COMPLEMENT SYSTEM Flashcards by Iseoluwa Ojo

Research on complement began in the 1890s, when Jules Bordet at the Institut Pasteur in Paris showed that sheep antiserum to the bacterium Vibrio cholerae caused lysis of the bacteria and that heating the antiserum destroyed its bact eriolytic activity.
 He named those substances as ______ .
 Paul Ehrlich coined the term _________.

Alexins

complement

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It is named “complement system” because it was first identified as a _____-labile component of serum that “_________ or ________” antibodies in the killing of bacteria.

heat

complemented or augment

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Complement system

Consists of ______ and ___________ involved in defense against ______ and tissue damage mediated by ________

serum and cell surface proteins

pathogens; antibodies

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The Complement system is the (minor or major?) effector of ____________________ branch of immune system.

Major

cellular and humoral

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Complement system

Plays major role in only innate immunity

T/F

Plays major role in both innate and adaptive immunity

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Complement system represents a group of about _____ proteins which augment or complement the immune response.

Most of these proteins are found in ______ or on _______

serum; cell surfaces.

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Complement proteins

Synthesized in _____ as (active or inactive?) precursors and are activated by ________ during their interaction in a ________ manner.

liver

Inactive ; proteolysis; sequential

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Complement proteins

Also produced by blood ______, tissue ________ and _______ cells of the ______________ and _____________ tract.

monocytes

macrophages; epithelial

gastrointestinal and genitourinary

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General properties

Present in ______ of all animals but its concentration is maximum in ______ of ——-

serum

serum of guinea pig.

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General properties

Complement of one species are able to react with antibodies of other species and to the same extent.

T/F

Complement of one species are able to react with antibodies of other species but not to the same extent.

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General properties

C- proteins constitute about ——% of normal serum protein

Are _________.

Are synthesized (slowly or rapidly?) in inflammatory responses – hence are called ________________

glycoproteins; rapidly

acute phase proteins.

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General properties

Heat (stable or labile?) and lost activity at ____0 C for _____ and inactivated.

Immunoglobulins are inactivated at
this temperature.(T/F)

Labile

56; 30mins

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Complement proteins Binds with __________ of immunoglobulns .

Fc potion

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Three main effects of complement are:

_____ of cells (bacteria, allografts, tumor cells)
Generation of ___________

3.______________: ______ of ______

Lysis

mediators of inflammation

Opsonization

enhancement of phagocytosis

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Complement functions

Host benefit:
– _________ to enhance phagocytosis
– phagocyte_______ and. ______
–_____ of bacteria and infected cells
– regulation of _____ responses
– clearance of _________
– clearance of ________

opsonization

attraction and activation

lysis; antibody

immune complexes

apoptotic cells

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Complement functions

• Host detriment:
–__________,__________

Inflammation, anaphylaxis

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Complement system

 Complement components-
- Components are designated by _____ (E.g. ;___-____) or ______ (E.g. :______)

numbers; C1 – C9

letters; Factor D

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Complement system

Complement receptors

Located on_________

recognize _____ components)

Cell surface

activated

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Complement system

Regulatory proteins of complement

-both in ———- and ______

-they inhibit _________ components

serum and cell surface

activated

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Complement proteins: are proenzymes

T/F

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Complement proteins: are proenzymes that are activated by _________.

cleavage

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Example:

a = ———- fragment. - _______

b= ______ fragment. - _________

Exception is : _____

a = ____ fragment
b =_____ fragment

smaller

Diffusion

larger

remains bound to microbe

Large; small

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Complement Pathway
Three pathway of complement activation

Classical pathway:- Is ______ dependent pathway and triggered by formation of _________________ or by binding of the __________ to _________ on the ————

antibody

soluble antigen-antibody complex

antibody to the antigen present on the target cell surface.

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Complement Pathway
Three pathway of complement activation

Alternative pathway:- Is ______________ pathway stimulated by ________ eg. Bacterial cell surface components.

antibody independent

antigen directly

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Complement Pathway Three pathway of complement activation Lectin Pathway:- Also a ________ pathway but resembles _______ pathway.

antibody independent classical

Stages of complement Activation Three main stages in the activation of complement by any pathway are Formation of __________ Formation of ____________ Formation of _____________

C3 convertase C5 convertase membrane attack complec(MAC)

Stages of complement Activation The initiation and formation of C3 convertase are (the same or different?) in classical and alternative pathway .

different

Stages of complement Activation These classical and alternative pathways then follow the parralel route to merge at _________ stage and finally generate the ______ by a _____ route

C5 convertase MAC common

Of these pathways, the ______ and ______ pathways are more important the first time we are infected by a microorganism because ????

lectin and the alternative the antibody required to trigger the classic pathway is not present.

The lectin pathway but not the alternative pathway is a participant in the innate arm of the immune system. T/F

F The lectin pathway and the alternative pathway are, therefore, participants in the innate arm of the immune system.

All three pathways lead to the production of ____, the central molecule of the complement cascade. The presence of ____ on the surface of a microbe marks it as ________ and ______ it for ________

C3b C3b foreign and targets it for destruction.

C3b has two important functions: (1) It combines with other complement components to generate ________, the enzyme that leads to the production of the ________________ (2) It _______ bacteria because phagocytes have _____________ on their surface.

C5 convertase membrane attack complex opsonizes receptors for C3b

C-activation: _____ of C proteins such that they _________________

alteration interact with the next component

C-fixation: ________ of C by __________

utilization Ag-Ab complexes

C-inactivation: ———— (usually by _____) of _______ ___-component resulting in ____________

denaturation Heat an early C loss of hemolytic activity

Convertase/esterase: ____ C-protein which acts as a _______ for _________

Altered proteolytic enzyme another C-component

Classical pathway •In the classic pathway, ________ activate C1 to form a ______, which cleaves _______________ to form a _______ complex, ___________ split off. •The ________ is ________, which cleaves _______ molecules into two fragments, _________ •_____forms a complex with ________ producing a new enzyme, ________ (_________), which cleaves ____ to form ____________ •C5b binds to _____ to form a complex that interacts with ________ to produce the _______(___________), which causes cytolysis.

antigen–antibody complexes protease C2 and C4 ; C4bC2a; C2b and C4a C4bC2a is C3 convertase C3; C3a and C3b. C3b; C4b,2a, ; C5 convertase ; C4b2a3b C5; C5a and C5b C6 and C7; C8 and C9; membrane attack complex ; C5b,6,7,8,9

Note that generally the "____" fragment continues in the main pathway, whereas the "___" fragment is split off

b a

Only Ig___ and Ig___ fix complement.

M G

___ molecule of IgM can activate complement activation by IgG requires __________ IgG molecules.

One two cross-linked

Of the IgGs, only Ig___, Ig____, and Ig___ subclasses fix complement; Ig____ does not.

G1 G2 G3 G4

C1 is bound to a site located in the____ region of the _____ chain. C1 is composed of _____ proteins, _______________

Fc heavy three C1q, C1r, and C1s.

C1q is an aggregate of ____ polypeptides that binds to the ____ portion of _____________  It is multivalent and can ____________ molecules.

18 Fc IgG and IgM. cross-link several immunoglobulin

C1s is a ______ that is cleaved to form ________

proenzyme an active protease.

Functions: C1q C1r C1s

Binds to antibody that has bound antigen, activates C1r. Cleaves C1s to activate protease function. Cleaves C2 and C4.

Functions: C2a . C2b

Unknown. Active enzyme of classical pathway; cleaves C3 and C5.

Functions: C3a C3b

Mediates inflammation; anaphylatoxin. Binds C5 for cleavage by C2b. Binds cell surfaces for opsonization and activation of alternate pathway.

Functions C4a C4b

Mediates inflammation. Binds C2 for cleavage by C1s. Binds cell surfaces for opsonization

Functions C5a C5b

Mediates inflammation; anaphylatoxin, chemotaxin. Initiates assembly of the membrane-attack complex (MAC).

Functions C6 C7.

Binds C5b, forms acceptor for C7. Binds C5b6, inserts into membrane, forms acceptor for C8.

Functions C8 C9n

Binds C5b67, initiates C9 polymerization. Polymerizes around C5b678 to form channel that causes cell.

Alternative pathway Antibody (dependent or independent ?) pathway.

Independent

Alternative pathway In the alternative pathway, many ___________ substances, e.g., ________,________,_________,______ can initiate the process by binding ________________ •This complex is cleaved by a protease, _________, to produce __________. •This acts as a _______ to generate more ____.

unrelated cell surface bacterial lipopolysaccharides (endotoxin), fungal cell walls, and viral envelopes, C3 and factor B. factor D; C3bBb C3 convertase; C3b

__________ pathways are more important the first time we are infected

Alternative

Alternative pathway Usually activated by _________ like ______________ • Other activators include: 1. Complexes containing Ig___ 2. Some ___-infected cells (e.g. EBV) 3. Many gram negative and gram positive organisms 4. Parasites – Trypanosomes, Leishmania 5._________ 6._________ (agarose)

products of micro-organisms like endotoxin A virus Erythrocytes; Carbohydrates

Functions B Ba Bb

Binds membrane bound C3b. Cleaved by Factor D. Unknown. Cleaved form stabilized by P produces C3 convertase.

Functions Factor D P(Properdin)

Cleaves Factor B when bound to C3b. Binds and stabilizes membrane bound C3bBb.

Lectin Pathway Also known as the ______(________________) Pathway

MBL mannose-binding lectin

Lectin Pathway In the lectin pathway, ___________ binds to the surface of microbes bearing ________ •Binding causes __________(_______________) that ____________ and _________

mannose-binding lectin (MBL) mannan activation of MASP MBP-associated serine proteases cleave C2 and C4 and activate the classic pathway.

Lectin Pathway mannan A _______ of the ______, _____

polymer of the sugar, mannose

Lectin Pathway this process bypasses ___________________ and so is _________________ before __________

the antibody-requiring step protective early in infection antibody is formed.

Membrane attack complex C5 structurally homologous to _____________ Lacks __________ bond

C3 and C4 internal thioester

Membrane attack complex _____ initiates formation of MAC (complex of ____,_____,_____,_____, and ——— ) •C5b binds to ________, recruits ___ and complex ______________ into the membrane.

C5 C5b, C6, C7, C8 and multiple C9 molecules C6, and C7 ; C8; penetrates more deeply

Membrane attack complex C9, a _____-forming molecule with homology to _______. The complex of C5b678 forms a ____ for C9________ and _________

pore perforin nidus binding and polymerization

Membrane attack complex Penetrates membrane bilayers to form ———— Disrupt the ___________, leading to _______ and ——— of susceptible cells

pores osmotic barrier swelling and lysis

Biologic Effects of complement: 1. Opsonization • ______ and _____ •enhance ________

C3b & C1q phagocytosis

Biologic Effects of complement: Chemotaxis • ______ and ___________ complex attract neutrophils • C5a – enhance _________ of ———— to ________

C5a and C5,6,7 adhesiveness of neutrophils to the endothelium

Biologic Effects of complement: Anaphylatoxin •_______________ • Cause _______ of ________ cells • Bind directly to ______ of ________, leading to ________

C3a,C4a,C5a degranulation of mast smooth muscles bronchioles bronchospasm

Opsonization increases phagocytosis by _______ fold

1,000

Biologic Effects of complement: Cytolysis •_________ • Disrupt the ______ & the ______________________ into the cell

MAC membrane entry of water and electrolytes

Biologic Effects of complement: Enhancement of antibody production • Binding of ____ to its receptors on the surface of activated B cells leads to enhanced antibody production

C3b

Regulation of Complement System 1. C1inhibitor • Important regulator of ____ pathway • A ___________ (serpin) • (Reversibly or Irreversibly?) binds to and inactivates ____ and ____, as well as _____ in lectin pathway

classic serine protease inhibitor Irreversibly C1r ; C1s MASP

Regulation of Complement System FactorH • Regulate ______ pathway • Reduce amount of ________ available •With both cofactor activity for the factor I- mediated C3b cleavage, and decay accelerating activity against C3bBb (C3 convertase)

alternative C5 convertase

Regulation of Complement System Properdin • Protects _____ and stabilizes _______

C3b C3 convertase

Regulation of Complement System FactorI • Cleaves cell-bound or fluid phase _____________ •inactivates _____ and ——-

C3b and C4b C3b and C4b

Regulation of Complement System Decay accelerating factor(DAF) •is a _______ on surface of human cells • Prevents ___________ or accelerates ________________ leading to ____________ • Acts on _______________ pathway

Glycoprotein assembly of C3bBb disassembly of preformed convertase no formation of MAC both classical and alternative

Regulation of Complement System C4b-bindingprotein(C4BP) • Inhibits the action of C4b in ______ pathway • Splits _______ and is a cofactor for ____

classical C4 convertase factor I

Regulation of Complement System ComplementReceptor1(CR-1) • Co-factor for _____, together with _____

factor I CD46

Regulation of Complement System Protectin and Vitronectin • Inhibits _______ by binding _______ •Present on “______” cells to prevent ___________

formation of MAC C5b678 self complement from damaging them

Protectin( ________) Vitronectin( _______)

CD59 Sprotein

_______(CD59) ________(Sprotein)

Protectin Vitronectin

Clinical Aspects of complement 1. Deficiency of C5-C8 &Mannan-binding lectin • Predispose to _______ _______ _______

severe Neisseria bacteremia

Clinical Aspects of complement Deficiency of C3 • Severe, recurrent _________ and __________

pyogenic sinus & resp. tract infections

Clinical Aspects of complement Deficiency of C1 esterase inhibitor • _____________ due to increased ————- and ________

Angioedema capillary permeability and edema

Clinical Aspects of complement Deficiency of DAF • Increased _________________ leading to ____________

complement-mediated hemolysis paroxysmal nocturnal hemoglobinuria

Clinical Aspects of complement Transfusion mismatches • Activation of complementgenerate large amounts of anaphylatoxins & MAC red cell hemolysis 6. Autoimmunediseases • Immune complexes bind complement  low complement levels + activate inflammationtissue damage 7. Severeliverdisease • Deficient complement proteins predispose to infection with pyogenic bacteria

Clinical Aspects of complement Transfusion mismatches • Activation of complement generate large amounts of anaphylatoxins & MAC leading to _______________

red cell hemolysis

Clinical Aspects of complement Autoimmunediseases • Immune complexes bind complement leading to (low or high?) complement levels + activate _________ causing tissue damage

Low inflammation

Clinical Aspects of complement Severe liver disease • Deficient complement proteins predispose to ________ with _____

infection with pyogenic bacteria

Clinical Aspects of complement Factor I deficiency • Low levels of ____ in plasma due to unregulated activation of _____ pathway leads to —————- in children • Mutations in factor I gene has been implicated in development of ______________

C3 alternative recurrent bacterial infections Hemolytic Uremic Syndrome