Tolerance and Autoimmunity

Question 1

Define autoimmunity

Answer 1

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

Question 2

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

Answer 2

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 3

Give examples of genetic and environmental factors that contribute to autoimmune disease

Answer 3

Women more susceptible 
Inflammatory environments
Obesity, high fat
Stress
Microbiome

Question 4

Describe the epidemiology of autoimmune diseases

Answer 4

~5% of people in developed countries are affected by autoimmune disease.
~75% of these are female
The incidence of autoimmunity, like hypersensitivity/allergy, is increasing (via the hygeine hypothesis).

Question 5

What are the major autoimmune diseases

Answer 5

Rheumatoid arthritis (RA)
Type I diabetes mellitus (T1DM)
Multiple sclerosis (MS)
Systemic lupus erythematosus (SLE / lupus)
Autoimmune thyroid diseases e.g. Hashimoto’s and Graves’ disease

Question 6

Describe the mechanisms of autoimmune reactions

Answer 6

Autoimmune reactions use the same mechanisms as immune responses to pathogens.
This involves breaking T cell tolerance
As ‘self’ tissue is always present, autoimmune diseases are always chronic conditions.
The effector mechanisms resemble type II, III, and IV hypersensitivity.

Question 7

Describe the role of autoantibodies in autoimmune diseases using an example

Answer 7

Autoantibodies (aAbs) and levels thereof have a direct link with autoimmune disease.

Autoantibodies to RBCs are responsible for haemolytic anaemia via clearance and also complement activation, which causes systemic effects beyond a lack of RBCs.
Type II and type III hypersensitivity pathways are both involved in this

Question 8

Give examples of immune reactions that 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

Give an example of a disease that is due to type II hypersensitivity and describe it

Answer 9

Graves’

Autoantibodies bind to the TSH receptor on thyroid follicular cells, causing hyperthyroidism

Question 10

Give an example of a disease that is due to type IV hypersensitivity and describe it

Answer 10

T1DM
cell-mediated
T cells react to pancreatic beta-cell antigens and kill the cells

Question 11

What is the role of MHC in antigen presentation

Answer 11

Antigens are presented to T cells by MHC expressed on the surface of antigen-presenting cells

Question 12

What is the role of HLA/MHC

Answer 12

Dominant genetic factor affecting susceptibility to autoimmune disease.

Question 13

Define immunological tolerance

Answer 13

Inability to respond to an antigenic stimulus

Question 14

What are the criteria for immunological tolerance (3A)

Answer 14

Acquired: tolerance involves cells of the acquired/adaptive immune system and is ‘learned’

Antigen-specific

An active process in neonates, the learnings of which are maintained through life

Question 15

Describe the selection of T cells in central tolerance

Answer 15

Immature T cells in the thymus recognise peptides presented on MHCs.
Those that can’t recognise any peptides die by apoptosis
Those that recognise ‘self’ strongly are actively signalled to die by apoptosis (-ve selection)
Those that see MHC weakly are signalled to survive.

Question 16

What percentage of thymocytes survive selection

Answer 16

~5% of immature T cells

Question 17

Describe the selection of B cells in central tolerance

Answer 17

Cross-linking of B cell surface immunoglobulins by polyvalent antigens on bone marrow stromal cells facilitates deletion versus survival

Question 18

Give an example of a disease resulting from failure of central tolerance

Answer 18

APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy)

Question 19

Describe APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy)

Answer 19

Rare
Results from the thymus failing to delete self- reactive T cells
Caused by genetic mutations in a transcription factor called AIRE (autoimmune regulator) which stop it working, so other tissue-specific genes for tolerance-building aren’t expressed.

Question 20

Which tissues are affected by APECED

Answer 20

Endocrine glands
Thyroid
Kidneys
Chronic mucocutaneous candidiasis
Gonadal failure
Diabetes mellitus
Pernicious anaemia

Question 21

What is the importance of development of tolerance in the periphery

Answer 21

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

Question 22

What are the mechanisms of preventing mature lymphocytes becoming auto-reactive and causing disease (peripheral tolerance)

Answer 22

Anergy
Suppression by regulatory T cells
(Ignorance of antigen)

Question 23

What is anergy

Answer 23

Absence of costimulation
Most cells on the body lack costimulatory molecules like CD80/86/40 (found on APCs)
Without costimulation, T cells do not proliferate or produce factors.

Question 24

When does immunological ignorance occur

Answer 24

When antigen concentration is too low in the periphery

When the antigen presenting molecule is absent (most cells have no MHC class II)

Question 25

Where does immunological ignorance occur

Answer 25

At immunologically privileged sites where immune cells can’t normally penetrate, so they lack tolerance to the autoantigens there e.g. the eyes, testes, nervous system

Question 26

Give an example of failure of ignorance and describe it

Answer 26

Sympathetic ophthalmia
When eye trauma allows autoantigens into the blood and into contact with intolerant T cells. The activated T cells then attack those antigens in both eyes.

Question 27

Which cells are involved in control of auto reactive T cells and which receptors are found on it

Answer 27

T-reg

CD4+
CD25+
CTLA-4+
FOXP3+

Question 28

Give an example of a disease that occurs due to a failure of peripheral T cell regulation

Answer 28

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance)
A fatal recessive genetic disease that presents early in childhood
Mutation in FOXP3 (gene encoding a transcription factor essential for T-reg development)
Autoreactive T-cells accumulate

Question 29

What are the clinical features of IPEX

Answer 29

T1DM
Eczema
Severe enteropathy 
Infections
Crazier autoimmune phenomena

Question 30

How can infections break peripheral tolerance

Answer 30

changing expression of ‘self’ proteins (e.g. MHC, costimulatory molecules), affecting T-reg cells, and damaging tissue at privileged sites

Question 31

Give an example of a disease that is due to type III hypersensitivity and describe it

Answer 31

Systemic Lupus Erythematosus
Immune complex deposition in the glomerulus
DNA, histones, ribosomes, snRNP, scRNP
Leads to glomerulonephritis, vasculitis and arthritis

Question 32

What is AIRE

Answer 32

Autoimmune regulator
important for the expression of “tissue-specific” genes in the thymus
Involved in the negative selection of self reactive T-cells in the thymus