Tolerance and autoimmunity

Question 1

What is autoimmunity?

Answer 1

Adaptive (lymphocytes and antibodies) immune responses with specificity for self ‘antigens’ (autoantigens).

Question 2

What is the difference between normal autoimmunity and autoimmune disease?

Answer 2

Genetic and environmental factors cause a breakdown in self tolerance to result in disease from normal autoimmunity.

Question 3

What are the mechanisms of autoimmunity?

Answer 3

Adaptive immune reactions against self use the same mechanism as immune reactions against pathogens (and environmental antigens).
Autoimmune diseases involve breaking T-cell tolerance.
Effector mechanisms resemble those of hypersensitivity reactions, types II, III and IV.

Question 4

What makes autoimmune diseases chronic?

Answer 4

Self tissue is always present.

Question 5

What is the impact of autoimmune disease?

Answer 5

Approximately 100 chronic disorders have been identified which relate to aberrant immune responses causing the body to attack its own tissues.
Approximately 8% of individuals are affected by autoimmune disease.
Approximately 80% of affected individuals are women.
The incidence of autoimmune disease (and hypersensitivity) is increasing (hygiene hypothesis).

Question 6

How are autoimmune diseases described/classified in humans?

Answer 6

Organs affected.
Involvement of specific autoantigens.
Types of immune responses.

Question 7

What is the issue with classifying autoimmune diseases based on the organs affected?

Answer 7

There is a spectrum of autoimmune diseases from organ-specific (e.g. Graves’) to multisystemic (e.g. SLE).

Question 8

Which immune reactions are known to play a direct role in the pathology of human autoimmune disease?

Answer 8

Antibody response to cellular or extracellular matrix antigen (type II).
Immune complex formed by antibody against soluble antigen (type III).
T-cell mediated disease (delayed type hypersensitivity reaction, type IV).

Question 9

List examples of type II (antibody to insoluble antigen) autoimmune diseases.

Answer 9

Autoimmune haemolytic anaemia.
Autoimmune thrombocytopaenia purpura.
Goodpasture's syndrome.
Pemphigus vulgaris.
Acute rheumatic fever.
Graves' disease.
Myasthenia gravis.

Question 10

Give an example of a type III (immune complex disease) autoimmune disease.

Answer 10

Systemic lupus erythematosus- immune complex deposition in glomerulus, joints, skin, etc.

Question 11

Give examples of type IV (T-cell mediated diseases) autoimmune diseases.

Answer 11

Insulin-dependent diabetes mellitus.
Rheumatoid arthritis.
Multiple sclerosis.

Question 12

What is the pathology of rheumatoid arthritis?

Answer 12

Joint inflammation and destruction.

Question 13

What is the normal T cell response to antigens?

Answer 13

Antigen is presented to T cells by MHC expressed on the surface of antigen-presenting cells.
MHC II = CD4
MHC I = CD8
Proliferation.

Question 14

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

Answer 14

Human MHC (HLA) class II.

Question 15

Explain the concept of immunological tolerance.

Answer 15

Acquired inability to respond to an antigenic stimulus.
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 16

What are the 2 types of immunological self tolerance?

Answer 16

Central tolerance
Peripheral tolerance
Failure of these mechanisms may result in autoimmune disease.

Question 17

What are the mechanisms underlying peripheral immunological tolerance?

Answer 17

Anergy
Active suppression (regulatory T cells)
Immune privilege, ignorance of antigen

Question 18

What is central tolerance?

Answer 18

Lymphocytes are derived from stem cells in bone marrow.
Precursors migrate to thymus to develop into T cells.
Rigorous selection process in thymus.
Mature selected T cells enter periphery.
B cells develop in bone marrow and become antibody secreting plasma cells when activated.

Question 19

What are the possible outcomes of selection of T cells in the thymus?

Answer 19

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’.
Only 5% of thymocytes survive selection.

Question 20

How are T cell receptors derived?

Answer 20

Rearrangement of gene segments- random process, potential to develop receptors reactive against self.

Question 21

How do B cells develop in the bone marrow if they do not detect self antigen?

Answer 21

Develop into mature cells and enter periphery, expressing IgM and IgG.

Question 22

How do B cells develop in the bone marrow if they detect multivalent cross-linking antigen?

Answer 22

(e.g. self MHC molecule abundant on surface).
Causes clonal deletion of that cell by apoptosis, or receptor editing- rearrange light chain of surface receptor to become non-autoreactive mature B cell.

Question 23

How do B cells develop in the bone marrow if they detect soluble self molecule?

Answer 23

Migrates to periphery, anergic B cells (non-responsive, can’t be activated by T helper cells), low IgM, express IgE.

Question 24

How do B cells develop in the bone marrow if they detect low-affinity non-cross-linking self molecule?

Answer 24

High levels of surface IgM and IgD expressed, migrate to periphery as clonally ignorant mature B cells- potential to become autoreactive B cells because self molecules are present.

Question 25

What is APECED?

Answer 25

Autoimmune
Polyendocrinopathy
Candidiasis
Ectodermal
Dystrophy
(autoimmune polyglandular disease, APD)
Rare autoimmune disease which affects the endocrine glands: thyroid, kidneys, chronic mucocutaneous candidiasis, gonadal failure, diabetes mellitus, pernicious anaemia.

Question 26

What causes APECED?

Answer 26

Results from a failure to delete T cells in the thymus.
Caused by mutations in the transcription factor AIRE (autoimmune regulator) gene.
AIRE is important for the expression of ‘tissue-specific’ genes in the thymus.
Involved in the negative selection of self-reactive T cells in the thymus.

Question 27

What can failure in central immunological tolerance lead to?

Answer 27

Autoimmunity.

In most diseases, a complex interaction of multiple factors is usually involved.

Question 28

What defects and genetic traits are most autoimmune diseases associated with?

Answer 28

SLE: genes affecting multiple biological pathways may lead to a failure of tolerance (40-50 genes have been implicated in genetic susceptibility).
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 29

What mechanisms are required to prevent mature lymphocytes becoming autoreactive and causing disease?

Answer 29

Anergy
Suppression by regulatory T cells
Ignorance of antigen

Question 30

What is anergy?

Answer 30

Absence of costimulation.
Naive 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.
Without costimulation then cell proliferation and/or factor production does not proceed.
Subsequent stimulation leads to a refractory state- anergy.

Question 31

When may immunological ignorance occur?

Answer 31

Antigen concentration is too low in the periphery.
Relevant antigen presenting molecule is absent: most cells in the periphery are MHC class II negative.
At immunologically privileged sites where immune cells cannot normally penetrate, e.g. in the eye, central and peripheral nervous system and testes. In this case, cells have never been tolerised against the autoantigens.

Question 32

Give an example of failure of immunological ignorance.

Answer 32

Sympathetic ophthalmia.

Question 33

What is the pathogenesis of sympathetic ophthalmia?

Answer 33

Trauma to one eye results in the release of sequestered intraocular protein antigens.
Released intraocular antigens are carried to lymph nodes and activate T cells.
Effector T cells return via bloodstream and attack antigen in both eyes.

Question 34

What is CD25?

Answer 34

Interleukin-2 receptor.

Question 35

What is the role of CTLA4 in suppression/regulation of T cells?

Answer 35

Binds to B7 and sends negative signal.

Question 36

What is FOXP3?

Answer 36

Transcription factor required for regulatory T cell development.

Question 37

What is IPEX?

Answer 37

A failure in the regulation of peripheral tolerance.
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 cells.

Question 38

What are the symptoms of IPEX?

Answer 38

Early onset insulin dependent diabetes mellitus
Severe enteropathy
Eczema
Variable autoimmune phenomena
Severe infections
Accumulation of autoreactive T cells.

Question 39

How can infections affect the tolerant state?

Answer 39

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: 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 40

What does induction and maintenance of peripheral immunological tolerance depend upon?

Answer 40

Site of antigen expression (MHC expression, immune privilege)
Timing of antigen expression
Amount of antigen expression
Costimulation
T cell help for B cell responses
Regulation