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 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 complement in innate, adaptive and eosinophil-dependent immunity to the nematode Nippostrongylus brasiliensis

Complement may be important for immunity to infection with parasitic helminths, by promoting the recruitment of leukocytes to infected tissues and by modulating the function of cytotoxic effector leukocytes. However, the importance of complement in vivo during helminth infection is poorly understood. In this study, mice lacking classical (C1q-deficient), alternative (factor B-deficient) or all pathways of complement activation (C3-deficient) were used to assess the role of complement in immunity to the nematode Nippostrongylus brasiliensis. Double-mutant complement-deficient/IL-5 transgenic (Tg) mice were used to determine if complement is required for the strong eosinophil-dependent resistance to this parasite. Complement activation on larvae (C3 deposition), extracellular eosinophil peroxidase activity, larval aggregation and eosinophil recruitment to the skin 30 min post-injection (p.i.) of larvae were reduced in factor B-deficient mice. Inhibition of the C5a receptor with the antagonist PMX53 impaired eosinophil and neutrophil recruitment to the skin. C3 deposition on larvae was minimal by 150 min p.i. and at this time cell adherence, larval aggregation, eosinophil recruitment and degranulation were complement-independent. Factor B and C3 deficiency were associated with higher lung larval burdens in primary infections. Complement-deficient/IL-5 Tg mice were highly resistant to N. brasiliensis, suggesting that eosinophils can limit infection in a complement-independent manner. Potent secondary immunity was similarly complement-independent. In conclusion, although the alternative pathway is important for parasite recognition and leukocyte recruitment early in N. brasiliensis infections, the parasite soon becomes resistant to complement and other factors can compensate to promote eosinophil-dependent immunity.     

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.     

Evolution of complement as an effector system in innate and adaptive immunity

For a long time, the complement system in mammals has been regarded as a biological system that plays an essential role in innate immunity. More recently, it has been recognized that the complement system contributes heavily to the generation and development of an acquired immune response. In fact, this ancient mechanism of defense has evolved from a primitive mechanism of innate immune recognition in invertebrate species to that of an effector system that bridges the innate with the adaptive immune response in vertebrate species. When and how did complement evolve into a shared effector system between innate and adaptive immunity? To answer this question, our group is interested in understanding the role of complement in innate and adaptive immune responses in an evolutionary relevant species: the teleost fish. The attractiveness of this species as an animal model is based on two important facts. First, teleost fish are one of the oldest animal species to have developed an adaptive immune response. Second, the complement system of teleost fish offers a unique feature, which is the structural and functional diversity of its main effector protein, C3, the third component of the complement system.     

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 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 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 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 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 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 the induction of autoimmunity

The autoimmune diseases are a diverse group of conditions characterized by abnormal B and T cell reactivity in association with autoantibody production. Among these diseases, systemic lupus erythematosus (SLE) is notable for the expression of antibodies to DNA, with these antibodies representing diagnostic markers. While mammalian DNA is immunologically inert, DNA from bacteria can potently stimulate the innate immune system, activating both toll-like receptors (TLRs) as well as non-TLR internal receptors. Since the sera of normal humans contain antibodies specific for bacterial DNA, this molecule appears to be immunogenic during infection. In pre-autoimmune mice, immunization with bacterial DNA can induce anti-DNA autoantibody production, suggesting a role in initiating this response. The immune properties of DNA are mutable, however, since mammalian DNA can acquire immunological activity when bound to certain proteins or anti-DNA antibodies to form immune complexes. In SLE, these immune complexes can drive the production of interferon by plasmacytoid dendritic cells, thereby intensifying autoimmunity. Together, these observations suggest that DNA can induce innate as well as adaptive immune responses and promote the pathogenesis of SLE because of its intrinsic immunostimulatory activity.     

Role of complement in innate immunity and host defense

The complement system is an important part of the innate immune defense. Next to its role as an effector mechanism of the innate immune system, complement also plays a major role in shaping the adaptive immune response. The complement system is also involved in several other physiological processes such as tissue regeneration and clearance of immune complexes and dead cells. Unfortunately complement is also involved in pathology by contributing to tissue damage, induction of autoimmune reactions and chronic inflammation. Tight regulation of complement activation by both fluid-phase and membrane bound complement inhibitors is essential to maintain a good balance between optimal protection with as little as possible damage to the host. Alterations in this balance and hence the function of complement, by influence of auto-antibodies, or genetic variants, may render the complement system into a harmful player in tissue damage and pathology.     

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.     

Mast cells and complement system: Ancient interactions between components of innate immunity

The emergence and evolution of the complement system and mast cells (MCs) can be traced back to sea urchins and the ascidian Styela plicata, respectively. Acting as a cascade of enzymatic reactions, complement is activated through the classical (CP), the alternative (AP), and the lectin pathway (LP) based on the recognized molecules. The system's main biological functions include lysis, opsonization, and recruitment of phagocytes. MCs, beyond their classic role as master cells of allergic reactions, play a role in other settings, as well. Thus, MCs are considered as extrahepatic producers of complement proteins. They express various complement receptors, including those for C3a and C5a. C3a and C5a not only activate the C3aR and C5aR expressing MCs but also act as chemoattractants for MCs derived from different anatomic sites, such as from the bone marrow, human umbilical cord blood, or skin in vitro. Cross talk between MCs and complement is facilitated by the production of complement proteins by MCs and their activation by the MC tryptase. The coordinated activity between MCs and the complement system plays a key role, for example, in a number of allergic, cutaneous, and vascular diseases. At a molecular level, MCs and complement system interactions are based on the production of several complement zymogens by MCs and their activation by MC-released proteases. Additionally, at a cellular level, MCs act as potent effector cells of complement activation by expressing receptors for C3a and C5a through which their chemoattraction and activation are mediated by anaphylatoxins in a paracrine and autocrine fashion.     

Leptospirosis: aspects of innate immunity, immunopathogenesis and immune evasion from the complement system

Leptospirosis is a neglected infectious disease caused by spirochetes from the genus Leptospira. It constitutes a major public health problem in developing countries, with outcomes ranging from subclinical infections to fatal pulmonary haemorrhage and Weil's syndrome. To successfully establish an infection, leptospires bind to extracellular matrix compounds and host cells. The interaction of leptospires with pathogen recognition receptors is a fundamental issue in leptospiral immunity as well as in immunophatology. Pathogenic but not saprophytic leptospires are able to evade the host complement system, circulate in the blood and spread into tissues. The target organs in human leptospirosis include the kidneys and the lungs. The association of an autoimmune process with these pathologies has been explored and diverse mechanisms that permit leptospires to survive in the kidneys of reservoir animals have been proposed. However, despite the intense research aimed at the development of a leptospirosis vaccine supported by the genome sequencing of Leptospira strains, there have been relatively few studies focused on leptospiral immunity. The knowledge of evasion strategies employed by pathogenic leptospires to subvert the immune system is of extreme importance as they may represent targets for the development of new treatments and prophylactic approaches in leptospirosis.     

The complement system in regulation of adaptive immunity

The serum complement system, which represents a chief component of innate immunity, not only participates in inflammation but also acts to enhance the adaptive immune response. Specific activation of complement via innate recognition proteins or secreted antibody releases cleavage products that interact with a wide range of cell surface receptors found on myeloid, lymphoid and stromal cells. This intricate interaction among complement activation products and cell surface receptors provides a basis for the regulation of both B and T cell responses. This review highlights fundamental events, explaining how complement links innate and adaptive immunity as well as describing more recent studies on how this large family of proteins functions locally in peripheral lymph nodes to enhance B and T cell responses.