L10 - K Okkenhaug - Autoimmunity Flashcards
whats teh hygiene ypothesis
that the immune system is no longer conditioned by early exposure to infection.
autoimmunity has increased as infections such as measles, mumps and TB have declined in incidence.
more recent proposal is that it is not necessarily infection with pathogens that condition the immune system early in life but exposure to diverse commensals (‘friendly’ bacteria) that comprise your microbiome
isit possible that some autoimmune conditions actually arent auto?
yes!
caused by infectious organisms that have not been identified:
is there a spectrum of auto immune diseases?
yes!
Common organs affected in organ-specific autoimmunity include thyroid (X ,X), adrenals, stomach (X) and pancreas (X). This may be because ….
Common organs affected in organ-specific autoimmunity include thyroid (Hashimoto’s thyroiditis, Grave’s disease), adrenals, stomach (pernicious anaemia) and pancreas (type 1 diabetes). This may be because they are well vascularised and make organ-specific proteins.
There are __ general types of mechanism for autoimmune conditions
There are three general types of mechanism
No autoimmune diseases are mediated by ___ which is characteristic of type I hypersensitivity.
No autoimmune diseases are mediated by IgE which is characteristic of type I hypersensitivity.
what are the 3 general mechanisms of autoimmunity
- Direct antibody mediated effects
- Immune complex mediated effects.
- T cell mediated (cellular immune) (e.g. T1D (type 1 diabetes or IDDM), RA (rheumatoid arthritis), MS (multiple sclerosis)
describe . Direct antibody mediated effects
- almost all autoimmune patients have some autoantibodies
- may be directly effective / or a secondary consequence
- ppor card i know
describe graves disease
Graves disease: This is due to antibody to TSH receptor. Unlike the natural ligand, TSH, the antibody is not subject to feedback inhibition, resulting in overproduction of thyroid hormones and hyperthyroidism.
Graves may be a ‘Th2 type’ response, in which there is little inflammation or lymphocyte infiltration.
describe Hashimoto’s thyroiditis
Hashimoto’s thyroiditis is mostly a ‘Th1 response’ as Th1 lymphocytes infiltrate the organ.
Nevertheless, antibodies are generated which block hormone production, causing hypothyroidism.
describe Myasthenia Gravis
autoantibodies to the acetylcholine receptor diminish neuromuscular transmission from cholinergic neurons by blocking the binding of acetylcholine and by causing downregulation (degradation) of its receptor.
Rheumatic fever is another example of direct tissue pathology following antibody binding.
(direct antibody effects)
describe how Immune complex mediated effects can cause autoimmunity
- immune complexes cleared by binding comlement components
- which bind complement receptor 1 on erythrocytes
- cleared in liver and spleen
certain
organs are especially
sensitive to immune complex deposition,
which in particualr
Kidney!
describe Systemic Lupus Erythematosus (SLE)
wide variety of anti-cytoplasmic and anti-nuclear auto-antibodies.
characteristic ‘butterfly’ or ‘wolf’ rash on the face.
significant depletion of complement
complement deficiencies that impair immune clearance, such as C1, C2, C4 are predisposing factors.
SLE is more common in African and Asian women.
Immune complexes fail to be cleared effectively and are deposited on endothelium, kidney, joints and elsewhere causing inflammation
describe rheumatoid arthritis
T cell mediated
describe t cell mediated autoimmune disease
T cell mediated damage leads to tissue destruction without requiring the production of autoantibody.
Mechanisms may include:
- cytotoxicity by CD8 T cells;
- direct destruction by TNF;
- recruitment of macrophages and subsequent bystander killing;
- and induction of apoptosis by Fas Ligand.
toughy
what are most autoimmune disease associated with?
one or more HLA allotype
how do HLA allotypes influence / predispose people to autoimmune diseases
relative RISK
conferes increased liekly hood. but not definitive.
in comparison with HLA- DQ6-ve people, HLA-DQ6+ves are 12 times more likely to develop multiple sclerosis. But HLA-DQ6 is common in normal healthy individuals. Conversely, not all patients who develop the disease have this allotype and only a fraction of DQ6+ves will succumb.
Most autoimmune conditions have an MHC association but different HLA types are associated with different diseases
T or F
T
are autoimmune disorders often multigenic?
yep
lots of genetic loci involved
autoimmune disorders - balance between women and men
Most autoimmune diseases do not occur with equal frequency in males and females. For example Grave’s and Hashimoto’s are 4-5 times, and SLE 10 times, more common in females. Ankylosing Spondylitis is 3-4 more frequent in males.
twin concordance rate for autoimmune disorders?
20-40%
environment must play a large role too
childhood infections
are some autoinfections diseases a direct effect from other infections?
give exmaples
direct effect: rheumatic fever can follow Streptococcal infection; reactive arthritis after Yersinia, Shigella or Chlamydia. Non-specific infection is known to cause a flare-up of MS
It is estimated that environmental factors contribute about 50% of the susceptibility to T1D. The MHC contributes about 25% and the other 25% comprises a variety of other genes.
T or F
T
describe autoimmune sympathetic ophthalmia
Release of sequestered antigen
e.g. In the case of autoimmune sympathetic ophthalmia, damage to one eye leads to subsequent autoimmune attack of the contralateral eye.
how can smoking lead to autoimmune disorders?
smoking = mutations = neoproteins - breaks tolerance
describe how molecular mimicry can lead to autoimmune diseases?
which autoimmune disease is predisposed to by smoking?
Rheumatoid arthritis (RA) may be caused by protein citrullination by peptidylarginine deiminase.
Initially this may occur in the lung and there is a strong link between RA and smoking. Antibodies to the modified proteins: ACPA (anti-citrullinated protein antibodies) are present in most patients with RA.
Periodontitis often precedes ..
Periodontitis often precedes RA.
which treatments are showing promise in RA?
Blocking reagents such as anti-TNF antibodies or soluble receptor
Th1 produce cytokines that activate what?
and do what?
Th1 produce cytokines that activate (M1) macrophages to destroy intracellular microbes
are Th1 response short or long lived?
tent to be destructive so short lived
Th2 make____
Th2 make IL-4.
Th2 main role appears to be to…
respond to parasite infection
Th2 activate which cells?
M2 macrophages -less destructive and may have evolved as factors involved in tissue repair mechanisms
Th2 cells direct ____ production and help …. wihch cells…… to deal with chronic infections.
Th2 cells direct IgE production and help eosinophils, basophils and mast cells to deal with chronic infections.
why shouldnt a destructive approach be used against parsites?
Parasites are difficult to remove and may be resident for a long time so destructive responses are not appropriate.
are you aware of how the main immunosuppressive drugs work
treatments for autoimmunity?
- Organ specific treatments - thyroxine for hypothyroidism
- immunosuppressive drugs - long term bad side effects
- Antibodies to TNFα or its receptor have proved to be effective in RA
- New: CTLA4-Ig is a fusion protein which binds CD80 and CD86 with high affinity, hence preventing costimulation of T cells via CD28. CTLA-4Ig is approved for the treatment of RA.
fat
mamba
