lecture 12 Flashcards
- immunological tolerance -- central tolerance -- peripheral tolerance - when tolerance fails -- autoimmune diseases -- allergy
1
Q
What is immunological tolerance?
A
- key feature of the adaptive immune system
- self/non-self discrimination
- occurs in both T cells and B cells
- specific unresponsiveness to an antigen following prior exposure to that antigen
- self antigen
- non-self antigen
2
Q
Who discovered acquired immunological tolerance? How?
A
- Sir Frank Macfarlane Burnet and Sir Peter Medawar
- nobel prize in physiology or medicine in 1960
- showed that the neonatal period is fundamental in the development of tolerance and that it can be produced
- in mice - introduced strain B graft into adult strain A mice –> rejected
- introduced strain B graft into strain A mice that had been injected with spleen cells from strain B during the neonatal period –> accepted
3
Q
Why is tolerance important?
A
- specificity of the adaptive immune system critical
- results from the processes that drive both T cell and B cell diversity during lymphocyte development
- 10^11 different antibody (B cells) and TCR specificities
- self-reactivity can occur and result in host damage
- immune system is in balance between immunity and tolerance
4
Q
What are key factors determining whether an immune response (or tolerance) occurs?
A
- [Ag]
- avidity
- costimuli
- timing and duration
5
Q
What are T cell tolerance mechanisms?
A
Central tolerance
- occurs in the thymus
- positive/negative selection of immature T cells
Peripheral tolerance
- occurs in peripheral tissues
- ‘regulatory’ responses involving mature T cells
- anergy - cell is there but receives no costimulation
- inducing apoptosis
6
Q
What is something B cells can do in the development of central tolerance?
A
- change receptors: receptor editing
7
Q
What happens in T cell selection in the thymus?
A
- occurs as the T cell matures
- dependent on affinity of TCR binding to self antigen
- in the initial phase positive selection
- T cells are selected for based on their recognition of antigen both self and non-self, in the context of MHC and the TCR
- cells where the affinity for the antigen is very low, they undergo apoptosis by neglect - signalling too low, considered to be an unwanted immune response so they die
- if the affinity is too high they are negatively selected
- it is only a small fraction of maturing T cells, that have intermediate affinity for antigen in the context of MHC, that survive
- these cells enter the periphery
8
Q
How is peripheral tolerance generated?
A
- self reactive T cells that enter the circulation are regulated by peripheral tolerance
- mechanisms include:
- clonal anergy (lack of costimulation)
- ignorance (do not encounter their antigen) (e.g. proteins in the eye are immune privileged)
- suppression by cytokines (e.g. TGF-beta)
- specific regulation (Treg induction)
- negative regulation (engagement of CTLA4)
9
Q
How do B cells generate tolerance?
A
- occurs in the bone marrow
- needs T cell tolerance to be intact
- self-reactive B cells can be:
- deleted when high affinity for antigen
- made anergic when antigen is soluble and at high concentration
- ignorance when lack of T cell help or low antigen concentration
10
Q
What happens when tolerance fails?
A
- autoimmune disease can occur when mechanisms of immunological tolerance break down
- “Horror autotoxicus” (Ehrlich)
- can be caused by:
- acquisition of T cell help
- molecular mimicry
- failure of regulatory networks
11
Q
What is autoimmunity?
A
- immune response against self-antigen
- involve both self-reactive T and B cells
- presence of autoreactive lymphocytes does not necessarily result in autoimmunity
- naturally occurring autoantibodies (thought to be involved in mopping up debris etc)
12
Q
What is the pathogenesis of autoimmunity?
A
- multifactorial
- genetic susceptibility
- environmental influence e.g. infection, smoking, drugs
- lead to the presence of an autoantigen
- combined lead to autoimmunedisease
13
Q
What is molecular mimicry?
A
- similar/identical epitopes between microbe and host
- could be linear or conformational
- important when host antigen has important biological function
- e.g. streptococcal protein and bacterial endocarditis
14
Q
What is the Treg function in autoimmunity?
A
- major mechanism in the development of autoimmunity
- contact and contactless
- IL-10 and TGF-beta important cytokines in suppressing a response
- also inhibition via cell-cell contact through TCR
- key feature is to render cells non-responsive
- if that fails either genetically or through some environmental factor you can get loss of regulation and those self-reactive T cells in the periphery that might normally be kept in check can be left and expand and become pathogenic
15
Q
What are Milgrom and Witebsky’s criteria for autoimmune diseases?
A
- lymphocytic infiltration of the target organ
- presence of circulating autoantibodies and/or cellular immunity against the target organ
- identification of the specific antigen(s)
- production of humoral and/or cellular autoimmune response in animals sensitised by autologous antigen
- close association with other autoimmune disorders
16
Q
What is the spectrum of autoimmune diseases?
A
- from very organ specific (hashimoto thyroiditis) to widespread (systemic lupus erythematosus)
- also insulin-dependent diabetes mellitus
17
Q
What are pathogenic autoantibodies?
A
- key autoantibodies associated with autoimmune diseases
- non-organ specific
- anti-DNA antibodies: SLE
- anti-cytoskeleton antibodies
- organ specific
- anti-glomerular basement membrane: SLE, Goodpasture’s syndrome
- anti-thyroglobulin antibodies: thyroiditis
- anti-myelin basic protein: multiple sclerosis
- anti-mitochondrial antibodies: primary biliary cirrhosis
18
Q
How do we diagnose autoantibodies?
A
- autoantibody patterns
characteristic of non-organ specific autoimmune diseases
- actin-binding protein (actinin): AI hepatitis, Rheumatoid arthritis, very intense bright spots = accumulation
- intermediate filament (vimentin): Sjogren’s syndrome
- Cartilage (Glycosaminoglycans): rheumatoid arthritis
characteristic of organ-specific autoimmune diseases
- kidney, anti-mitochondrial Ab, primary biliary cirrhosis
- parietal cell - stomach intrinsic factor autoimmune gastritis
- kidney - glomerular basement membrane, goodpasture’s syndrome
19
Q
What is diabetes?
A
- group of diseases affecting insulin production and/or function
- organ-specific autoimmune disease (type 1)
- targets the islets of langerhans cells of the pancreas – important for insulin secretion
- secondary damage to kidneys, eyes, nerves, blood vessels
- onset from first year of life to older adulthood
20
Q
What are the types of diabetes?
A
Type 1 diabetes (5-10% of cases)
- pancreatic beta cell destruction
- insulin deficiency
Type 2 diabetes (90-95% of cases)
- relative insulin deficiency
- inadequate production or peripheral resistance to insulin action
Other types
- gestational diabetes
- latent autoimmune diabetes in adults (LADA)
- maturity onset diabetes of youth (MODA)
21
Q
What is LADA?
A
- latent autoimmune diabetes in adults
- a form of autoimmune diabetes which is diagnosed in individuals who are older than the usual age of onset of type 1 diabetes
- also known as “late-onset autoimmune diabetes of adulthood”, “slow onset type 1” diabetes, and sometimes also “Type 1.5”
- LADA patients often thought to have type 2 diabetes due to their age at diagnosis
- patients usually aged >25 years
- clinical presentation “masquerading” as non-obese type 2 diabetes
- initial control achieved with diet alone or diet and oral hypoglycaemic agents
- insulin dependency occurs within months but can take 10 years of more
- other features of type 1 diabetes
- low fasting and post-glucagon stimulated C-peptide
- HLA susceptibility alleles
- JCA+
- GADA
22
Q
What is the pathogenesis of type 1 diabetes?
A
Genetic
- HLA-DR3/4
- HLA-DQ8
- CTLA-4
- Insulin
- CD25
Environmental
- infections esp viral
not vaccine
- gradual failure of T cell tolerance:
- interaction between susceptibility and protection genes
- evidence of insulitis
- over diabetes
all in conjunction with immune dysregulation, environmental triggers, autoantibody appearance etc
- progressive accumulation of inflammatory cell infiltrate
- CD4 and CD8 T cells
23
Q
What are the immunological events in diabetes?
A
Failure of T cell tolerance
- defective clonal deletion (central)
- regulatory response altered (peripheral)
Prior to clinical symptoms
- autoreactive T cells become activated
- autoantibodies are produced
- destroy islets of Langerhans in pancreas
- occur over many years until nearly all beta cells affected
24
Q
What are the autoantibodies in diabetes?
A
Major autoantibodies are reactive to 4 islet autoantigens (termed islet cell autoantibodies, ICA)
- insulinoma-associated antigen-2 (ICA512)
- insulin (micro-insulin autoantibodies, IAA)
- glutamic acid decarboxylase 65 (GAD65) (most common in general)
- zinc transporter 8 (ZnT8)
Important role for B cells in pathogenesis
25
Q
Give a summary of type 1 diabetes.
A
Clinical
- onset: usually childhood and adolescence
- normal weight or weight loss preceding diagnosis
- progressive decrease in insulin levels
- circulating islet autoantibodies (anti-insulin, anti-GAD, anti-ICA512)
- diabetic ketoacidosis in absence of insulin therapy
Genetics - major linkage to MHC class I and II genes; also linked to polymorphisms in CTLA4 and PTPN22, and insulin gene VNTRs
Pathogenesis
- dysfunction in regulatory T cells (Tregs) leading to breakdown in self-tolerance to islet auto-antigens
Pathology
- insulitis (inflammatory infiltrate of T cells and macrophages)
- Beta-cell depletion, islet atrophy
26
Q
What is systemic lupus erythematosus?
A
- multi-system chronic autoimmune disease
- remitting and relapsing
- acute or insidious in onset
- many organs are affected
- skin
- kidney
27
Q
What are the criteria for SLE classification?
A
- malar rash - very common, wolf-like feature across cheekbones
- discoid rash
- photosensitivity - sensitivity to sunlight
- oral ulcers
- arthritis
- serositis
- renal disorder
- neurologic disorder
- hematologic disorder
- immunological disorder
- antinuclear antibody - critical, characteristic diagnostic feature - over 90% of cases
28
Q
What do antibodies in SLE target?
A
- diverse structures
- typical non-organ specific autoimmune disease
- autoantibodies detected against:
- nuclear antigens
- cytoplasmic antigens
- cell-surface antigens
- pathogenic in nature
- diagnostic feature is the presence of antinuclear autoantibodies
- antibodies to Sm antigen and dsDNA are diagnostic of SLE
- others include:
- anti-lymphocyte
- anti-platelet
- antiphospholipid
29
Q
What are anti-nuclear autoantibody patterns?
A
- Speckled Sm, RNPs
- peripheral dsDNA
- nucleolar RNA
- homogeneous chromatin, histones
30
Q
Whatis the pathogenesis of SLE?
A
- susceptibility genes
- external triggers (e.g. UV radiation)
- failure of self tolerance
- release of self-reactive antigens
31
Q
What is the pathological mechanism of SLE?
A
- type III hypersensitivity (immune complex)
- DNA-anti DNA complex
- Affected sites are kidneys and small blood vessels
- glomerulonephritis
- skin involvement
32
Q
What is type III hypersensitivity?
A
- immune complexes formed mainly in organs where blood is filtered (e.g. kidneys, joints)
- acute inflammatory response
- IgG and IgM (complement fixing)
- phagocytosis
33
Q
What are the hallmark lesions in SLE?
A
- glomerulonephritis: mesangium and capillary wall
- skin lesions: dermoepidermal junction
34
Q
What is the clinical course of SLE?
A
- disease course can be variable
- 90% survival (5 years); 80% 10 years
- most common cause of death is renal failure
- treatment:
- corticosteroids
- immunosuppressants
