Describe Central and Peripheral tolerance
Central: Autoreactive lymphocytes not deleted in bone marrow and thymus
Peripheral: Normal inhibitory mechanisms fail in the periphery.
What are some pre-disoposing factors of autoimmunity
Factors influencing development
- ->Abnormalities of lymphocytes and APC’s
- -> Genetic predisposition
- -> Microbial infections
Tissue injury can be brought about by:
- -> autoreactive CTL’s
- -> Circulating autoantibodies
- -> immune complexes
Define Vertical transmission of antibodies
Maternal autoimmune IgG may affect developing fetus/neonate
- -> effects disappear after birth when antibodies are catabolized
- -> some organ damage may be irreversible, e.g. developing heart is damaged by autoantibodies.
Define Autoimmune Hemolytic anemia (organ specific)
- -> RBC antibodies produced against RBC membrane proteins
- -> causes RBC lysis and anemia
- -> opsonization –> removal by phagocytic cells in spleen
Goodpasture syndrome (organ specific)
- -> Autoantibodies to the alpha3 chain of type IV collage (basement membrane collage) of the lung (alveoli) and the kidney (glomeruli)
- -> causes complement activation –> kidney damage, pulmonary hemorrhage, death (within few months)
- -> Smooth, ribbon like appearance
Pernicious anemia (organ specific)
- -> Autoantibodies to intrinsic factor and or gastric parietal cells
- -> decreased absorption of vitamin B12 –> abnormal erythropoiesis/anemia
Hasimotos thyroiditis (organ specific)
- -> Hypothyroid state
- -> Autoantibodies and autoreactive T cells to thyroid gland proteins
Idiopathic thrombocytopenia purpura (ITP) (organ specific)
- -> platelets destroyed by autoantibodies to platelet membrane proteins
- -> “purpura” = purple skin lesions due to epidermal hemorrhage
- -> IVIG can prevent destruction of platelets
Vitiligo (organ specific)
depigmentation of skin by destruction of melanocytes
Graves Disease (organ specific(
- -> autoantibodies against TSH receptor
- -> causes hyperthyroidism
Myasthenia gravis (organ specifc)
- -> autoantibodies to alpha chain of nicotinic acetylcholine receptor on skeletal muscle cells at neuromuscular junctions
- -> blockage of neuromuscular transmission leads to muscle weakness and paralysis
Type 1A diabetes (organ specific)
- -> Autoantibodies to beta-cells. Despite diagnostic worth of antibodies, autoreactive T cells mediate destruction of beta-cells
- -> damage to beta cells result in decrease in insulin and increase in blood glucose levels
Multiple Sclerosis (organ specific)
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
- -> Therapies = interferon and steroid injections
Systemic Lupus erythematosus (systemic)
- -> Broad loss of regulatory control that sustains self-tolerance
- -> Autoantibodies against numerous antigens including DNA, RNA, proteins and ribonucleoproteins
- -> most organ systems can be affected (skin, joints, kidney more frequently)
- -> more common in females than males
- -> Most tissue injury mediated by immune complex (TYPE III autoimmunity)
- -> principal danger = kidney failure due to the passage of immune complexes through the glomerulus and deposition on renal podocytes (express CR1 protein that binds C3b on the immune complex which initiates damage)
Describe the predisposition of Sytemic lupus erythematosus
- Genetic factors involved –> family members have increase incidence of SLE
- Non genetic factors –> drugs and some viruses (reverses upon removal of drug
- Immunologic factors –> B cell hyperactivity, increased T-helper activity and or decrease Treg activity
Define Rheumatoid arthritis (RA) (systemic)
Progressive inflammatory disease of joints –> destruction of joint cartilage and inflammation of synovium:
–> association of RA with HLA-DR4 haplotype
- -> TH1 and TH17 macrophages, B cells and plasma cells creat an inflammatory enviornement consisting of secretion of leukocyte-recruiting cytokines
- -> rheumatoid factor –> IgM/IgG to Fc portion of IgG leads to immune complex
Sjogren’s syndrome (systemic
Dry eyes + dry mouth caused by destruction of lacrimal and salivary glands:
- ->B and T cell influx into glands, but not known whether CMI or humoral immunity responsible for damage
- -> occurs alone or in conjunction with RA or SLE
Scleroderma (progressive systemic sclerosis (systemic))
Excessive deposition of collagen –> skin, kidneys, GI tract, heart, muscles, lungs:
–> T cells infiltrate dermis –> may have a hypersensitivity to collagen that results in release of Il-1 and TNF-alpha which causes production of collagen and propagates the vicious cycle
Polymyositis-dermatomyositis (systemic)
Polymyositis = muscle injury possibly brought about by CD4+ and CD8+ T lymphocytes infiltration of muscles
Dermatomyositis = skin rash that often accompanies polymyositis
–> 25% have autoantibodies to histidyl t RNA synthetase (diagnostic)
–> coxsackie B viruses could play a role as it has been isolated from some patients
Describe nonspecific immunosuprressent autoimmune treatment options
Corticosteroids: Prednisone = anti-inflammatory effects
Azathioprine and cyclophosphamide: Cytotoxic drugs that interfere with DNA synthesis –> eliminates dividing lymphocytes
Cyclosporine and tacrolimus: Block activity of calcineurin –> blocks transcription of IL-2 etc.
Plasmapheresis: removes Ag-Ab complexes –> short-term alleviation of symptoms
Describe Antagonism of TNF-alpha treatments
Antagonism of TNF-alpha relive the symptomes of some diseases:
- Infliximab = humanized anti-TNF-alpha monoclonal antibody
- Etanercept = soluble TNF-alpha receptor fusion protein that binds TNF-alpha
- Adalimumab = recominant human IgG1 monoclonal
Very potent anti-inflammatories that may be used to treat crohn’s disease, rheumatoid arthritis, juvenile chronic arthritis and ankylosing spondylitis
