The roles of complement in humoral immunity can be illustrated by the characterization of mice bearing deficiencies in both complement components and CRs Studies have demonstrated the importance of an intact complement classical pathway C1q, C3, or C4 in humoral response to both thymus-dependent and thymus-independent antigens These and other studies highlight the critical role complement plays in the generation of robust antibody response at several levels of B-cell biology.
In view of the impressive repertoire of activities mediated by complement that influence the generation of effective humoral responses, involvement of complement in the other wing of adaptive immunity, the T-cell response, would be expected. Indeed, Janeway's conceptualization of the 'adjuvant effect' being due to the influence of the innate immune system on acquired immunity, nearly two decades ago, provided a framework for studying the contributions of innate immunity to T-cell-mediated immune responses However, the finding that priming of both CD4 and CD8 T cells was reduced in C3-deficient mice during pulmonary influenza challenge suggested a more generalized role of complement A potential role of complement in T-cell immune responses to viral and alloantigens has now been demonstrated in a number of other studies , , , The mechanisms of this influence are not as well characterized as those related to humoral immunity, and as such represent a crucial area of study in understanding the roles complement plays in regulating adaptive immune responses.
Characterization of the potential role of complement in T-cell immunity has been facilitated by the use of a DAF-deficient mouse model , DAF deficiency led to increased complement activation in various in vivo settings, and this presumably allowed the potential modulating effect of complement on T-cell immunity to be amplified and more easily detectable than otherwise in normal mice.
AP-mediated production of C3a and engagement of C3aR have also been proposed to occur in normal i. One issue that could potentially contradict these hypotheses, and thus remains to be resolved by more careful studies, is whether anaphylatoxin receptors are actually expressed in T cells and professional APCs i.
At the whole animal level, C5aR has been shown to be essential for the modulating effect of complement on T-cell immunity in various models. For example, it has been demonstrated that mice treated with C5aR antagonists produced fewer antigen-specific CD8 T cells, following infection with influenza type A Adding further support is the observation that mice bearing a targeted C5aR deficiency show reduced response to pulmonary infections with Pseudomonas aeruginosa , characterized by impaired pulmonary clearance, despite seemingly normal neutrophilic infiltration C5aR has also been shown in mice to mediate a synergistic effect with Toll-like receptor TLR -4 in eliciting a stronger inflammatory response with signaling from both innate immune receptors than with either alone This link is credible because, like complement, the TLR system recognizes conserved pathogenic motifs and is often activated simultaneously with the complement system, indicating that it is plausible that these two effectors of the innate immune system may cooperate in their functions with potential effects on T-cell immune responses , Cross-linking of CD46 on macrophages by certain pathogenic antigens, such as the pili from Nesseria or Hemagglutinin from measles virus leads to the impairment of IL production by APCs , The measles virus is notorious for suppressing T-cell responses during the course of infection, and the suppression of IL production by APCs through subversion of CD46 may be one such mechanism for this pathogenic activity Cross-linking of CR1, which has regulatory properties discussed previously, on T cells has been shown to inhibit proliferation and reduce IL-2 production DAF, in addition to those roles seen previously in suppressing T-cell responses in vivo , may also play a role in costimulation.
Overall, these results serve to illustrate a functional role of complement activation with regard to T-cell biology. There seems to be sufficient evidence supporting a link between complement activation and enhanced T-cell immune response at the organismal level. Although various hypotheses have been proposed, there is yet to be a consensus regarding the precise mechanism by which complement regulates T-cell immunity.
Ongoing studies in this field should provide an improved understanding of this question and contribute to the development of complement-based therapeutic strategies in human diseases relating to microbial infection, autoimmune disorders, and organ transplantation. Infectious diseases represent a major health, social, and economic burden.
The importance of complement to host defense, and the control of infection, as a whole can be appreciated by the consequences observed when complement functions are compromised as a result of genetic deficiency, pathogenic interference, or other mechanisms. Given that complement has coevolved with pathogens for millions of years, it is perhaps not surprising to find that pathogens have developed mechanisms to inhibit complement activation and effector functions, thereby subverting or avoiding this powerful component of innate immunity and increasing their ability to survive and replicate within the host.
Given the disease burden associated with infection with microorganisms and the requirement of novel and effective antibiotics in order to combat them, the study of complement and its roles in defense has significant clinical implications.
As discussed throughout, animals deficient in various complement components have a variety of phenotypes related to host defense, including increased susceptibility to infection, impaired T- and B-cell responses, reduction in phagocytic activity, and ability to clear pathogens and other immune complexes, among many others. In humans, individuals deficient in one of the major complement effector pathways, most commonly opsonization and lytic pathways, present with increased susceptibility to infection 1 , 11 , Deficiency or defect in opsonization pathways, including the production of antibody and phagocytic ability, results in early and recurrent infections with pyrogenic bacteria with the most common organisms being S.
Defect in the assembly or function of the MAC, or deficiency in the components needed for its generation, is associated with neisserial disease, especially infection with Neisseria meningitidis Due to the central role of C3 in the complement system, deficiency of C3 results in defects in both opsonization and lysis, and thus is strongly associated with recurrent infections by the organisms mentioned above Deficiency of AP components properdin and Factor D is rare, but is also a risk factor in some cases for infection with the same organisms as C3 deficiency, while deficiency in unique classical pathway components e.
Interestingly, endemic meningococcal infections are associated with deficiency of MAC proteins, especially C6, in which prevalence of meningococcal infection is increased but mortality is decreased Finally, deficiency of MBL predisposes children to recurrent pyrogenic infection the ages of which 6 months to 2 years suggest that the MBL is critical during the interval between the loss of passively acquired maternal antibody and maturation of their personal immune system 1 , Therefore, complement is indispensable for host defense against certain pathogens and represents an effective innate defense against common infections.
Many organisms, recognizing the potency of complement activity, have devised strategies to circumvent or subvert complement to increase survival or enhance their virulence.
A given pathogen may utilize multiple strategies and molecules to evade host complement attack, as overcoming the powerful, immediate role of complement is imperative from a pathogenic perspective. Bacteria can interfere with complement on nearly every level of complement activation Staphylococcus aureus produces a membrane protein, Staphylococcal protein A SpA , whose predominant biological function is the binding to the Fc region of IgG, which not only is effective in inhibiting Fc-receptor-mediated phagocytosis but also is highly capable of limiting complement activation via the classical pathway by interfering with the binding of C1q Similar immunoglobulin-binding proteins, such as protein G and protein L can be found in an array of other pathogens Furthermore, opsonization by C3 fragments can be inhibited.
For instance, Pseudomonas aeruginosa secretes active proteases that cleave C3b and prevent C3b deposition, and S. Inhibition of MAC assembly and reduction of cytolytic ability can be achieved simply by virtue of having a thick cell wall, as is the case for Gram-positive bacteria , In other cases, pathogens can inhibit the assembly or function of the MAC as in the case of Borrelia burgdorferi , which encodes a 80 kDa surface protein that shares functional similarities with human CD59, the inhibitor of MAC assembly Pathogens utilize other mechanisms to escape complement as well.
They may interact with host regulators, such as binding Factor H, which increases the degradation of C3b and reduces formation of C3 convertase, thereby limiting complement activity This phenomenon is well characterized in the Nesseria family of pathogens, including N.
Interestingly, recent structural determinations of the N. In addition to Factor H binding, both viruses and bacteria may incorporate or recruit other host complement regulatory proteins, encode structural mimics of complement regulatory proteins, or simply encode unique regulatory proteins that serve to inhibit complement activity and thereby render the pathogen resistant to complement effectors , Alternatively, pathogens may inhibit chemotaxis and recruitment of leukocytes by interfering with receptors that mediate these activities, most notably C5aR and the related formyl peptide receptor The chemotaxis inhibitory protein of S.
Some pathogens go further and subvert the complement system in order to enhance their virulence. This was alluded to previously when discussing the complement regulatory protein CD46, which was first described as a receptor for the measles virus and may contribute to the ability of measles to suppress the immune system , CD46 may also act as a cellular receptor for major bacterial strains, including N.
DAF is a receptor for many picornaviruses, such as echoviruses and coxsakieviruses, which use different binding locations on DAF and require accessory molecules such as ICAM-1 in order to internalize , CR2, as discussed above, plays a crucial role in B cells in the binding of C3 fragments. Human immunodeficiency virus exploits complement on multiple levels to increase its virulence It activates complement in the absence of antibody, which seems counterintuitive as this would normally result in virolysis.
However, this is avoided by complement regulators contained in the viral membrane including DAF, which is subverted during the budding process from infected cells, and Factor H, which is attached secondarily Furthermore, C3b deposition allows the virus to utilize CRs to enhance the efficiency of infection The role of complement in the immune system, and consequently on human health, has expanded dramatically.
It is a well-characterized and an evolutionarily ancient component of host defense, impairment of which leads to susceptibility to infection. It has the ability to recognize well-conserved antigens derived from common pathogens, and to do so immediately and robustly.
Activation of proteolytic cascades leads to the identification and persecution of the surface identified as foreign and allows complement to contain, control, and finally clear invading microorganisms.
In performing these functions, complement represents a cornerstone of the innate defense against infection and provides a vital first-line barrier to invading pathogens. It is not surprising that the most evolutionarily successful pathogens have developed ways to circumvent or subvert complement in order to utilize host resources. The ways in which pathogens manipulate complement continue to be uncovered at a rapid rate and represent an exciting avenue of research.
Further understanding of host-pathogen interactions and the roles complement plays in these interactions may help to develop more effective pharmacological agents against infection and reduce health-care burden. On top of these important contributions to innate immunity, complement plays a vital role in shaping adaptive immune responses, functionally integrating it into the ability of the host to combat invasion from a wide range of pathogens.
Since complement represents such an evolutionarily well-conserved mechanism of host defense, it is not surprising to find that it has been integrated into the relatively newer acquired immune responses. Complement has now been shown to play a role in both B- and T-cell responses at the organismal level. However, the exact mechanism s by which complement mediates T-cell immunity has yet to be determined.
A careful, integrated study of complement effects on B- and T-cell biology will provide valuable insight into the in vivo biology of complement and may have implications for infectious disease as well as immunological disorders, such as in the cases of multiple sclerosis and organ transplantation.
In conclusion, complement is a multifaceted and robust effector, which bridges the innate and adaptive immune systems. It is vital to host defense, and the extent of its influence is becoming increasingly appreciated as additional information regarding the far-reaching effects of its activation is uncovered.
Further study should produce significant dividends in our understanding of host defense as an integrated process and the roles complement plays in bridging innate and adaptive immunity.
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Blood —6. Antiviral protein viperin promotes toll-like receptor 7- and toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Immunity 34 — These types of signals usually elicit quick responses that last only a short amount of time. In order to keep the response localized, paracrine ligand molecules are normally quickly degraded by enzymes or removed by neighboring cells. Removing the signals will reestablish the concentration gradient for the signal, allowing them to quickly diffuse through the intracellular space if released again.
One example of paracrine signaling is the transfer of signals across synapses between nerve cells. A nerve cell consists of a cell body, several short, branched extensions called dendrites that receive stimuli, and a long extension called an axon, which transmits signals to other nerve cells or muscle cells.
The junction between nerve cells where signal transmission occurs is called a synapse. A synaptic signal is a chemical signal that travels between nerve cells. Signals within the nerve cells are propagated by fast-moving electrical impulses. When these impulses reach the end of the axon, the signal continues on to a dendrite of the next cell by the release of chemical ligands called neurotransmitters by the presynaptic cell the cell emitting the signal. The neurotransmitters are transported across the very small distances between nerve cells, which are called chemical synapses.
The small distance between nerve cells allows the signal to travel quickly; this enables an immediate response. Synapsis : The distance between the presynaptic cell and the postsynaptic cell—called the synaptic gap—is very small and allows for rapid diffusion of the neurotransmitter.
Enzymes in the synapatic cleft degrade some types of neurotransmitters to terminate the signal. Signals from distant cells are called endocrine signals; they originate from endocrine cells. In the body, many endocrine cells are located in endocrine glands, such as the thyroid gland, the hypothalamus, and the pituitary gland.
These types of signals usually produce a slower response, but have a longer-lasting effect. The ligands released in endocrine signaling are called hormones, signaling molecules that are produced in one part of the body, but affect other body regions some distance away. Hormones travel the large distances between endocrine cells and their target cells via the bloodstream, which is a relatively slow way to move throughout the body. Because of their form of transport, hormones get diluted and are present in low concentrations when they act on their target cells.
This is different from paracrine signaling in which local concentrations of ligands can be very high. Autocrine signals are produced by signaling cells that can also bind to the ligand that is released. This means the signaling cell and the target cell can be the same or a similar cell the prefix auto- means self, a reminder that the signaling cell sends a signal to itself.
This type of signaling often occurs during the early development of an organism to ensure that cells develop into the correct tissues and take on the proper function. Autocrine signaling also regulates pain sensation and inflammatory responses. Further, if a cell is infected with a virus, the cell can signal itself to undergo programmed cell death, killing the virus in the process. In some cases, neighboring cells of the same type are also influenced by the released ligand.
In embryological development, this process of stimulating a group of neighboring cells may help to direct the differentiation of identical cells into the same cell type, thus ensuring the proper developmental outcome. Gap junctions in animals and plasmodesmata in plants are connections between the plasma membranes of neighboring cells. These water-filled channels allow small signaling molecules, called intracellular mediators, to diffuse between the two cells.
The specificity of the channels ensures that the cells remain independent, but can quickly and easily transmit signals. The transfer of signaling molecules communicates the current state of the cell that is directly next to the target cell; this allows a group of cells to coordinate their response to a signal that only one of them may have received. In plants, plasmodesmata are ubiquitous, making the entire plant into a giant communication network.
Receptors, either intracellular or cell-surface, bind to specific ligands, which activate numerous cellular processes. Receptors are protein molecules in the target cell or on its surface that bind ligands. There are two types of receptors: internal receptors and cell-surface receptors. Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane.
Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis to mediate gene expression.
When the ligand binds to the internal receptor, a conformational change exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, binds to specific regulatory regions of the chromosomal DNA, and promotes the initiation of transcription. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers. Intracellular Receptors : Hydrophobic signaling molecules typically diffuse across the plasma membrane and interact with intracellular receptors in the cytoplasm.
Many intracellular receptors are transcription factors that interact with DNA in the nucleus and regulate gene expression. Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal.
Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.
Each cell-surface receptor has three main components: an external ligand-binding domain extracellular domain , a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The size and extent of each of these domains vary widely, depending on the type of receptor.
Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors. Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through.
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