Immunology 2: Tolerance and autoimmunity Flashcards
Describe the changes from normal autoimmunity to autoimmune disease
Genetic and environmental factors can cause the break down of self tolerance leading to autoimmunity.
Define autoimmunity
Adaptive immune responses with specificity for self antigens (autoantigens)
What are the criteria for disease to be autoimmune?
- Evidence of disease-specific adaptive immune response (B cells/T cells) in the affected target tissue, organ or blood
- Passive transfer of autoreactive cells or antibodies replicates the disease. IgG across the placenta if mother has graves disease.
- Elimination of the autoimmune response modifies disease
- History of autoimmune disease (personal or family), and/or MHC associations
List the genetic and environmental factors that cause autoimmunity?
Genes: twin and family studies, GWAS (e.g. 40 key loci in SLE). If 1 identical twin has type 1 DM then the other twin will most likely have it as well.
Sex: women more susceptible. 80% of all cases in females. (e.g. 9:1 in SLE). See slide 10 - there is a difference in incidence between the diseases.
Infections: inflammatory environment
Diet: obesity, high fat, effects on gut microbiome: diet modification may relieve autoimmune symptoms
Stress: physical and psychological, stress-related hormones
Microbiome: gut/oral microbiome helps shape immunity, perturbation (dysbiosis) may help trigger autoimmune disease (sex differences?)
Describe the mechanisms of autoimmunity
Adaptive immune reactions against self use the same mechanisms as immune reactions against pathogens (and environmental antigens)
Autoimmune diseases involve breaking T-cell tolerance
Because self tissue is always present, autoimmune diseases are chronic conditions (often relapsing)
Effector mechanisms resemble those of hypersensitivity reactions, types II, III, and IV
What is the impact of autoimmune diseases?
See slides for figures
The incidence of autoimmune disease (and hypersensitivity) is increasing (hygiene hypothesis)
List examples of important autoimmune diseases
- Rheumatoid Arthritis
- Type I diabetes
- Multiple Sclerosis
- Systemic Lupus Erythematosus (SLE)
- Autoimmune thyroid disease (ATD): including Hashimoto’s and Graves’ disease
See slides for figures
How do you describe autoimmune reactions in humans?
Organs affected - can be organ specific or multi-sysetmic. slide 13 for examples
Involvement of specific autoantigens
Types of immune responses
What is responsible for autoimmune haemolytic anaemia in humans?
Autoantibodies against red blood cells were responsible for autoimmune haemolytic anaemia in humans. Specific autoantigens identified for various autoimmune diseases.
Result in the clearance or complement-mediated lysis of autologous erythrocytes
Direct link between autoantibodies and disease (also antibody transfer experiments)
What are the immune reactions known to play a direct role in the pathology of human autoimmune disease?
Antibody response to cellular or extracellular matrix antigen (type II) - Antigens on the surface of cells or matrix.
Immune complex formed by antibody against soluble antigen (type III). e.g antigens-antibody complexes in blood vessels
T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV) - not antibody mediated. CD4+ T helper
Describe Goodpasture’s syndrome
Autoantigen: Non-collagenous domain of basement membrane collagen type IV
Glomerulonephritis, pulmonary haemorrhage
What causes Graves’ disease
Caused by the stimulation of TSH receptors by anti-TSH receptor antibody.
Give an example of type III immunity?
SLE - systemic lupus erythematosus
Autoantigen: DNA, histones, ribosomes, snRNP, scRNP
Causes: Glomerulonephritis (because immune complexes often get deposited in the glomerulus), vasculitis, arthritis
Type II vs type III
Mechanism is the same just the location is different:
Type II - matrix
Type III - circulation
List some type IV autoimmunity diseases (T-cell mediated)?
Insulin-dependent DM,
Autoantigen: Pancreatic beta-cell antigen - results in beta cell destruction
Rheumatoid arthritis, Autoantigen: Unknown synovial joint antigen
Multiple Sclerosis
Autoantigen: Myelin basic protein, proteolipid protein
Cytotoxic (CD8+) and helper (CD4+) T cell responses can be involved
What is the normal T-cell response to antigens?
Antigen is presented to T-cells by MHC expressed on the surface of antigen-presenting cells.
TCR = T cell receptor
MHC I = TCR CD8
MHC II = TCR CD4
The response is proliferation and function? T cells can either be CD4 or CD8
What is the dominant genetic factor affecting susceptibility to autoimmune disease?
Human MHC (HLA region) class II –> targets CD4 T cells
Give evidence for the concept of tolerance against self?
See slide 26 - evidence that if you’re exposed to something in utero you won’t have an immune reaction to it when you’re an adult.
TIMING AND EXPOSURE IS IMPORTANT.
TOLERANCE ALSO HAS SPECIFICITY.
Define immunological tolerance?
The 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 two types of tolerance?
Central tolerance - is the process of eliminating any developing T or B lymphocytes that are reactive to self.
Peripheral tolerance
- anergy
- active suppression
- immune privilege, ignorance of antigen
Failure in one or more of these mechanisms may result in autoimmune disease
Describe central tolerance
See slide 30 and 31.
Pre-T-cells go to thymus. T-cells recognise peptides present on MHC in the thymus.
What is the thymus selection?
T cells: only 5% survive
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”
Describe B-cell tolerance
This takes place in the bone marrow. See slide 35
What is APECED?
Caused by mutations in one protein - AIRE (autoimmune regulator) This is a transcription factor expressed in the thymus and is involved in the negative selection of self reactive T-cells in the thymus.
Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy. RARE
Slide 38
38
What are the mechanisms required to prevent mature lymphocytes becoming auto-reactive and causing disease?
- anergy
- suppression by regualtory T cells
- (ignoarance of antigen)
What is anergy?
Naïve 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 termed ‘ANERGY’
What is immunological ignorance?
Occurs when antigen concentration is too low in the periphery
Occurs when relevant antigen presenting molecule is absent: most cells in the periphery are MHC class II negative
Occurs at immunologically privileged sites where immune cells cannot normally penetrate: for example in the eye, central and peripheral nervous system and testes. In this case, cqells have never been tolerised against the auto-antigens
Describe the failure of ignorance?
Example: Sympathetic opthalmia.
Slide 43. add
Suppression/regulation
slide 44
Describe a condition wher the failure in the regulation of peripheral tolerance occurs?
IPEX
Does infection ‘break’ peripheral tolerance?
Yes - streptococci rheumatic fever
How can infections affect the tolerant state?
- Molecular mimicry of self molecules
- Induce changes in the expression and recognition of self proteins
- Induction of co-stimulatory 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
