Lecture 4- Autoimmunity Flashcards
Autoimmunity:
Immune response against the host due to the loss of immunological tolerance of self- antigen(s)
Autoimmune disease:
Disease caused by tissue damage or disturbed physiological responses due to an auto-immune response
autoimmunity –> autoimmune disease
- organ specific or
- non-organ specific
autoimmune disease is driven by the presence of
auto antibodies or auto reactive T cells resulting in organ fibrosis.
risk factors of autoimmune disease
- Disease development is driven by genetic and environmental factors making familial history very important.
- 80% of patients are female, usually presenting after puberty suggesting a strong link to hormonal factors but the link remains unknown.
Autoimmune disease can also be triggered by
infectious microbes that have a similar epitope to one present withing the body – mimicry.
common autoimmune diseases and their target autoantigens: hashimotos thyroiditis
thyroid peroxidase and thryoglobulin–> causes hypothyroidism
(Type IV hypersensitivity reaction- involves lymphocytes and macrophages)
common autoimmune diseases and their target autoantigens: type 1 DM
pancreatic islet cells- hyperglycaemia (Type IV)
common autoimmune diseases and their target autoantigens: Multiple sclerosis
myelin sheath (nerve fibers)- demyelinating disease (IV)
common autoimmune diseases and their target autoantigens: good pastures disease
glmerular/alveolar basement membrane (kidney)- glomerulonephritis (type II hypersensitity- insoluble IgM/IgG)
common autoimmune diseases and their target autoantigens: addisons disease
steroid-21 hydroxylase (adrenal cortex)- adrenal insufficiencys (Type II-IV)
common autoimmune diseases and their target autoantigens: myasthenia gravis
acetylcholine receptor (NMJ)- skeletal muscle weakness
common autoimmune diseases and their target autoantigens: graves
thryoid stimulating hormone receptro- hyperthryoidism (Type II)
common autoimmune diseases and their target autoantigens: pernicious anaemia
intrinsic factor (terminal ileum)- vitamin B12 deficiency- Type II
common autoimmune diseases and their target autoantigens: autoimmune haemolytic anaemia
red blood cell antigens- anaemia- Type II
common autoimmune diseases and their target autoantigens: RA
rheumatoid factor (FC portion of the IgG)- inflammatory arthritis and systemic features (type IV)
common autoimmune diseases and their target autoantigens: SLE
double stranded DNAA (dsDNA) and other nuclear proteins (histones)- mutisystem disease (type III- soluble IgG and IgM)
common autoimmune diseases and their target autoantigens: Sjorens syndrome
nuclear antigens (Ro and La)
dry eyes, drymouth and arthritis - Type IV
Auto immune disease can be divided in to 2 groups:
Organ specific
When the auto antigen is only present in one organ resulting in organ/tissue specific damage
Non Organ specific
When the autoantigen is found in multiple sites resulting in damage throughout the body. Usually type III hypersensitivity.
Hypersensitivity reactions triggered by autoimmune disease
(organ specific or non-organ specific) cause tissue fibrosis (non-reversible (no drugs to treat))
Hypersensitivity reactions which cause fibrosis= Type IV, II and III
Via…
-
Autoantibody driven
- Complement activation
- Antibody-mediated cell
- Cytotoxicity
- Neutrophil activation
-
Autoreactive T cell driven
- Cytotoxic T cells
- Macrophage
Non-organ specific= systemic inflammation
Set of criteria for the diagnosis of a disease as autoimmune
types of autoantibodies
primary (rare) and secondary (come later in disease)
Primary autoantibodies
driving the disease.
- Anti-TSHR antibodies in Graves’ disease
- Anti-acetylcholine receptor antibodies in Myasthenia gravis
- Anti-voltage-gated Ca2+ channel antibodies in Lambert-Eaton myasthenia syndrome
- Anti-anti-Glomerular basement membrane antibodies in Goodpasture’s syndrome
Secondary autoantibodies
occurring much later is the disease course, they do not drive the disease.
- Anti-nuclear antibodies in SLE
- Anti-gastric parietal cell antibodies in pernicious anaemia
- Anti-thyroid peroxydase antibodies in Hashimoto thyroiditis
- Anti-Rheumatoid Factor antibodies in Rheumatoid arthritis
Primary antibodies can be cleared using
plasmapheresis
detection fos erum autoantibodies and autoimmune disease
Auto immune disease presents with the presence of auto reactive T cells / auto antibodies, determined by serology and biopsy, at a level of which correlates with disease severity and activity. The severity of the disease and clinical outcome that arises, depends upon the organ effected and the type of hypersensitivity reaction.
imaging of Detection of autoantibodies/ autoreactive T cells at the site of tissue damage
can mother pass autoimmune disease to neonates
Autoimmune disease can be transferred to neonates as maternal autoantibodies can be transferred but this effect diminishes by 6 months when maternal IgE/IgG fades.
- in the third trimester
example of women with autoimmune disease and neonate
Induction of autoimmunity
Breakdown of central tolerance
- Failure to delete autoreactive T cells
Breakdown of peripheral tolerance
- Regulatory T cells (Treg) defects
- Impaired immunomodulation
- Altered self-antigens
Activation of autoreactive B cells
- T cell-independent activation of B cells
- Carrier effect (complex foreign-self antigens)
What triggers autoimmunity?
Genetic factors
- Increased risk with an affected sibling (8X)
- Increased risk with an affected identical twin (30X)
- AIRE mutations (APECED syndrome) that affect central tolerance
- Autoimmune disease associated with MHC variants (HLADR3/DR4)
Environmental factors
- Hormones
- Infections
- Drugs
hormonal factors and autoimmunity
infectious factors and autoimmunity
therapeutic drugs and autoimmunity
x2 clinical examples of what triggers autoimmunity
Current and future therapeutic strategies for autoimmune diseases
Treatments available include
❖ Plasma exchange to remove auto antibodies
❖ immunosuppressive drugs to suppress autoreactive T cells ( no specific targeted therapies exist and these will have adverse side effects within the patients)
❖ anti-inflammatory drugs (corticosteroids) to treat the tissue damage
❖ replacement therapy surgery to treat organ dysfunction.
monoclonal antibodie and autoimmune diseases
huge advances in the treatment of autoimmune disease with the development of targeted monoclonal antibodies which although expensive have the potential to offer a dramatic improvement in patient quality of life.
Which drug for which autoimmune disease
replacement e.g. injecting insulin to make up for faulty pancreas
