A regulatory role for complement in innate immunity and autoimmunity

The complement system comprises a strong defense against various pathogens and is a major component of our innate immune system. While earlier studies have established a crucial role of complement in recognition, opsonization and enhanced phagocytosis of microorganisms by professional phagocytes such as polymorphonuclear leukocytes and macrophages, recent studies delineate an additional role of complement in initiation and maintenance of the acquired immune response. In addition, it seems that opsonization of apoptotic cells by complement may lead to polarization of the response of professional antigen-presenting cells to a more inflammatory or tolerogenic response. The present review summarizes these different contributions of complement to the shaping of the immune balance.     

The role of ficolins in innate immunity

Ficolins are a group of proteins containing both a collagen-like domain and a fibrinogen-like domain and are found in varying tissues. Ficolins present in sera have a lectin activity toward N-acetylglucosamine through their fibrinogen-like domains. The domain organizations between ficolins and mannose-binding lectin (MBL) are very similar in that both consist of a collagen-like domain and a carbohydrate-binding domain, although their carbohydrate-binding moieties are different. MBL acts as an opsonin and activates complement in association with MBL-associated serine proteases (MASPs) and sMAP, a truncated protein of MASP-2, via the lectin pathway. Like MBL, two types of human serum ficolins, L-ficolin/P35 and H-ficolin, are associated with MASPs and sMAP, and activate the lectin pathway. In addition, L-ficolin/P35 acts as an opsonin. These findings indicate that serum ficolins play an important a role in innate immunity in a similar manner to MBL.     

B-lymphocytes, innate immunity, and autoimmunity

Having evolved to generate a huge Ag-specific repertoire and to mount T cell-dependent responses and long-term memory, the B lymphocyte is a central player in the adaptive branch of immune defense. However, accumulating evidence indicates that B-1 cells of the peritoneal cavity and marginal zone (MZ) B cells of the spleen also can play innate-like immune functions. Their anatomical locations allow frequent Ag encounter. Secreting essentially germline-encoded, polyreactive Abs, and responding rapidly and vigorously to stimulation, these two B cell subsets have evolved to impart potentially protective responses. With their additional capacities to secrete factors that can directly mediate microbial destruction and to express Toll-like receptors (TLR), B cells provide an important link between the innate and adaptive branches of the immune system. Currently, the relevance of these innate-like B cells to the pathogenesis of autoimmune disease is the focus of investigation. In experimental models of autoimmunity, the sequestration of autoreactive B cells in the MZ has been proposed to be essential for the maintenance of self-tolerance. The low activation threshold of MZ B cells makes them particularly reactive to high loads and/or altered self-Ags, potentially exacerbating autoimmune disease. Their expansion in autoimmune models and their association with autoantibody secretion indicate that they may participate in tissue damage. The demonstration that B cell depletion therapies may represent a highly beneficial therapeutic goal in autoimmune disorders suggests that specific elimination of B-1 and MZ B cells may represent a more efficient immunointervention strategy in systemic autoimmunity.     

The role of the complement system in innate immunity

Complement is a major component of innate immune system involved in defending against all the foreign pathogens through complement fragments that participate in opsonization, chemotaxis, and activation of leukocytes and through cytolysis by C5b-9 membrane attack complex. Bacterias and viruses have adapted in various ways to escape the complement activation, and they take advantage of the complement system by using the host complement receptors to infect various cells. Complement activation also participates in clearance of apoptotic cells and immune, complexes. Moreover at sublytic dose, C5b-9 was shown to promote cell survival. Recently it was also recognized that complement plays a key role in adaptive immunity by modulating and modifying the T cell responses. All these data suggest that complement activation constitutes a critical link between the innate and acquired immune responses.     

The role of innate immunity in HBV infection

Hepatitis B virus (HBV) infection is one of the main causes of chronic liver diseases. Whether HBV infection is cleared or persists is determined by both viral factors and host immune responses. It becomes clear that innate immunity is of importance in protecting the host from HBV infection and persistence. However, HBV develops strategies to suppress the antiviral immune responses. A combined therapeutic strategy with both viral suppression and enhancement of antiviral immune responses is needed for effective long-term clearance and cure for chronic HBV infection. We and others confirmed that bifunctional siRNAs with both gene silencing and innate immune activation properties are beneficial for inhibition of HBV and represent a potential approach for treatment of viral infection. Understanding the nature of liver innate immunity and their roles in chronic HBV progression and HBV clearance may aid in the design of novel therapeutic strategies for chronic HBV infection.     

The role of innate immunity in Alzheimer's disease

The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain-resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses.     

The role of innate immunity in myasthenia gravis

Myasthenia gravis (MG) is a T cell-driven, B cell-mediated and autoantibody-dependent autoimmune disorder against neuromuscular junctions (NMJ). Accumulated evidence has emerged regarding the role of innate immunity in the pathogenesis of MG. In this review, we proposed two hypothesis underlying the pathological mechanism. In the context of gene predisposition, on the one hand, Toll-like receptors (TLRs) pathways were initiated by viral infection in the thymus with MG to generate chemokines and pro-inflammatory cytokines such as Type I interferon (IFN), which facilitate the thymus to function as a tertiary lymphoid organ (TLO). On the another hand, the antibodies against acetylcholine receptors (AChR) generated by thymus then activated the classical pathways on thymus and neuromuscular junction (NMJ). Futher, we also highlight the role of innate immune cells in the pathogenic response. Finally, we provide some future perspectives in developing new therapeutic approaches particularly targeting the innate immunity for MG.     

The role of CpG motifs in innate immunity

Pattern recognition receptors of the innate immune system are able to distinguish certain prokaryotic DNAs from vertebrate DNAs by detecting unmethylated CpG dinucleotides in particular base contexts ('CpG motifs'). Recent studies have begun to define the molecular mechanisms of actions of CpG motifs and have demonstrated their stimulatory effects on leukocytes from humans and vertebrates other than mice. Oligodeoxynucleotides containing CpG motifs are highly effective Th1-like vaccine adjuvants through multiple routes of immunization and show promise as immunotherapeutic agents for cancer and allergic diseases.     

The role of IL-18 in innate immunity

IL-18 - a novel cytokine with potent IFN-gamma-inducing activities - plays an important role in the Th1-mediated immune response in collaboration with IL-12. IL-18 is a member of the IL-1 family. The IL-18 receptor system and its signal transduction pathway are analogous to those of the IL-1 receptor. Mice deficient in IL-18 have demonstrated its critical role in natural killer cell activity and in vivo Th1 response.     

The role of nitric oxide in innate immunity

Summary: Type 2 nitric oxide synthase (iNOS or NOS2) was originally described as an enzyme that is expressed in activated macrophages, generates nitric oxide (NO) from the amino acid l-arginine, and thereby contributes to the control of replication or killing of intracellular microbial pathogens. Since interferon (IFN)-g is the key cytokine for the induction of NOS2 in macrophages and the prototypic product of type 1 T-helper cells, high-level expression of NOS2 has been regarded to be mostly restricted to the adaptive phase of the immune response. In this review, we summarize data that demonstrate a prominent role of NOS2/NO also during innate immunity. During the early phase of infection with the intra­cellular pathogen Leishmania major , focally expressed NOS2/NO not only exerts antimicrobial activities but also controls the function of natural killer cells and the expression of cytokines such as IFN-g or transforming growth factor-b. Some of these effects result from the function of NOS2/NO as an indispensable co-factor for the activation of Tyk2 kinase and, thus, for interleukin-12 and IFN-a/b signaling in natural killer cells.     

The role of matrix metalloproteinase 7 in innate immunity

Matrix metalloproteinase 7 (MMP-7), or matrilysin, is a secreted protease expressed by glandular and mucosal epithelial cells, keratinocytes, fibroblasts and macrophages. As with other MMPs it can act on the extracellular matrix and thereby regulate cell migration and tissue repair. In addition, MMP-7 has an important role in the maintenance of innate immunity in organs such as the lungs and intestines where it proteolytically activates anti-bacterial peptides such as pro-defensins. MMP-7 is also important for mediating proteolytic release of TNF from macrophages. Consistent with its role in innate immunity, MMP-7 is induced by microbial products and also, unexpectedly, by hypoxia.     

The role of innate immunity in donor organ procurement

Solid organ transplantation is a life saving procedure for patients with end-stage organ disease, and great care is taken to ensure that healthy organs are procured from deceased or live donors. Despite rigorous efforts to avoid injury, all organs experience some degree of damage from a process called ischemia reperfusion injury (IRI). The first part of the injury (ischemia) occurs when the donor organ's blood supply is compromised, and the second part (reperfusion) occurs when the blood supply is reestablished. The pathophysiology of the IRI is complex, but data from many laboratories have demonstrated that the inciting events of ischemia/reperfusion injury are triggered through a phylogenetically conserved system called the innate immune system. The innate immune system is a complex array of molecules, receptors and cellular elements present in species as diverse as plants to humans. This review discusses the role of the innate immune system in renal IRI and focuses on mechanisms of injury during organ procurement and transplantation. Although there are overlapping complex mechanisms, blockade of the innate immune system will likely provide a novel approach to preventing the earliest events associated with renal ischemia. Potentially, blockade of innate immune activation will provide the opportunity to increase the use marginal donors, especially those from patients deceased after cardiac death.     

The role of innate immunity system in the course of adenomyosis

The investigation of leukocytic elastase (LE) and alpha1-proteinase inhibitor (alpha1-PI) from patients with different stage adenomyosis and in control group was found activation innate immunity system in all the patients with adenomyosis. The degree of LE activity is a prevalence rate of adenomyosis. The degree of alpha1-PI activity is correlated with antiproteolytic potential that blocks the effects shown by LE. It can lead the prognose of disease and timely treatment.     

The role of chemokines in linking innate and adaptive immunity.

It is becoming clear that chemokine function is necessary to translate an innate-immune response into an acquired response. Dendritic cells activated by innate stimuli and loaded with foreign antigen travel to regional lymph nodes to activate the acquired-immune system. Subsequently, the activated acquired-immune cells move into tissue, where the innate immune system sets-off the danger signal. The chemokine system has emerged as an essential regulator of this dendritic cell and lymphocyte trafficking, which is necessary to turn an innate immune response into an adaptive response.     

The role of scavenger receptors in pathogen recognition and innate immunity

Scavenger receptors represent a large family of structurally unrelated distinct gene products, expressed by myeloid and selected endothelial cells and able to recognise modified low-density lipoproteins. They also bind and internalise a variety of microbial pathogens, as well as modified or endogenous molecules derived from the host, and contribute to a range of physiological or pathological processes.     

The role of innate immunity in occupational allergy: recent findings

PURPOSE OF REVIEW: Discovery of a system of pattern recognition receptors has opened an entirely new field in inflammation research. This paper reviews studies from the last 18 months focusing on mechanisms of immune stimulation after exposure to microbial components and other exposures that induce or modulate innate immune responses. RECENT FINDINGS: Perhaps the most studied pattern recognition receptor response pathway is endotoxin upregulation of cytokine production via lipopolysaccharide binding protein (LBP), soluble and membrane bound CD14, v-myb-dependent gene 2 (MD-2) and toll-like receptor (TLR) 4. This interaction, and that of synthetic TLR2-agonist (Pam3Cys4) with toll-like receptors TLR1 and TLR2, has recently been characterized at the structural level, and has been confirmed by a blunted response in knockout mice. Dectin-1 recognizes the hyphal form, but not the spores of Aspergillus fumigatus, giving the first known function of the dectin receptor. Martinez has hypothesized that inconsistencies relating to the protective effect of lipopolysaccharide exposure on allergy might be explained by a gene-environment interaction. SUMMARY: We are on the brink of understanding the complex nature and interaction of the pattern recognition receptors and the cellular events following their binding of ligands. Further elucidation of gene-environment interactions will probably lead to important discoveries in the near future.