L17- Immunological Tolerance and Autoimmunity

Question 1

Define immune tolerance

Answer 1

The failure to mount an immune response to an antigen

Question 2

Define self-antigen

Answer 2

A molecule which can induce an immune response in another organism but to which the healthy immune response of the parent organism is tolerant

Question 3

Define non-self

Answer 3

Molecules that originate outside the host and which can induce an immune response in the host

Question 4

Define self-tolerance

Answer 4

The state in which the host immune system includes mature lymphocytes do not function when self-antigen is recognized.

Question 5

Define autoimmunity

Answer 5

A breakdown or failure of self-tolerance such that lymphocytes specific for self-antigen are activated

Question 6

Define autoantibodies

Answer 6

Antibodies produced against self-antigen. Autoreactive T cells are those T cells that are activated by self-antigen

Question 7

Define central tolerance

Answer 7

Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides.

Question 8

Where does central tolerance occur for B cells?

Answer 8

For B cells, this is dependent on self antigens being available in the bone marrow so that recognition can occur

•  Some autoreactive B cells emigrate from the bone marrow, these must be eliminated or inactivated in the periphery – this is called peripheral tolerance

Question 9

Where does central tolerance occur for T cells?

Answer 9

In the thymus

Question 10

What process assists central tolerance?

Answer 10

This process, known as V(D)J recombination, is important because it increases the receptor diversity which increases the likelihood that B cells and T cells will have receptors for novel antigens.

Question 11

Why is junctional diversity so important?

Answer 11

Junctional diversity occurs during recombination and serves to further increase the diversity of BCRs and TCRs. The production of random TCRs and BCRs is an important method of defense against microbes due to their high mutation rate. This process also plays an important role in promoting the survival of a species because there will be a variety of receptor rearrangement within a species meaning that there is a very high chance of at least one member of the species having receptors for a novel antigen.

Question 12

What process has to occur after V(D)J recombination takes place, what needs to happen for differentiation into an immature B cell?

Answer 12

Once a rearrangement light has paired with a μ chain, IgM can be expressed on the pre-B cell surface and it differentiation into an immature B cell. At this stage the BCR is tested for reactivity to self-antigen.

Question 13

Why are autoreactive B cells eliminated, and where are they eliminated?

Answer 13

Elimination or inactivation of autoreactive B cells ensures the B cell population will be tolerant of self-antigen. Eliminated in the bone barrow as central tolerance.

Question 14

What happens if self-reactive B cells escape central tolerance and leave the bone marrow?

Answer 14

Self-reactive B cells are eliminated in a series of checkpoints that are triggered by antigen binding. Recent reports have shown that in addition to the processes of elimination at the immature B-cell stage, B-cell anergy and regulation of T-cell help, self-reactive cells are also controlled by follicular competition, Fas-mediated elimination by T cells and censoring in the germinal centres. Each checkpoint operates at a threshold that reflects the need to maintain immune diversity at the same time as suppressing autoimmune disease.

Question 15

Can a typical multivalent self molecule induce clonal deletion is MHC?

Answer 15

Yes

Question 16

There are four possible fates for self-reactive immature B cells, depending on the nature of the ligand to which they are capable of binding. What are they?

Answer 16

1. Cell death by apoptosis
2. The production of a new receptor by receptor editing
3. The induction of a permanent state of unresponsiveness to antigen
4. Clonal ignorance

Question 17

What is the outcome for B cells under central tolerance for no self reaction?

Answer 17

Migrates to periphery to become immature B cell as normal

Question 18

What is the outcome for B cells under central tolerance for low-affinity non-crossing self molecule?

Answer 18

Migrates to periphery. =Clonally ignorant

Question 19

What is the outcome for B cells under central tolerance for soluble self antigen?

Answer 19

Migrates to periphery. Anergic B cell. CENTRAL TOLERANCE.

Question 20

What is the outcome for B cells under central tolerance for multivalent self molecule?

Answer 20

Clonal deletion or receptor editing. Apoptosis or generation of a non-autoreactive mature B cell. CENTRAL TOLERANCE

Question 21

What is the outcome for T cells under central tolerance?

Answer 21

Mechanism: Deletion editing

Site of action: Thymus, bone marrow

Question 22

Where does peripheral tolerance occur?

Answer 22

Failure of peripheral tolerance in secondary lymphoid tissue

Question 23

Explain how the strength of TCR binding to MHC determines positive or negative selection.

Answer 23

No interaction: Death by neglect; apoptosis.

Low-affinity interaction: T cell survives. Becomes a CD4 or CD8. Positive selection.

High-affinity interaction: Apoptosis (negative selection), central tolerance

Question 24

Define anergy

Answer 24

Anergy is a term in immunobiology that describes a lack of reaction by the body’s defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal immune response against a specific antigen, usually a self-antigen. Lymphocytes are said to be anergic when they fail to respond to their specific antigen. Anergy is one of three processes that induce tolerance, modifying the immune system to prevent self-destruction (the others being clonal deletion and immunoregulation).

Question 25

Anergic B cells cannot be activated by helper T cells. T or F?

Answer 25

True

Question 26

A typical multivalent self molecule which can induce clonal deletion is...?

Answer 26

MHC

Question 27

What does the autoimmune regulator gene ‘AIRE’ promote?

Answer 27

Promotes the expression of some host tissue antigens in thymic medullary cells, causing the deletion of immature thymocytes that can respond to these antigens. Without AIRE, T cells reactive to tissue-specific antigens mature and leave the thymus where they can cause destruction on tissues with that antigen e.g. endocrine issues

Question 28

People with defective AIRE expression develop an autoimmune syndrome called...?

Answer 28

autoimmune polyendocrinopathy-­‐candidiasis-­‐ectodermal dystrophy (APECED) (also known as Whitaker syndrome)

Question 29

What is Whitaker syndrome?

Answer 29

Also known as AIRE- Leads to the destruction of multiple endocrine Issues, including the insulin-producing pancreatic islets

Question 30

What happens to auto reactive T cells that emerge from the thymus?

Answer 30

Autoreactive lymphocytes which encounter their cognate antigen for the first time in the periphery can undergo deletion or anergy, or they can survive

Question 31

Self antigen is also known as...?

Answer 31

Autoreactive cells

Question 32

What happens if auto-reactive lymphocytes encounter their cognate antigen in the periphery for the first time?

Answer 32

They undergo deletion via apoptosis or anergy, or they can survive (can become autoimmune disease)

Question 33

Interaction of a lymphocyte receptor with cognate antigen in the absence of co-stimulation induces tolerance. Explain this.

Answer 33

Infection induces inflammation, which upregulates the expression of co-­stimulatory molecule on the antigen‐presenting dendritic cell and the production of cytokines promoting lymphocyte activation. In the absence of infection/Inflammation DC can still process and present antigen to CD4 T cells but co-­stimulatory molecules are not present and ligation of the DC MHC/peptide complex by the CD4 TCR results in T cell anergy

Question 34

What is GRAIL?

Answer 34

Gene Related to Anergy in Lymphocytes

Question 35

What does GRAIL do?

Answer 35

GRAIL is another way in which there is blocking of TCR signalling and subsequent proliferation in auto-reactive cells. It does this by targeting components of CD3 (the signalling component of the TCR) for degradation in the proteosome.

Question 36

APC’s deliver three kinds of signals to naïve T cells. What are they and why are they not enough alone?

Answer 36

1. MHC to TCR (Activation) 2. B7 to CD28 (Survival) 3. Cytokines (Differentiation) B7 to CD28 is a co-stimulatory molecule. Alone it has no effect on T cell. MHC to TCR is an antigen specific signal but activated alone will cause inactivation (anergy) or deletion of the T cell.

Question 37

What are the requirements for the development of autoimmune diseases?

Answer 37

1. Genetic factors 2. Infection and environment exposure 3. Immune regulation 4. Autoimmunity In genetically predisposed individuals, autoimmunity may be triggered as a result of the failure of intrinsic tolerance mechanisms and/or environmental triggers such as infection.

Question 38

Lymphocytes that bind self antigens with low affinity usually ignore them but can sometimes be activated. Provide an example how they can become activated.

Answer 38

Autoimmune diseases can be caused by activation of ignorant B cells for example, B cells which are specific for unmethylated CpG DNA •  Unmethylated CpG DNA is more common in bacterial than mammalian DNA, but is enriched in mammalian cells undergoing apoptosis. During infection, extensive cell death and inadequate clearance of apoptotic fragments can result in activation of the previously ignorant specific B cell.

Question 39

Anti-antibodies are produced in autoimmune diseases. Name one disease effected by this.

Answer 39

SLE- systemic lupus erythematosis.

Question 40

What are immunologically privileged sites?

Answer 40

Tissue grafts placed in certain sites of the body do not induce immune responses. *   Antigens from these sites do leave and interact with T cells, this interaction induces tolerance instead of T cell activation that is destructive to tissue *   Privileged sites are generally surrounded by tissue barriers that exclude naïve lymphocytes (eg. the blood-­brain barrier)

Question 41

Name a few immunologically privileged sites

Answer 41

``` Brain Eyes Testis Uterus Hamster cheek pouch ```

Question 42

How does autoimmunity occur around immunologically privileged sites if they’re in areas that don’t induce an immune response?

Answer 42

These sites are surrounded by extracellular fluid which is able to communicate with other body systems through lymphatics, CSF etc. Antigens in these sites can activate lymphocytes if the encounter occurs outside the site. If these activated lymphocytes are not tolerized autoimmune disease can result.

Question 43

What is an example of an autoimmune disease from an immunologically privileged site?

Answer 43

Brain: Multiple sclerosis Eye: Sympathetic opthalmia

Question 44

What is sympathetic opthalmia?

Answer 44

Trauma to one eye results in the release of sequestered intraocular protein antigens. These antigens migrate to lymph nodes and activate T cells. The effector T cells return via periphery to eyes to encounter antigen. This often attacks both eyes. Immunosuppression or removal of the damaged eye to remove source of antigen is only way to protect other eye.

Question 45

What is the role of regulatory T cells?

Answer 45

To suppress the immune system.

Question 46

Regulatory T cells (Treg) can suppress self-­reactive T cells that recognize antigens from those recognized by the Treg –What is this process called?

Answer 46

Regulatory tolerance

Question 47

What type of cells are Treg?

Answer 47

Mainly CD4+ T cells

Question 48

What do Treg release in order to stop T cell proliferation?

Answer 48

CD4+ Treg express CD25, and express the transcription factor FoxP3, which prevents transcriptional activation of the IL­‐2 gene and production of IL‐2 •  Treg produce the cytokines TGF­‐β and IL‐10, which are immunosuppressive and inhibit T cell proliferation, and reduce expression of MHC Class II and co­stimulatory molecules

Question 49

What cytokines are released to inhibit T cell proliferation and reduce expression of MHC class Ii and co-stimulatory molecules? They can also inhibit other self reactive T cells.

Answer 49

TGF-β and IL-10

Question 50

What is the role of CD25+ natural Tregs?

Answer 50

CD25+ natural Tregs play an important role in suppressing the development of allergic reactions to innocuous environment substances.

Question 51

What is the important role of FoxP?

Answer 51

Transcription factor for Treg is crucial for maintaining suppression of the immune system by preventing transcriptional activation of the IL-2 gene and production of IL-2.

Question 52

What are natural Tregs?

Answer 52

Natural’ Treg cells are CD4+CD25+FoxP3+ T cells that escape deletion in the thymus and when activated in the periphery do not differentiate into cells that can initiate an autoimmune response •  Instead, they inhibit other self-­reactive T cells that recognise self antigen in the same tissue and prevent their differentiation into self-­reactive effector T cells

Question 53

What are induced Tregs?

Answer 53

‘Induced’ Treg develop in the peripheral immune tissues in response to antigens recognised on immature DC’s that produce TGF­‐β in absence of pro-inflammatory cytokines. TGF-­β is immunosuppressive and inhibits IL-2 secretion and also inhibits activation of CD8+ CTL and CD4+ helper T cells.

Question 54

What does TGF-­β do?

Answer 54

TGF-­β is immunosuppressive and inhibits IL-2 secretion and also inhibits activation of CD8+ CTL and CD4+ helper T cells. It is expressed on Treg cells

Question 55

Which type of Treg is involved in oral tolerance, generated in response to food antigens which pass across intestinal mucosa?

Answer 55

Induced Treg. | produce TGF-­β to inhibit IL-2 secretion and activation of CD8+ CTL and CD4+ helper T cells

Question 56

Explain how Treg is important for autoimmune diseases such as colitis

Answer 56

CD4+CD25+ Treg inhibit colitis by migrating to the colon and mesenteric lymph nodes, where they interact with dendritic cells and hyper-­reactive effector T cells. Treg produce IL­‐10, TGF-­β and other regulatory cytokines which reduce T cell activation and inflammation

Question 57

What happens if Treg is absent from autoimmune diseases such as colitis?

Answer 57

Depletion of CD4+CD25+ Treg exacerbates or causes disease

Question 58

Explain the immune dysfunction in HIV infection.

Answer 58

HIV infection is chronic and in the absence of highly active antiretroviral therapy (HAART) high levels of circulating virus provide persistent antigen challenge to virus­‐specific T cells. *   HIV is tropic for CD4+ T cells; infected CD4+ T cells express viral antigen peptide in the context of MHC Class I molecules on their cell surface and are targets for HIV-specific CD8+ CTL. *   CD8+ effector function is suppressed by Treg, the CD8+ response does not clear infection *   CD4+ numbers decline, CD4+ unable to provide T cell help to B cells – reduced class switching and production of neutralizing antibody

Question 59

What happens with chronic T cell activation

Answer 59

Chronic T cell activation leads to exhaustion: anergy and loss of effector function, decreased proliferative potential, increased apoptosis

Question 60

Persistent expression of PD-‐1 on activated CD8+ T cells is associated with ...?

Answer 60

Loss of effector function

Question 61

What does PD-1 do?

Answer 61

PD-1 (programmed cell death-1) acts as an off switch for T cells Binding of PD-1 to PD-1L expressed on potential target cells down regulates T cells effector function

Question 62

How does PD-1 behave in acute and chronic phases of HIV infection?

Answer 62

•  In acute HIV infection; PD-­1 is transiently expressed on CD8+ T cell, does not interfere with viral clearance •  In chronic infection; PD-­1 and its ligand PD­‐1L persistently expressed on on CD8+ T cells and infected cells; CD8+ T cells are constantly activated, become ‘exhausted’: cytokine expression is decreased, cytotoxicity decreased

Question 63

What is molecular mimicry?

Answer 63

Auto-reactive T cells and B cells can be activated through a mechanism of molecular mimicry that involves cross‐recognition of a pathogen antigen that has structural similarities to self antigen. Such auto reactive lymphocytes were not deleted in the bone marrow or thymus and are therefore present in the periphery as ignorant lymphocytes.

Question 64

What can cause auto-reactive T cells to become active at site of infection/inflammation?

Answer 64

Strong pro-inflammatory signals with molecular mimicry.

Question 65

What is a disease that involves auto-reactive T cells becoming active in the form of molecular mimicry?

Answer 65

Rheumatic fever is a disease that frequently occurs after a sore throat or scarlet fever, caused by Streptococcus pyogenes infection. Similarity of epitopes on Strep pyogenes and heart muscle leads to B and T cell responses directed against heart muscle.

Question 66

Many autoimmune diseases are more common in females than males. T or F?

Answer 66

True.

Question 67

Explain how genetic and environment factors can cause autoimmunity.

Answer 67

NOD mice are more likely to develop diabetes, and female mice develop diabetes at a younger age than male mice •  The intestinal microbiota of NOD mice contribute to diabetes: treatment with broad spectrum antibiotics, which reduce or clear commensal bacteria can delay or eliminate disease onset.

Question 68

Predisposition to most autoimmune diseases is due to combined effects of multiple genes. Can you also get mono genie diseases?

Answer 68

Yes. E.g. IPEX is caused by a missense mutations in the FOXP3 gene, which encodes a transcription factor important for differentiation of Treg – outcome is early death. Treg numbers in blood are the same as those for normal humans but cell function is impaired.

Question 69

Autoimmune disease alleles are usually recessive or X-­‐linked. T or F?

Answer 69

True

Question 70

What does IPEX stand for?

Answer 70

IPEX: Immune dysregulation, polyendrocrinopathy, enteropathy, X-­‐linked syndrome

Question 71

Explain how auto-reactive B cells can be stimulated by antigens released from damaged tissue.

Answer 71

*   Intracellular auto-antigens are targets in Systemic Lupus Erythematosis. They are released from injured/dying cells and bind to the BCR of auto-reactive B cells. *   B cell presents peptide to auto-reactive T cell, which activate B cell to differentiate into plasma cell secreting large amounts of antibody *   This anti-­self antibody initiates an inflammatory response and causes more cell damage, in turn activating more auto-reactive B cells.

Question 72

What are some of the symptoms of systemic lupus erythematosis?

Answer 72

1. Butterfly rash on face 2. Pleural effusions 3. Heart problems 4. Lupus nephritis 5. Arthritis 6. Raynaud’s syndrome Symptoms can vary widely between individuals

Question 73

What is multiple sclerosis?

Answer 73

Multiple sclerosis is a chronic demyelinating CNS disease caused by myelin basic protein‐specific T cells; sclerotic plaques form in brain leading to muscle weakness, ataxia, and other symptoms

Question 74

What is multiple sclerosis?

Answer 74

MS is a T cell mediated chronic neurological disease caused by destructive immune response against several brain antigens, including myelin basic protein (MBP) Sclerotic plaques form in brain leading to muscle weakness, ataxia and other symptoms. These plaques show dissolution of the myelin that normally sheathes nerve cell axons, along with inflammatory infiltrates of lymphocytes and macrophages. Activated CD4+ T cells auto-reactive for brain antigens can cross the blood-brain barrier and encounter their specific antigen presented by microglial cells, are phagocytic macrophage like cells resident in brain . •  Inflammation causes increased vascular permeability and the influx of T cells and B cells; Auto-reactive B cells produce autoantibodies against myelin antigens with help from T cells •  Final result is demyelination