Immunology 2: Tolerance and Autoimmunity

Question 1

Tolerance: explain the concept of immunological tolerance, and the mechanisms that underlie such tolerance

Autoimmune disease: explain how defects in tolerance lead to autoimmune diseases, and list factors that may lead to breakdown of self-tolerance

Clinical disease: list examples of important autoimmune diseases, and outline their immunological mechanisms

Answer 1

-

Question 2

Define autoimmuity

Answer 2

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

–> breakdown of self tolerance leads to autoimmune diseases

Question 3

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

Answer 3

• Evidence of disease-specific adaptive immune response e.g B cells, T cells etc. 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 4

what are the 6 genetic/environmental factors that contribute to autoimmunity?

Answer 4

• genes
  e. g if one twin has diabetes –> 50% chance other will also have diabetes
• sex
  (women more susceptible) - 8:2 ratio
• infections (increases inflammatory environment)
• diet (obesity, high fat)
• stress (physical + psychological stress related hormones)
• microbiome

Question 5

describe the mechanism of autoimmunity

Answer 5

• all involve adaptive immune reactions
• all autoimmune disease = involve breaking T cell tolerance
• autoimmune diseases are chronic (usually due to relapsing)

“autoimmunity” = hypersensitivity - against self

Question 6

give examples of important autoimmune diseases.

Answer 6

• Rheumatoid Arthritis
• Type I diabetes:
• Multiple Sclerosis:
• Systemic Lupus Erythematosus (SLE)
• -> tends to be multi systemic disease
• Autoimmune thyroid disease (ATD):
• Graves’ disease
• -> more organ specific disease

Question 7

What are the different types of hypersensitivity diseases?
explain them .

type II
type III
Type IV

Answer 7

• 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 8

Type II, antibody to insoluble antigen
describe:

a) Goodpasture’s syndrome
b) Graves’disease

Answer 8

Goodpasture’s syndrome

• affects kidney
• influx of neutrophils –> cause damage

Graves’ disease

• antibody stimulates TSH receptor
• there is increase in production of thyroid hormones –> hyperthyroidism

Question 9

Describe Type III: immune complex disease

give an example + explain mechanisms

Answer 9

Type III: immune complex disease

• mainly affects the kidneys
• Classic example is SLE - immune complexes deposit e.g. in glomerulus
• Causes glomerulonephritis, vasculitis, arthritis
• Since soluble antigens –> soluble complexes form –> circulate around body + deposit in many sites –> causes inflammation at site of deposition
• different to Type II –> type II has direct binding on cell surface/ECM in given tissue

Question 10

Describe Type IV: T-cell mediated disease?

give an example + explain mechanisms

Answer 10

• e.g Insulin dep diabetes mellitus, rheumatoid arthritis, Multiple Sclerosis
• Cytotoxic (CD8+) + helper (CD4+) T cell responses can be involved

Question 11

evidence for concept of tolerance against self

Answer 11

e.g mice
adults skin graft of mouse = normally rejected
give to neonate mouse –> then give skin graft to adult mouse –> then accepted

–> timing of exposure = also important in autoimmunity

Question 12

What are the mechanisms which normally prevent our

immune system from attacking our own tissues?

Answer 12

???

Question 13

define immunological tolerance ?

what are the 3As ?

Answer 13

acquired inability to respond to an antigenic stimulus

‘The 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 14

what are the 2 main mechanisms underlying immunological tolerance?

Answer 14

CENTRAL TOLERANCE

• T cells = made in thymus
• immature T cells migrate to thymus for maturation –> spread into periphery
• selection process occurs (cant bind to MHC, binds self strongly –> removed, bind weakly to MHC = survives )
• base on peptides –> t cells recognise peptides present on MHC cells in the thymus
• only 5% of thymocytes survive selection
• -> failure = autoimmune diseases

PERIPHERAL TOLERANCE
- Some antigens may not be expressed in thymus or bone marrow, and may be expressed only after maturation of immune system

• Mechanisms needed to prevent mature lymphocytes becoming auto-reactive (in peripheral tolerance)
• -> Anergy
• -> Suppression by Treg cells
• -> (Ignorance of antigen = not coming into contact w/ antigen)

Question 15

Describe B cell tolerance

Answer 15

• Occurs in bone marrow (diagram)
• Anergic B cells = non-responsive, won’t react to T cells; relatively short half-life
• No self-reaction/presentation –> IgM/D surface receptors
• But if developing B cell sees multivalent self-molecule –> cross-linking –> apoptosis or receptor editing = rearrange light chain of surface receptor to become not self-reactive
• When bind soluble self, even if cross-linking –> anergic – short-half-life
• Clonally ignorant cells can become autoreactive b/c recognise self-molecules, even though just weakly

Question 16

what is APECED?

Why does APECED occur?

Answer 16

• multisystem autoimmune disease
• affects many different organs
• caused by mutation in 1 protein = AIRE protein
  AIRE = TF expressed in thymus –> ensures that samples of self cells = presented in thymus (acts as autoimmune regulator) –> if T cell = self reactive they are removed
  (affects negative selection of self reactive T cells)

Question 17

note:
Most autoimmune diseases are associated
with multiple defects and genetic traits

some = linked to

• induction of tolerance
• apoptosis
• clearance of antigen

Answer 17

-

Question 18

What are the 3 mechanisms to prevent mature lymphocytes becoming auto-reactive and causing disease?

Answer 18

• Anergy
• Suppression by regulatory T cells
• (Ignorance of antigen)

Question 19

Describe how anergy occurs?

Answer 19

Naïve T-cells require costimulation for full activation: e.g CD80, CD86 and CD40

• These are absent on most cells of the body

Without costimulation:

• cell proliferation / factor production does not proceed
• -> Subsequent stimulation leads to a refractory state termed ‘ANERGY’

Question 20

Describe immunological ignorance

i.e how does it occur?

Answer 20

• Occurs when antigen concentration = too low in the periphery
• Occurs when relevant APC is absent: most cells in the periphery = MHC class II negative
• Occurs at immunologically privileged sites where immune cells cannot normally penetrate: e.g eye, CNS, PNS, testes. In this case, cells have never been tolerised against the auto-antigens

Question 21

What happens when immunological ignorance fails?

i.e what happens in e.g sympathetic ophthalmia?

Answer 21

e. g sympathetic ophthalmia
- 1 eye hurt –> release of antigens not normally expressed in the eye –> intraocular antigens = exposed to non-tolerised T cells –> T cells activated + now target intraocular antigens in both eyes –> goes damage to both eyes

Question 22

note: don’t have to remember:
regulatory t cells help regulation other cell types

e. g
- CD4+
- CD25+
- FOXP3

Answer 22

FOXP3 = expressed in high level in Treg development

Question 23

What is IPEX?
when does it present?
why does it occur?
what are the symptoms?

Answer 23

• failure in the regulation of peripheral tolerance
• presents early in childhood
• Mutation in the FOXP3 gene –> encodes a transcription factor critical for the development of regulatory T-cells

symptoms:
- early onset insulin dependent - diabetes mellitus
- severe enteropathy
- eczema
- variable autoimmune phenomena
- severe infections

Question 24

How do infections affect tolerant state?

Answer 24

How infections can affect tolerant state:

1. Mimicry of self-molecules by microbe molecule
   - -> pathogen mimics self molecules
   - -> T cells then recognizes self tissues
2. Change in expression + recognition of self-proteins
   - -> things not normally expressed are Expressed
3. APC activation - upregulates co-stimulatory molecules or inappropriate MHC II expression e.g. in pro-inflammatory environment
4. Failure in regulation: affects Treg cells
5. Immune deviation: shift in type of immune response e.g. Th1 –> Th2
   e. g in pregnancy
6. Damage at immunologically privileged sites
   e. g antibodies released in immunologically privileged sites

Question 25

note: IgG antibodies passes across the placenta

Answer 25

-

Question 26

note:
when pregnant - antibody linked = symptoms e.g SLE gets worse
rheumatoid arthritis - when pregnant - get better –> then after birth –> symptom returns

–> due to shift in immune response during pregnancy

Answer 26

-

Question 27

note: MHC class II genes –> dominant genetic factor affecting susceptibility to autoimmune diseases

–> T1DM = DR3/4, Grave’s = DR3, MS = DR2 alleles

Answer 27

HLA associations imply role of T cells in initiating autoimmune disease

Question 28

note: Both B (antibody) + T cells can be involved in AI reactions

Answer 28

-

Question 29

note:
e. g streptococci
- antibodies against streptococci reacts w heart muscle

Answer 29

-

Question 30

induction and maintenance of peripheral tolerance depends on:

Answer 30

• Site of antigen expression
• Timing of antigen expression
• Amount of antigen expression
• Costimulation
• T cell help for B cell responses
• Regulation