Let’s look at the benefits of innate and adaptive immunity
1 infection time course Normal individual = infection is cleared by combined effects of innate and adaptive immunity
Lack of innate immunity = uncontrolled infections, i.e. adaptive immune response cannot be deployed
Lack of adaptive immunity = infection is initially controlled by innate immunity, but cannot be cleared from the body
Infectious diseases are caused by pathogens of diverse types that live and replicate in the human body
4 Human pathogen types
Viruses, bacteria and fungi
Pathogens are diverse in their
Manner of exploiting the human body
Type of damage to tissue
Tissue damage and disease symptoms can be caused
Pathogens damage tissue in different ways
Phagocytes degrade microbe, endotoxins released cytokines
Infected cells killed /damaged
Different components of the immune system contribute to immunity against different types of microbes in different locations
Some pathogens, all stages are extracellular
accessible to soluble components of the immune system.
Others, exploit intracellular sites to grow and replicate
not able to use soluble components.
Extracellular vs. intracellular infections can be further subdivided
Different sites affect the type of immune mechanism used to eliminate the pathogen
Extracellular are accessible to soluble immune system molecules
Intracellular forms are not accessible to soluble immune system molecules
Intracellular pathogens in nucleus or cytosol attacked by killing the infected host cell
Interferes with the pathogen’s life cycle
Exposes the released pathogens from the killed cells to soluble immune system molecules
Intracellular pathogens in vesicles
Activate the infected cell to intensify its antimicrobial activity
Almost all viruses, bacteria, fungi or parasites are at some time in the extracellular system Abs
Most pathogens infect only a few related host species
Therefore humans are infrequently infected via another vertebrate species
Most of time infection is via directly or indirectly by another person
Parasites may require an intermediate passage through distantly related organism
To complete it’s life cycle
Pathogen’s ability to persist outside of the body varies
Determines the ease with which a particular disease is spread
Anthrax = spores = resistant to heat/desiccation
HIV sensitive to environment change therefore requires intimate contact or exchange of infected body fluids
C3 is by far the most important molecule in the complement cascade.
The biggest difference in the different pathways is how they are activated.
1) The quickest of the 3 complement pathways is the alternative pathway
It starts depositing C3b on the surface of the pathogen at the beginning of infection.
2) The lectin pathway can begin as soon as an infection is realized but takes a little time to become effective.
3) The Classical pathway is part of both the innate and adaptive immune response and can be activated by C-reactive protein (innate) or antibody (adaptive) binding to the pathogen.
Complement activation by the alternative pathway tags microorganisms for destruction
1st immune system components to be activated = complement
Ubiquitous in blood and lymph
Soluble proteases that circulate in an inactive form called zymogens
A molecular defense that can be utilized immediately
The Thioester Bond
1 st Step in the alternative pathway involves spontaneous hydrolysis and activation of complement component C3
This process occurs continuously at low rate in blood, lymph and extracellular fluids
Rate increases in vicinity of certain pathogens
iC3 is the product of C3 hydrolysis
iC3 binds to factor B in the blood or ECF making factor B susceptible to cleavage by factor D
at pathogen’s surface
iC3Bb is produced (soluble form of C3 convertase)
iC3Bb cleaves C3 into C3a and C3b
Some of C3b becomes bound to pathogen’s surface
C3 convertase of the alternative pathway
Factor B binds to C3b fragments and is cleaved by factor D, the complex of C3bBb is formed on the pathogen‘s surface = C3 convertase of the alternative pathway
Assembly of some C3 convertase molecules results in more C3 being cleaved and more C3b attached to the pathogen’s surface assembly of even more convertase…process of progressive amplification that rapidly coats the pathogen with C3b
High density C3b fragments on the pathogen surface form effective ligands for complement receptors (CR1) of macrophages in infected tissue
Covalently coupled C3b fragments tag the pathogen for destruction by phagocytosis
C3b Tags Pathogens for Phagocytosis
Opsonin – a protein bound to the surface of a pathogen that facilitates its phagocytosis.
CR1 – Complement Receptor 1 – bind to C3b deposited on microbial surfaces phagocytosis
Also plays a protective roll on human cell surfaces by disrupting C3 convertase.
How is the sequence of complement-activating reactions continued?
Binding of C3b to existing C3bBb complexes at pathogens surface forms the alternative C5 convertase = C3b 2 Bb (C4b2a3b in classical pathway)
Activates C5 terminal components of complement (C6-C9)
Pores transmembrane channels pathogen lysis
C5a recruits neutrophils to infection site
Most potent anaphylatoxin
What about protecting the host cell? Regulatory Proteins
Proteins controlling complement activation
Ensure C3b is densely deposited on microbial surfaces; not on the surfaces of human cells
Plasma protein = properdin (factor P)
Factor P binds to C3 convertase (C3bBb) on microbial surfaces and protects it from inhibition by factor H
Factor H plasma protein reduces complement reactions by making C3b susceptible to cleavage by factor I
On human cells the complement pathway is stopped by human cell-surface proteins decay-accelerating factor (DAF) and membrane co-factor protein (MCP) .
DAF and MCP control proteins destroy C3 convertase activity by binding to C3b and displaces Bb and/or renders C3b susceptible to cleaved by factor I
What about protecting the host cell? Regulatory Proteins
When C3bBb is formed on a human cell surface it is rapidly disrupted by the action of one of two membrane proteins: decay accelerating factor (DAF) or membrane cofactor protein (MCP)
These regulatory proteins ensure that much complement is fixed to pathogen surface and little is fixed to human cell surfaces
Complement activation limits bacterial infections…but some bacteria mimic human cells to evade the actions of complement
Ex. Streptococcus pyogenes and Staphylococcus aureus
C3b bound on these pathogen’s surfaces is readily inactivated by factor H
Abs coat the bacterial surface and mask sialic acids before complement is bound therefore these bacterial are only resistant to the effects of complement when no specific antibacterial antibody is present
C3a and C5a contribute to acute inflammation
Also referred to as anaphylatoxins
C5a is more stable and potent than C3a
What exactly do they do?
bind mast cells, phagocytes and endothelial cells
release of histamine
Histamine increases blood vessel permeability and blood flow
Activate endothelial cells direct phagocytes to site of infection
C5a Increases the adherence of monocytes and neutrophils to blood vessel walls and acts as a powerful chemotactic factor
What’s this mean?
C5a is able to attract phagocytes to areas where complement has been fixed.
The leukocytes follow a gradient of the C5a back to the site of infection.
Several classes of plasma protein limit the spread of infection
Protease inhibitors such as 2 -macroglobulin inhibit potentially damaging proteases
Microbe invasion and colonization of human tissues is dependent on microbial proteases
In response human plasma is loaded with protease inhibitors
-macroglobulins first trap the protease with a “bait” region
protease cleaves the bait -macroglobulin binds covalently through activation of thioester group
surrounds the protease (still active) but cannot access other protein substrates
Serpins and -macroglobulin inhibit potentially damaging proteases
Antimicrobial Peptides - Defensins
Two types of defensins - -defensins and -defensins .
Amphipathic (both hydrophobic and hydorphilic) regions.
Penetrates the microbial membrane and disrupts it.
Produced mainly by neutrophils and Paneth cells (specialized epithelial cells of the small intestine)
Expressed mainly by epithelial cells of the respiratory tract the urogenital tract and the skin.
Phagocytosis by macrophages provides a first line of cellular defense against invading microorganisms
Ligand binding to neutrophil surface receptor changes in neutrophil adhesion molecules
Assist neutrophils in migrating out of blood capillaries
The homing of neutrophils to infected tissues is induced by inflammatory mediators
Inflammatory mediators (Cytokines) secreted by macrophages change the ligand expression for the neutrophil receptors on the surface of endothelial cells near the site of infection.
This allows the neutrophils to exit the blood near the site of infection = Extravasation
Note that the WBC’s at some point will do something analogous to this process, we are just using neutrophil homing as our model.
Step 1 cytokines/inflammatory mediators induce selectin expression on vascular endothelium to bind neutrophils Transient interaction between neutrophil (sialyl-Lewis X) and selectin on the endothelium
Step 2 Rolling adhesion tight binding migration to infection site Interactions between LFA-1 to ICAM-1 Strong interaction is induced by CXCL8 held on ECM proteoglycans chemokine attraction neutrophil squeezes between endothelial cells
Terms to know
leukotriene LTB4, C5a, histamine
Neutrophils are potent pathogen killers but are themselves programmed to die
Phagocytosis by neutrophils
Phagocytosis of complement opsonized pathogens
On availability of specific Abs
Opsonized with antibody and complement
Neutrophil process of phagocytosis is similar to that of macrophages, but
> range of particulate engulfed
2 types of granules
devoted to storage & delivery of antimicrobial weaponry
Two types of Granules for Killing
Bacterial agents produced or released by phagocytic cells on the ingestion of microorganisms (macrophage & neutrophil) Are toxins or bind to essential nutrients
Pathogen engulfed by neutrophil degradative enzymes/toxins fusion of phagosomes with neutrophil granules