Lecture 19

Question 1

What is immune homeostasis?

Answer 1

This is the balance between healthy immune reactions and destructive autoimmune reactions and involves the maintenance of different cell pools such as naïve, effector and memory cells in an equilibrium

Question 2

What are the different major forms of tolerance?

Answer 2

There is central or thymic tolerance where most self-reactive T cells are deleted, peripheral tolerance where there are mechanisms of anergy, deletion and costimulators
There are also populations of regulatory T cells

Question 3

What is the in vivo evidence for regulatory T cells?

Answer 3

Using adoptive transfer models (animals models all have the same MHC molecule) it was found that tolerance could be made to be infectious through the transfer of CD4+ T cells, this effect was also possible through using anti-CD4,8 and CD2 antibodies
The CD4 T cells were found to be suppressive towards other CD4 T cells as well as CD8 T cells they both actively suppressed other T cells and guided naïve T cells into a state of tolerance
They are restricted by antigen presented by MHC as other T cells
The regulatory T cells are highly dependent on a continuous supply of antigen and it is thought that they are of intermediate/low affinity for MHCII

Question 4

What are the four T cells with regulatory capacity?

Answer 4

Tr1 and Th3 cells (these may potentially be part of the same subset)
iTregs (inducible)
nTregs (natural)

Question 5

What are the makers of Tr1/Th3 cells?

Answer 5

CD4+, lo CD25, low-mediumCTLA4, lack of FoxP3

Question 6

Where are Tr1/Th3 cells derived from?

Answer 6

Th0, Dendritic cells with the secretion of IL-10/TGFbeta

Question 7

What is the mechanism of action of Tr1/Th3 cells?

Answer 7

They secrete IL-10 and TGFbeta

Question 8

What are the markers of iTreg cells?

Answer 8

CD4+, hi CD25 and CTLA4 and Fox P3+

Question 9

What is the derivation of iTreg cells?

Answer 9

Th0 and Dendritic cells with the presence of TGF-beta

Question 10

What is the mechanism of action of iTreg cells?

Answer 10

These secrete TGFbeta

Question 11

What are the markers of nTreg cells?

Answer 11

CD4+, hi CTLA5 and CD25, FOXP3+

Question 12

What is the derivation of nTreg cells?

Answer 12

Thymic precursors

Question 13

What is the mechanism of nTreg cells?

Answer 13

Cell-cell contact

Question 14

What are the characteristics of CD4+ CD25+FoxP3+ T cells?

Answer 14

CD25 is the IL-2Ralpha chain which is upregulated at T cell activation
These cells express CD25 consituitively in contrast to other T cells and comprise 10% of the peripheral CD4+ T cell population
They suppress induction of autoimmune disease in thymectomized mice or diabetes in NOD mice
They are totally dependent on exogenous IL-2, have an anergic phenotype and are resistant to Sag-induced deletion
The cells originate in the thymus rather than the periphery
Cytokines do not seem to play a role in the actual suppression, instead is mediated by cell-cell contact
They require TCR stimulation to exert their regulatory function

Question 15

What are the characteristics of CD4+CD4RB low T cells?

Answer 15

These are antigen experienced cells as determined by their presence of low CD45RB
They are protective in an autoimmune model for inflammatory bowel disease mediated by naïve T cells
Mediate their regulation through the cytokines TGFbeta and IL-10

Question 16

What are the characteristics of Th3 cells and mucosal tolerance?

Answer 16

Oral administration of myelin basic protein an auto antigen in multiple sclerosis and its mouse model EAE leads to the generation of tolerogenic Tcells
These Th3 cells are autoreactive, recognize MBP as well as the disease inducing Th1 cells
Mechanism of suppression is cytokine mediated through TGFbeta
Intranasal administration of MBP-peptide lead to IL-10 driven protection in EAE
Cells with I-10 and TGFbeta profile were also protective in diabetes and myasthenia gravis model

Question 17

What are the characteristics of Tr1 cells?

Answer 17

These are characterised in mice and humans and are known as type 1 regulatory T cells
Tr1 cells are generated by priming naïve T cells with Il-10 and antigen in vitro
Mechanism of suppression is cytokine-mediated through TGFbeta and IL-10

Question 18

What I the reason to believe that CD4+CD45RB(low)Tcells, Th3 cells and Tr1 cells are actually the same subset?

Answer 18

They are all involved in mucosal tolerance, secrete mainly IL-10 and TGFbeta and can deviate immune stimulation to tolerance by influencing the APCs

Question 19

What is the effect of IgG binding to receptors on B cells?

Answer 19

If a naïve B cell binds antigen and finds no antibody already bound to that antigen then it will go on to proliferate and produce antibody, however if an antibody is already bound to the antigen and the naïve B cell recognizes this through an Fc receptor then this will act as a negative feedback system preventing that B cell from going on to produce more antibody
However if a memory B cell binds antigen and the Fc region of an antibody bound to that antigen then this functions as a positive feedback mechanism to promote antibody production

Question 20

What are the features of the pool of B cells of the immune system?

Answer 20

Naïve B cells have a short life span and are continuously replenished and designed to meet new antigenic challenges
Memory B cells are long lived resulting in useful specificities remaining well represented
The pool is heterogeneous with regards to morphology, location and cell-surface molecules
This heterogeneity alters throughout life due to maturation in response to antigenic stimulation these distinct populations at different times of life

Question 21

What are the features of (CD5) B1 cells?

Answer 21

These are first produced in the fetus and are self-renewing with a high production of antibodies, degenerate specificity and production of much more IgM than IgG, they have no to low somatic hypermutation they respond to polysaccharide antigens and might respond to protein antigens

Question 22

What are the features of (conventional) B2 cells?

Answer 22

These are first produced after birth and renewed through replacement in the bone marrow, these have low production of antibodies they have precise specifities and secrete more IgG than IgM, they have high somatic mutation, might respond to polysaccharide antigens but typically respond to protein antigens

Question 23

What are the properties of B-1 cells?

Answer 23

Expression of the CD5 surface protein which can bind to another B cell surface protein called CD72 which may promote mutual interaction between these B cells
Express IgM with little or no IgD
Relatively low numbers in lymph nodes or spleen
Predominates in pleural and peritoneal cavities
Produce much of the immunogolobulin found in normal serum
Produce predominately IgM
Arise early in ontogeny from immature stem cells most active in the prenatal period
Ig receptors are dominated by VH gene segments closest to D gene segments
Low diversity of V(D)J junctions when compared with conventional B-2 B cells
Few nucleotide insertions in joining regions because TdT is not active in progenitors
Do not undertake somatic hypermutation to form high affinity antibodies
Receptors are polyspecific
Specificity preference for other immunoglobulins, self antigens and common bacterial polysaccharides if the T-independent type
Form an interconnected network

Question 24

What is the relationship between B1 and B2 cells?

Answer 24

B1 cells are produced early and thought to constitute a highly connected network of cells that recognize self antigens and some antigens of common pathogens and may form the initial means of distinguishing self from non-self
During development there is a gradual switch to the production of more convential B cells with a more diverse repertoire of V gene use and rearrangements, these B2 cells thend to be less polyspecific, less self-reactive and more specific for foreign antigens than B1 cells

Question 25

What is the difference in selection by self antigens in B1 and B-2 cells?

Answer 25

B1 cells undergo positive selection through reacting to self while B2 cells undergo negative selection through reacting with self

Question 26

What are thought to be the functions of B-1 cells?

Answer 26

Generation of an idiotype network which may be concerned with self tolerance
Response to conserved microbial antigens
Maintenance of the V gene pool
Idiotypic regulation of B2 cells
Natural antibodies as a preexisiting first line of IgM defence against common organisms, these are generated in germ free animals as a consequence of anti-self responses

Question 27

What is isotypic variation of antibodies?

Answer 27

This is defined by the constant region immunoglobulin chains
Gamma, mew, alpha, eta and delat in Ig Heavy chains
Kappa and lambda in Ig light chains
Alpha, beta, gamma and delta in T cell receptor isotypes

Question 28

What is allotypic variation?

Answer 28

This is the term given to the intraspecies variability seen in the Ig and TcR chains

Question 29

What is idiotypci variation?

Answer 29

This refers to the diversity found within the antigen binding site of Ig and TcR molecules and in particular relates to the hypervariable regions

Question 30

How can idiotypes lead to the formation of an immune network?

Answer 30

Like any other shapes idiotypes are potential antigens, though due to the enormous diversity within hypervariable regions any particular idiotype is likely to be represented in a very low concentration within the receptor repertoire meaning they are not usually in sufficient quantities to be recognized as antigens or be the subject of self tolerance
However when an immune response is generated effectors such as antibodies with specific antigen-binding site structures are produced in large numbers the immune system is then able to respond to this idiotype as if it was a new antigen leading to the production of another idiotype and another reaction etc

Question 31

What are the two types of anti-idiotype antibodies?

Answer 31

Internal images which mimic epitopes of the original antigen and therefore could potentially be used as surrogate antigens for immunisation
Regulatory set which do not mimic the original antigen but can regulate the behaviour of the initial responding cells