Immunity to infection

Most microorganisms arriving at the

external surfaces of the body fail to

establish a colony.

Those which are able to colonize, have the

ability to overcome the physical and

physiological barriers which protect the

surfaces of the body.

Even then the majority of colonizing

organisms do not penetrate the body's

surface and are called commensal bacteria.

Those organisms which are capable of

both colonizing and invading are called

pathogens.

Exceptions are those organisms (almost

all are intestinal bacteria) that cause

disease by secreting toxins which damage

the host without the organisms themselves

penetrating the body surface.

The defense systems can be divided into

Immediate

Early

Late

The Immediate defence systems

The immediate defence (first wave) of the body

against an invasion must be in the hands of

preformed molecules.

Complement

The most important immediate defender is

the C3 component of complement.

The activated C3 which initiates alternative

pathway, is continually generated at a low

rate (C3 'tickover').

Normally activated C3 is short lived but it can

covalently attach to a protein or carbohydrate

surface, recruit the serum factor B which is a

substrate for the protease factor D, generating

the active C3 convertase.

In a host cell, regulators of the complement

system rapidly inactivate the C3 convertase.

However a pathogen lacks the host regulatory

proteins and thus the C3 convertase rapidly

amplifies itself.

In addition some microbes catalyse the

binding of another serum component, P

(properdin) which significantly stabilizes the

convertase and prevents its' inactivation by the

soluble inhibitor factor H.

Complement alone is able to destroy some pathogens, primarily gram +ve bacteria by

activation of the terminal complement

components and assembly of the membrane

attack complex.

Complement also serves to activate the acute inflammatory response.

The C5a fragment is a potent chemoattractant for neutrophils and activates vascular

endothelium directly.

C5a also activates mast cells which amplify the inflammatory signals by releasing their

preformed vasoactive mediators.

Phagocytes

Macrophages are resident in almost all

tissues and are found in particularly large

numbers in mucosal tissues.

Neutrophils are present in the blood in very

large numbers, they can be rapidly

recruited to any site which activates

complement.

Both types of phagocytes possess

receptors which enable them to bind and

phagocytose microbial organisms.

These receptors recognize carbohydrate

structures which are not present on host cells

including certain mannose linkages (Mannose-

fructose receptor) and lipopolysaccharide on

gram -ve bacteria (CD14).

Both type of phagocytes also possess receptors

for C3b which potently stimulate phagocytosis.

Once organisms are engulfed, they are subject to

a battery of chemical and enzymatic attacks

which in many cases destroy them.

'Natural' antibody

Even when an organism is encountered for

the first time there may be some IgM

antibody which may bind to its' surface

structures. This is called 'natural' antibody.

Even very low affinity reactions with IgM

can produce binding and classical pathway

complement activation when the target is a

bacterial carbohydrate due to the density

of epitopes on the microbial surface.

Early Immune responses (4-96 hrs)

The second wave of defence is primarily

triggered by the de novo synthesis of cytokines.

MacrophagesThe secondary effects of recognition of

microbial pathogens via either the innate

carbohydrate receptors or the complement

receptors is to activate macrophages to

synthesize cytokines.

In particular TNF, IL12 and IL1 play an important role in the second phase response.

TNF is critical in activating local vascular endothelium.

This results in increased vascular permeability

leading to supply of complement (and other serum

effector proteins when present) and increased fluid

drainage to the lymph node.

This leads to recruiting of polymorphs and

macrophages which in turn activates platelet

activation and clotting.

The effect of local vessel clotting is important to

prevent spread of the pathogen into the blood stream.

TNF also 'primes' neutrophils, causing them to activate oxygen-dependent intracellular killing

mechanisms and making them more effective.

In synergy with IL1, TNF stimulates the

acute phase response which triggers massive

increases in the serum concentration of Mannose

Binding Protein and C Reactive protein.

These molecules provide additional means

to recognize the invaders.

Both bind simple chemical structures on

microbial cells, both have specific receptors on

phagocytes and both are capable of activating

the complement system mimicking C1q and IgM

respectively.

Natural Killer (NK) cells

These lymphocytes lack the antigen

specific receptors of T and B cells.

They are part of the innate immune

system and they play an important role in

viral infections.

They are activated by the cytokines

IL12 and IFN /.

NK cell attacking an infected cell

Interferon

Interferon / are produced by a variety of cells in response to viral infection. They have an

important role in limiting viral infection in the

early phase.

They do this both directly and indirectly.

They act on a wide variety of cell types to

induce the synthesis of a series of proteins which

interfere with viral replication both by degrading

RNA and by inhibiting protein synthesis.

They also potently activate NK cells.

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B-Late Immune responses

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Summary of the phases of the immune response

Immediate Early Late

0-4hrs 4-96hrs >96hrs

Type Innate Innate Specific

Key molecules Complement Complement IgM and IgG antibody Histamine etc IL-1,TNF ,IL12 IL2,IL4,IL12,IFN

IFN /MBP, CRP

Key cells Macrophages Macrophages T cells Mast cells Neutrophils B cells

Neutrophils NK cells Macrophages

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After nearly 4 days the specific immune response

starts.

During the early phase APC have carried

peptides resulting from the degradation of the

proteins from the infecting microorganism to the

local lymph node and presented them in MHC

bound form to T cells.

This process allows the rare (~1 per 106)

antigen specific T cells to encounter the

presented peptide-MHC complex as the T cells

traffic through the lymph node.

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One of the early responses to this specific recognition is 'shut down', i.e., inhibition of exit of

lymphocytes from the local lymph node resulting

in accumulation of cells at the site of infection.

Antigen-specific B cells acquire antigen via their surface IgM, process and present this antigen via

their MHC class II molecules.

The innate response also plays a significant role.i.e.

It has been shown that activation of the antibody response is many times more efficient if the

antigen is bound to C3d.

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The activation of T cells leads to the clonal proliferation of antigen-specific cells and to the

production of effector T cells, such as TH1 cells

and cytotoxic T cells (CTL).

Essentially two types of effector T cells are vital

in the clearance of different sorts of infection.

TH1 cells recruit and activate

macrophages by secreting appropriate

cytokines.

CTL are able to recognize cells harbouring

intracellular pathogens which are out of reach

of humoral immunity

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Specific Antibody

The interaction of specific TH cells with B cells leads to the generation first of a primary IgM-led

antibody response and later to a shift to IgG, IgA

and/or IgE production and to higher affinity

antibodies (affinity maturation).

Specific antibody clearly plays an important role in clearing many primary infections.

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The presence of IgM is detectable after 5 days following antigen entry and peaks between 2-3

weeks.

The IgG response is delayed by about 4-5 days and persists much longer.

IgM primarily acts as an activator of the complement system.

IgG can also do this but in addition it signals further effector mechanisms via the Fc receptors

on phagocytes, eosinophils and mast cells.

.

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Different immune effectors protect against

different pathogens

The immune system has to cope with a

spectrum of pathogens which have distinct

lifestyles and obviously different arms of

the immune system are needed in different

situations.

On top of this many pathogens have

evolved specific counter measures which

limit or inhibit the effectiveness of the

immune response.

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We can divide the type of pathogens as

follows:

Extracellular organisms

bacteria

multicellular eukaryotes (parasites)

Intracellular organisms

bacteria

protozoa

viruses

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Extracellular organisms

Bacteria

These are probably the simplest type

of organism to combat and in many cases

the innate immune system may be able to

clear an infection using complement and

phagocytosis.

Specific antibody is highly effective,

both by directing complement lysis and

inducing opsonisation and phagocytosis.

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Bacteria

Some bacteria have evolved capsules whichprevent recognition by innate mechanisms and

require both antibody and complement

opsonisation to promote efficient clearance by

phagocytes.

Where toxins are produced, antibody is of course vital to neutralize it (antitoxin).

IgA plays an important role againstorganisms that infect mucosal surfaces

(respiratory tract, gut, genito-urinary tract).

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Parasites

Large, multicellular parasites present a special problem to the immune system and indeed are rather

poorly eliminated.

The mechanisms deployed include antibody directed complement attack and ADCC, in particular

by eosinophils.

Innate immunity is generally ineffective.

The parasites employ many evasion strategies including complement inhibitors, release of large

quantities of soluble antigen and acquisition of host

proteins.

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Intracellular organisms

Bacteria and Protozoa

Many bacteria have evolved resistance to

the killing mechanisms used by phagocytes.

These pathogens actively replicate inside

cells, either in the phagosome or, in some cases

where a specific adaptive mechanism has been

acquired, in the cytoplasm.

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Bacteria and Protozoa

This type of bacteria cannot be eliminated by immediate immune mechanisms.

T cell activation is required and a TH1 response is necessary for clearance of the organism.

Memory T cells are the key players in protecting against most intracellular bacteria and parasites.

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Viruses

Viruses are a very diverse group of obligateintracellular pathogens.

Almost every form of immunity comes into playagainst some types of virus.

Enveloped viruses can be damaged bycomplement attack, and some directly bind C1q

or homologous collectins.

Phagocytes can take up and destroy antibodyand complement coated viruses.

However the key players in antiviral immunityare interferon, NK cells, antibody, CTL and TH1

cells taken in a time-specific order in a first

encounter.

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Viruses

Protection against subsequent challengevaries with the behaviour of the virus but

antibody is highly effective in preventing

reinfection if it is of the right type and against the

appropriate epitope.

Because of the slower response time, T cellmemory is rarely able to prevent the

establishment of a secondary infection but is of

considerable importance in limiting its' spread.