What is complement how does it cause

MBL deficiency is a common condition associated with several pathologies, including increased susceptibility to infections in childhood.

Keizer et al. The potential drug targets described encompass LP pattern recognition proteins, serine proteases MASPs, factors B and D , the central component C3, and complement regulators factors H and I, properdin. Drug candidates include antibodies, peptides, and selective protease inhibitors for use in the growing number of complement-mediated pathologies. In a search for new complement inhibitors acting at different levels of the complement cascade, Hertz et al. They could inhibit both CP and LP, exhibiting unique complement-regulatory and anti-inflammatory properties and thus contribute to the emerging field of complement therapeutics.

Screening of therapeutic complement inhibitors and known C3b-binding proteins from human, bacteria or ticks revealed that all molecules tested inhibited C5 conversion in both AP and CP, but only some of them inhibited the C3 convertase. These models open the way to the identification and development of specific convertase inhibitors for treatment of complement-mediated diseases. Urinary tract infections belong to the most common infectious diseases worldwide.

Song et al. Furthermore, higher urine C5a concentrations were found in UTI patients compared with controls. Infections, including UTI, are particularly common and often severe in patients suffering from diabetes mellitus. Barkai et al. They found higher functional activity of ficolindependent lectin and alternative pathways, accompanied by lower concentrations of C4d and sC5b-9, in plasma samples, compared with those of non-diabetic patients.

Indeed, lack of ficolindependent activation and AP amplification were found associated with higher 3-months mortality in diabetic patients. Another E. The recognition was followed by complement activation, partially inhibitable when ficolin-2 or factor D inhibitors were used and completely blocked when used together.

Inhibition of complement activation protected bacteria from direct killing. Therefore, again, although LP activation accompanied by AP amplification is an effective mechanism of elimination of pathogens, many EAEC strains have evolved to evade that.

Man-Kupisinska et al. For most strains, the lectin target was LPS core oligosaccharide. N-acetyl-D-glucosamine and L-glycero-D-mannoheptose were identified as the ligands. They are accessible to MBL in vivo when constituting the terminal outer core sugars and the O-polysaccharide is relatively short or when LPS is released due to bacterial cell damage.

Using Hafnia alvei as a model, it was demonstrated that MBL-LPS interaction not only initiates the complement cascade but also induces early-phase lipid A-independent endotoxic shock in mice. Thus, MBL may be involved in life-threatening events in the course of Gram-negative sepsis. Pertussis whooping cough , caused by Bordetella pertussis , is still one of the most deadly childhood diseases. Hovingh et al. That interaction results not only in rescuing bacteria from complement-dependent elimination as suggested previously but also in contact system activation.

Such an effect was observed when recombinant Vag8 or wild-type B. Contact system activation may be additional to the complement evasion mechanism of B. Another major public health problem is tuberculosis. It is estimated that a quarter of the global population is infected with Mycobacterium tuberculosis. The lack of sufficiently specific and sensitive biomarkers makes diagnosis difficult as well as differentiation between active and latent infection.

Lubbers et al. The C1q serum concentrations were significantly higher in TB patients, compared not only with healthy controls but also with individuals with latent M. Importantly, after half-yearly treatment, C1q levels in the TB group dropped to within the control range.

Furthermore, the potential usefulness of that molecule as an active disease marker was supported by data from the non-human primate, Macaca mulatta. Zika virus infections have spread rapidly in recent years. Schiela et al. The natural specific against insect components but not against virus IgM-dependent classical pathway was found to be the major player in complement activation, although direct binding of C1q to NS1 regulator of viral RNA transcription and ZIKV envelope were influential as well.

Coinfections with other pathogens, including HBV and HCV are clinically important, aggravating factors, associated with increased mortality. Tizzot et al. Larsen et al. Although recombinant PfEMP1, opsonised by IgG was demonstrated to activate complement via the classical pathway efficiently, no activation was observed when native protein was exposed on the surface of erythrocytes. As ability to initiate complement activation depends on antigen orientation, the authors suggested that exposure of PfEMP1 in electron-dense protrusions knobs on the cell surface prevents on-target IgG hexamerization and thus consequent C1q binding.

Therefore, although antibody response against PfEMP1 is dominated by IgG1 and IgG3 subclasses, it does not lead to complement-dependent lysis of infected erythrocytes.

A special attention was paid to Porphyromonas gingivalis , the keystone pathogen of periodontitis. Moreover, those molecules contribute to the increase of C1 deposition on the cell surface. Interaction of gingipains with C5 results in C5a anaphylatoxin production, generally associated with antimicrobial events. However, C5a suppresses intracellular killing of P. Furthermore, gingipains at higher concentrations degrade C5b as well as C3 and C4 which prevents complement-dependent cell lysis.

Finally, bacterial peptidyl arginine deiminase PPAD is able to citrullinate C5a C-terminal Arg residue leading to loss of its chemotactic activity. Therefore, it is supposed that P. This section includes papers clarifying a variety of microbial-complement interactions, both beneficial and detrimental for the host, and discussion of application of new disease biomarkers and treatment strategies.

Last but not least it offers an overview of contemporary methodology for complement research. Multiway involvement of the complement system in cancer is widely discussed in the literature.

Such strategies were depicted in two review papers included in this issue. Some cancer cells take advantage of local inflammation mediated by anaphylatoxins which may be intensified by endogenous C5 production and C5a generation with their own serine proteases.

The detrimental effects of anaphylatoxins, contributing to the proliferation and invasiveness of cancer cells expressing C3a and C5a receptors, was underlined as well in another review, by Kochanek et al.

This paper is focused on complement-mediated promotion of cancer metastasis. The invasion-metastasis cascade, leading to spreading of tumor cells through blood or lymph is a complex process involving events in primary tumor, circulation and target sites. Further, the formation of the premetastatic niche including vascular alterations, activation of resident cells, remodeling of extracellular matrix, and recruitment of immunosuppressive cells as well as proven experimentally or suspected involvement of complement system in that process are discussed in details.

Therefore, targeting some complement factors seem to be promising for development of new life-saving therapeutic strategies. Two other, experimental papers, concern associations of complement lectin pathway factors with malignancy. Cervical cancer is one of the most common cancers affecting women, evolving from persistent infection with oncogenic types of human papilloma virus HPV.

Maestri et al. Hematologic malignancies derive from various cells of the immune system. Patients are severely immunocompromised due to disease and therapy what is a reason for high susceptibility to infections and mortality. Swierzko et al. Furthermore, serum concentrations of CL-LK a complex of collectin and collectin were higher in multiple myeloma patients before chemotherapy than in healthy controls.

Furthermore, post-GC B cells require complement on FDCs for an efficient maintenance of long-term memory B cells, affinity maturation, and effective recall responses 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. Walport MJ.

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Activation of the loop is promoted in the presence of bacterial and fungal cell walls, but is inhibited by molecules on the surface of normal mammalian cells. This pathway is activated by the binding of mannose-binding lectin MBL to mannose residues on the pathogen surface. This pathway is initiated by the splitting of C5 , and attachment of C5b to a target. C6, C7, C8 and C9 unite with C5b, and this membrane-attack complex MAC , when inserted into the outer membrane of some bacteria, can contribute to their death by lysis.

Red cells which have antibody bound to the cell surface can also activate the classical and lytic pathways, and become susceptible to lysis. The complement system plays a critical role in inflammation and defence against some bacterial infections.

Complement may also be activated during reactions against incompatible blood transfusions, and during the damaging immune responses that accompany autoimmune disease. Deficiencies of individual complement components or inhibitors of the system can lead to a variety of diseases Table 1 , which gives some indication of their role in protection against disease.

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