Immunology 2: Tolerance and Autoimmunity Flashcards
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
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Define autoimmuity
adaptive immune responses with specificity for self “antigens” (autoantigens)
–> breakdown of self tolerance leads to autoimmune diseases
What are the criteria for disease to be ‘autoimmune’?
- 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
what are the 6 genetic/environmental factors that contribute to autoimmunity?
- 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
describe the mechanism of autoimmunity
- 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
give examples of important autoimmune diseases.
- 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
What are the different types of hypersensitivity diseases?
explain them .
type II
type III
Type IV
- 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)
Type II, antibody to insoluble antigen
describe:
a) Goodpasture’s syndrome
b) Graves’disease
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
Describe Type III: immune complex disease
give an example + explain mechanisms
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
Describe Type IV: T-cell mediated disease?
give an example + explain mechanisms
- e.g Insulin dep diabetes mellitus, rheumatoid arthritis, Multiple Sclerosis
- Cytotoxic (CD8+) + helper (CD4+) T cell responses can be involved
evidence for concept of tolerance against self
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
What are the mechanisms which normally prevent our
immune system from attacking our own tissues?
???
define immunological tolerance ?
what are the 3As ?
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
what are the 2 main mechanisms underlying immunological tolerance?
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)
Describe B cell tolerance
- 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
what is APECED?
Why does APECED occur?
- 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)
note:
Most autoimmune diseases are associated
with multiple defects and genetic traits
some = linked to
- induction of tolerance
- apoptosis
- clearance of antigen
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What are the 3 mechanisms to prevent mature lymphocytes becoming auto-reactive and causing disease?
- Anergy
- Suppression by regulatory T cells
- (Ignorance of antigen)
Describe how anergy occurs?
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’
Describe immunological ignorance
i.e how does it occur?
- 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
What happens when immunological ignorance fails?
i.e what happens in e.g sympathetic ophthalmia?
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
note: don’t have to remember:
regulatory t cells help regulation other cell types
e. g
- CD4+
- CD25+
- FOXP3
FOXP3 = expressed in high level in Treg development
What is IPEX?
when does it present?
why does it occur?
what are the symptoms?
- 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
How do infections affect tolerant state?
How infections can affect tolerant state:
- Mimicry of self-molecules by microbe molecule
- -> pathogen mimics self molecules
- -> T cells then recognizes self tissues - Change in expression + recognition of self-proteins
- -> things not normally expressed are Expressed - APC activation - upregulates co-stimulatory molecules or inappropriate MHC II expression e.g. in pro-inflammatory environment
- Failure in regulation: affects Treg cells
- Immune deviation: shift in type of immune response e.g. Th1 –> Th2
e. g in pregnancy - Damage at immunologically privileged sites
e. g antibodies released in immunologically privileged sites
