Innate immunity

Innate Immunity

The first and the initial response to invading

pathogens
Often used to eliminate pathogens even in
adaptive immune responses
Stimulates adaptive immune response and
influences the nature and effectivity
Components of Innate Immunity :

Barriers
Epithelial layers
Defensins
Intraepithelial lymphocytes

Circulating Effector Cells

Neutrophils
Macrophages
NK Cells
Circulating effector proteins
Complement
C-Reactive protein
Mannose Binding Protein/lectin
Coagulation factors
Cytokines
(IFNg, IL-1, IL-12, TNF, IL-10)
Inflammation
Acute phase response
Fever
 Complement system
Complement system contains more than 30 glycoprotein present in
the serum in the form of components and factors
Activation involves the sequential proteolysis of proteins to
generate proteolytic enzymes
The products of complement activation become covalently attached
to microbial cell surface or to antibodies bound to microbial surface
or other antigens
Complement activation is inhibited by regulatory proteins present
on normal host cell to minimize complement mediated damage to
host cell
Complement cascade also interact with other trigered-enzyme
cascade : coagulation, kinin and fibrinolysis
 Complement activation
The central event of complement activation is
proteolysis of complement protein C3 to generate
biologically active product C3b

Pathways of complement activation :

The classical pathway
The alternative pathway
Lectin pathway
Clasical Lectin Alternative
Pathway Pathway Pathway
MBP

C1r C1r
C1s MASP C1s P
C4 C4 C4 D
C2 C2 C2 B
C3

C3b

C5b6789 / MAC / Membrane Attack Complex

COMPLEMENT ACTIVATORS

Classical Pathway :
immune complex : IgG & IgM
Alternative Pathway :
endotoxin , CVF
virus , parasite , bacteria
Lectin pathway :
carbohydrate(mannose)
 MAC : Membrane Attack Complex

C5a C9
C7
C6
C8

C5

C6 C6 C
C6

C5b 6
C5b C5b C5b
C5 convertase C9
C7 C7 C7
C8 C8
Alternative pathway

D
B
C3B
 C3
C3
C3 Ba

D
Bb
C3B C3 convertase
 C3a
C3a C3a
C3a
C3B
C3B
Bb C5 convertase
C3B C3B
 Classical pathway

C1q r s

C4
C2

C4a

C4b
 C2a

C4a

C3
C4b
C3 convertase
C2b
 C2a

C3a C4a

C3b
C4b
C5 convertase C2b
C3b
MASP: MBL associated serine protease
 MAC : Membrane Attack Complex

C9
C7
C6
C8

C5

C5 convertase
 MAC : Membrane Attack
Complex

C5a C9
C7
C6
C8

C5b
C5 convertase
 MAC : Membrane Attack Complex

C9

C8

C6

C5b
C5 convertase

C7
 MAC : Membrane Attack Complex

C9

C6

C5b
C5 convertase
C7
C8
 MAC : Membrane Attack Complex

C
C6
6
C5b
C5 convertase C9
C7
C8
MAC : Membrane Attack Complex

C6 C6 C6 C6

C5b C5b C5b C5b

C9 C9 C9 C9
C7 C7 C7 C7
C8 C8 C8 C8
MAC : Membrane Attack Complex

C6 C6 C6 C6

C5b C5b C5b C5b

C9 C9 C9 C9
C7 C7 C7 C7
C8 C8 C8 C8
MAC : Membrane Attack Complex

C6 C6 C6 C6

C5b C5b C5b C5b

C9 C9 C9 C9
C7 C7 C7 C7
C8 C8 C8 C8
 Complement regulatory mechanisms

C1INH : inhibits proteolytic activity of C1r and C1s

DAF : binds C4b and C3b

Factor I : degrades cell associated C4b and C3b

C59 : inhibits formation of MAC

 Classical Pathway Alternative Pathway
Antigen-antibody complex Pathogen surfaces

C1,4,2 C3,B,D

C 3 / C 5 convertase

C 4a , C 5a , C3a C 3b C 5b , C 6 --- C 9

Inflammation Opsonization MAC

of pathogens
Phagocyte Lysis of
recruitment pathogens and
cells
Biological effects of Complement system

Lysis of microbes

Inflammation

Phagocytosis of
opsonized microbes
The Complement system in Disease

Two general ways :

1. Deficiencies of complement
components or its regulators
2. Activation of normally functioning
complement in response to abnormal
stimuli
Clasical Lectin Alternative
Pathway Pathway Pathway
C1q MBP C3b

C1r C1r
C1s MASP C1s P
C4 C4 C4 D
C2 C2 C2 B
C3

C3b

C5b 6 7 8 9 / MAC / Membrane Attack Complex

Complement deficiencies :

1. Failure to clear up circulating I.C

2. Failure in solubilization of large I.C
3. Failure in antigen mediated signal for B cell
which may induce autoimmunity
4. Increased susceptibility to infection
Classical Pathway deficiencies
Ciq, C1r, C1r, C4, C2, C3

C4 and C2 deficiencies :
50% associated with Auto Immune Disease (SLE)
Not usually associated with increased susceptibility
to infection
C3 deficiency :
Frequent pyogenic bacterial infection
Alternative Pathway deficiencies
Factor D, B and Properdin
Increased susceptibility to pyogenic bacterial infection
Terminal complement components deficiencies
C5, C6, C7, C8, C9
Increased susceptibility to Neisseria bacterium
Complement Regulators deficiencies :
DAF deficiency :
Paroxysmal nocturnal Hburia
C1INH deficiency
Hereditary angioneurotic edema
Regulators /
inhibitors of
complement
 Complement Receptors

Receptors Ligands Cell distributions Functions

CR1/CD35 C3b,C4b,iC3b MNC,neutrophils Phagocytosis

erythrocytes, B and T Clearance of I.C
FDCs, eosinophils

CR2/CD21 C3d, iC3b B lymphocytes Co-receptor for

B cell activation

CR3/Mac-1 iC3b, ICAM-1 MNC, neutrophils Phagocytosis

C11b-C18 NK cells Adhesion mol.

CR4/C11c-CD18 iC3b MNC, neutrophils Phagocytosis

NK cells