Immuno 2: Tolerance & autoimmunity

Question 1

Define autoimmunity

Answer 1

adaptive (i.e. b and t cell) immune responses with

specificity for self “antigens” (autoantigens)

Question 2

What leads to autoimmue disease

Answer 2

Normal autoimmunity –>autoimmune after

BREAKDOWN OF SELF TOLERANCE (affected by genetic and environmenta factors)

Question 3

T/f health people have no autoimmunity

Answer 3

F..

Question 4

What are the criteria for the disease to be autommune

Answer 4

Evidence of disease-specific adaptive immune response in the affected target tissue, organ or blood

Passive transfer of autoreactive cells or antibodies replicates the disease

Elimination of the autoimmune response modifies disease

History of autoimmune disease (personal or family), and/or MHC associations

Question 5

Why might a baby experience graves at the beginning of life but not after

Answer 5

At first, maternal IgG can cross the placenta

This can be auto-IgG

But after a while then the baby will make their own antibodies (which might not include a graves autoantibody)

Question 6

What are the genetic evidence relating to AI disease

Answer 6

twin and family studies, GWAS (e.g. 40 key loci in SLE)

Question 7

What environmental factors can affect chances of AI disease

Answer 7

Sex

Infections

Diet

Stress

Microbiome

Question 8

T/F men are more likely to get SLE than females

Answer 8

F (e.g. F:M is 9:1 in SLE)

Question 9

Why do infections predispose to AI

Answer 9

inflammatory environment

Question 10

How does sex affect chances of AI disease

Answer 10

women more susceptible

Question 11

How can diet affect chances of AI disease

Answer 11

obesity, high fat, effects on gut microbiome: diet modification may relieve autoimmune symptoms

Question 12

How can stress affect chances of AI disease

Answer 12

physical and psychological, stress-related hormones

Question 13

How can microbiome effect AI isease

Answer 13

gut/oral microbiome helps shape immunity, perturbation (dysbiosis) may help trigger autoimmune disease (sex differences?)

Question 14

What are the mechanisms of autoimmunity

Answer 14

Autoimmune diseases involve breaking T-cell tolerance (even in antibody mediated, IgG antibodies are present, so class switching must take place)

Effector mechanisms resemble those of hypersensitivity reactions, types II, III, and IV

Chronic conditions

Adaptive immune reaction

Question 15

How is body’s response to autoantigens different to pathogen

Answer 15

Adaptive immune reactions against self use the same mechanisms as immune reactions against pathogens (and environmental antigens)

Question 16

Why are autoimmue disease chronic conditions

Answer 16

Because self tissue is always present, autoimmune diseases are chronic conditions (often relapsing)

Question 17

How many autoimmune diseases

How many affected by AI disease

What proportion of AI are in women

Answer 17

100

8%

80% in women

Question 18

T/F there is a higher number of males with Diabetes mellitus than female

Answer 18

T (so not always the case that more common in female)

Question 19

What happens to rheumatoid and SLE in pregnancy and why

Answer 19

Rheumatoid can get better (due to less inflammatory responses in pregnancy)

SLE worse as antibody mediated

Question 20

List examples of important AI disease

Answer 20

Multiple Sclerosis
Rheumatoid Arthritis
Type I diabetes
SLE 
Autoimmune thyroid disease

Question 21

How have autoimmue reactions between described

Answer 21

Organs affected

Involvement of specific autoantigens

Types of immune responses

Question 22

Which diseases are mostly organ-specific, which are systemc and which are both

Answer 22

Graves’ disease Thyroid

Hashimoto’s thyroiditis Thyroid

Type I diabetes Pancreas

Goodpasture’s syndrome Kidney

Pernicious anaemia Stomach

Primary biliary cirrhosis Liver, Bile

Myasthenia gravis
Muscles

Dermatomyositis/Polymyositis Skin/ Muscles

Vasculitis
Blood vessels

Rheumatoid Arthritis Joints

SLE
Multiple targets

Question 23

How was it shown that autoantibodies play a role in autoimmune disease

Answer 23

Early experiments showed that autoantibodies against red blood cells were responsible for autoimmune haemolytic anaemia in humans

• Result in the clearance or complement-mediated lysis of autologous erythrocytes
• Direct link between autoantibodies and disease (also antibody transfer experiments)

Question 24

What are the immune reactions involved in autoimmunity

Answer 24

Antibody response to cellular or extracellular matrix antigen (Type II)

Immune complex formed by antibody against soluble antigen (Type III) (go into circulation i.e immune complex)

T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV)

Question 25

Examples of type II immune reactions in AI

Answer 25

ANTIBODY TO INSOLUBLE ANTIGEN E.g. Goodpasture's, leads to Ab binding to type 4 collagen e.g. in BM of kidney --> neutrophil and complement recruitment. IgG (needs T cell breakdown of tolerance to allow this class switching from IgM) E.g in Grave's, AB binds to TSH receptor, stimulates it so that it doesn't have negative feedback (i.e. it is constitutively on, ignoring the fact that TSH would be low)

Question 26

Outline type 3 immune reactions example

Answer 26

SLE.... immune compexes with DNA, histones, ribosomes, snRNP and scRNP Immune complex deposition in glomerulus Glomerulonephritis

Question 27

Differentiate type II and type III disease

Answer 27

Basically the same mechanism -Inflammatory cells (neutrophils and macrophages) are activated by Fc receptor of Ab bound to auto-antigen, and also activated by complement -The difference is that the type II is happening against EC matrix./membrane bound insoluble antigen, and antibody binding causes cell destruction, whereas type III involves soluble antigen, which are not bound to cell surface. Only when the immune complex gets deposited, will it recruit the immune cells.

Question 28

Give examples of type IV disease. Name the autoantigen and the pathologyin each case

Answer 28

Mostly T cell mediated , both CD8+ and CD4+ Initial triggers are mostly T cell, but then can have antibody too Insulin-dependent diabetes mellitus (NOTE, YOU MIGHT THINK THIS WOULD BE TYPE II BUT IT'S NOT!): Autoantigen: Pancreatic b-cell antigen Pathology: b cell desturction RA: AA:Unknown synovial joint antigen Pathology: Joint inflammation and destruction MS AA: Myelin Basic Protein, Proteolipid protein Pathology: Brain degeneration (demyelination), weakness/paralysis

Question 29

Ho are antigens presented in normal T cell response

Answer 29

MHC II- CD4 receptor MHC I- CD8 receptor

Question 30

Which genes are associated with AI disease

Answer 30

Human MHC (HLA) CLASS 2!!!! Is the dominant genetic factor affecting susceptibility to autoimmune disease especially on the DR (remmeber that these genes are highly polymorphic, and some variations are associated with increased risk of AI disease)

Question 31

What do HLA associations imply

Answer 31

HLA associations strongly imply a role for T cells in initiating autoimmune disease

Question 32

Define immunological tolerance

Answer 32

Defined as the acquired inability to respond to an antigenic stimulus

Question 33

What is immunological tolerance based on

Answer 33

3 As: Acquired -involves cells of the acquired immune system and is ‘learned’ Antigen specific Active process in neonates, the effects of which are maintained throughout life

Question 34

How does self tolerance work How can it lead to autoimmune disease

Answer 34

Central tolerance -deletion of auoreactive cells in primary lymphoid organ Peripheral tolerance - Anergy - Active suppression using regulatory T cells - immune privilege, ignorance of antigen (note that this is difference to B cell ignorance in the bone marrow, where the bone marrow does not contain high enough amounts of the autoantigen, so the b cell is released into periphery and can cause autoimmune disease) Failure in one or more of these mechanisms may result in autoimmune disease

Question 35

Outline T cell maturation with regard to tolerance

Answer 35

Central tolerance T cell precurosrs go from bone marrow to thymus Selection process after generation of the TCR Based on the peptides presented by the thymic epithelium cells and dendritic cells (enabled by AIRE) CD4+ selected on MHC II presenting peptides CD8+ selected on MHC I presenting peptides. 95% of developing lymphocytes do not survive! Those that remain will see self-MHC and bind it weakly and not cause autoimune disease

Question 36

Outline B cell maturation

Answer 36

If there is no self reaction, they become mature B cell and express IgG and IgM, and migrate to periphery *Crosslinking of surface immunoglobulin by polyvalent antigens expressed on bone marrow stromal cells facilitates deletion (or receptor editing* If cells react with soluble self antigen with fairly low affinity, they are released into the circulation but they are ANERGIC and express IgD (non-functional). Reside in 2o lymphoid tissue IMPORTANT: Finally, they can react weakly or not at all with self antigen, but have receptors that would recognise autoantigen, if it was presented in the bone marrow in high enough amounts, and thus migrate to periphery and have potential to cause autoimmune disease. I.e. they are ignorant in the bone marrow, but could then see their antigen in the periphery

Question 37

Outline T cell selection in the thymus

Answer 37

Useless (can’t see MHC): die by apoptosis Useful (see MHC weakly): receive signal to survive. “Positive selection” Dangerous (see self strongly): receive signal to die by apoptosis. “Negative selection”

Question 38

Which types of B cells can cause the autoimmue disease

Answer 38

The B cells which bind with low affinity, and don't cross link when exposed to self molecule in the bone marrow, can migrate to the periphery as a mature B cell. These can cause autoimmune disease

Question 39

What can cause APECED

Answer 39

``` Autoimmune PolyEndocrinopathy- Candidiasis- Ectodermal Dystrophy ``` Caused by mutations in AIRE (autoimmune regulation) AIRE is important for the expression of “tissue-specific” genes in the thymus, contained in medullary thymic epithelial cell (mTEC) Involved in the negative selection of self reactive T-cells in the thymus You get persistence of autoreactive cells, and this shows central tolerance is necessary

Question 40

What is AIRE

Answer 40

A transcription factor

Question 41

.....

Answer 41

......

Question 42

t/f like APECED, most AI disease are monogenic

Answer 42

F Most autoimmune diseases are associated with multiple defects and genetic traits In SLE genes affecting multiple biological pathways may lead to failure of tolerance 40-50 genes implicated in genetic susceptibility

Question 43

What gene defects might lead to SLE

Answer 43

induction of tolerance (B lymphocyte activation: CD22, SHP-1): autoantibody production apoptosis (Fas, Fas-ligand): failure in cell death clearance of antigen (Complement proteins C1q, C1r and C1s): abundance/persistence of autoantigen

Question 44

When might peripheral tolerance be needed

Answer 44

Some antigens may not be expressed in the thymus or bone marrow, and may be expressed only after the immune system has matured

Question 45

Why would you not get T reaction when it is presented with a self antigen

Answer 45

Naïve T-cells require costimulation for full activation: CD80, CD86 and CD40 are examples of costimulatory molecules expressed on APC These are absent on most cells of the body So not likely to activate T cells, and the cells then become anergic

Question 46

Give an example of costimulation

Answer 46

CD80/86 (APC) and CD28 (T cell) APCs upregulate costimulation due to PRRs

Question 47

When does immunological ignorance occur

Answer 47

Occurs when antigen concentration is too low in the periphery Occurs when relevant antigen presenting molecule is absent: most cells in the periphery are MHC class II negative (remember, you need MHC II for T cells to mount a response) Occurs at immunologically privileged sites where immune cells cannot normally penetrate: for example in the eye, (central and peripheral nervous system) and testes. In this case, cells have never been tolerised against the auto-antigens

Question 48

Give an example of breakage of ignorance

Answer 48

Sympathetic opthalmia Trauma to one eye result in release of sequestered intraocular protein antigens Released intraocular antigens are carried to lymph odes and activate T cells Effector T cells return via blood stream vand attack antigens in both eyes

Question 49

What are Tregs?

Answer 49

Autoreactive T-cells may be present but do not respond to autoantigen DUE TO PRESENCE OF: Regulatory T-cells…..CD4+CD25+CTLA-4+FOXP3+

Question 50

How does Treg work

Answer 50

CD25 is the Interleukin-2 Receptor CTLA-4 binds to B7 and sends a negative signal FOX P3 is a transcription factor required for regulatory T-cell development CONTROL BOTH CD4+ AND CD8+ T CELLS

Question 51

What happens when FOXP3 is mutated

Answer 51

IPEX (not that this is a failure in regulation of PERIPHERAL tolerance, whereas AIRE and the APECED associated with it, are failures of CENTRAL tolerance) IPEX: Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome Fatal recessive disorder presenting early in childhood Mutation in the FOXP3 gene which encodes a transcription factor critical for the DEVELOPMENT of regulatory T-cel

Question 52

What are the symtpoms of IPEX

Answer 52

``` early onset insulin dependent diabetes mellitus severe enteropathy eczema variable autoimmune phenomena severe infections ```

Question 53

Give example of infeciton associated with developing an AI disease

Answer 53

Rheumatic fever/myocarditis: streptococci

Question 54

How could tolerance deplete self tolerance?

Answer 54

Molecular mimicry of self molecules (if pathogen has similar molecule to self molecules) Induce changes in the expression and recognition of self proteins Induction of co-stimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment Failure in regulation : effects on regulatory T-cells Immune deviation: shift in type of immune response e.g. Th1-Th2 Tissue damage at immunologically privileged sites

Question 55

What is anergy

Answer 55

Costimulation is required to mature a naive T cell. Costimulatory molecules include CD80/CD86/CD40. They are expressed on APC. But absent on most cells in the human body. Without costimulation, the T cell will not proliferate, nor will factors be produced. Subsequent stimulation of the T cell leads to a refractory state= ANERGY