Tolerance and autoimmunity Flashcards by Anas A

What type of immune response is involved in autoimmunity?

Hence, state which cell type is always involved in autoimmunity?

Adaptive immune response with specificity for self “antigens” (autoantigens)

Lymphocytes

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What proportion of people have lymphocytes with the capability of recognising self-antigens?

ALL of us – this is normal autoimmunity

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What factors cause the breakdown of self tolerance which results in the transition from normal autoimmunity to autoimmune disease?

Genetic susceptibility

Environmental factors

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What are the criteria for disease to be ‘autoimmune’?

Evidence of disease-specific adaptive immune response
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

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Give more details on the genetic/environmental factors associated with autoimmune diseases.

Sex - women more susceptible
Infections
Diet - obesity, high fat, effects on gut microbiome
Stress
Microbiome - perturbation may help trigger autoimmune disease

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Why are autoimmune conditions chronic?

Because self-tissue is always present

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The effector mechanisms in autoimmunity resemble those of which type of immune reaction?

Hypersensitivity reactions (types 2, 3 and 4)

*Mechanisms are the same as in normal responses against foreign antigens (both B cells (antibody) and T cells can be involved)

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What proportion of people affected by autoimmune disease are female?

Approx. 80%

note that this changes between diseases

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What is a possible reason for the increase in incidence of autoimmune disease?

Hygiene hypothesis

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List examples of important autoimmune diseases

Rheumatoid Arthritis
Type I diabetes
Multiple Sclerosis
Systemic Lupus Erythematosus (SLE)
Autoimmune thyroid disease (ATD)

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The description of autoimmune reactions in humans is based on…?

Organs affected
Involvement of what specific autoantigens
Types of immune responses

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Describe the pathophysiology of autoimmune haemolytic anaemia.

There are autoantibodies against red blood cells, which bind to red blood cells and activate complement
This results in clearance and complement-mediated lysis of the autologous erythrocytes

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What is a type II hypersensitivity reaction?

Antibody response against cellular or ECM antigens (insoluble antigens)

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What is a type III hypersensitivity reaction?

Immune complex formed by antibody against soluble antigen (tend to be more systemic than type 2)

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What is a type IV hypersensitivity reaction?

T cell mediated disease – delayed type hypersensitivity

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Give important examples of type 2 hypersensitivity autoimmune diseases.

Autoimmune haemolytic anaemia
Goodpasture's syndrome
Grave's disease
Myasthenia gravis
Pemphigus vulgaris

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In Goodpasture’s syndrome, IgG antibodies bind to what autoantigen? What does this result in?

IgG antibodies bind to the non-collagenous domain of basement membrane type IV collagen in the glomerulus.
This results in deposition of autoantibodies in the renal corpuscle and activation of complement => neutrophil infiltration and kidney damage

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State the autoantigen in Grave’s disease

TSH receptor

State an important type 3 hypersensitivity autoimmune disease. What are the autoantigens?

Systemic Lupus Erythematosus (SLE)

e.g. DNA, histones, ribosomes

As well as complement, how else do type II and type III immune reactions recruit inflammatory cells?

Inflammatory cells are recruited via the binding of inflammatory cells to the Fc portion of antibodies via their Fc receptors

Give three important examples of type 4 hypersensitivity autoimmune diseases.
What T cells can be involved?

Insulin-dependent diabetes mellitus
Rheumatoid arthritis
Multiple Sclerosis

Cytotoxic (CD8+) and helper (CD4+) T cell responses
can be involved

What is the autoantigen in multiple sclerosis?

Myelin basic protein

Recall the normal T-cell response to antigens.

T-cell receptor of T-helper cell binds to antigen presented on MHC II (by APC), with co-stimulation by its CD4 receptor.
T-cell receptor of cytotoxic T-cell binds to antigen presented on MHC I (by APC), with co-stimulation by its CD8 receptor.

What is the dominant genetic factor affecting susceptibility to autoimmune disease?

HLA class II alleles

What did the freemartin cattle and experiment show about tolerance?

It showed that early exposure to foreign antigens allows the development of tolerance to those specific antigens

Define immunological tolerance.

The acquired inability to respond to an antigenic stimulus

What are the main features of immunological tolerance?

It is acquired It is antigen specific It is an active process in neonates, the effects of which are maintained throughout life

What are the two types of immunological tolerance?

``` Central Tolerance (happens during lymphocyte development) Peripheral Tolerance ```

What are the three main mechanisms of peripheral tolerance?

- anergy - active suppression (regulatory T cells) (- immune privilege, ignorance of antigen)

Describe the selection process for T-cells in the thymus which explains central tolerance (of T-lymphocytes)

Those that are useless – don’t recognise MHC at all => die by apoptosis Those that are useful – associate weakly with MHC => receive signal to survive (“Positive selection”) Those that are dangerous – associate too strongly with MHC => receive signal to die by apoptosis (“Negative selection”)

What percentage of thymocytes survive selection?

What class of immunoglobulin are the B cell surface receptors?

IgD and IgM

- Where do B cells get selected for and where do they mature? - What happens to B cells that recognise soluble autoantigens?

Bone marrow; they then migrate to secondary lymphoid organs where they mature. - They will migrate to the periphery but they do not express normal levels of IgM and they are anergic (they are not very responsive)

What is the role of the AIRE transcription factor?

It is important for the low-level expression of a large variety of self-peptides in the thymus (by Medullary Thymic Epithelial Cells), against which the T cells are selected

What is APECED caused by?

(= Autoimmune polyendocrinolpathy candidiasis ectodermal dystrophy) Caused by a mutation in the AIRE transcription factor => no clonal deletion of self-reactive T cells so they get released into the circulation and can cause autoimmune disease

Most autoimmune diseases are associated | with multiple defects and genetic traits, for example...

In SLE: Genes affecting multiple biological pathways (in induction of tolerance, apoptosis, clearance of antigen) may lead to a failure of tolerance .

Why is peripheral tolerance important?

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

What is anergy caused by?

Naïve T-cells require costimulation for full activation: CD80, CD86 and CD40 are examples of costimulatory molecules expressed on APC. Without costimulation then cell proliferation and/or factor production does not proceed Subsequent stimulation leads to a refractory state termed ‘ANERGY’

When/where does immunological ignorance occur?

- Occurs when the antigen concentration is too low - Occurs when relevant antigen presenting molecule is absent - Occurs at immunologically privileged sites where immune cells cannot normally penetrate e.g. in the eye, CNS/PNS and testes This is ignorance – the T cells never see their antigen

State and describe an example of a failure of ignorance.

Sympathetic ophthalmia Damage to the eye can release eye antigens into the lymphatics and lymph nodes These antigens are recognised by T cells, which become activated against the eye antigens The T cells then go back to both eyes and cause damage

What are the main receptors expressed by for regulatory T-cell? State an essential transcription factor for regulatory T-cell development.

CD4 CD25 = IL-2 receptor, which is an important growth factor for T cells CTLA-4 – binds to B7 and sends a negative signal FOXP3 – essential transcription factor for Treg development

Give an example of a rare disease caused by a failure in the regulation of peripheral tolerance through regulatory T-cells.

IPEX

What is IPEX caused by?

Mutation in FOXP3 | => leads to the accumulation of autoreactive T cells

State 7 ways in which infections can affect the tolerant state?

- Molecular mimicry of self-molecules - Induce changes in the expression and recognition of self proteins - Induction of costimulatory molecules or inappropriate MHC class II expression (by the pro-inflammatory environment) - Effects on Tregs - Immune deviation: shift in type of immune response - Activation of APCs by pathogens leading to upregulation of costimulatory molecules - Tissue damage at immunologically privileged sites