Immuno 2: Tolerance & autoimmunity Flashcards
Define autoimmunity
adaptive (i.e. b and t cell) immune responses with
specificity for self “antigens” (autoantigens)
What leads to autoimmue disease
Normal autoimmunity –>autoimmune after
BREAKDOWN OF SELF TOLERANCE (affected by genetic and environmenta factors)
T/f health people have no autoimmunity
F..
What are the criteria for the disease to be autommune
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
Why might a baby experience graves at the beginning of life but not after
At first, maternal IgG can cross the placenta
This can be auto-IgG
But after a while then the baby will make their own antibodies (which might not include a graves autoantibody)
What are the genetic evidence relating to AI disease
twin and family studies, GWAS (e.g. 40 key loci in SLE)
What environmental factors can affect chances of AI disease
Sex
Infections
Diet
Stress
Microbiome
T/F men are more likely to get SLE than females
F (e.g. F:M is 9:1 in SLE)
Why do infections predispose to AI
inflammatory environment
How does sex affect chances of AI disease
women more susceptible
How can diet affect chances of AI disease
obesity, high fat, effects on gut microbiome: diet modification may relieve autoimmune symptoms
How can stress affect chances of AI disease
physical and psychological, stress-related hormones
How can microbiome effect AI isease
gut/oral microbiome helps shape immunity, perturbation (dysbiosis) may help trigger autoimmune disease (sex differences?)
What are the mechanisms of autoimmunity
Autoimmune diseases involve breaking T-cell tolerance (even in antibody mediated, IgG antibodies are present, so class switching must take place)
Effector mechanisms resemble those of hypersensitivity reactions, types II, III, and IV
Chronic conditions
Adaptive immune reaction
How is body’s response to autoantigens different to pathogen
Adaptive immune reactions against self use the same mechanisms as immune reactions against pathogens (and environmental antigens)
Why are autoimmue disease chronic conditions
Because self tissue is always present, autoimmune diseases are chronic conditions (often relapsing)
How many autoimmune diseases
How many affected by AI disease
What proportion of AI are in women
100
8%
80% in women
T/F there is a higher number of males with Diabetes mellitus than female
T (so not always the case that more common in female)
What happens to rheumatoid and SLE in pregnancy and why
Rheumatoid can get better (due to less inflammatory responses in pregnancy)
SLE worse as antibody mediated
List examples of important AI disease
Multiple Sclerosis Rheumatoid Arthritis Type I diabetes SLE Autoimmune thyroid disease
How have autoimmue reactions between described
Organs affected
Involvement of specific autoantigens
Types of immune responses
Which diseases are mostly organ-specific, which are systemc and which are both
Graves’ disease Thyroid
Hashimoto’s thyroiditis Thyroid
Type I diabetes Pancreas
Goodpasture’s syndrome Kidney
Pernicious anaemia Stomach
Primary biliary cirrhosis Liver, Bile
Myasthenia gravis
Muscles
Dermatomyositis/Polymyositis Skin/ Muscles
Vasculitis
Blood vessels
Rheumatoid Arthritis Joints
SLE
Multiple targets
How was it shown that autoantibodies play a role in autoimmune disease
Early experiments showed that autoantibodies against red blood cells were responsible for autoimmune haemolytic anaemia in humans
- 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 involved in autoimmunity
Antibody response to cellular or extracellular matrix antigen (Type II)
Immune complex formed by antibody against soluble antigen (Type III) (go into circulation i.e immune complex)
T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV)
Examples of type II immune reactions in AI
ANTIBODY TO INSOLUBLE ANTIGEN
E.g. Goodpasture’s, leads to Ab binding to type 4 collagen e.g. in BM of kidney –> neutrophil and complement recruitment. IgG (needs T cell breakdown of tolerance to allow this class switching from IgM)
E.g in Grave’s, AB binds to TSH receptor, stimulates it so that it doesn’t have negative feedback (i.e. it is constitutively on, ignoring the fact that TSH would be low)
Outline type 3 immune reactions example
SLE…. immune compexes with DNA, histones, ribosomes, snRNP and scRNP
Immune complex deposition in glomerulus
Glomerulonephritis
Differentiate type II and type III disease
Basically the same mechanism
-Inflammatory cells (neutrophils and macrophages) are activated by Fc receptor of Ab bound to auto-antigen, and also activated by complement
-The difference is that the type II is happening against EC matrix./membrane bound insoluble antigen, and antibody binding causes cell destruction, whereas type III involves soluble antigen, which are not bound to cell surface. Only when the immune complex gets deposited, will it recruit the immune cells.
Give examples of type IV disease.
Name the autoantigen and the pathologyin each case
Mostly T cell mediated , both CD8+ and CD4+
Initial triggers are mostly T cell, but then can have antibody too
Insulin-dependent diabetes mellitus (NOTE, YOU MIGHT THINK THIS WOULD BE TYPE II BUT IT’S NOT!):
Autoantigen: Pancreatic b-cell antigen
Pathology: b cell desturction
RA:
AA:Unknown synovial joint antigen
Pathology: Joint inflammation and destruction
MS
AA: Myelin Basic Protein,
Proteolipid protein
Pathology: Brain degeneration (demyelination), weakness/paralysis
Ho are antigens presented in normal T cell response
MHC II- CD4 receptor
MHC I- CD8 receptor
Which genes are associated with AI disease
Human MHC (HLA) CLASS 2!!!! Is the dominant genetic factor affecting susceptibility to autoimmune disease
especially on the DR
(remmeber that these genes are highly polymorphic, and some variations are associated with increased risk of AI disease)
What do HLA associations imply
HLA associations strongly imply a role for T cells in initiating autoimmune disease
Define immunological tolerance
Defined as the acquired inability to respond to an antigenic stimulus
What is immunological tolerance based on
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
How does self tolerance work
How can it lead to autoimmune disease
Central tolerance
-deletion of auoreactive cells in primary lymphoid organ
Peripheral tolerance
- Anergy
- Active suppression using regulatory T cells
- immune privilege, ignorance of antigen (note that this is difference to B cell ignorance in the bone marrow, where the bone marrow does not contain high enough amounts of the autoantigen, so the b cell is released into periphery and can cause autoimmune disease)
Failure in one or more of these mechanisms may result
in autoimmune disease
Outline T cell maturation with regard to tolerance
Central tolerance
T cell precurosrs go from bone marrow to thymus
Selection process after generation of the TCR
Based on the peptides presented by the thymic epithelium cells and dendritic cells (enabled by AIRE)
CD4+ selected on MHC II presenting peptides
CD8+ selected on MHC I presenting peptides.
95% of developing lymphocytes do not survive! Those that remain will see self-MHC and bind it weakly and not cause autoimune disease
Outline B cell maturation
If there is no self reaction, they become mature B cell and express IgG and IgM, and migrate to periphery
Crosslinking of surface immunoglobulin by polyvalent antigens expressed on bone marrow stromal cells facilitates deletion (or receptor editing
If cells react with soluble self antigen with fairly low affinity, they are released into the circulation but they are ANERGIC and express IgD (non-functional). Reside in 2o lymphoid tissue
IMPORTANT: Finally, they can react weakly or not at all with self antigen, but have receptors that would recognise autoantigen, if it was presented in the bone marrow in high enough amounts, and thus migrate to periphery and have potential to cause autoimmune disease. I.e. they are ignorant in the bone marrow, but could then see their antigen in the periphery
Outline T cell selection in the thymus
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”
Which types of B cells can cause the autoimmue disease
The B cells which bind with low affinity, and don’t cross link when exposed to self molecule in the bone marrow, can migrate to the periphery as a mature B cell.
These can cause autoimmune disease
What can cause APECED
Autoimmune PolyEndocrinopathy- Candidiasis- Ectodermal Dystrophy
Caused by mutations in AIRE (autoimmune regulation)
AIRE is important for the expression of “tissue-specific” genes in the thymus, contained in medullary thymic epithelial cell (mTEC)
Involved in the negative selection of self reactive T-cells in the thymus
You get persistence of autoreactive cells, and this shows central tolerance is necessary
What is AIRE
A transcription factor
…..
……
t/f like APECED, most AI disease are monogenic
F
Most autoimmune diseases are associated
with multiple defects and genetic traits
In SLE genes affecting multiple biological pathways may lead to failure of tolerance
40-50 genes implicated in genetic susceptibility
What gene defects might lead to SLE
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
When might peripheral tolerance be needed
Some antigens may not be expressed in the thymus or bone marrow, and may be expressed only after the immune system has matured
Why would you not get T reaction when it is presented with a self antigen
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
So not likely to activate T cells, and the cells then become anergic
Give an example of costimulation
CD80/86 (APC) and CD28 (T cell)
APCs upregulate costimulation due to PRRs
When does immunological ignorance occur
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 (remember, you need MHC II for T cells to mount a response)
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, cells have never been tolerised against the auto-antigens
Give an example of breakage of ignorance
Sympathetic opthalmia
Trauma to one eye result in release of sequestered intraocular protein antigens
Released intraocular antigens are carried to lymph odes and activate T cells
Effector T cells return via blood stream vand attack antigens in both eyes
What are Tregs?
Autoreactive T-cells may be present but do not respond to autoantigen
DUE TO PRESENCE OF:
Regulatory T-cells…..CD4+CD25+CTLA-4+FOXP3+
How does Treg work
CD25 is the Interleukin-2 Receptor
CTLA-4 binds to B7 and sends a negative signal
FOX P3 is a transcription factor required for regulatory T-cell development
CONTROL BOTH CD4+ AND CD8+ T CELLS
What happens when FOXP3 is mutated
IPEX (not that this is a failure in regulation of PERIPHERAL tolerance, whereas AIRE and the APECED associated with it, are failures of CENTRAL tolerance)
IPEX:
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-cel
What are the symtpoms of IPEX
early onset insulin dependent diabetes mellitus severe enteropathy eczema variable autoimmune phenomena severe infections
Give example of infeciton associated with developing an AI disease
Rheumatic fever/myocarditis: streptococci
How could tolerance deplete self tolerance?
Molecular mimicry of self molecules (if pathogen has similar molecule to 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
What is anergy
Costimulation is required to mature a naive T cell.
Costimulatory molecules include CD80/CD86/CD40. They are expressed on APC.
But absent on most cells in the human body.
Without costimulation, the T cell will not proliferate, nor will factors be produced.
Subsequent stimulation of the T cell leads to a refractory state= ANERGY
