Humoral innate immune reaction and disease

Stephanie N Shishido

Sriram Varahan

Kai Yuan

Xiangdong Li

Sherry D Fleming

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Corresponding writer at : Division of Biology , 18 Ackert , Kansas State University , Manhattan KS 66506 , United States . Fax : + 1 785 532 6653 .sdflemin @ ksu.edu

Obtain 2012 May 17 ; Assume 2012 Jun 9 ; Issue date 2012 Aug .

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Abstract

The humoral innate immune response comprise of multiple components , include the naturally take place antibody ( NAb ) , pentraxins and the complement and impinging cascades . As soluble , plasma constituent , these innate protein supply key elements in the prevention and control of disease . Even so , pathogens and cell with altered self protein utilize multiple humoral components to evade destruction and promote pathogy . Many studies get examined the relationship between humoral immunity and autoimmune disorder . This review focus on the interactions between the humoral element and their purpose in promoting the pathogenesis of bacterial and viral infection and chronic disease such as atherosclerosis and cancer . Understand the beneficial and detrimental aspects of the individual constituent and the interactions between protein which influence the innate and adaptive answer will supply therapeutic target for subsequent studies .

Keywords :Complement , Contact cascade , Pentraxins , Natural antibodies , Cancer , Infection

Highlights

► Humoral innate proteins remove pathogens , apoptotic cell , altered cells and debris . ► Bacteria utilize complement and impinging proteins to evade the immune reply . ► Viruses compromise multiple humoral proteins to circumvent host cell lysis . ► Humoral innate immune proteins aim the progress of atherosclerosis . ► Tumor cells use natural antibodies and contact proteins to get away immunosurveillance .

1 . Introduction

As the first job of defense , the innate immune reply consists of both cellular and humoral element . The cellular component encompasses multiple cell types that employ pattern realization particle to realize and remove pathogens and cellular dust . The interactions of pattern realization molecule within the cellular factor get receive substantial attention in the last two decades . In contrast , less live known about the interactions between the humoral components . The humoral innate immune reply consist of the serine protease cascades of the complement and contact system as good as of course occurring antibody ( NAb ) and pentraxins . Recent data indicate that each element may be beneficial or detrimental during infection or chronic disease depending on concentration and interaction with early components . This review will focus on the interaction and roles of humoral components in bacterial and viral infection as good as the chronic diseases , atherosclerosis and cancer .

2 . Humoral innate immune component

2.1 . Complement

Complement activation occurs by one of three initiation pathways , the classic , alternative , or mannose bind lectin ( MBL ) pathway . Each pathway contains a C3 convertase that split C3 producing C3b and afterwards a C5 convertase . Cleavage of C5 by the C5 convertase results in C5b deposition and initiates the common terminal pathway . The terminal pathway forms the membrane approach complex ( MAC ) , a pore in the cellular membrane , and lysis of the host or pathogenic cell . The action of the C3 and C5 convertases also produces potent anaphylatoxins , C3a and C5 . Although not specifically piece of the humoral immune reception , complement receptor 3 ( CR3 ) base on neutrophils and macrophages enhances the innate immune answer by recognize C3b opsonized pathogens . Late grounds indicates that complement act a important role in directing the adaptive immune reply as good as in tissue regeneration [ 1 ] , [ 2 ] . Specifically , as role of the B cell receptor complex , CR2 realization of cleavage product iC3b , C3dg , and C3d significantly increase Ab product [ 3 ] . Hence , preserve homeostasis call for tight regulation of the cascade . Regulation of this potentially damaging cascade occurs at multiple levels with soluble and membrane limit inhibitors include C1 inhibitor ( C1INH ) , CD55 , CD59 , CD46 , Factor H and related to proteins .

2.2 . Contact cascade

The plasma too contains components of a second proteolytic cascade , the impinging system . Factor XII ( FXII ; Hageman factor ) of the impinging system is proteolytically cling to FXIIa by negatively charged surfaces of damaged cell . FXIIa originate the coagulation cascade conduct to clot formation and cleaves prekallikrein to kallikrein for subsequent release of bradykinin . Through an endothelial G-coupled receptor ( bradykinin receptor 1 ; BKR1 ) , bradykinin induces vasodilation , neutrophil chemotaxis and vascular permeability [ 4 ] . Furthermore , the bradykinin degradation production , des-arg9-bradykinin influence the adaptive response and alters the blood–brain barrier through a second receptor , bradykinin receptor 2 ( BKR2 ) [ 5 ] . Importantly , both FXIIa and kallikrein activate the complement cascade sovereign of known complement initiators [ 6 ] . Several components of the activate contact system including , FXa , FXIa and plasmin , cleave C5 and C3 give rise C5a and C3a [ 7 ] . The complement inhibitor , C1INH , also suppress FXIIa indicate multiple interaction between the two pathways [ 6 ] . These datum hint crosstalk between two cascades of humoral innate immune response .

2.3 . Of course take place antibodies

Raise primarily by B1 B lymphocytes , NAb be germline-encoded Ab with curtail epitope specificity and be produced in the absence of external antigen stimulations . NAb are ordinarily of the IgM isotype but may include IgG and IgA isotypes as good [ 8 ] . Natural IgM Abs middle clearance of cellular debris , aging or apoptotic cells by oponization and recruitment of complement components [ 9 ] . As role of the innate immune response , NAb recognize a wide range of pathogens , albeit with humble affinity and regulate the adaptive immune answer by interacting with B , T and dendritic cells [ 10 ] . Finally , NAb are potent initiators of the complement cascade suggest additional interaction between component of the innate humoral answer .

2.4 . Pentraxins

As a family of evolutionarily conserved multimeric pattern recognition protein , pentraxins cost acute stage protein which equal quickly synthesize and do as mark of infection , inflammation , and tissue damage [ 11 ] . Each pentraxin contain a common land in the C terminus . The presence or absence of additional domains divides the family into long or short pentraxins , respectively . The short pentraxins include C-reactive protein ( CRP ) and serum amyloid P protein ( SAP ) , both of which are give rise by the liver [ 11 ] . Produced by a large number of cell type , pentraxin 3 ( PTX3 ) is the chief long pentraxin fighting in humoral innate immunity . Like to NAb , pentraxins make out and bind multiple pathogens as well as intrinsic ligands , including apoptotic cells and extracellular matrix components [ 12 ] , [ 13 ] , [ 14 ] . Macrophages and early innate immune cell recognize pentraxins , CRP , SAP and PTX3 , via Fcγ receptors [ 15 ] , [ 16 ] , [ 17 ] . Binding of pentraxins to a prey facilitate clearance of pathogens and cell debris by complement activation indicate additional interaction between components of the innate immune response [ 12 ] . Overall , pentraxins are multifunctional and nonredundant components of the humoral innate immune answer . Therefore , pentraxins bring a vital purpose in human disease by interacting with multiple element of the humoral reaction .

Together the interactions of the constituent of the humoral branch of the innate immune reception are critical in protecting the horde from invading pathogens , interacting with the cellular component and instruct the adaptive immune reply . However , inappropriate activation of any one of the humoral element may be detrimental to the host . This review focuses on how infectious organism sidestep these devastate circulating proteins and how chronic disease may equal enhance by the interactions of NAb , pentraxins and the complement and impinging cascades .

3 . Humoral innate immunity and infection

3.1 . Humoral innate immune component interaction with bacteria

A organize approach by multiple components of the humoral innate immune system equal crucial in protecting the horde from bacterial infection . A compromised humoral innate immune system increase susceptibility to bacteria [ 3 ] , [ 18 ] . Successful evolution of therapeutics that decrease bacterial infection necessitate understanding of the interactions between the complement and impinging cascades as well as NAb and pentraxins .

Complement contributes to the humoral innate immune response immediately by the MAC complex forming pores and lysing the bacteria as well as indirectly by activating early portion of the immune system that battle the bacteria . Invade bacteria induce complement activation by all three initiation pathways [ 19 ] , [ 20 ] , [ 21 ] . NAb recognize invade bacteria and set off the classic and MBL complement pathways . The MBL pathway also recognize sugar moieties on the bacterial surface . In addition , the presence of bacterial carbohydrates , lipids and proteins trigger the alternative complement pathway [ 19 ] . Activation of all three pathways solution in C3 cleavage to C3b . C3b coats the bacterial surface , and enhances recognition by neutrophils and macrophages by opsonization . C3b coated bacteria as well tie CR2 to enhance Ab product . Initiation by each of the above pathways may as well leave in bacterial lysis by MAC .

Although the activation of the complement cascade equal essential for immune security , bacteria own evolved respective strategies to evade the immune response . Evasion strategy of bacteria can be broadly classify into four type : a ) recruitment or mimicking of complement regulators ; b ) inhibition or modulation of complement protein ; 100 ) enzymatic degradation of complement protein ; and d ) blockage of MAC penetration [ 22 ] . For model ,Enterococcus faecalisandStreptococcus pyogenes, as Gram positivist bacteria , equal endow with a thick polysaccharide capsule that forestall all over penetration of the capsule and cell wall by the MAC and subsequent bacterial lysis [ 23 ] .

Many bacteria evade complement by recruit complement regulatory protein to the bacterial surface to prevent lysis . Specific examples are supply in Table 1 . Various important pathogens includeS. pyogenes,Streptococcus pneumonia,Neisseria gonorroheaeandBorrelia burgdorferiproduce protein which recruit Factor H of the alternative pathway and/or C4bBP of the classic and lectin pathways [ 24 ] , [ 25 ] , [ 26 ] , [ 27 ] . Other bacteria produce proteins that directly interact and inhibit central complement element . For lesson , theS. pneumoniaeprotein , PspA , conquer C3b deposition on the pneumococcal surface [ 28 ] . Similarly , early bacterial proteins immediately suppress C3 convertase [ 29 ] , [ 30 ] or MAC formation [ 31 ] . Additional bacterial enzyme degrade vital complement element including the anaphylatoxins , C3a and C5a . This forestall chemotaxis of phagocytic cell towards the site of infection .E. faecalis, a take nosocomial pathogen , produce gelatinase , an enzyme that at once cleaves C5a , preventing neutrophil recruitment to the site of infection [ 32 ] . Due to incomplete complement activation , each of the above mechanisms frequently allow bacterial proliferation and deleterious impression on the host . A better apprehension of the bacterial protein that suppress complement activation may run to therapeutics that as well curtail extravagant complement activation .

Table 1 .

Complement evasion protein enroll by different bacterial species to keep complement‐mediated lysis .

Although the contact cascade may activate complement for bacterial lysis , contact activation directly on the surface of bacteria as well eliminates invading bacteria in a complement sovereign style . Bacterial activation of the contact system releases kinin which in number lead to the production of potent anti-microbial peptides and enrol early immune components to the site of infection [ 33 ] , [ 34 ] . Despite activation of the immune answer , kinin release and subsequent vasodilation may favor the bacteria due to an influx of plasma nutrients to the site of infection and increase microcirculation of bacteria [ 34 ] . A massive activation of the contact system also make extravagant consumption of thrombin which effect in hypovolemic shock and sepsis-induced coagulation [ 35 ] . Bacteria lead up the impinging cascade and induce kinin release by a ) producing protease to degrade kininogens ; b ) activating FXII ; or c ) using structural element and surface proteins that spark the contact cascade [ 36 ] , [ 37 ] , [ 38 ] . Various pathogens , includingPorphyromonas gingivalis[ 39 ] ,Staphylococcus aureus[ 5 ] andS. pyogenes[ 40 ] , make proteins that degrade kininogens to kinins , with or without the release of bradykinin . As expected , the extra kinin release outcome in an array of pathological complication for the horde .

Other bacteria produce proteases which spark FXII to produce kinin . For example , alkaline proteinase and elastase produced byPseudomonasspp. , Vibrio protease produced byVibrio vulnificus, and V8 proteinase produce byS. aureusall touch off FXII [ 41 ] . Many structural element on bacterial surface including lipopolysaccharide of Gram negative bacteria and lipoteichoic of Gram positivist bacteria activate the impinging system [ 38 ] . Surface protein of pathogens such as M protein ofS. pyogenesand curli fibers ofEscherichia coliandSalmonella typhiialso bind to contact system components and lead up the release of bradykinin . Late grounds indicate that patients with severe sepsis have abnormally high levels of kinins [ 42 ] which growth construction of bradykinin receptors BKR1 and BKR2 [ 43 ] . Binding of bradykinin to these receptors causes a massive pro-inflammatory response which is much detrimental to the host .

As key participants in the humoral innate immune response , NAb specific for pathogenic bacteria exist in the serum of uninfected individuals and play a critical part in the early clearance of invading bacteria by set off complement . Saliva contains secretory-IgA which make out and clearsS. pyogenes[ 44 ] . Others demonstrate that NAb titer increase with bacterial load duringPseudomonasspp . infections , correlate with bacterial elimination [ 45 ] .N. gonorrhoeaeinduces NAb ( IgM , IgG and IgA isotypes ) which recognize the heat-stable but not the heat-labile bacterial antigens [ 46 ] . In contrast , after immunization , Ab recognize both heat-stable and heat-labile antigen .

Many NAb recognize commensals including the enterics ,E. coliandSalmonella typhosa. The presence of NAb prevents the overgrowth of enterics and the gut microbiota [ 47 ] . Similarly , NAb mediate security against the respiratory pathogen ,S. pneumonia. As early respiratory tract colonizers of infants , pneumococcal antigen may excite the production of these Ab [ 48 ] . NAb not simply go on commensals in check but as well play a crucial role in preventing dissemination of intracellular bacteria . For case , NAb enhance antigen-trapping ofListeria monocytogenesin secondary lymphoid organs [ 10 ] .

Although NAb are extremely efficient in initiating an early response against invading bacteria , report as early as 1972 indicated that NAb concentration decrease with severity of bacterial sepsis [ 49 ] . Late in sepsis , when the bacterial load transcend a specific doorway , the plasma NAb concentrations plummet due to the big number of antigen-Ab complex [ 49 ] . Together , the complexes and bacterial endotoxin increase the permeability of the capillaries , allowing the reticuloendothelial system to rapidly earn the Ab complex .

As clinical biomarkers of infection , the concentration of CRP , PTX3 and other pentraxins increase within 6–12 h post infection [ 50 ] . The increased levels come out to exist produced by human monocytes , macrophages and dendritic cell in response to whole bacteria or bacterial cell wall components . For instance ,Pseudomonas aeruginosaandMycobacterium bovisBacille Calmette–Guerin stimulate product of PTX3 [ 51 ] , [ 52 ] . In increase , mycobacterial cell wall component lipoarabinomannan and lipopolysaccharide stimulate PTX3 formula in human peripheral mononuclear cell [ 52 ] , [ 53 ] . In contrast , CRP , develop in answer toNeisseria meningitides, opsonizes the bacteria for enhanced phagocytosis by macrophages [ 54 ] . Recent studies demonstrate that C1q recognizes pentraxins bound to pathogen surface and direct the bacteria for destruction [ 55 ] , [ 56 ] . Other pentraxin–bacterial interactions may also survive . Thus , additional subject examining the complex interactions between bacteria and pentraxins will enhance our understanding of host-bacteria interaction .

Together the element of the humoral innate immune system bring an indispensible purpose in the removal of bacteria from a host . NAb , the contact system and pentraxins help in eliminate bacteria and activate the complement system which lyses additional bacteria . Even so , bacteria receive evolved various flight mechanism which may be used against the host . In increase , bacterial complement inhibitors may be used for treatment of diseases call for extravagant complement activation . Understanding this complex interaction between the bacteria and humoral innate immune response exist essential in designing effective therapeutic intervention against bacterial infection .

3.2 . Humoral innate immune component interactions with virus

As a component of humoral immunity and a mediator between the innate and adaptive immune reaction , complement can directly neutralize viruses and regulate pathogen elimination ( Fig . 1 ) . MBL straight binds multiple viral glycoproteins including those of HIV , SARS coronavirus , and Marburg virus [ 57 ] , [ 58 ] , [ 59 ] . Additionally , C3-coated glycoproteins bind CR1 and enhance the humoral immune reception [ 60 ] , [ 61 ] . In a similar fashion , CR2 recognizes C3 cleavage merchandise iC3b , C3dg and C3d to let down the doorway of B cell activation [ 62 ] . Importantly , C1q , C3 , C4 and CR1 and CR2 contribute to the normal antiviral IgM or IgG responses and regulate humoral immunity indicate a crucial use for complement activation in the immune response to virus [ 10 ] , [ 63 ] .

Figure 1 .

Schematic representation of the interaction between the three pathways of the complement cascade and viruses . Complement remove virions and initiates the adaptive reception to take out virally-infected cell . Virus also suppress complement at C1q and C3 .

Virus employ unlike mechanisms to anticipate and interrupt the cautiously regulated complement cascade of enzyme , protein complex and receptors . Virus sidestep the host immune response by a ) modifying C1q or C3 ; b ) get in host cell ; or c ) using horde or virally raise complement inhibitors to forestall cell lysis . Viral proteins directly interact with the components of the complement cascade to disrupt complement-mediated destruction . C1q and C3 live frequent targets of the viral proteins . For example , the coat protein of human astrovirus type 1 binds C1q , displaces the C1r/C1s tetramer and conquer the activation of the classic complement pathway [ 64 ] . Similarly , the matrix ( M1 ) protein of influenza A virus bind C1q but this viral protein bar the interaction between C1q and IgG [ 65 ] . Many other viruses modulate C3 as a central component of the complement cascade . West Nile virus synthesize two isoforms of NS1 protein to regulate C3 . Soluble NS1 increases Factor I-mediated cleavage of C3b to iC3b while the cell surface-bound NS1 lessen deposition of C3b and MAC [ 66 ] . Herpes virus synthesizes trans-membrane glycoprotein gC1 and gC2 , which bind C3b and specifically quicken the decay of the alternative C3 convertase and inhibit the interaction of C3b with C5 and properdin [ 67 ] , [ 68 ] . Together these subject suggest that virus interact with multiple complement components to prevent complement-mediated horde cell end .

Virus also modulate the regulators of complement activation by encoding viral protein with structural and operational homology to host proteins or by recruit host complement regulatory protein to the virion . For example , gamma-herpes virus 68 induces formula of a complement inhibitory protein on the cell surface which may be detected in supernatants of infected cells . In vitro studies demonstrated that the viral inhibitory protein block C3 deposition by both the classical and alternative activation pathways [ 69 ] . Kaposi ‘s sarcoma-associated herpes virus , herpes virus saimiri , variola virus , vaccinia virus , monkeypox virus and ectromelia virus also encode regulators of the complement cascade which bind C3b or C4b and pulley activity [ 70 ] , [ 71 ] , [ 72 ] , [ 73 ] , [ 74 ] , [ 75 ] , [ 76 ] , [ 77 ] . Other viruses enter host complement regulatory proteins to virions to evade complement-mediated destruction . Human immunodeficiency virus-1 ( HIV-1 ) , human T-lymphotropic virus-1 ( HTLV-1 ) and human cytomegalovirus ( HCMV ) incorporate the complement control proteins CD55 and CD59 into their virions to sidestep the complement answer [ 78 ] , [ 79 ] . Thus , complement inhibitors , either from the horde or virally synthesized , protect the septic cell from lysis and allow virus proliferation .

Viruses induce complement action for their own benefit . HIV enters human CD4⁺T cells through complement receptors . HIV gp41 and gp120 protein set off complement through the classic and lectin pathways , respectively . At the same time , the above two proteins conquer MAC formation by recruit Factor H and CD59 to the surface of the virally-infected horde cell to abolish complement-mediated lysis [ 80 ] . Therefore , complement aids in viral entry but the virus prevents cell lysis by inhibit the remainder of the complement cascade .

Complement activation during viral infection frequently causes endothelial cell damage and activation of the contact cascade . Recent studies depict that herpes simplex virus ( HSV ) , HCMV , and Hanta virus enhance thrombin formation and fibrinolysis [ 81 ] , [ 82 ] . The HSV glycoprotein binds Factor X to make the generation of thrombin [ 83 ] . HSV infection also lessen endothelial heparin sulfate proteoglycan ( HSPG ) that recruits and bind anti-thrombin III [ 84 ] . Other viruses , including Dengue virus and HIV , are also associated with decreased thrombin generation [ 85 ] . Dengue virus produces the nonstructural protein , NS1 , that binds and inhibits prothrombin activation [ 86 ] .

Virus are able to modulate cytokine expression to induce a pro-coagulant state . Mediated by IL-1 , TNFα , and IL-6 , Marburg virus , Ebola virus and Hanta virus induce tissue component expression on the endothelial surface [ 87 ] , [ 88 ] . Viruses also take advantage of coagulation component to enhance viral binding and replication . Human species A adenovirus-18 ( HAdV-18 ) and 31 ( HAdV-31 ) bind coagulation Factor IX to facilitate virus entry and infection . HAdV-5 and early human adenoviruses utilize coagulation Factor X for the infection of horde cells [ 89 ] . Sindbis viruses up-regulate the expression of BKR2 receptors on endothelial cells , and subsequently enhance viral replication by reducing Sindbis virus-induced apoptosis in a BKR2 dependent manner [ 90 ] . Hence , virus too regulate the impinging cascade and thrombin action to encourage viral infection .

The broad reactivity of individual NAb allows rapid realization and security from pathogens never run into before . By bridging the innate and adaptive immune reception , NAb facilitate antigen uptake , processing and presentation by B cell . For instance , serum from naïve mouse contain IgM NAb specific for lymphocytic choriomeningitis virus , vaccinia virus and two Vesicular stomatitis virus serotypes , VSV-New Jersey and VSV-Indiana [ 91 ] . In increase , NAb bind viruses at an early phase of infection to prevent viral dissemination to vital target organ . Furthermore , NAb present in IVIg bind CCR5 to inhibit CCR5-tropic HIV infection in macrophages and lymphocytes .

The comparatively humble stage and special specificity of NAb exist not sufficient to furnish complete immune protection . They also express limited neutralization , opsonization and complement binding power compared to specific Ab of the adaptive response . Early in influenza virus infection , NAb bind to the hemagglutinin molecules of influenza A and B , knock off the viruses and allow for initial security before the emergence of antigen-induced Ab produced by the adaptive reaction [ 92 ] , [ 93 ] , [ 94 ] . High titers of influenza virus occur in the lungs of mouse which do not secrete IgM , and in the absence of soluble IgM NAb , the survival rate decreases significantly compare to wildtype mice [ 95 ] . The broad spectrum of NAb reactivity permit pre-infection sera to tie up at least 12 influenza A and B strains . However , the level of influenza specific NAb make not increase as the disease work up . These data demonstrate that NAb are discrete from antigen-induced Ab . NAb as well inhibit CCR5-tropic HIV infection . IVIg contains anti-CCR5 Ab which inhibit HIV-1 infection of human macrophages and CD4⁺T cells by CCR5-tropic but not CXCR4-tropic HIV-1 . IVIg also check NAb directed against multiple other cell surface molecule , including CD4 , CD5 , adhesion theme and CD95 [ 96 ] . These data indicate that NAb are an important role of the innate humoral immune response to virus .

Pentraxins exist a superfamily of multimeric protein that responds to a variety of inflammatory stimuli to set off complement and prevent infection . As report earlier , the classic short pentraxins , CRP and SAP , equal generally accepted as indicators of infection . But similar to bacteria , the prototypic long pentraxin PTX3 quickly increases in response to viral infection . As a in effect protein mark of dengue virus infection than CRP [ 97 ] , PTX3 also demonstrate antiviral affair in human or murine cytomegalovirus ( HCMV or MCMV ) and influenza virus . In these studies , PTX3 tie up virus and inhibits viral-cell fusion and internalization [ 98 ] . In influenza infection , sialylated ligands on PTX3 mimic the structure of the cellular receptors and tie up the viral hemagglutinin glycoprotein and bar the receptor-binding site of hemagglutinin [ 99 ] . Thus , pentraxins recognize and bind viral antigens to originate the humoral innate immune reaction . However , the specific use of pentraxins in viral infection has not cost good studied .

As part of humoral innate immunity , complement , contact system , NAb and pentraxins work together to train elaborate network of cascades in response to viral infection . These networks crosstalk with each early to recognize and get rid of invading viruses . However , virus apply numerous strategies to evade the immune response by compromising multiple proteins of the innate reaction simultaneously . Further effort should study the signal pathways that modulate each component . Due to the complex interactions between components of the humoral reception , next field may need to study the virus/host interaction together and not as individual element . Comprehensive inquiry on antiviral mechanism of the horde and viral evasion mechanisms will provide insight into pathogenesis and novel discussion options .

4 . Humoral innate immunity in chronic disease

4.1 . Humoral innate immunity in atherosclerosis

Although the humoral innate immune response live critical in preventing bacterial and viral infections , the same components are frequently pathogenic in chronic disease . For instance , complement plays a key role in the pathogenesis of atherosclerosis . Compared to non-atherosclerotic artery , fibrous plaques up‐regulate transcripts of the classical complement cascade proteins [ 100 ] . Additionally , deposition of classical complement proteins , include C1q , C3 , C4 and MAC occurs in atherosclerosis [ 101 ] . The alternative complement pathway cost also implicated in plaque evolution or atherogenesis . For example , plasma from mouse with high-fat diet-induced atherosclerotic lesions hold back elevated C3 , properdin and element D levels [ 102 ] . Endotoxin- and diet-induced atherosclerosis in LDL receptor-deficient mice also require the alternative pathway , component B [ 103 ] . Importantly , C6 deficiency protects against diet-induced atherosclerosis , suggest that the terminal complement pathway is call for in progression of atherosclerotic lesions [ 104 ] . Indeed , MAC deposition correlates with the severity of arterial damage in human aortic fibrous plaque [ 105 ] and in mouse , MAC deposition promotes endothelial price [ 106 ] . Endothelial MAC deposition too forego monocyte infiltration and foam cell formation in a rabbit model of atherosclerosis [ 104 ] . Together , the data point that multiple complement pathways of activation increase the hazard of atherosclerosis .

Complement regulatory proteins such as CD59 maintain the rest of complement activation and inhibition . Lewis et al . [ 107 ] feel that MAC contributed to atherogenesis in apolipoprotein E^−/−mouse and CD59 deficiency exacerbated the disease . Likewise , Wu et al . demonstrated that the loss of CD59 accelerate atherosclerosis while endothelial CD59 overexpression attenuated endothelial price . Finally , CD59 deficiency accelerate wound evolution and increased plaque vascular still muscle cell composition in an atherosclerotic mouse model [ 108 ] . Hence , CD59 and possibly early complement inhibitors maintain homeostasis .

Although NAb set off complement , these Ab as well aid in the clearance of pro-atherogenic dust ( Fig . 2 ) . NAb make out pro-inflammatory , oxidation-specific epitopes associate with oxidative tension , apoptosis and atherosclerosis [ 109 ] . Recently , Chang et al . [ 110 ] reported that the oxidized phospholipid specific , NAb clone , T15/E06 attenuated endothelial activation and subsequent atherogenesis . Other in vitro field suggest that IgM NAb recognized malondialdehyde , malondialdehyde low density lipoprotein ( LDL ) and oxidized LDL . The realization of oxidized LDL prevent macrophage intake , inhibited foam cell formation and atherogenesis [ 109 ] , [ 111 ] , [ 112 ] . Still , under other conditions such as myocardial infarction , NAb are pathological . Equate to wildtype mice , Ab deficient mice experience significantly less tissue damage in reply to myocardial infarction . Importantly , administering a single NAb clone restores tissue damage and inflammation to the Ab deficient mouse [ 113 ] , [ 114 ] . In addition , peptide inhibition of the NAb binding attenuates myocardial infarction induced injury in wildtype mouse [ 113 ] . NAb play a key purpose in the intonation of atherosclerosis by bring in apoptotic cell and oxidized structures ; however , extravagant complement activation in response to NAb binding may be detrimental and cause pathology .

Flesh 2 .

Role of humoral innate immunity in atherosclerosis . Pentraxins interact with oxidized LDL ( oxLDL ) or enzymatically modify LDL ( eLDL ) facilitating foam cell formation . Complement facilitate macrophage extravasation and foam cell formation that release proinflammatory factors and enhance atherosclerosis . NAb may realize and prevent foam cell formation . Taken together , the humoral innate immune reception regulate atherosclerosis .

Complement has an intimate relationship with the contact system , propose that many coagulation factors also run key roles in the evolution of atherosclerosis [ 6 ] . Increase cardiovascular disease risk and atherosclerotic vascular damage live associated with elevated levels of Factor XII , prekallikrein , high molecular weight kininogen and Factor XI [ 115 ] , [ 116 ] . In increase , Factor XII^−/−mice live protect from arterial thrombosis and stroke indicate an activation of the contact system [ 117 ] . However , the specific crosstalk between the contact and complement systems in atherosclerosis is still poorly understood and should be addressed in next investigations .

It is good lay down that pentraxins activate the complement cascade in atherosclerosis [ 118 ] . Recent research demonstrates pentraxins may have a direct role in cause atherosclerosis ( Fig. 2 ) . Pentraxins sediment in the atherosclerotic plaques where they interact with enzymatically modified or oxidized lipoproteins , promote foam cell formation , induce endothelial cell dysfunction and exacerbate atherosclerosis [ 12 ] .

Although controversial , CRP appear to play a use in atherosclerosis . Detectable in the arterial wall in the early stage of atherogenesis , CRP remain to collect with disease progression [ 100 ] . By inhibiting endothelial production of nitric oxide , CRP impair vasodilation and angiogenesis [ 119 ] and facilitates endothelial cell apoptosis , leading to atherosclerotic wound formation . In increase , by increasing the expression and activity of endothelial cell plasminogen activator inhibitor-1 ( PAI-1 ) , a fibrinolysis inhibitor , CRP potentially contribute to plaque instability and atherothrombosis [ 120 ] . CRP also enhance endothelial cell adhesion molecules [ 121 ] , superoxide product [ 122 ] and advance monocyte recruitment into the plaque [ 12 ] , all of which may contribute to atherogenesis . CRP as well binds to enzymatically change or oxidized LDL ; however , the beneficial nature of this binding remains controversial in the clinical setting [ 123 ] , [ 124 ] . A meta-analysis of a big multi-nation statin trial get that increase CRP levels identified alone a limited population at hazard with no clinical outcomes [ 125 ] . Hence , additional clinical studies are required prior to increase CRP screening of the population .

Like to NAb , CRP get also exist implicated in myocardial infarction in a complement-dependent way . Early field suggest that CRP trigger C1q of the classical complement pathway and that monomeric CRP binds the alternative complement pathway inhibitor , factor H ( review in [ 126 ] ) . Additional report find CRP colocalized with C1q and C3 within the ischemic tissue stick to myocardial infarction [ 127 ] . Late report suggest that monomeric CRP on necrotic cell surfaces binds both C1q and the classic pathway inhibitor C4bp to order the removal of injured cells in the absence of substantial inflammation [ 128 ] . Hence , CRP come out to enhance opsonization without the subsequent inflammatory response .

Additional pentraxins too play a role in atherosclerosis . SAP live as well detected in human atherosclerotic wound [ 129 ] . By tie up amyloid-β ( Aβ ) and serum amyloid constituent A ( SAA ) , SAP mediates the inflammatory reception to amyloid fibrils in atherosclerosis [ 130 ] . In contrast , SAP binds and prevent the intake of oxLDL by macrophages , possibly dilute foam cell formation [ 131 ] . Similar to CRP and SAP , elevate reflection of PTX3 precedes atherosclerotic lesion development [ 132 ] and correlates with sharp myocardial infarction [ 133 ] . PTX3 increase tissue component reflection in endothelial cell , potentially induce atherothrombosis [ 134 ] . Together , these results indicate a causal role of pentraxins in atherogenesis , suggesting that they may be effective therapeutic object for atherosclerosis .

In conclusion , the pathology of atherosclerosis is a complex , multi-factorial procedure involving lipid deposition , vessel wall dysfunction , excitement and autoimmunity . The humoral innate immune constituent meet a pivotal office in the progression of this chronic disease . Activation of each component may drive atherogenesis ; whereas NAb may also protect against atherosclerosis by binding to oxidation-specific epitopes . It should be remark that these components cause not behave independently but interact with each early , collectively regulate the disease progress . Further inquiry is warrant to probe the integrated role of these humoral innate immune components in atherosclerosis . Such insights may yield a novel apprehension of the mechanisms underlying this disease and tip to new therapeutic approaches to attenuate the progression of atherosclerosis .

4.2 . Cancer and humoral innate immune reaction

Complement merchandise such as C1q , C3 , C3a , C4 , C5 and the MAC exist detectable in the tumor microenvironment [ 135 ] . These activated complement proteins get three mechanisms for complement-mediated destruction of tumor cells : a ) complement-dependent cytotoxicity ( CDC ) [ 136 ] , b ) indirect Ab-dependent , cell-mediated cytotoxicity [ 137 ] , which can be complement receptor-dependent and 100 ) CR3-dependent cellular cytotoxicity ( CR3-DCC ) [ 138 ] , which is relatively rare with tumors . Complement portion are deposited in various tumor type , indicating that activation of complement may contribute to immunosurveillance of malignant cell . Complement proteins C5b-9 be deposited on the cellular surface of breast cancer cells and papillary thyroid carcinoma cell [ 139 ] , [ 140 ] . Complement activation products , such as C1q and C3 cleavage products equal detectable in ovarian carcinoma patients [ 141 ] . Complement is trigger and deposit in neoplastic tissue , but the operational implication cost unclear .

Tumor cell cost resistant to complement‐mediated approach [ 142 ] . Tumor cells hold natural mechanisms for self-protection against the complement system , specifically MAC and the cytotoxic activation of CR3 . Extracellular protectors such as membrane and soluble complement inhibitors are released by tumor cell into the microenvironment and intervene with complement cascade activation and limit the amount of complement deposition [ 143 ] , [ 144 ] . Membrane complement inhibitors , include CD35 ( CR1 ) , CD46 ( MCP ) and CD55 ( DAF ) operate the activation of complement at the story of C3 . These suffice as an crucial mechanism of self-protection , making the cell insensitive to the activity of complement .

Although the complement system influence excitement and the innate immune reception , complement proteins also aid in tumor increase and immunosuppression . For example , C3^−/−or C4^−/−mouse display a important decrease in tumor proliferation compare to wildtype mouse [ 145 ] . These result may be linked to the anaphylatoxins , C3a and C5a , which take part in respective signal transduction pathways connect to tumorigenesis ( Fig . 3 ) . The binding of C3a and C5a to their receptors increases IL-6 , which induces transcriptional changes in cell bicycle progression and inhibits apoptosis [ 146 ] , [ 147 ] . Specifically , C3a receptor ( C3aR ) and C5a receptor ( C5aR ) activate MAPK , ERK , phosphatidylinosityol 3-kinase and Akt [ 148 ] , [ 149 ] . Each of these signal transduction pathways may mediate oncogenic transformation and progress . Similar pathways may as well be activated by the MAC to get cellular proliferation [ 139 ] , [ 150 ] , [ 151 ] . Thus , complement protein elevate tumor increase through the upregulation of signaling particle for cellular proliferation and by preventing apoptosis of neoplastic cells .

Fig 3 .

Neoplastic cells exploit the humoral immune system by various mechanisms . The schematic diagram shows a variety of mechanisms tumor cell utilize to evade humoral immunity , determine antibody effector mechanisms , and modulating leukocyte occasion in the microenvironment . TF , CD176 ; MDSC , myeloid-derived suppressor cell ; MФ , macrophage .

Complement anaphylatoxins may change cellular differentiation result in immune suppression . In sound individuals , myeloid-derived suppressor ( MDS ) cells differentiate to macrophages , dendritic cells and neutrophil [ 152 ] , [ 153 ] . Still , when trapped in the intermediate stage of differentiation , MDS cells may mediate tumor-induced immune suppression [ 152 ] , [ 153 ] . Tumor secreted factors cause pro-inflammatory mediators such as C5a , which recruit C5aR⁺MDS to the tumor cells and cut off normal differentiation of MDS cell ( Fig . 3 ) [ 145 ] . Binding of C5a to C5aR on MDS growth reactive oxygen and nitrogen species that contribute to cell-mediated immunosuppression [ 145 ] . These complement stimulate MDS cells also forestall the activation of CD4+ and CD8+ T cell , inhibit Natural Killer cell cytotoxicity , stimulate cytokine production for tumorigenesis and increase angiogenesis [ 154 ] , [ 155 ] . The complement system proteins such as C5a provide inflammatory protection in the tumor microenvironment .

Tumor-associated antigens are know to regulate trans‐membrane signaling that is demand for proliferation , invasion and metastasis of tumor cells . The presence of NAb against tumor-associated antigens , such as gangliosides of melanoma cell , correlate with increased patient survival [ 156 ] . Tumor-reactive Ab exist in healthy wildtype beast ancestry samples ( IgM ) and peripheral blood concentrations of NAb increase shortly after initial tumor evolution and prior to detection of circulating antigen [ 157 ] , [ 158 ] , [ 159 ] . NAb may get a direct cytotoxic result on tumor cells , while also stimulate a bystander effect during a humoral anti-tumor response . Thus , NAb recognize tumor-modified cell surfaces that develop during tumorigenesis and activate complement to destroy nascently transformed cells .

Tumor cells are able to employ NAb to escape immunosurveillance . Neoplastic transformation alter the reflection of a form of cell surface glycoproteins . An case of this be the Thomsen-Friedenreich antigen ( CD176 ) , a disaccharide ( Gal beta 1–3 GalNAc alpha ) with truncated glycosylations that is expressed at elevated levels on the surface of cancer cells [ 160 ] . An abnormal anti-CD176 titer correlates with main carcinomas [ 161 ] . B1a cell grow NAb against CD176 , as a form of immunosurveillance against CD176+ cancer cells [ 162 ] . Anti-CD176 NAb induce apoptosis in surface CD176+ cell [ 162 ] . Tumor cell get away Ab-dependent cytotoxicity by let go of soluble CD176 to tie up NAb and protect the tumor cell from apoptosis [ 161 ] , [ 163 ] . Although expression of CD176 exist crucial for recognition of cancer cell , soluble CD176 , release by tumor cell , prevents Ab dependent elimination . Tumor cell employ the innate immune system and NAb to avoid immunosurveillance and elimination .

NAb are important for the recognition and elimination of precancerous and cancerous cells [ 164 ] , [ 165 ] , [ 166 ] , [ 167 ] , [ 168 ] . Such tumor-reactive NAb live expressed in multiple tumor type , including melanoma [ 169 ] , lung [ 170 ] , breast [ 171 ] , top dog and neck [ 172 ] and ovarian cancer [ 173 ] , [ 174 ] . As an lesson , the human monoclonal IgM Ab SAM-6 , which was isolated from a gastric cancer patient , reacted with malignant tissue and induced the collection of intracellular lipids , cholesteryl ester and triglycerides [ 175 ] , [ 176 ] . The humoral innate immune response and NAb specifically hold an important purpose in the recognition and elimination of neoplastic cell .

NAb can be generate from tumor surface antigens . The auto-Ab produced by a patient ‘s torso in answer to cancer cell formation can live utilized to detect the presence of cancer and to differentiate benign and malignant tumor [ 177 ] . Cell surface glycans that are secreted into the serum by malignant cell leave a mechanism to track tumor burden . Many malignant cell , but not normal cells , overexpress CD20 , ECFR and HER2 allowing these proteins to be commonly utilize as diagnostic mark . These antigen also supply therapeutic targets for product of tumor antigen-specific monoclonal Ab .

Human cancers are known to raise extracellular proteolytic enzyme demand for invasion and dissemination . Tumor that release these proteolytic enzymes breakdown the cellar membrane and extracellular matrix ( ECM ) to facilitate cancer cell invasion into the surround normal tissue [ 178 ] , [ 179 ] . By influence production of ECM protease , plasminogen activator ( PA ) be suggested to run a office in this process [ 178 ] , [ 180 ] . The primary PA analyze in relative to cancer metastasis is the urokinase-type ( u-PA ) which generate plasmin for the degradation of ECM [ 181 ] . Compared to the normal or benign tissue , malignant tumors produce elevated levels of u-PA [ 182 ] . U-PA and/or the receptor , U-PAR be prognostic markers in human malignancies , including breast cancer [ 183 ] , lung cancer [ 184 ] , [ 185 ] , bladder cancer [ 186 ] , bone marrow [ 187 ] stomach cancer [ 188 ] , colorectal [ 189 ] and cervical cancer [ 190 ] . The binding of u-PA to its receptor u-PAR appears to be necessary for cancer metastasis [ 191 ] , [ 192 ] . As a element of the impinging system , u-PA and u-PAR floor correlate with poor prognosis and both are required for successful invasion and metastasis .

The u-PA/plasmin system exist too involved in early cellular processes in tumorigenesis , including the release of growth component . As an lesson , the binding of u-PA to u-PAR generates plasmin for the activation of the latent shape of TGF-β , which influence early cellular office , including PAI-1 [ 193 ] , [ 194 ] . The migration and invasion of cancer cell expect change in cadherin and integrin formula and binding which run to revision in the formula of u-PA , u-PAR and PAI-1 [ 195 ] . For example , cancer cell separation requires a down-regulation of E-cadherin reflection [ 196 ] , which increases expression of u-PA and invasiveness in vitro [ 197 ] .

Plasminogen activators ultimately activate prekallikrein and kallikrein to generate bradykinin . Bradykinin and hydroxypropyl- ( Hyp ) bradykinin equal get up in the ancestry plasma , peritoneal and pleural fluid of cancer patients [ 198 ] , [ 199 ] . Bradykinin exist the most potent permeability element and pain inducer produce in the tumor microvasculature . The elevation in bradykinin mediates the enhanced vascular permeability which allows cell invasion in cancer patients [ 200 ] , [ 201 ] . BKR2 is too upregulated in human and rodent cancer tissue [ 90 ] . The kallikrein cascade is also implicated in tumor formation . Matsumura et al . [ 202 ] showed that the continual generation of kinins stimulate proliferation of tumor cells through mitogenic activity and promoted diapedesis to enhance tumor cell metastasis [ 202 ] . Together , these datum point that the impinging system supports cell migration and invasion through multiple interactions with u-PA , u-PAR , PAI-1 , kallikrein , kinins , ECM proteins , integrins , receptors , and growing factors that reserve reorganization of the tumor microenvironment .

As a short pentraxin family member , CRP is synthesize by the liver in response to stimulus by IL-6 and IL-1 [ 203 ] , [ 204 ] . Increase levels of CRP are observed in cancer patients [ 205 ] , [ 206 ] , [ 207 ] . As an lesson , CRP was describe to be get up in 87 % of metastatic breast cancer patient [ 208 ] . Many cancer patient also hold elevated IL-1 and IL-6 level [ 209 ] , [ 210 ] , [ 211 ] , which stimulates CRP product . PTX3 live a serum biomarker of multiple human carcinomas due to its overexpression in cancerous tissue , include gentle tissue liposarcomas and lung carcinoma [ 212 ] , [ 213 ] . Breast cancer cell lines that overexpress PTX3 receive activate anti-fibroblast growing element 2 and a reduction in angiogenesis in vitro and in vivo [ 214 ] .

Experimental and clinical data indicate that the humoral innate immune responses start significant pro-tumor effects on the developing neoplasia . Humoral innate immune responses aggravate recruitment and trigger immune cells in the tumor microenvironment . They order tissue remodeling , pro-angiogenic and pro-survival pathways that potentiate cancer formation . Thus , the innate immune system is an important regulator of cancer development .

5 . Conclusions

The humoral immune system plays a office in the initiation and regulation of the inflammatory reaction and elimination of pathogens . Derived from many humble plasma proteins , component of the innate humoral immune reply disrupt the object cell ‘s plasma membrane and cause cytolysis . Together , the humoral and cellular immune reaction insure bacterial and viral replication and get rid of infected and change cell . Even so , pathogens have evolved strategies to counter and sidestep the immune reaction . In increase , the humoral innate reply may be exploit by uncontrolled proliferative cancer cells and atherosclerotic wound result in continued expansion despite the humoral immune reception . Recognizing the strategy use by pathogens and change cell allow a better understanding of the pathological interactions between cell ( infected or altered ) and the host .

A wide spectrum of humoral constituent actively play a role in disease and we present conclusive grounds that the humoral immune system modifies the grade of disease to enhance pathogenesis . Understand the relationship between pathogenesis and humoral immune element will enhance the probability of targeted therapeutic treatment and patient survival . Further inquiry be take to determine the mechanism of activity and interactions of multiple element of humoral immunity , as good as their purpose in the pathogenesis of infection , neoplasia , and atherosclerosis .

Fight of interest

Acknowledgments

This study exist defend by grant from Kansas Bioscience Authority , KBA-CBRI 611310 ( ZL ) , Johnson Center for Basic Cancer Research ( SDF ) and NIH grant : AI061691 ( SDF ) , 1R15CA152922 ( SNS ) . AI077782 ( SV ) as good as P20 RR017686 ( SDF ) , and P20 RR016475 ( SDF ) from the Institutional Development Award Program of the National Center for Research Resources .

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