Lecture 1 – Innate Immunity
Innate Immunity
Exterior defences
• Most infectious agents prevented from entering body by biochemical and physical barriers
• Many barriers prevent pathogens from crossing epithelia open to outside and colonising
tissues (e.g GI tract)
• Surface epithelia provide mechanical, chemical and microbiological (microbiome) defences
against infection
Anti-microbial defensins produced in gut
• Paneth Cells
o Specialised cells deep in epithelial crypts
o In intestine
o Produce several kinds of antimicrobial proteins
• A-defensins (cryptdins)
, Antimicrobial lectin regIII
• A-defensins disrupt cell membranes of microbes
o by inserting into the lipid bilayer
o Leads to formation of pores in membrane
o Membrane loses integrity and collapses
o Leads to death of microbe
• REGIIIy produced
o C-type lectin
o Binds to peptidoglycans on bacteria cell wall
o Defensin preferentially kills gram-positive bacteria
• In gut, these defensins continuously secreted into gut lumen
o Protect from gut infections
• Lysozyme digests cell walls of gram + and - bacteria
o Cleaves B-(1-4) linkages between sugar and molecules
• Role of microbiome in gut
o Actively reacts with potentially pathogenic microbes
o Simultaneously remaining ignorant towards majority of non=pathogenic microbiota
o Disruption of delicate balance results in IBS
o TLR's, regulatory T cells, and TH 17 cells (pro-inflammatory T cells)
o Cytotoxic T cells clear out/destroy own epithelial cells infected by pathogenic bacteria
o Dendritic cells of immune system sample contents of gut lymen for any damaging
bacteria
• Alert B and T lymphocytes living in villi of small and large intestine
• Not enough commensal 'friendly' bacteria In gut lumen?
,Lecture 2 – Compliments
• Complement Is a collection of soluble proteins present in blood and other bodily fluids
• Opsonization
o Coating of a pathogen by antibodies or complement proteins
o More readily taken up and destroyed by phagocytic cells
• Composed of more than 30 different plasma proteins
• Proteins produced mainly by liver
• In presence of pathogen, complement system becomes ‘activated’
• 3 pathways of complement activation
• Activation of proteolysis is used
• Proteases of complement system synthesized as inactive pro-enzymes, or zymogens
o Only become enzymatically active after proteolytic cleavage
• Detection of pathogen activates initial zymogen
o Triggers cascade of proteolysis
o Complement zymogens activated sequentially
• 3 pathways
o 1) lectin pathway
▪ Initiated by soluble carbohydrate binding proteins, manose binding lectin
and ficolins
o 2) classical pathway
▪ Initiated when C1 either recognises microbial surface directly or binds to
antibodies already bound to antigen
o 3) alternative pathway
▪ Initiated by spontaneous hydrolysis and activation of C3
▪ Then binds to microbial surfaces
Basic role of complement proteins
• C4b2a is a pivotal C3 convertase (cuts C3) produced by both classical and lectin
complement pathways
• C2 is cut into C2a and C2b
• C4 is cut into C4a and C4b
, • C4b and C2a join to form an enzyme C4b2a
• C4b2a is called a C3 convertase
• C4b2a cuts C3 into C3a and C3b
• C3b binds to C4b2a to form C4b2a3b complex
• This C4b2a3b is called a C5 convertase
• C4b2a3b cuts C5 to C5a and C5b
• C5b will initiate the formation of the Membrane attack complex (MAC) composed of
C5b, C6, C7,C8 and lots of C9!.
• The MAC punches holes in the membrane of the pathogen leading to cell lysis
• C3bBb is a pivotal C3 convertase produced by the alternative pathway
• C3 is spontaneously hydrolysed to C3a and C3b, triggered by pathogen PAMPs such
as LPS of gram negative bacteria or zymosan on yeast cell walls.
• Surface bound C3b and Factor D cuts Factor B into Ba and Bb
• C3b then binds to Bb to form C3bBb which is a C3 convertase
• C3 convertase cuts more C3 to C3a and C3b
• Some of the C3b produced then binds to C3bBb to form C3bBbC3b which is a C5
convertase
• C3bBbC3b convertase cuts C5 to C5a and C5b
• C5b will initiate the formation of the Membrane attack complex (MAC) composed of
C5b, C6, C7,C8 and lots of C9.
• The MAC punches holes in the membrane of the pathogen leading to cell lysis of the
organism
Comparison of the three pathways of complement activation and the production of the pivotal C3
and C5 convertases
Innate Immunity
Exterior defences
• Most infectious agents prevented from entering body by biochemical and physical barriers
• Many barriers prevent pathogens from crossing epithelia open to outside and colonising
tissues (e.g GI tract)
• Surface epithelia provide mechanical, chemical and microbiological (microbiome) defences
against infection
Anti-microbial defensins produced in gut
• Paneth Cells
o Specialised cells deep in epithelial crypts
o In intestine
o Produce several kinds of antimicrobial proteins
• A-defensins (cryptdins)
, Antimicrobial lectin regIII
• A-defensins disrupt cell membranes of microbes
o by inserting into the lipid bilayer
o Leads to formation of pores in membrane
o Membrane loses integrity and collapses
o Leads to death of microbe
• REGIIIy produced
o C-type lectin
o Binds to peptidoglycans on bacteria cell wall
o Defensin preferentially kills gram-positive bacteria
• In gut, these defensins continuously secreted into gut lumen
o Protect from gut infections
• Lysozyme digests cell walls of gram + and - bacteria
o Cleaves B-(1-4) linkages between sugar and molecules
• Role of microbiome in gut
o Actively reacts with potentially pathogenic microbes
o Simultaneously remaining ignorant towards majority of non=pathogenic microbiota
o Disruption of delicate balance results in IBS
o TLR's, regulatory T cells, and TH 17 cells (pro-inflammatory T cells)
o Cytotoxic T cells clear out/destroy own epithelial cells infected by pathogenic bacteria
o Dendritic cells of immune system sample contents of gut lymen for any damaging
bacteria
• Alert B and T lymphocytes living in villi of small and large intestine
• Not enough commensal 'friendly' bacteria In gut lumen?
,Lecture 2 – Compliments
• Complement Is a collection of soluble proteins present in blood and other bodily fluids
• Opsonization
o Coating of a pathogen by antibodies or complement proteins
o More readily taken up and destroyed by phagocytic cells
• Composed of more than 30 different plasma proteins
• Proteins produced mainly by liver
• In presence of pathogen, complement system becomes ‘activated’
• 3 pathways of complement activation
• Activation of proteolysis is used
• Proteases of complement system synthesized as inactive pro-enzymes, or zymogens
o Only become enzymatically active after proteolytic cleavage
• Detection of pathogen activates initial zymogen
o Triggers cascade of proteolysis
o Complement zymogens activated sequentially
• 3 pathways
o 1) lectin pathway
▪ Initiated by soluble carbohydrate binding proteins, manose binding lectin
and ficolins
o 2) classical pathway
▪ Initiated when C1 either recognises microbial surface directly or binds to
antibodies already bound to antigen
o 3) alternative pathway
▪ Initiated by spontaneous hydrolysis and activation of C3
▪ Then binds to microbial surfaces
Basic role of complement proteins
• C4b2a is a pivotal C3 convertase (cuts C3) produced by both classical and lectin
complement pathways
• C2 is cut into C2a and C2b
• C4 is cut into C4a and C4b
, • C4b and C2a join to form an enzyme C4b2a
• C4b2a is called a C3 convertase
• C4b2a cuts C3 into C3a and C3b
• C3b binds to C4b2a to form C4b2a3b complex
• This C4b2a3b is called a C5 convertase
• C4b2a3b cuts C5 to C5a and C5b
• C5b will initiate the formation of the Membrane attack complex (MAC) composed of
C5b, C6, C7,C8 and lots of C9!.
• The MAC punches holes in the membrane of the pathogen leading to cell lysis
• C3bBb is a pivotal C3 convertase produced by the alternative pathway
• C3 is spontaneously hydrolysed to C3a and C3b, triggered by pathogen PAMPs such
as LPS of gram negative bacteria or zymosan on yeast cell walls.
• Surface bound C3b and Factor D cuts Factor B into Ba and Bb
• C3b then binds to Bb to form C3bBb which is a C3 convertase
• C3 convertase cuts more C3 to C3a and C3b
• Some of the C3b produced then binds to C3bBb to form C3bBbC3b which is a C5
convertase
• C3bBbC3b convertase cuts C5 to C5a and C5b
• C5b will initiate the formation of the Membrane attack complex (MAC) composed of
C5b, C6, C7,C8 and lots of C9.
• The MAC punches holes in the membrane of the pathogen leading to cell lysis of the
organism
Comparison of the three pathways of complement activation and the production of the pivotal C3
and C5 convertases
