lecture 6

Question 1

The time course of an infection can be divided into several distinct phases

Answer 1

Exposure to infective particles from an infected source

First contact with infectious particles often through a mucosal surface, always across an epithelial barrier

Establishment of a focus of infection

Establishment of the disease with accompanying pathology

Stimulation of adaptive immunity

Question 2

The first events following infection

Answer 2

Following infection the first thing to happen is that the tissue becomes inflamed.

This is initially due to the activation of macrophages by bacterial LPS

Then cytokine release (eg TNF alpha) induces cell surface changes on surrounding endothelial cells

P selectin and E selectin are released and up-regulated respectively

This causes changes in the adhesive properties of endothelial surfaces for lymphocytes such that the cells roll and eventually stick to the blood vessel walls, and penetrate the infected area

Question 3

The next event after initial infection stages

Answer 3

Dendritic cells, present in most tissues, take up antigen and become activated.

These cells are then carried away from the site of infection and enter the secondary lymphoid system.

Here they initiate the adaptive immune response by stimulating T cells which can then help in the humoral response and initiate the cellular response.

Question 4

Infections and the responses to them can also be divided into stages

Answer 4

• local infection, penetration of epithelium
• local infection of tissues
• lymphatic spread
• adaptive immunity

Question 5

how many infections are cleared by innate immune mechanisms

Answer 5

it isn’t clear how many infections are cleared by innate immune mechanisms

Deficiencies in non-adaptive immunity are rare, therefore it is difficult to assess their impact.

But- mice that lack macrophages and Polymorphonuclear lymphocytes fail to keep levels of infectious organisms down even though they have an intact adaptive response.

RAG- and SCID humans and animals (-T and B cells) also fail to clear infections

Question 6

The balance of T cell subtype development … stuff?

Answer 6

The balance of T cell subtype development is regulated by cytokines released from dendritic cells

High TGF β favours regulatory T cell development whilst high IL-6 favours TH17 production

The release of IL-17 from these cells induces epithelia to secrete chemokines that attract neutrophils

Question 7

th1 and th2 cells induced by ?

Answer 7

Th1 and Th2 cells are also induced by cytokines produced in response to different pathogens

DIAGRAM IN L6 S10

Question 8

what do T cells produce?

Answer 8

Each subset of T cells produces a characteristic set of cytokines which negatively regulate either the development or activity of other subsets. This can affect the nature of the immune response produced

Question 9

once stimulated, what happens to effector T cells?

Answer 9

Once stimulated , effector T cells change their cell surface adhesion molecules which allows homing to the site of infection.

Naïve T cells express L- selectin which binds to molecules like GlyCAM-1 and allows homing to the lymph nodes

Activated effectors loose L-selectin and express the integrin VLA-4 and increased levels of LFA-1

Effectors also express the shortened type of CD45, CD45RO, which makes the effectors more sensitive to antigen

Question 10

The CD8+ cytotoxic T cell response can occur with or without CD4+ T cell help

Answer 10

T cell help is required when the pathogen fails to cause inflammation.

Pathogens that do cause inflammation activate dendritic cells through the TLR to express costimulatory molecules like B7 and CD40.

Question 11

where does the Antibody response develop?

Answer 11

The Antibody response develops in lymphoid tissues under the direction of TFH cells

Antigen binding B cells express CCR7 and move to the T/B cell area boundary.

Antigen specific T cells are activated by antigen bearing dendritic cells to become TFH.

Interaction between T and B cells produces first a primary focus and then can go on to make a germinal centre

The germinal centres are the location of long-lived plasma cells and high affinity memory B cells.

The responses are also sustained in the bone marrow.

Question 12

what does protective immunity result from?

Answer 12

Protective immunity results from a combination of preformed immune reactants and immunological memory

Question 13

difference between the memory b cell responses and naive B cell responses?

Answer 13

Memory B cell responses differ from naïve B cell responses

naive B cells:
less frequent antigenic-specific B cells
makes more IgM than IgG antibodies
low affinity of antibodies
low somatic hypermutation

memory b cells:
more frequent antigenic-specific B cells
IgG, IgA antibodies
high affinity of antibodies
high somatic hypermutation

Question 14

Memory T cell characteristics

Answer 14

Memory T cells for a given antigen persist at a high level after the end of an immune response (100-1000x the level of initial frequency).

A long-lived population but one which is quite difficult to study.

Express survival molecules Bcl-2 and activation markers like CD44, CD45RO and reduction of L- selectin which prevents homing to the lymph nodes.

Memory T cells require several days to be activated to effector function.

Question 15

The immune system is clever…but pathogens are sometimes cleverer!

Answer 15

In a normal infection an innate response is the initial response followed by an adaptive response which eventually clears the infection.

There are situations when this fails, for example where the pathogen avoids or subverts the immune response, where there are inherited deficiencies in the immune response or where there is a generalised susceptibility to the infection as is the case in HIV infection.

Examples follow of antigenic variation, antigenic shift and drift and latency during infection.

Question 16

Antigenic variation e.g Streptococcus pneumoniae

Answer 16

antigenic variation like Streptococcus pneumoniae

individual infected with one type of S pneumoniae
response clears infection
subsequent infection with a different type of S pneumoniae is unaffected by response to first type
new response clears infection

Question 17

Antigenic variation e.g.Trypanosomes - Genetic rearrangement

Answer 17

The trypanosome has approximately 1000 genes encoding the coat protein VSG which are immunologically distinct.

Only one is expressed at a given time.

When an effective antibody is generated against the trypanosome, gene conversion brings a new gene to the active site of expression.

This has different immunological properties and hence evades existing antibody. The cycle then repeats

Question 18

Antigenic shift and drift e.g. Influenza virus

Answer 18

ANTIGENIC DRIFT

• neutralising antibodies against hemagglutinin block binding to cells
• mutations alter epitopes in hemagglutinin so that neutralising antibody no longer binds

ANTIGENIC SHIFT

• antigenic shift occurs when rna segments are exchanged between viral strains in a secondary host
• no cross protective immunity to virus expressing a novel hemagglutinin

Question 19

Persistence and reactivation e.g. HSV

Answer 19

Some viruses evade the immune response by ‘hiding’.

Some viruses enter a latent state where they do not make viral proteins and so are not eliminated.

Herpes is an example of this which infects epithelia and spreads to sensory neurons where it enters a latent state.

The immune response can clear the epithelial infection, but cannot clear the latent virus where viral proteins are not made.

The virus can be activated by a number of stimuli eg sunlight, hormonal changes where it re-infects epithelia after the initial immune response has died down.