Complement

ComplementHeat-labile series of 18 plasma proteins, many of which are enzymes or proteinasesMajor fraction of beta-1 and beta-2 globulins

Named with capital C and followed by a number (Ex. C1, C2)

Small letter after the number indicates that the protein is a smaller protein resulting from the cleavage of a larger precursor by a protease.

The larger is designated b and the smaller is a except for C2 where the larger fragment is designated a and the smaller is b.

Ex. C3a-smallerC3b-larger

C2a-largerC2b-smaller

Site : serum and all tissue fluids except urine and CSF

Synthesis : in liver appear in fetal circulation during 1st 13 W Function : Responsible for certain aspects of immune response and inflammatory response

Activation : antigen-antibody complex or endotoxin, capsule, series of proteins activated sequentially

Inactivation: inhibitors in plasma (short lived)

Biological effects: either beneficial or harmful to host

Activation of ComplementNormally, complements are present in inactive form.There are control proteins that inhibit uncontrolled complement activation:C1 INHFactor IFactor HC4-binding protein

Effects of complement activationPhysiologic consequences include:Blood vessel dilationIncreased vascular permeability

Cellular consequences include:Cytolysis/hemolysisOpsonizationCell activation, such as production of inflammatory mediators

Cytolysis: activated complement proteins polymerize on cell surfaces of bacteria or erythrocyte to form pores in its membrane (killing by osmotic lysis)

Opsonization:

binding of complement proteins opsonin (C3b) to surfaces of foreign organisms or particles

Phagocytic cells express specific receptors for opsonins, so promote phagocytosis

Inflammatory response : Small fragments released during complement activation have several inflammatory actions: a) C5a is chemotactic and attract neutrophiles and macrophages b) C5a activate phagocytes and neutrophils C) C3,C4 and C5 are anaphylatoxins Cause degranulation of mast cells and release of histamine and other inflammatory mediators

Miscellaneous effects:Induce alteration in the MW, composition and solubility of immune complexesMediating hypersensitivity reactions

These are initiated in various ways through the three pathways1. Classic Pathway2. Alternate Pathway3. Mannose-binding lectin Pathway

Classic Pathway - Complement is activated by antigen antibody complex (IgM or IgG) - Fc portion of the antibody form a binding site for C1q - The numerical sequence of the complement factors in the classic pathway is: C1q,r,s , C4, C2, C3, C5, C6, C7, C8, C9

1) Recognition stage: - C1q act as the recognition element - It binds to Fc portion of IgM or IgG - The activated C1 molecule can cleave many C4 molec.

2) Amplification of proteolytic complement cascade The complement components C4, C2, C3, C5, C6, C7, C8, C9 participate in that order

3) Membrane attack complex: Complement components C5, C6, C7, C8, C9 participate where cell membrane damage and cell lysis occur

Classical Complement PathwayBacteriaC1qrsantibody

Classical Complement PathwayC1q

Classical Complement PathwayC1qrs

BacteriaantibodyC1qrsClassical Complement PathwayAnimation complete

Classical Complement PathwayBacteriaC1qrsAnimation completeantibody

Cytolysis Caused by Membrane Attack Complex

B) Alternative pathwayThis pathway is initiated by: * Bacterial endotoxin, polysaccharide capsule, aggregates of IgE and properdin * It starts at C3 then C5, C6, C7, C8, C9 * The complement components. C1, C4, C2 are by-passed * Antibodies are not required to initiate activation of this pathway * This pathway provides a means of non-specific resistance

BacteriaAlternative Complement Pathway

BacteriaAlternative Complement Pathway

Alternative Complement PathwayAnimation completeBacteria

Alternative Complement PathwayAnimation complete

Classic And Alternative pathways Classic Pathway Alternative pathway

* Specific acquired immunity * Non-specific innate immunity

* Initiated by antibody * Bacterial endotoxin, capsule

* Interaction of all components * C1, C4, C2 are by-passed

* Properdin system not involved * Properdin system is involved

Lectin Binding Complement Pathway

Lectin Binding Complement Pathway

Lectin Binding Complement Pathway

Lectin Binding Complement PathwayAnimation complete

Lectin Binding Complement PathwayBacteriaMBPAnimation complete

Alteration in Complement LevelsElevated levelsAre of limited clinical significanceDecreased levels---Suggests the ff biological effects:Complement has been excessively activated recentlyComplement is currently being consumedA single complement component is absent because of genetic defect

Diagnostic evaluation:Assessment of complementCan be used in diagnostic immunologyC2Most common complement deficiencyC3An acute-phase proteinElevated levelIndicates an acute inflammatory disease

Decreased levelSeen in post streptococcal glomerulonephritisC3 deficiencySevere liver diseaseSLE patients with renal diseaseC4Most sensitive indicator of disease activityAlso an acute-phase reactantDemonstrate inflammation or infection

C5Decreased levelIncreased susceptibility to bacterial infectionC6Decreased level---Increased susceptibility to Neisseria infectionsC7Decreased level---Associated with Raynauds phenomenon,scleodactyly, telangiectasia, and severe infection by Neisseria species

C8Decreased level---Associated with SLEIncreased susceptibility to Neisseria infectionsProperdin Acts to stabilize Alternative pathway C3 convertaseDecreased level---Leads to bacterial infections often meningococcemia

CytokinesPolypeptide products of activated cells that control a variety of cellular responses and thereby regulate immune responseReleased in response to specific antigensHave multiple activities and act on numerous cell typesEx: CSF(colony-stimulating factors) and Interleukins have effect on hematopoietic and lymphoid lineageHave variety of roles in host defenseEx. inflammatory responseVery potent even in minute concentrationsActs on other cells by bonding to receptors on the surface of the cells

MIF(Migratory Inhibitory Factor)Immobilizes macrophage migration, which may cause retention and accumulation of phagocytes at sites of inflammation.

InterleukinsProteins and petides that mediates local interactions between leukocytes but do not bind antigenRegulates growth, mobility, differentiation of lymphoid cells

InterferonsGroup of cytokines discovered in virally infected cultured cells.One of the bodys natural defensive response to foreign componentsMost broadly active physiologic regulators, enhancing the expression of specific genes, inhibiting cell proliferation and augmenting immune effector cells.

Interferons: Type I IFNMediate early innate response to viral infections

IFN-gammaPrincipal macrophage-activating cytokine and serves a critical function in innate immunity and in specific cell-mediated immunity

Tumor Necrosing factorPrincipal mediator of the acute inflammatory response to gram negative bacteria and infectious microbesFunctions:Stimulate recruitment of neutrophils and monocytes to the site of infectionActivate these cells to eradicate microbes

Hematopoietic StimulatorsStem Cell Factor(c-kit ligand)Interacts with a tyrosine kinase membrane receptorNeeded to make bone marrow stem cells responsive to other CSFs

Colony Stimulating Factors(CSF)Has ability to stimulate hematopoietic progenitor cells to form colonies in semi-solid mediumUsed to increase circulating leukocytes in patients with AIDS, and other immunocompromised patients, and bone marrow transplant recipient

Transforming Growth Factors (TGF)Products of virally infected cellsTGF-BInhibits proliferatio and activation of lymphocytes and other leukocytesChemokinesStimulate transendothelial movement from the blood to tissue site of infection and regulate the migration of PMNs and mononuclear leukocytes within tissues.

Acute Phase ProteinsAka acute phase reactantsRise at different rates and in varying levels in response to tissue injurry.Increase takes place shortly after trauma and initiated by pro-inflammatory cytokines

Includes:CRPInflammatory mediators(C3 and C4)Transport proteins(haptoglobin)Inhibitors(a1-antitrypsin)A1-acid glycoprotein

CRPComplement Reactive ProteinProminent because of its sensitivityDirect and quantitative measure of the acute-phase reaction.Becomes elevated within the first 12 hours of tissue injuryhas a half-life of 5-7 hours, falls rapidly when the patient recovers

Used clinically for monitoring infection, autoimmune disorder and healing after a myocardial infarction.Both CRP and LDL cholesterol are known to be elevated in persons at risk for cardiovascular disease.

Other Acute-Phase Reactants:Alpha1-antitrypsin Increase in acute inflammatory reactionsCeruloplasminSerum copperUsed to monitor Hodgkins disease, indicators of relapse

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