Immunology

Question 1

What does immunological tolerance do?

Answer 1

Serves to protect us from self-reactive lymphocytes.

Question 2

What tissues comprise central tolerance?

Answer 2

Thymus - T cells

Bone marrow - B cells

Question 3

What tissues comprise peripheral tolerance?

Answer 3

Secondary lymphoid organs

Peripheral tissue

Question 4

What are the 4 mechanisms used to induce tolerance to self-reactive lymphocytes?

Answer 4

To delete (eliminate the problem)

To anergise (switch off the problem)

To ignore (ignore the trigger)

To regulate (contain the problem)

Question 5

What mechanisms are used for central B cell tolerance?

Answer 5

Deletion and anergy

Question 6

What mechanisms are used for peripheral B cell tolerance?

Answer 6

Ignorance/anergy/death - lack of co-stimulation/T cell help

Question 7

Which is more efficient - T or B cell tolerance?

Answer 7

T cell tolerance is more efficient

Question 8

What happens in central B cell tolerance when there’s a low-affinity non-cross-linking self molecule?

Answer 8

There’s binding to one arm, but there’s no cross-linking, meaning there’s not enough affinity to trigger the immature B cell. The cell can still mature because it has the antigen receptors on its surface, but because of its low affinity, it is clonally ignorant.

Question 9

What happens to an immature B cell in central tolerance when it encounters a multivalent self molecule?

Answer 9

There is extensive cross-linking and rather than turning off the cell, the cell death program is initiated in the immature B cell and it apoptoses.

Question 10

What happens to an immature B cell in central tolerance when it encounters a soluble self molecule, e.g. a serum protein?

Answer 10

B cell is triggered, but because it is immature, it migrates to the periphery, resulting in an anergic B cell.

Question 11

In peripheral B cell tolerance, which 2 signals are needed for a mature B cell to respond and survive?

Answer 11

1. Signals via the surface Ig-Ag interaction
2. T cell help – CD40L, and some cytokines

Question 12

How long is B cell life span in the absence of T cell help?

Answer 12

Short

Question 13

When does peripheral B cell tolerance also occur?

Answer 13

Post-somatic hypermutation

Question 14

What will happen when a naïve B cell sees an antigen?

Answer 14

Naïve B cell can see the antigen

Activation of the CD4 compartment simultaneously, providing the ligand.

Initial response will be crosslinking and a commitment to differentiating into a plasma cell

Because the signals from CD4 aren’t there, it will be short lived with a low affinity antibody and won’t be isotype switched in the domain

B cell dies

Question 15

What happens when a naive B cell sees an antigen as well as CD4?

Answer 15

Cells transition into germinal centre of lymph node

Isotype switching

High affinity antibodies from plasma cells or generation of memory

Question 16

What does peripheral B cell tolerance rely on?

Answer 16

T cell tolerance working

If a CD4 T cell is not self-reactive then there’s no way a self-reactive B cell is going to be able to get going very well.

Question 17

In the absence of CD4 T cell help, will there be production of antibody from a naive B cell?

Answer 17

Yes, but it’s transient

The antigen is low affinity and because the plasma cells are terminally differentiated, it dies off.

Question 18

Why are self-antigens often seen after infection?

Answer 18

There is release of self-antigens from damaged cells and it may trigger self-reactive B cells in the periphery.

Question 19

Why won’t self antigens released from damaged cells after infection trigger self-reactive B cells in the periphery?

Answer 19

Because there’s no CD4 help that is specific for the self-antigens, there’s no cognate help and therefore no robust response in the domain.

Question 20

How is antigen recognition different between B and T cells?

Answer 20

B cells see whole proteins (or components of whole proteins/pathogens)

T cells see peptide fragments that are processed and presented in the context of MHC molecules

Question 21

Why are T cells technically self-reactive?

Answer 21

Because they have to see a self antigen (the MHC complex)

Question 22

Where do T cells develop?

Answer 22

In the thymus

Question 23

How do T cells develop in the thymus?

Answer 23

Early T-lineage precursor receives signals and progresses through different stages to DN thymocyte.

DN thymocytes are commited to T cell lineage but don’t express co-receptors like CD8.

Beta chain is rearranged (checkpoint):

If functional, commited to double positive stage (alpha chain of the alpha-beta heterodimer (the receptor) is expressed at cell surface).

If they see MHC I they will commit to CD8, if they see MHC II they will commit to MHC II.

This is called positive selection.

Question 24

What is positive selection of thymocytes (T cell precursors)?

Answer 24

Double positive (DP) thymocytes undergo 2 selection processes following the expression of a TCR

Thymocytes that express TCRs capable of recognising self-MHC are selected to survive.

Only thymocytes that express TCRs capable of recognising self-MHC are selected to survive.

Question 25

What is negative selection of thymocytes (T cell precursors)?

Answer 25

Removal of immature lymphocytes that have strong reactivity to self-peptide. This is the major mechanism by which T cells are deleted if they react too well to self MHC and self-peptides. Removal of immature lymphocytes that have strong (e.g. too good) reactivity to self peptide.

Question 26

What is T cell selection dependent on?

Answer 26

Receptor affinity for self pMHC (Goldilocks Theory) If there’s not enough interaction (not positive selection) or if the TCR sees self and MHC too well, T cells will die. There’s a sweet spot, where positive selection and commitment to a mature T cell occurs.

Question 27

What is AIRE?

Answer 27

**A**uto**i**mmune **r**egulator of **e**xpression. Some tissue specific antigens are expressed in thymic medullary epithelial cells under control of the AIRE (autoimmune regulator of expression) transcription factor AIRE randomly distributes itself wherever DNA is accessible or open and can turn on gene expression non-specifically.

Question 28

What does AIRE do?

Answer 28

AIRE randomly distributes itself wherever DNA is accessible or open and can turn on gene expression non-specifically. Two things happen here: Gene expression that is not normally associated with the thymus, e.g. pancreatic tissue, in the medullary epithelial cells. As a consequence, there is processing of the proteins and presentation by MHC class I and if an immature thymocytes sees it, it will be deleted. Because there’s a massive deregulation of transcription in these cells, death will often be induced. Resident dendritic cells will then pick up the dead cells/debris and present them to an auto-reactive T cell and then there will be deletion.

Question 29

What happens if there's a defect in AIRE?

Answer 29

A defect in AIRE is a defect in the ability to present antigens that would be used to delete T cells, which is why carriers of the mutation present with multisystem/multiorgan autoimmune disease.

Question 30

What does central T cell tolerance involve?

Answer 30

Immature/developing lymphocytes and occurs in primary lymphoid organs: Deletion Selection of T_regs

Question 31

What does peripheral T cell tolerance involve?

Answer 31

Mature lymphocytes and occurs in secondary lymphoid organs and peripheral tissues: Deletion Anergy Ignorance Regulation

Question 32

What is the schamatic for naive lymphocyte circulation in ignorance?

Answer 32

Naive lymphocytes enter lymh nodes from blood Antigens from sites of infection reach lymph nodes via lymphatics Lymphocytes and lymph return to blood via the thoracic duct.

Question 33

What is the two signal theory for activation of naive T cells in anergy?

Answer 33

In the periphery, 2 main signals are needed to induce a mature T cell response: Stimulation via the TCR on the T cell Co-stimulation via CD28 and CD80 on the dendritic cell. Without co-stimulation, T cell becomes anergic

Question 34

What do T_reg cells express?

Answer 34

High levels of IL-2 receptor alpha TGF-beta IL-10 Expression associated with FOX-P3 transcription

Question 35

What is a key identifier of T_reg cells?

Answer 35

FOX-P3 (transcription factor)

Question 36

What can T_regs do?

Answer 36

Suppress all manner of helper T cell and CD8 cell responses. It’s not just in terms of tolerance that they’re important but also to help attenuate inflammatory responses against viral infections.

Question 37

What are the most prominent suppressors of immune suppression?

Answer 37

T_regs

Question 38

What are the 2 different types of T_regs?

Answer 38

nTregs (natural) – derived from the thymus during T cell development iTregs (induced) – derived following activation of naïve CD4 T cells in the presence of TGF-beta

Question 39

What do iT_regs do?

Answer 39

Secrete immunosuppressive cytokines – IL-10 and TGF-beta Express CTLA4 and inhibit co-stimulation Release molecules that create a suppressive environment

Question 40

How does CTLA4 work?

Answer 40

CTLA4 also binds B7, but it’s also a competitor for CD28 in that it has higher affinity for the costimulatory molecules. As a consequence, if there are high levels or a high concentration of CTLA4 on the cell surface, it can start to inhibit the ability of naïve T cells to sustain their activation.

Question 41

What is autoimmunity?

Answer 41

Loss of the tolerance mechanism

Question 42

What happens in loss of tolerance?

Answer 42

Immature developing lymphocytes in primary lymphoid tissue that react to self antigens are removed (clonal selection) Failure to remove the auto-reactive lymphocyte leads to generation of loss of tolerance.

Question 43

Which 3 key components are needed in the pathogenesis of autoimmune disease?

Answer 43

**Genetic susceptibility:** especially for T cell autoimmune diseases, like diabetes or MS. **Environmental:** e.g. stress or malnutrition **Loss of self-tolerance: **Can be induced by either of the two above

Question 44

Why are circulating autoreactive lymphocytes not always activated?

Answer 44

Antigen is not available Absence of signal 2 - To get immune response need danger signal to activate DCs, supply co-stimulation - might get T cell help from somewhere else

Question 45

What is the difference between autoimmune response and autoimmune disease?

Answer 45

Continued damage promotes lymphocyte activation. There’s inflammation, so there’s secondary signals and there are going to be self-antigens that might otherwise be sequestered. See image

Question 46

Do autoimmune responses always result in autoimmune diseases?

Answer 46

No

Question 47

Do all autoimmune diseases involve autoimmune responses?

Answer 47

Yes

Question 48

What does autoimmunity result from?

Answer 48

**Chronic** (ongoing) autoimmune responses with **ongoing tissue damage**.

Question 49

What are the 2 classifications of autoimmune diseases?

Answer 49

Organ-specific and systemic

Question 50

What is organ-specific autoimmune disease?

Answer 50

Confined to particular organs or cell types and the antigens recognized are organ specific. E.g. thyroid, ovarian, islet cells, gastric parietal cell (pernicious anaemia); neurological: MS, myasthenia gravis

Question 51

What is systemic autoimmune disease?

Answer 51

Multiple tissues of the body are targeted and the antigens recognised are more ubiquitous. E.g. rheumatoid arthritis, systemic lupus erythematosus (SLE)

Question 52

What are the normal effector mechanisms in response to self antigens?

Answer 52

**B cells – production of auto-antibodies**: Type II (including ligand mediated reactions), immune complex deposition (Type III) **CD4 and CD8 T cells: ** DTH responses (TH1 activation of macrophages, cytokine production, pro-inflammatory mediator release) CTL killing of stromal cells Provision of B cell help **Macrophages** Nitric oxide, proteases, oxidative radicals

Question 53

What can loss of central self tolerance be due to?

Answer 53

Autoimmune polyendocrinopathy-candiadiasis ectodermal dystrophy **Defect in the AIRE gene** Decreased central tolerance Multi-system autoimmunity

Question 54

What can loss of peripheral tolerance be due to?

Answer 54

Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked Defect in the Foxp3 gene Loss of Tregs and peripheral tolerance mechanism Multi-system autoimmunity

Question 55

What are some diseases resulting from B cell mediated autoimmunity?

Answer 55

Grave’s disease (stimulating Ab) Myasthenia Gravis (inhibitory Ab) SLE (immune complex deposition)

Question 56

What are some diseases resulting from T cell mediated autoimmunity?

Answer 56

Insulin dependent diabetes mellitus (IDDM) Multiple sclerosis

Question 57

What happens in Type 1 insulin dependent diabetes mellitus (IDDM) Juvenile onset diabetes?

Answer 57

Organ specific, T cell mediated (both CD4 and CD8) Autoimmune destruction of pancreatic β-cells (insulin producing) Characterised by infiltration of lymphocytes, weak autoantibody response, T cell reactivity to islet proteins Gradual loss of insulin secretion, and resultant insulin dependence Occurs more frequently in people with HLA DR3-DQ2 and DR4-DQ8

Question 58

What happens in multiple sclerosis?

Answer 58

Polygenic degenerative disorder of the CNS that results in episodes of paralysis during formative disease, with chronic paralysis in the latter stages CD4 T cells specific for myelin antigens promote an inflammatory response and degrade the myelin sheaths covering nerve axons Th1 and Th17 responses are detrimental Th2 responses associated with remission Dysregulation of Tregs has been associated with MS HLA-DR15 and HLA-DQ6 associated with disease

Question 59

How do autoimmune diseases begin?

Answer 59

Circulating B cell binds self antigens released from injured cells B cell is activated by a T cell specific for self peptide B cells differentiate into plasma cells, secreting large amounts of self-antigen specific antibody At sites of injury, self-antigen specific antibody initiates an inflammatory response, causing more injury More B cells bind self antigens, amplifying the cycle of tissue damage

Question 60

What is the role of infection in initiation of autoimmune disease?

Answer 60

Infection with microorganism Get exposure of self antigens due to dying cells Infection can activate DCs (e.g. TLR signalling), providing co-stimulation

Question 61

What is the role of autoreactive lymphocyte activation in initiation of autoimmune disease?

Answer 61

**Molecular mimicry** Antigens from pathogen are similar in shape to autoantigens Able to cross react with autoreactive T cells/B cells