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What is immunological tolerance?

- 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


Who discovered acquired immunological tolerance? How?

- 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


Why is tolerance important?

- 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


What are key factors determining whether an immune response (or tolerance) occurs?

- [Ag]
- avidity
- costimuli
- timing and duration


What are T cell tolerance mechanisms?

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


What is something B cells can do in the development of central tolerance?

- change receptors: receptor editing


What happens in T cell selection in the thymus?

- 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


How is peripheral tolerance generated?

- 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)


How do B cells generate tolerance?

- 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


What happens when tolerance fails?

- 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


What is autoimmunity?

- 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)


What is the pathogenesis of autoimmunity?

- multifactorial
- genetic susceptibility
- environmental influence e.g. infection, smoking, drugs
- lead to the presence of an autoantigen
- combined lead to autoimmunedisease


What is molecular mimicry?

- 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


What is the Treg function in autoimmunity?

- 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


What are Milgrom and Witebsky's criteria for autoimmune diseases?

- 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


What is the spectrum of autoimmune diseases?

- from very organ specific (hashimoto thyroiditis) to widespread (systemic lupus erythematosus)
- also insulin-dependent diabetes mellitus


What are pathogenic autoantibodies?

- 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


How do we diagnose autoantibodies?

- 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


What is diabetes?

- 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


What are the types of diabetes?

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)


What is LADA?

- 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+


What is the pathogenesis of type 1 diabetes?

- HLA-DR3/4
- CTLA-4
- Insulin
- CD25

- 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


What are the immunological events in diabetes?

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


What are the autoantibodies in diabetes?

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


Give a summary of type 1 diabetes.

- 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

- major linkage to MHC class I and II genes; also linked to polymorphisms in CTLA4 and PTPN22, and insulin gene VNTRs

- dysfunction in regulatory T cells (Tregs) leading to breakdown in self-tolerance to islet auto-antigens

- insulitis (inflammatory infiltrate of T cells and macrophages)
- Beta-cell depletion, islet atrophy


What is systemic lupus erythematosus?

- multi-system chronic autoimmune disease
-- remitting and relapsing
- acute or insidious in onset
- many organs are affected
-- skin
-- kidney


What are the criteria for SLE classification?

1. malar rash - very common, wolf-like feature across cheekbones
2. discoid rash
3. photosensitivity - sensitivity to sunlight
4. oral ulcers
5. arthritis
6. serositis
7. renal disorder
8. neurologic disorder
9. hematologic disorder
10. immunological disorder
11. antinuclear antibody - critical, characteristic diagnostic feature - over 90% of cases


What do antibodies in SLE target?

- 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


What are anti-nuclear autoantibody patterns?

- Speckled Sm, RNPs
- peripheral dsDNA
- nucleolar RNA
- homogeneous chromatin, histones


Whatis the pathogenesis of SLE?

- susceptibility genes
- external triggers (e.g. UV radiation)
- failure of self tolerance
- release of self-reactive antigens


What is the pathological mechanism of SLE?

- type III hypersensitivity (immune complex)
-- DNA-anti DNA complex

- Affected sites are kidneys and small blood vessels
-- glomerulonephritis
-- skin involvement


What is type III hypersensitivity?

- immune complexes formed mainly in organs where blood is filtered (e.g. kidneys, joints)
- acute inflammatory response
- IgG and IgM (complement fixing)
- phagocytosis


What are the hallmark lesions in SLE?

- glomerulonephritis: mesangium and capillary wall
- skin lesions: dermoepidermal junction


What is the clinical course of SLE?

- disease course can be variable
- 90% survival (5 years); 80% 10 years
- most common cause of death is renal failure
- treatment:
-- corticosteroids
-- immunosuppressants