Tolerance and Autoimmunity Flashcards
Central Tolerance
immature T lymphocytes move to the medulla and any cells that recognize high avidity self antigens presented on MHC class II or class I are KILLED through apoptosis
Characteristics of APECED (Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy)/ Autoimmune polyendocrine syndrome
autoimmune adrenal and parathyroid disease, hypothyroidism, vitiligo, pernicious anemia, fungal infections, due to defect in AIRE gene, so defect in getting rid of self reactive T cells in the thymus so body attacks itself
Characteristics of ALPS (Autoimmune lymphoproliferative syndrome)
widespread lymphadenopathy, splenomegaly, autoimmune cytopenias, due to mutations in Fas FAS LIGAND, so lymphocytes that would normally die via apoptosis are not dying, so we have high IgG, IgA, IgM, high CD4/CD8
Characteristics of (IPEX) immune dysregulation polyendocrinopathy X linked
affects BOYS in infancy, severe eczema and food allergies, type 1 diabetes mellitus thyroiditis, hemolytic anemia, hypergammaglobulinemia, high IgE, low albumin, Fe deficiency, hyperglycemia, due to mutation in FOX P3 and loss of T regulatory cells
what are T regulatory cells?
sooo. central tolerance causes some cells to be deleted, however some self reactive cells are not deleted and become T regs, express Fox p3, when activated they suppress the immune response
what is one of the strongest loci for susceptibility of autoimmune disease?
HLA
what is HLA-B27 a risk factor for?
ankylosing spondylitis, but prevalence is 0.5%
What is Type 1 hypersensitive characterized by?
Th2 cells REQUIRED, IgE antibody, mast cells, eosinophils, reaction to allergens EX: allergic rhinitis, asthma, eczema, food allergies
What is Type 2 hypersensitivity characterized by?
IgM, IgG antibodies against cell surface or extracellular matrix antigens via several mechanism: complement activation leading to inflammation, cross linking Fc receptors on macrophage/neutrophils lead to activation and inflammation, phagocytosis, function blocking or activating antibodies
What is Type 3 hypersensitivity characterized by?
due to the production of IgG against a soluble antigen; immune complexes of circulating antigens and IgM or IgG antibodies deposited in vascular basement membrane; immune complexes can cause damage by activating FcR expressing cells as well as activating complement at sites of deposition; damage usually in kidneys, vessels, joints, and skin
What is Type 4 hypersensitivity characterized by?
delayed type hypersensitivity; DOES NOT INVOLVE ANTIBODY, CD4 T cells, CD8 CTLS, causing inflammation and cell lysis and tissue injury,
what are the characteristics of rheumatic fever?
JONES: joints, heart, nodules, erythema marginatum, sydenham’s chorea, example of a TYPE 2 hypersensitivity reaction!
what is the pathophysiology of Acute Rheumatic Fever?
M proteins are expressed by S. progenies as virulence factors, structurally similar to heart muscle, example of a type 2 reaction, example of antigen presented in with inflammation, human is unable to distinguish bacterial proteins from their own
what is Good pasture’s syndrome?
target antigen: non collagenous protein in basement membranes of kidney glomeruli and lung alveoli, causes nephritis, lung hemorrhages
what are the characteristics of systemic lupus erythematosus?
type 3 hypersensitivity!! autoimmune disease involving auto-antibody production particularly to DNA, butterfly rash, stiff hands, discoid rash, photosensitivity, oral/nasal ulcers, low serum protein, can also cause NEPHRITIS
what can lead to early onset systemic lupus erythematosus?
complement defects- C1, C2, C4, complement thought to be important to clear immune complexes!
what are the characteristics of rheumatoid arthritis?
aggregates of lymphocytes and macrophages, swelling, pain on movement, three main cytokines: IL-1, IL-6, TNF
what are the characteristics of Dermatomyositis?
proximal muscle weakness, rash on knuckles and elbows and bridge of nose and cheeks, capillary changes, microvascular injury with vessel destruction leading to capillary dilation, diffuse muscle fiber death via CD 8 cells , example of a TYPE 4 hypersensitivity
what is multiple sclerosis characterized by?
Type 4 hypersensitivity disease, auto-reactive T cells and activated macrophages demyelinate CNS motor and sensory neurons
what is myasthenia gravis characterized by?
antibody inhibits cetycholine binding, down modulates receptors, causes muscle weakness and paralysis, TYPE 2 HYPERSENSITIVITY
what is thrombocytopenia?
autoantibodies directed against platelets
what is Guillain -Barre syndrome?
antibodies to Schwann cell membranes, typically arrives in susceptible individuals after viral or Campylobacter infection, ascending paralysis
what is Hashimotos thyroiditis?
auto-antibodies to thyroglobulin, thyroid inflammation, hypothyroidism
what is Celiac disease?
gluten enteropathy, becomes immunogenic, antibodies attack intestinal wall
why are IL-4 and IL-6 responsible for?
released by Th2 cells in exposure to allergen, simulate class switching of B cells to IgE
what is the difference between allergens and irritants?
allergens: IgE mediated disease that requires sensitization, irritants: not mediated through IgE (dose dependent), will affect everyone at a high enough dose! examples of irritants include: perfume, nitrogen dioxide, tobacco smoke
what receptor do mast cells/basophils express for IgE?
FceRI
what toxic mediator do mast cells release immediately?
histamine–increases vascular permeability and causes smooth muscle contraction
what enzyme is released immediately from preformed storms by mast cells?
tryptase (remains identifiable in the serum for up to 4 hours!!), only mast cells make this!, leads to remodeling of connective tissue matrix
what is the pattern of allergic reactions on skin?
flare and wheal! flare=vasodilation at edge of lesion, wheal=edema
what cytokines are released form mast cells?
release is delayed (4-6 hours after degranulation), IL-4 and IL-13: associated with Th2 cells and lead to Ig class switching to IgE; Il-3, IL-5, GM-CSF: promote the survival and activation of eosinophils; TNF: activates endothelium and leads to adhesion molecule expression
what chemokines are released from mast cells?
must be made after 4-6 hours; MIP-1alpha, RANTES (CCL5 binds to CCR3) and Eotaxin (CCR3 is its receptor, CCL11 is what it is also called)
what lipid mediators are released by mast cells?
Leukotrienes C4, D4, E4: lead to eosinophil migration, smooth muscle contraction, vascular permeability and mucus hyper secretion; Platelet Activating Fxr: attracts eosinophils and other leukocytes
what do steroids do?
induce rapid apoptosis of eosinophils, and decrease the production of IL-5, leading to decreased release from the marrow
what does IL-5 do during allergic responses?
activates eosinophils, enhances leukotriene production and cytotoxicity for parasites; eosinophils look like crystalloid granules with a core and matrix surrounding this core
what is the responsibility of eosinophils?
secrete enzymes and cationic granule proteins like MBP and ECP
around how much of population suffers from asthma?
5%
pathophysiology of asthma
inflammatory cell infiltrate consists of eosinophils and lymphocytes, denudation of airway epithelium, mucus gland hyperplasia and hyper secretion, smooth muscle hyperplasia, thickened basement membrane
what are leukotrienes responsible for in terms of anaphylaxis?
smooth muscle contraction, vascular permeability and dilation
what is Arthus reaction?
Type 3 hypersensitivity, reaction seen in skin when sensitized individuals are exposed to specific antigen; involves activation of mast cells and other leukocytes via FcyRIII and no tcomplement
what is serum sickness?
a systemic reaction from injection of large quantities of foreign protein (antiserum from horse, anti-thymocyte globulin, streptokinase); usually occurs 7-10 days after exposure to antigen, patients have flu-like symptoms with an urticarial rash, arthritis and glomerulonephritis,
what is Farmer’s lung?
an alveoli tis due to a type 3 reaction against hay dust, may lead to inflammation and destruction of the alveolar wall with impairment in gas exchange
what is the tuberculin response an example of?
Type 4 hypersensitivity reaction, swelling occurs within 48-72 hours
what are contact hypersensitivity reactions indicative of?
type 4 hypersensitivity ractions, caused by chemical exposure to the skin, compounds then bind with self proteins and generate a response with extensive macrophage mediated inflammation
what are chemokines responsible for?
recruit macrophages to site of antigen deposition
what is IFN-y responsible for?
induces expression of vascular adhesion molecules
what is TNF responsible for?
causes local tissue destruction, increase expression of adhesion molecules
what is IL-3/GM-CSF responsible for?
stimulate monocyte production by bone marrow stem cells
