Autoimmunity Flashcards
Autoimmune diseases
a) Psoriasis
b) Sjogren’s syndrome
c) Crohn’s disease
a) Autoreactive T cells against skin-associated antigens. Causes inflammation of the skin with formation of scaly patches or plaques
b) Autoantibodies and autoreactive T cells against ribonucleoprotein antigens. Causes lymphocyte infiltration of exocrine glands, leading to dry eyes and/or mouth. Other organs may be involved, leading to systemic disease
c) Autoreactive T cells against intestinal flora antigens. Intestinal inflammation and scarring
a) define autoimmunity
b) define hypersensitivity
c) what are the different classes of autoimmunity, and which type of hypersensitivity does this correspond to
a) immune responses against self antigens
b) immunity against innocuous foreign antigens
c) 1 - direct antibody mediated effects (type II hypersensitivity)
2 - immune complex mediated effects (type III hypersensitivity)
3 - T cell mediated (cellular immune) (type IV hypersensitivity)
Class 1 - Direct antibody mediated effects
a) Grave’s disease
b) Hashimotos thyroiditis
c) Myasthenia gravis
a) Autoantibodies against TSH, leading to overproduction of thyroid hormones (hyperthyroidism) - cause goitre
b) Infiltration of Th1 cells in the thyroid gland. Autoantibodies also contribute to organ destruction (less specific than Grave’s) - causes goitre
c) Autoantibodies against the ACh receptor interferes with synaptic transmission of signals between nerves and muscles, leading to muscle weaknes. Can be fatal
a) Overview of class 2, immune complex-mediated autoimmunity
b) Systemic lupus erythematosis (SLE)
a) Failure to remove immune complexes can cause pathology when the immune complexes are deposited in the kidneys and vascular endothelium. Complement (C1q, C2 and C4) can facilitate clearance of immune complexes, so complement deficiency can predispose to immune-complex diseases
b) Systemic autoimmune disease affecting the skin, joints and kidneys. Antibodies are produced against nuclear components, including DNA (can be triggered by neutrophil NETosis). Immune complexes fail to be cleared effectively and are deposited on endothelium, kidneys, joints and elsewhere, causing inflammation.
Class 3 - T cell mediated autoimmunity
a) Multiple sclerosis
b) Type I diabetes
c) Rheumatoid arthritis
a) A Th1 and Th17 mediated disease. Demyelination of neurons occurs due to Th1 cells and Th17 cells being specific for myelin basic protein, leading to imparied nerve transduction.
b) Caused by T cell-mediated destruction of the insulin-producing β cells in the pancreas.
c) An unknown trigger sets up an initial focus of inflammation in the synovial membrane, attracting leukocytes. Autoreactive CD4 T cells activate macrophages, resulting in the production of pro-inflammatory cytokines and sustained inflammation. Cytokines induce the production of MMP and RANK ligand by fibroblasts. MMPs attack tissues. RANK ligand activates the bone-destroying osteoclasts and results in joint destruction.
Susceptibility to autoimmunity
a) Genetic factors
b) Endocrine factors
a) A single amino acid residue in an MHC molecule can be associated with increased risk of autoimmunity. A residue at position 57 of the β chain in HLA-DQ is protective when the aa is charged, but not is it is hydrophobic. Rare mutants are also seen in AIRE and Foxp3.
b) Most autoimmune diseases are more prevalent in women than in men. Could potentially be mediated by hormonal differences. SOme key immune-regulatory genes (eg TLR7) are on the X chromosome, and females may have a higher dose of the protein due to imperfect X-inactivation
Susceptibility to autoimmunity - environmental factors
a) Microbial mimicry
b) Protein modification
a) eg streptococcal cell wall causes an antibody response, some antibodies can cross-react with heart valve tissue and cause rheumatic fever. Reactive arthritis is also thought to be caused by enteric infections. In both cases, lymphocytes with low affinity for a self antigen may have passed negative selection, but upon activation by similar pathogen-associated antigens, a high affinity immune response against self antigens is inadvertently also elicited.
b) Rheumatoid arthritis may be caused by protein citrullination, which initially may occur in the lung, with a strong link between RA and smoking. Coeliac disease (although not strictly autoimmune as it is dependent on eating gluten) generates autoantibodies. In those with coeliac disease, peptides produced from gluten (normally have no effect) are modified by tTG enzyme, allowing them to bind to MHCII. This then activates gluten-specific CD4 T cells which kill mucosal epithelial cells by binding Fas, as well as secreting IFNγ that activates the epithelial cell to secrete cytokines that recruit other inflammatory cells
Immunosuppressive drugs
a) corticosteroids
b) azathioprine, cyclophosphamide, mycophenolate
c) cyclosporin A, tacrolimus
d) Rapamycin
e) Fingolimod
a) Inhibit inflammation, inhibits many targets including cytokine production of macrophages
b) Inhibit proliferation of lymphocytes by interfering with DNA synthesis
c) Inhibit the calcineurin-dependent activation of NFAT, block IL-2 production by T cells, and block proliferation of T cells
d) Inhibits proliferation of effector T cells by blocking Rictor-dependent mTOR activation
e) Blocks lymphocyte trafficking out of lymphoid tissues by interfering with signalling by the sphingosine 1-phosphate receptor
