Toll-like receptors and innate immunity in B-cell activation and antibody responses

It has been known for almost 30 years that mouse B cells proliferate and differentiate to antibody-secreting cells when stimulated by microbial products such as lipopolysaccharide or CpG-containing DNA, but the relevance of these polyclonal responses remained elusive until recently. A breakthrough in the field has been the discovery of endosomal Toll-like receptors in B cells and their role in the production of autoantibodies. Since then, several reports have extended the role of Toll-like receptors in B-cell responses to thymus-independent and thymus-dependent antigens, and in antibody class switch in lymphoid and extralymphoid tissues. Considering the complexity of the system it is perhaps not surprising that the literature contains some contradictory findings. However, the scientific fecundity in this rapidly evolving field will probably give rise to discoveries that could be translated into more effective vaccines and immunotherapies.     

Toll-like receptors and innate immunity

The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses, and play a major role in innate immunity. However, TLRs recognize pathogens either on the cell surface or in the lysosome/endosome compartment. Recently, cytoplasmic PRRs have been identified to detect pathogens that have invaded cytosols. In this review, we focus on the functions of PRRs in innate immunity and their downstream signaling cascades.     

Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity

Serine proteases are well known as enzymes involved in digestion of dietary proteins, blood coagulation, and homeostasis. Only recent groundbreaking studies revealed a novel role of serine proteases as signaling molecules acting via protease-activated receptors (PARs). Important effects of PAR activation on leukocyte motility, cytokine production, adhesion molecule expression, and a variety of other physiological or pathophysiological functions have been described in vitro and in vivo. The crucial role of PAR activation during disease progression was revealed in animal models of different gastrointestinal pathologies, neuroinflammatory and neurodegenerative processes, skin, joint and airway inflammation, or allergic responses. This review focuses on the findings related to the impact of PAR deficiency in animal models of inflammatory and allergic diseases. Additionally, we observe the role of PAR activation in the regulation of functional responses of innate and adaptive immune cells in vitro. Understanding the mechanisms by which PARs exert the effects of serine proteases on immune cells may lead to new therapeutic strategies in inflammation, immune defense, and allergy.     

Toll-like receptors in innate immunity

Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders.     

Pattern-recognition receptors in plant innate immunity

Perception of pathogen-associated molecular patterns (PAMPs) constitutes the first layer of plant innate immunity and is referred to as PAMP-triggered immunity (PTI). For a long time, part of the plant community was sceptical about the importance of PAMP perception in plants. Genetic and biochemical studies have recently identified pattern-recognition receptors (PRRs) involved in the perception of bacteria, fungi and oomycetes. Interestingly, some of the structural domains present in PRRs are similar in plants and animals, suggesting convergent evolution. Lack of PAMP perception leads to enhanced disease susceptibility, demonstrating the importance of PAMP perception for immunity against pathogens in vivo. Recently, proteins with known roles in development have been shown to control immediate PRR-signalling, revealing unexpected complexity in plant signalling. Although many PAMPs recognised by plants have been described and more are likely to be discovered, the number of PRRs known currently is limited. The study of PTI is still in its infancy but constitutes a highly active and competitive field of research. New PRRs and regulators are likely to be soon identified.     

Scavenger receptors in innate immunity.

Scavenger receptors (SR) are expressed by myeloid cells (macrophages and dendritic cells) and certain endothelial cells. They play an important role in uptake and clearance of effete components, such as modified host molecules and apoptotic cells. They bind and internalise micro-organisms and their products including Gram-positive bacteria (lipoteichoic acid), Gram-negative bacteria (lipopolysaccharide), intracellular bacteria and CpG DNA. SR can alter cell morphology and their expression is affected by various cytokines. SR are involved in lipid metabolism and bind modified low-density lipoproteins.     

Evolution of effectors and receptors of innate immunity

The bony fishes are derived from one of the earliest divergent vertebrate lineages to have both innate and acquired immune systems. They are considered by some to be an ideal model to study the underpinnings of immune systems precisely because of their phylogenetic position and the fact that their adaptive immune systems have not been elaborated to the extent seen in mammals. By the same token, examination of innate immune systems in invertebrates and early chordates can provide insight into how homologous systems operate in fish and higher vertebrates. Herein, we provide an overview of the molecular evidence that we hope helps clarify the evolutionary relationships of innate immune molecules identified in bony fishes. The innate immune systems being considered include select chemokines (CC and CXC chemokines and their receptors), cytokines (IL-1, IL-8, interferons, TGF-β, TNF-), acute phase proteins (SAA, SAP, CRP, 2M, and the complement components—C3–C9, MASP, MBL, Bf), NK cell receptors, and molecules upstream and downstream of the Toll signaling pathways.     

Toll-like receptors and innate antiviral responses

Toll-like receptors (TLRs) have a unique and important role in detecting the presence of pathogenic infection. TLRs can recognize conserved structures from a wide variety of microorganisms, such as bacteria, mycobacteria, spirochetes and yeast. However, they are generally not thought to play a major role in viral infection. Several reports have now identified distinct viral ligands for the TLRs, and evidence is accumulating for a functional role of the TLRs in mediating antiviral effector mechanisms.     

Toll-like receptors, innate immunity and HSV pathogenesis

In the last decade, substantial progress has been made in understanding the molecular mechanisms involved in initial host responses to viral infections, and how viral recognition leads to the innate responses that ultimately shape the adaptive immune response. Viruses, including herpes simplex virus (HSV) types 1 and 2, trigger toll-like receptors (TLRs) that elicit cytokine and chemokine production. In turn, this can create local resistance and modulate T- and B-cell-mediated immunity. TLR activation by HSV-produced molecules (or other synthetic agonists) leads to the remodelling of draining lymph nodes. This enhances the screening of naive T-cells, from which antigen-specific lymphocytes can be selected and expanded. The innate response thereby serves to direct a timely and effective acquired immune response, through the initial TLR recognition of viral pathogen-associated molecular patterns that can limit or possibly exacerbate viral pathogenesis. Recently, these findings have been exploited by strategies that utilize synthetic TLR agonists as prophylactic or therapeutic devices. Such devices prime innate immune responses, enhancing host resistance to viral infections, including experimental HSV infections.     

Mechanisms of innate immune responses mediated by Toll-like receptors

The innate immune response is thought to be a rapid and nonclonal host defense. The recent discovery of Toll-like receptors (TLRs) and analyses of their physiological roles have established the notion that TLRs play a central role in innate immunity. Accumulating evidence suggests that individual TLRs recognize distinct ligands derived from bacterial components to generate specific cellular immune responses. In this review, we delineate the relationships between TLRs and microbial components, the TLR-mediated signaling pathways mainly based on cytoplasmic adaptor molecules containing Toll/interleukin-1R domains, the mechanism of TLR-mediated gene expression, and the involvement of TLRs in septic shock, including up-to-date observations.     

Autophagy and pattern recognition receptors in innate immunity

Summary:  Autophagy is a physiologically and immunologically controlled intracellular homeostatic pathway that sequesters and degrades cytoplasmic targets including macromolecular aggregates, cellular organelles such as mitochondria, and whole microbes or their products. Recent advances show that autophagy plays a role in innate immunity in several ways: (i) direct elimination of intracellular microbes by digestion in autolysosomes, (ii) delivery of cytosolic microbial products to pattern recognition receptors (PRRs) in a process referred to as topological inversion, and (iii) as an anti-microbial effector of Toll-like receptors and other PRR signaling. Autophagy eliminates pathogens in vitro and in vivo but, when aberrant due to mutations, contributes to human inflammatory disorders such as Crohn's disease. In this review, we examine these relationships and propose that autophagy is one of the most ancient innate immune defenses that has possibly evolved at the time of α-protobacteria–pre-eukaryote relationships, leading up to modern eukaryotic cell–mitochondrial symbiosis, and that during the metazoan evolution, additional layers of immunological regulation have been superimposed and integrated with this primordial innate immunity mechanism.     

Circadian rhythms in innate immunity and stress responses

Circadian clocks are a common feature of life on our planet, allowing physiology and behaviour to be adapted to recurrent environmental fluctuation. There is now compelling evidence that disturbance of circadian coherence can severely undermine mental and physical health, as well as exacerbate pre-existing pathology. Common molecular design principles underpin the generation of cellular circadian rhythms across the kingdoms, and in animals, the genetic components are extremely well conserved. In mammals, the circadian timing mechanism is present in most cell types and establishes local cycles of gene expression and metabolic activity. These distributed tissue clocks are normally synchronized by a central pacemaker, the suprachiasmatic nuclei (SCN), located in the hypothalamus. Nevertheless, most clocks of the body remain responsive to non-SCN-derived hormonal and metabolic cues (for example, re-alignment of liver clocks to altered meal patterning). It has been demonstrated that the clock is an influential regulator of energy metabolism, allowing key pathways to be tuned across the 24-hr cycle as metabolic requirements fluctuate. Furthermore, clock components, including Cryptochrome and Rev-Erb proteins, have been identified as essential modulators of the innate immune system and inflammatory responses. Studies have also revealed that these proteins regulate glucocorticoid receptor function, a major drug target and crucial regulator of inflammation and metabolism.     

Limiting inflammatory responses during activation of innate immunity

The idea of the importance of mounting an inflammatory response for effective immunity is supported by a multiplicity of experimental data. It is also well understood that resolution of inflammation is essential for maintaining the balance between health and disease. When the normal regulatory mechanisms are disturbed, the potential for developing chronic inflammatory diseases is increased. Inflammation is a key element in the response of the innate immune system to a variety of challenges, including those provided by bacterial and viral infection as well as by damaged or dying host cells. Here we review elements of innate immunity that lead to inflammation and some of the host mechanisms that allow for the resolution of the inflammatory responses.     

Protease-activated receptors: novel PARtners in innate immunity

Protease-activated receptors (PARs) belong to a family of G protein-coupled receptors activated by serine proteases via proteolytic cleavage. PARs are expressed on epithelial cells, endothelial cells, and leukocytes, indicating a role in controlling barrier function against external danger. During inflammation, microorganisms as well as host immune cells release various proteases activating PARs. Thus, PARs can be viewed as an integral component of the host antimicrobial alarm system. When stimulated, PARs regulate various functions of leukocytes in vivo and in vitro, revealing a novel pathway by which proteases affect innate immune responses. Understanding protease-immune interactions could lead to novel strategies for the treatment of infectious and immune-related diseases.     

Analysis of differential immune responses induced by innate and adaptive immunity following transplantation

The roles of innate and adaptive immunity in allograft rejection remain incompletely understood. Previous studies analysing lymphocyte deficient or syngeneic graft recipients have identified subsets of inflammatory chemokines and cytokines induced by antigen independent mechanisms. In the current study, we analysed a panel of 60 inflammatory parameters including serum cytokines, intragraft chemokines and cytokines, receptors, and cellular markers. Our results confirmed the up-regulation of a subset of markers by innate mechanisms and also identified a subset of parameters up-regulated only in the context of an adaptive response. Thus, we successfully differentiated markers of the innate and adaptive phases of rejection. Current paradigms emphasize that innate signals can promote a subsequent adaptive response. Interestingly, in our studies, expression of the markers induced by innate mechanisms was markedly amplified in the allogeneic, but not syngeneic or lymphocyte deficient, recipients. These results suggest that inflammatory mediators can have functional overlap between the innate and adaptive responses, and that the adaptive component of the rejection process amplifies the innate response by positive feedback regulation.     

Toll-like receptors and their function in innate and adaptive immunity

Over the past 3 years our knowledge about how we sense the microbial world has been fundamentally changed. It has been known for decades that microbial products, such as lipopolysaccharide, lipoproteins, or peptidoglycan, have a profound activity on human cells. Whereas the structure of many different pathogenic microbial compounds has been extensively studied and characterized, the molecular basis of their recognition by the cells of the innate immune system remained elusive for a long time. It was Charles Janeway [Cold Spring Harb Symp Quant Biol 1989;54/1:1-13] who developed the idea of microbial structures forming pathogen-associated molecular patterns that would be recognized by pattern recognition receptors. The discovery of the family of Toll receptors in species as diverse as DROSOPHILA and humans, and the recognition of their role in distinguishing molecular patterns that are common to microorganisms have led to a renewed appreciation of the innate immune system. Moreover, it is now clear that the activation of the innate immune system through mammalian Toll-like receptors has also an instructive role for the responses of the adaptive immune response and, thus, may influence allergic diseases such as asthma.     

Toll-like receptors and their crosstalk with other innate receptors in infection and immunity

Toll-like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play a central role in host cell recognition and responses to microbial pathogens. TLR-mediated recognition of components derived from a wide range of pathogens and their role in the subsequent initiation of innate immune responses is widely accepted; however, the recent discovery of non-TLR PRRs, such as C-type lectin receptors, NOD-like receptors, and RIG-I-like receptors, suggests that many aspects of innate immunity are more sophisticated and complex. In this review, we will focus on the role played by TLRs in mounting protective?immune responses against infection and their crosstalk with other PRRs with respect to pathogen recognition.