Complement

Complement

Heat-labile series of 18 plasma proteins, many of which are enzymes or proteinases Major 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-smaller
C3b-larger

C2a-larger C2b-smaller

Site CSF

: serum and all tissue fluids except urine and

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 Complement
Normally, complements are present in inactive form. There are control proteins that inhibit uncontrolled complement activation:

C1

INH Factor I Factor H C4-binding protein

Effects of complement activation

Physiologic consequences include:

Blood

vessel dilation Increased vascular permeability

Cellular consequences include:

Cytolysis/hemolysis Opsonization

Cell

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 complexes Mediating hypersensitivity reactions

These are initiated in various ways through the three pathways 1. Classic Pathway 2. Alternate Pathway 3. 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 Pathway

C1qrs antibody C4b C4

C2 C3 C5 C4a

Bacteria

Classical Complement Pathway

C1q antibody C4b C4

C2 C3 C5 C2b C4a C2a

Bacteria

Classical Complement Pathway

C1qrs antibody C4b C4

C2 C3 C5 C2b C3b C4a C2a C3a

Bacteria

Classical Complement Pathway

C1qrs antibody C4b C4

C2 C3 C5 C2a C3b C5b C4a C2b C3a C5a

Bacteria

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Classical Complement Pathway

C1qrs antibody C4b C2a C3b C5b C6 C7 C8 C9 C9 C9 C9 C9 C9 C6 C7 C8 C9

Bacteria

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Cytolysis Caused by Membrane Attack Complex

B) Alternative pathway
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 components. C1, C4, C2 are bypassed * Antibodies are not required to initiate activation of this pathway * This pathway provides a means of non-specific resistance

Alternative Complement Pathway

C3 B C5 C3b C3a

Bacteria

Alternative Complement Pathway

C3 B C5 C3b

Bb
C3a

Bacteria

Alternative Complement Pathway

C3 B C5 C3b

Bb
C5b C3a C5a

Bacteria

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Alternative Complement Pathway

C6 C3b Bb C5b C6 C7 C8 C7 C8 C9 C9

Bacteria

C9 C9 C9

C9 C9 C9

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Classic And Alternative pathways

Classic Pathway Alternative pathway
* Non-specific innate immunity

* Specific acquired immunity

* Initiated by antibody
* Interaction of all components * Properdin system not involved

* Bacterial endotoxin, capsule

* C1, C4, C2 are by-passed * Properdin system is involved

Lectin Binding Complement Pathway

MBP C4 C4b

C2 C3 C5 C4a

Bacteria

Lectin Binding Complement Pathway

MBP C4 C4b

C2 C3 C5 C2b C4a C2a

Bacteria

Lectin Binding Complement Pathway

MBP C4 C4b

C2 C3 C5 C2a C3b C4a C2b C3a

Bacteria

Lectin Binding Complement Pathway

MBP C4 C4b

C2 C3 C5 C2b C3b C5b C4a C2a C3a C5a

Bacteria

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Lectin Binding Complement Pathway

MBP

C4b C2a C3b C5b C6 C7 C8 C9 C9 C9

C6 C7 C8 C9 C9 C9 C9

Bacteria

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Alteration in Complement Levels

Elevated levels
Are

of limited clinical significance

the ff biological effects:
has been excessively activated

Decreased levels-- Suggests

Complement

recently Complement is currently being consumed A single complement component is absent because of genetic defect

Diagnostic evaluation:

Assessment of complement
Can
C2
Most

be used in diagnostic immunology

common complement deficiency

C3
An

acute-phase protein Elevated level Indicates an acute inflammatory disease

Decreased level
Seen

in post streptococcal glomerulonephritis C3 deficiency Severe liver disease SLE patients with renal disease

C4
Most

sensitive indicator of disease activity Also an acute-phase reactant Demonstrate inflammation or infection

C5
Decreased
Increased

level

susceptibility to bacterial infection

C6
Decreased
Increased

level---

susceptibility to Neisseria infections

C7
Decreased
Associated

level---

with Raynauds phenomenon,scleodactyly, telangiectasia, and severe infection by Neisseria species

C8
Decreased

level---

Associated

with SLE Increased susceptibility to Neisseria infections

Properdin
Acts

to stabilize Alternative pathway C3 convertase Decreased level-- Leads

to bacterial infections often meningococcemia

Cytokines

Polypeptide products of activated cells that control a variety of cellular responses and thereby regulate immune response Released in response to specific antigens Have multiple activities and act on numerous cell types

Ex: CSF(colony-stimulating factors) and Interleukins have effect on hematopoietic and lymphoid lineage

Have variety of roles in host defense

Ex. inflammatory response

Very potent even in minute concentrations Acts 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.

Interleukins

Proteins and petides that mediates local interactions between leukocytes but do not bind antigen Regulates growth, mobility, differentiation of lymphoid cells

Interferons

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

Interferons:
Type

I IFN
early innate response to viral infections

Mediate

IFN-gamma
Principal

macrophage-activating cytokine and serves a critical function in innate immunity and in specific cellmediated immunity

Tumor Necrosing factor

Principal

mediator of the acute inflammatory response to gram negative bacteria and infectious microbes Functions:
Stimulate

recruitment of neutrophils and monocytes to the site of infection Activate these cells to eradicate microbes

Hematopoietic Stimulators

Stem Cell Factor(c-kit ligand)

Interacts

with a tyrosine kinase membrane receptor Needed 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 medium Used to increase circulating leukocytes in patients with AIDS, and other immunocompromised patients, and bone marrow transplant recipient

Transforming Growth Factors (TGF)

Products
TGF-B

of virally infected cells

Inhibits proliferatio and activation of lymphocytes and other leukocytes

Chemokines
Stimulate

transendothelial movement from the blood to tissue site of infection and regulate the migration of PMNs and mononuclear leukocytes within tissues.

Acute Phase Proteins

Aka acute phase reactants Rise 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:
CRP
Inflammatory

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

CRP

Complement Reactive Protein Prominent because of its sensitivity Direct and quantitative measure of the acutephase reaction. Becomes elevated within the first 12 hours of tissue injury has 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 reactions

Ceruloplasmin

Serum copper Used to monitor Hodgkins disease, indicators of relapse