complement 2015(1).pdf

8/18/2019 complement 2015(1).pdf

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Dr. Pratiwi S Gunawan, drg.,MKes.,PAH(K)


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Complement was discovered by Jules Bordet as aheat-labile component of normal plasma thatcauses the opsonisation and killing of bacteria.

The complement system refers to a series of >20proteins, circulating in the blood and tissue fluids.


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Most of the proteins are normally inactive, but in responseto the recognition of molecular components ofmicroorganisms they become sequentially activated in anenzyme cascade – the activation of one protein

enzymatically cleaves and activates the next protein in thecascade.


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Complement can be activated via three different pathways(Figure 1), which can each cause the activation of C3,cleaving it into a large fragment, C3b, that acts as anopsonin, and a small fragment C3a (anaphylatoxin) that

promotes inflammation. Activated C3 can trigger the lyticpathway , which can damage the plasma membranes ofcells and some bacteria. C5a, produced by this process,attracts macrophages and neutrophils and also activates

mast cells.


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Continued next page…

Classical Pathway Alternative PathwayMannose Binding Lectin (MBL)

Pathway

Antigen-Antibody complex Activating surfaces Pathogen surfaces

C1

C4

C2

C3b C4

C2

MBL

MASP-1

MASP-2

C3 Convertase

C3b

C3b

C3a

C3

C5b-9

C5aC5

C5 Convertase

Lytic Pathway

C5bC6C7C8C9

Membrane attack complex (MAC)

Anaphylatoxin

Activates mast cells

Chemotactic

Factor B

Factor DFactor H

Factor I


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There are 3 major pathways1. Classical pathway triggered when IgM or certain

subclassed of IgG ( IgG1 & IgG3 )

2. Alternative pathway

triggered when abreakdown product of C3 hydrolis ( C3b ) isdeposited on the surface of microbe

3. Lectin pathway initiated in the absence of

antibody by the attachment of plasma mannose-binding lectin ( MBL ) to microba


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A) Classical 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 theclassic pathway is:

C1q,r,s , C4, C2, C3, C5, C6, C7, C8, C9


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The reaction sequence divided into three

stages: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) Activation stage:The complement components C4, C2, C3, C5, C6,C7,

C8, C9 participate in that order

3) Membrane attack stage:Complement components C5, C6, C7, C8, C9participate where cell membrane damage and cell

lysis occur


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This 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 compon. C1, C4, C2 are by-passed

* Antibodies are not required to initiateactivation of

this pathway

* This pathway provides a means of non-specificresistance


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Classical Pathway C1

C4 C2

C3 Alternative pathway

C5

C6

C7

C8

C9

Membrane damage


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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


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2) Opsonization:

- binding of complement proteins opsonin (C3b)

to surfaces of foreign organisms or particles

- Phagocytic cells express specific receptors for

opsonins, so promote phagocytosis


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3) Inflammatory response :

Small fragments released during complement

activation have several inflammatory actions:

a) C5a is chemotactic and attract neutrophiles andmacrophages

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


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4) Immune complex clearance:- C3b facilitate binding of immune complex to severalsurfaces (erythrocytes) and enhance removal by liver

and spleen

- binds erythrocytes to blood vessels , make them as

easy prey for phagocytosis

- C3 deficiency associated with Immunocomplex

disease and susceptibility to recurrent infections


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5-Enhancement of antibody production:

- Binding of C3b to its receptors on activated B cells

(CR2) greatly enhances antibody production

- Patient who are deficient in C3b produce

much less antibody than normal individuals and

more susceptible to pyogenic infection


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Harmful effects:

- If complement activate systematically on a largescale (Cm – ve bacilli)

- If activated by an autoimmune response to host cells


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The complement system plays a critical role ininflammation and defence against some bacterialinfections. Complement may also be activatedduring reactions against incompatible blood

transfusions, and during the damaging immuneresponses that accompany autoimmune disease.Deficiencies of individual complementcomponents or inhibitors of the system can lead to

a variety of diseases (Table ), which gives someindication of their role in protection againstdisease


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Complement Deficiency Disease

C3 and Factor B Severe bacterial infections

C3b-INA, C6 and C8 Severe Neisseria infections

Deficiencies of early C components C1, C4, C2. Systemic lupus erythematosus (SLE),

glomerulonephritis and polymyositis

C1-inhibitor Hereditary angioedema


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Thanks

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