregulation were activated in cultured human neuronal cells by the PRRs TLR3, MDA5, or RIG-I in a ligand-specific manner. Furthermore, genome-wide transcriptional array and targeted genetic and pharmacologic analyses identified PI3K signaling as crucial for the induction of innate immune pathways in neurons. These results indicate that human neuronal cells possess specific and functional PRR pathways essential for the effective induction of innate immune responses, and suggest that neurons can play an active role in defense against neurotropic pathogens.

Rationally-designed vaccine adjuvants: separating efficacy from toxicity

Adjuvants, substances included in many vaccines in order to improve immune responses, are challenging to develop and license because adjuvant compounds that stimulate strong protective immunity also frequently induce significant toxicity. Adjuvant design and development has until recently been largely empirical; but with the current knowledge that most adjuvants act via receptors of the innate immune system, molecular-based approaches are rapidly advancing the field. Data support the concept that proinflammatory pathways induced by innate immune receptor triggering underlie many of the observed toxic effects. Importantly, the cellular signaling pathways that lead to inflammation are known, for a number of innate immune receptors, to be distinct from those that are involved in the costimulation of protective adaptive immune responses, leading to approaches for attenuating inflammatory signaling that should lead to safer and more effective vaccine adjuvants. This article addresses whether there is a clear rationale for the separation of toxicity from efficacy in the function of adjuvants based upon innate immune receptor ligands.