Flashcards in L12: Autoimmunity Deck (25):
What is autoimmunity? What mechanisms must be breached?
- Immune response against self antigens as a result of central and peripheral tolerance mechanisms being breached.
What causes tissue damage in autoimmunity?
- Autoreactive CTLs
- Circulating autoantibodies
- Immune complexes
Theories underlying autoimmunity
1.) Inflammation and upregulation of co-stimulatory molecules by DCs leads to self-reactive T cells
2.) Microbial protein homology with human proteins (molecular mimicry)
3.) Inappropriate expression of MHC proteins (linked to other genes that make one susceptible?) – cells that don’t normally express MHC molecules may do so and activate T lymphocytes, also during T cell selection binding to elicit negative selection might not be strong enough
HLA allele associated with ankylosing spondylitis
Examples of organ-specific autoimmune diseases
1.) autoimmune hemolytic anemia
2.) Goodpasture’s syndrome
3.) Pernicious anemia
4.) Hashimoto’s thyroiditis
5.) Idiopathic thrombocytopenia purpura (ITP)
7.) Grave’s disease
8.) Myasthenia gravis
9.) Type 1A diabetes
10.) Multiple sclerosis
What is autoimmune hemolytic anemia?
- RBC abs produced against RBC membrane proteins leads to
a.) intravascular hemolysis via cell lysis in bloodstream – anemia
b.) extravascular hemolysis in spleen by phagocytosis via opsonization
What is Goodpasture’s syndrome?
- Autoabs to type IV collagen in BM of alveoli and kidney leads to complement activation and therefore kidney damage, pulmonary hemorrhage and death within a few months (~ 2 months)
What is pernicious anemia?
- Autoabs to intrinsic factor / or gastric parietal cells producing intrinsic factor leading to decreased absorption of vit B12 and therefore abnormal erythropoiesis and anemia
What is Hashimoto’s thyroiditis?
- Autoabs and autoreactive T cells to thyroid gland proteins leading to hypothyroidism
What is ITP?
- Idiopathic thrombocytopenia purpura is a disease characterized by autoabs to platelets resulting in destruction. Leads to purple skin lesions as a result of epidermal hemorrhage (purpura).
What is vitiligo?
- Autoimmune dz whereby skin is depigmented by destruction of melanocytes
What is Grave’s disease?
- Autoantibodies against TSH leads to hyperthyroidism and increased production of T3/4
What is myasthenia gravis?
- Autoabs to chain of nicotinic ACh receptor on skeletal muscle at NMJ. Blockage of NM transmission occurs leading to weakness and paralysis
True / False. Type 1A diabetes is characterized as a state of glucose intolerance and hyperglycemia through immune-mediated destruction of insulin-secreting beta cells in pancreas. This occurs through humoral-mediated destruction.
- False. Autoreactive T cells mediate destruction of beta cells
What is MS?
- MS is an autoimmune demyelinating disease of CNS. TH1 and TH17 cells specific for myelin antigens become activated, which drives macrophage activation and subsequent damage to myelin-containing nerve cells.
Examples of systemic autoimmune disease
3.) Sjögrens syndrome
4.) Scleroderma (progressive systemic sclerosis)
What is SLE? What is the principal concern/danger in this disease?
- Multisystem disease mediated by autoantibodies (most via complexes). There is broad loss of regulatory control of self-tolerance. Autoantibodies produced against DNA, RNA, proteins and ribonucleotides. Organ systems affected include: skin, joints, kidney. Higher frequency in females
- Danger = kidney failure d/t passage of complexes through glomerulus and deposition on renal podocytes, which express CR1 that binds C3b and C4b on complexes
What predisposes individuals to SLE?
- Genetic factors
- Drug-induced lupus
- B cell hyperactivity, T-cell activity increased and decrease in T reg activity
What is RA?
- Progressive inflammatory disease of joints that destroys joint cartilage, leads to inflammation of synovium. Systemic involvement with pulmonary, cardiac and ocular manifestations
- Possibility of synovium being previously infected with viral infection. TH1/17, macrophages and B cells/plasma create inflammatory environment
- Also, some pts have rheumatoid factor, which is a susbstance that binds IgM/G to Fc portion of IgG leading to complex formation. TNF-alpha plays role in disease process
Treatment of RA?
- Drugs to sponge up TNF-alpha
a.) etanercept: TNF-alpha type II receptor fused to IgG antibody
b.) infliximab: chimeric anti-TNF-alpha ab
c.) adalimubab: IgG monoclonal
What is Sjögren’s syndrome?
- Autoimmune destruction of lacrimal and salivary glands (leads to dry eye and mouth). B and T cells influx into glands, but unknown whether it is cell or humoral mediated. Can occur with RA or SLE, mostly in females.
What is scleroderma (progressive systemic sclerosis)?
- Disease that leads to excessive deposition of collagen in skin, kidneys, GI, heart, muscle lungs. Antinuclear abs found in 80% of cases without known roles. T cells infiltrate dermis and may have a hypersensitivity to collagen resulting in IL-1 and TNF-alpha and vicious cycle ensues
What is polymyositis-dermatomyositis?
- Muscle injury brought about by CD4+ and CD8+ T lymphocytes infiltrates. Skin rash often accompanies this disease. Antibodies seen against tRNA synthetase in 25% of cases. Coxsackie B viruses could play role
Treatment options for autoimmune disease?
1.) Cortisol: anti-inflammatory effects
2.) Azathioprine and cyclophsophamide: cytotoxic drugs that inferefere with DNA synthesis, therefore eliminating dividing lymphocytes – damage = bone marrow suppression and damage to intestinal epithelium
3.) Cyclosporine and tracolimus: block calcineurin, blocks transcription of IL-2 (nephrotoxicity of drugs however)
4.) Plasmapharesis: remove ab-ag complexes (short term alleviation)
5.) Antagonists of TNF-alpha can relive symptoms of some diseases: infliximab (anti-TNF-alpha mab), etanercept (soluble TNF-alpha receptor protein), adalimubab (IgG mab to TNF-alpha)