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Mechanism of Disease > Hypersensitivity Reactions > Flashcards

Hypersensitivity Reactions Flashcards

1
Q

Hypersensitivity Reaction definition

A

unwanted immune responses against endogenous or innocuous foreign antigens that produce tissue damage. endogenous reaction gets us autoimmune disease.

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2
Q

what are the 4 types of hypersensitivity reactions?

A

Type I: IgE-mediated immediate reactions (occurs w/in minutes of the exposure)
Type II: Anti-body-mediated cytotoxic reactions or antibody dependent cell-mediated cytotoxicity
Type III: immune complex reaction - antibody-antigen complex that causes the problem
Type IV: t-cell mediated delayed-type hypersensitivity reaction (in contrast to 1st three types that are antibody mediated, this one is t-cell mediated)

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3
Q

What is another name for Type 1 Hypersensitivity reaction?

A

Allergic reaction

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4
Q

What does IgE bind to?

A

soluble antigens - allergens

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5
Q

What is the effector mechanism of type I hypersensitivity reactions?

A

mast cell activation & release of cytokines, chemokines, and lipid mediators that cause inflammation & tissue damage

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6
Q

initial steps of type I hypersensitivity (first exposure to antigen)

A

1) sensitization - b-cells get activated upon exposure to antigen & produce IgE antibodies
1st exposure
2) once IgE antibody is made, it binds to mast cell surface on the high affinity Fepsilon receptors that can bind to IgE (affinity is so high, that you never see IgE antibodies in circulation . As soon as they are made, they bind to Fepsilon receptors on mast cells) - during these two steps, we don’t experience any symptoms of allergies

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7
Q

second exposure to antigen in type I hypersensitivity reaction

A 
subsequent exposures (after initial), allergens (antigens) bind to IgE antibodies that are presented on the surface of mast cells - causing clustering of antibodies on mast cell surface - cross-linking - that cross-linking sends signal to activate mast cells.
mast cells are activated & release granule contents - that makes new proteins - factors that cause tissue damage
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8
Q

do all allergic reactions have the same mechanism?

A

yes

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9
Q

What varies in allergic reactions?

A

route of entry of allergen & site of mast cell activation can make us experience different systems

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10
Q

How can we get systemic exposure with an allergen?

A

injection, insect sting, absorption across an epithelial surface

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11
Q

Why do we get a systemic response to an allergen?

A

mast cells lining all blood vessels get activated & that causes increase of vascular permeability, histamine release, decrease in vascular tone (leads to shock) and airway constriction (leads to difficulty in breathing)

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12
Q

What does systemic exposure to allergens cause in severe cases?

A

anaphylactic shock

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13
Q

What kinds of things can cause systemic anaphylaxis?

A

drugs, insect venom, food

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14
Q

What happens with subcutaneous exposure of allergen?

A

(drugs, dust mites, insect bites, food), mast cells that line epithelium get activated in the skin & release histamine that causes vasodilation & increase in vascular permeability. This causes swelling - called a wheal and flare. Initial swelling spot is wheal & spreads out to bigger area - brighter red flush - that’s the flare
Urticaria (hives)

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15
Q

What is urticaria?

A

Hives - wheal & flare

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16
Q

What kinds of manifestations can food allergy have?

A

depends on the site where mast cells are activated
systemic - we can get anaphylactic shock
localized in skin - urticaria
localized in gut - vomiting & diarrhea

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17
Q

what is the most common food that causes hypersensitivity reaction?

A

peanuts & shellfish

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18
Q

What is the most common route of entry in hypersensitivity I reactions?

A

inhalation
can be caused by pollens, dust mite feces, animal dander
in mild situation causes allergic rhinitis (edema and nasal mucosa irritation, coughing, runny nose, itchy eyes)
in severe forms - it is asthma , mast cells lining lower airways get activated & produce lipid mediators that cause broncho constriction

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19
Q

What is the mild symptom of inhaled hypersensitivity?

A

allergic rhinitis - edema and nasal mucosa irritation - coughing, runny nose, itchy eyes

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20
Q

what is the severe form of inhaled hypersensitivity?

A

asthma - mast cells lining lower airways get activated & produce lipid mediators that cause bronchoconstriction and increase production of fluid & mucus - & mast cells & a few other types of cells involved also cause inflammation
histamine is NOT playing an important role

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21
Q

why is asthma difficult to treat?

A

chronic inflammatory disease, never goes away

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22
Q

What is the second type of hypersensitivity reaction?

A

mediated by IgG or IgM antibodies - these antibodies recognize cell surface or extra cellular matrix- associated antigens (antigens are not free)

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23
Q

what is the effector mechanism of type II hypersensitivity?

A

Antibody Dependent Cell Mediated Cytotoxicity (ADCC)

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24
Q

What is the mechanism of type II hypersensitivity reaction?

A

Target cell has antigens on the cell surface - recognized by IgG or IgM antibody. Antibody binds to Fcgamma receptors on phagocytic cells (macrophages, neutrophils) express Fcgamma receptors that recognize IgG (unlike mast cells that express Fcepsilon that recognize IgE). Phagocytic cells express Fcgamma receptor that can bind to IgG - can recognize antibody that has already bound to antigen - can cause ingestion of target cell. Another event is when antibody recognizes antigen on cell surface, causes activation of complement, leads to C3B deposition on target cell. Also recognized by phagocytic cells by C3B receptor. These receptors can recognize IgG and C3B (the complement), when they recognize antibody or the complement, causes ingestion of the target cell by phagocytic cell, so target cell is dead - Phagocytic mediated death of target cell (Antibody dependent cell mediated cytotoxicity ADCC)

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25
Q

How is phagocytosis of apoptytic cells different from phagocytosis of antigen presenting target cells?

A

phagocytic ingestion of apoptized cells does not activate phagocytes. Ingestion of target cell with IgG and/or complement on it, phagocytic cell doesn’t just eat it up quietly, it gets activated & produces inflammatory mediators - called opsinization

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26
Q

What is opsinization?

A

IgG binding & complement deposition on cell surface is opsonization.
When phagocytic cells take up these cells, they undergo inflammatory activation

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27
Q

What do activated phagocytic cells produce?

A

cytokines & chemokines - recruit more neutrophils & macrophages to the site.
why we get tissue injury during type II hypersensitivity reaction

28
Q

What are some examples of type II hypersensitivity reaction?

A

Hyperacute graft rejection (target antigen: ABO antigen on vascular endothelium of the graft (kidney or heart) is recognized by preexisting antibodies in the recipient. Clinically dealt with by prescreening recipient to see if they have IgG antibodies against ABO antigens of the graft in their plasma.
Good pasture’s syndrome - individuals have auto antibodies that recognize non collagenous proteins in basement membranes of kidney glomeruli & lung alveoli - leads to complement & Fc receptor-mediated inflammation - in severe cases patients develop nephritis & lung hemorrhage - treatment is immunosuppressant drugs so they don’t make those antibodies

29
Q

What kind of reaction is hemolytic anemia

A

Type II hypersensitivity

30
Q

How many types of hemolytic anemia are there?

A

3 types:
hemolytic transfusion reaction: antibodies against ABO antigen in blood transfusion, red blood cells get opsonized, that causes accelerated clearance of red blood cells - hemolytic response
hemolytic disease of newborn: mother is Rh negative & she has Rh positive baby (not the first time - miscarriage or giving birth to Rh+ baby first time, Mom develops Rh+ antibodies against the Rh factor, so if she’s pg w/subsequent Rh+ baby, leads to hemolytic anemia b/c antibody will attack Rh factor. dealt with by screening if anyone is pg, they will screen for anti Rh factor antibodies
autoimmune hemolytic anemia - unknown antigen, but on red blood cell surface - patients develop antibodies against their own red blood cells, causes increased clearance of red blood cells in the spleen -> hemolytic anemia

31
Q

What is the mechanism of autoimmune diseases due to antibodies specific for cell surface receptors?

A

antibodies aren’t involved in killing cells - they compete with endogenous receptor for ligand so regular receptor binding doesn’t work, or antibody assimilates receptor

32
Q

What are examples of autoimmune diseases due to antibodies specific for cell surface receptors?

A

Myasthenia gravis: antibody binds to nicotinic receptor- blocks acetylcholine (endogenous ligand) from binding to nicotinic receptor - so that acetylcholine (ligand) can’t bind - leads to muscle fatigue & paralysis
severe type II diabetic patients - some develop antibodies that bind to insulin receptors - leads to hyperglycemia
Grave’s Disease - antibodies bind to thyroid stimulating hormone receptor, antibody simply stimulates receptor as if it’s a ligand binding - causes hyperthyroidism. (unlike other two examples where antibody prevents ligand from binding)
NO cell death in these diseases

33
Q

How are autoimmune diseases due to antibodies specific for cell surface receptors different from autoimmune diseases due to ADCC?

A

no cell death, like in ADCC, just antibody binding to receptors either blocking receptor function or over activate receptor

34
Q

What is type III hypersensitivity reaction?

A

also mediated by IgG or IgM (like type II)
recognizes soluble antigens
mechanism is similar to type II - immune complex complement activation
complement and antibody causes activation of neutrophils and macrophages and leads to tissue inflammation and injury

35
Q

what is the difference between type II hypersensitivity reactions and type III hypersensitivity reactions?

A

type II antigen is on cell surface (target cell w/antigen on it so it’s either on cell surface or extracellular matrix) type II reaction is very localized, where disease occurs is where the antigen is
in type III reaction, because it’s soluble, the antibody binds to the antigen, forms a complex that can travel throughout the body, so type III reaction tends to be more systemic rather than localized

36
Q

What determines whether a type III hypersensitivity reaction will occur?

A

the size of the immune complex:
if it’s too big or bigger than 1000kDa, removed by phagocytic system without causing harm.
if it’s too small, it will go through blood vessel without being noticed.
but if size is just around 1000kDa, it will get stuck on blood vessel wall, and neutrophils & macrophages cannot get rid of it, so they keep getting activated and producing cytokines and leukocytes, because they can’t get rid of it, and that’s what causes the disease
neutrophils play more important role - produce ROS, and protolytic enzymes that cause tissue damage & recruit more leukocytes & produce pro-inflammatory mediators

37
Q

Are there localized reactions with type III hypersensitivity?

A

Yes
Arthus reaction - usually occurs during vaccination booster - pre-existing antibodies bind to antigen at rejection site & that gets stuck in walls of small arteries at injection site, and that leads to cutaneous vasculitis
Farmer’s Lung - IgG antibodies bind to antigens derived from hay dust or mold spores - immune complex is deposited in alveolar wall of lung - causes alveolar membrane damage

38
Q

What are the majority of type III hypersensitivity reactions?

A

systemic

39
Q

What is serum sickness?

A

example of type III hypersensitivity reaction
occurs during treatment of xenogenic serum (from different species) - before antibiotic era, people used horse serum to treat pneumonia, we would immunize the horse, then use that to treat people - then we would develop antibodies against horse serum antigens (horse serum albumin for example) can cause serum sickness
horse serum is still used to treat bites from poisonous snake
in clinic, some treatments using antibodies is still xenogenic,

40
Q

What is an example of a xenogenic antibody treatment that is used today?

A

transplant rejection, use immunosuppressive drugs, one is anti CD3 antibody that’s generated in rodents - can cause serum sickness
mechanism is complement & antibody mediated phagocytic cell activation & inflammatory response.
clinical feature is like influenza = chills, fever, rash, because immune complex tends to deposit in small vessel walls, arthritis & glomerulonephritis is very common

41
Q

What is systemic lupus erythematosus?

A

typica systemic type III hypersensitivity reaction
patients have auto antibodies against self DNA molecules or nucleoproteins
forms immune complexes that travel throughout the body & tend to deposit in joints, and kidney so arthritis & glomerular nephritis is very common in these patients

42
Q

What is type IV hypersensitivity?

A

Delayed-type hypersensitivity reaction (DTH)
t-cell mediated response - antibody is not involved
antigen can be soluble or cell-associated

43
Q

what is the mechanism of type IV hypersensitivity?

A

cytotoxic t-cell response as well as macrophage activation
during initial sensitization (initial exposure) antigen presenting cell gets activated & presents antigen to t-helper cells. t-helper cells develop into TH1 (majority of cells die after antigen is gone). Small portion become t-memory cells.
When we are exposed to antigen again, these TH1 memory cells activated very quickly, recruited to site of antigen exposure, make chemokines to recruit macrophages
cytokines to (INF gamma) to activate macrophage and (GM-CSF) to promote bone marrow to produce more macrophages and IL-3 growth factors for macrophages
cytotoxic cytokines like tumor necrosis factor (both macrophages and t-cells can make TNF alpha that causes tissue damage)
that’s why mechanism is mediated by cytotoxic t=cells & macrophages & delayed because initial exposure takes 3-10 days & rechallenge takes 2-3 days.

44
Q

What is an example of type IV hypersensitivity?

A

Tuberculin test
inject mixture of peptides & carbohydrates derived from bacterium tuberculosis
elicitation - testing whether we already have antigen responsive t-cells - if we have already been primed before
give shot to bring out immune response
go back after 2-3 days & they measure the swelling on your arm - swelling is hard because it is full of immune cells - (not fluid, if it was fluid it would be soft), macrophages - come in & they are the ones that are producing tissue damaging factors, the swelling is full of these macrophages

45
Q

What is contact hypersensitivity?

A

a type IV hypersensitivity reaction(DTH)
poison ivy induced skin rash - not a protein in poison ivy but a group of small molecules called catechols - chemically reactive - bind to proteins in our skin - catechol protein conjugate that is the antigen that causes t-cell response. (small molecules are not normally seen by the immune system - they go undetected, BUT if they bind to endogenous proteins, they will become antigens)

46
Q

What are some autoimmune diseases caused by DTH?

A

Insulin-dependent diabetes mellitus (type I diabetes) - have CD4+ cytotoxic t-cells that kill beta cells & that’s why they can’t produce insulin

47
Q

What causes multiple sclerosis?

A

caused by DTH (delayed-type hypersensitivity reaction), CD4+ cytotoxic t-cell causes destruction of myelin - causes neurologic deficits

48
Q

What initiates rheumatoid arthritis?

A

t-cell activation (DTH reaction) for specific antigens in the joints - destruction of joint cartilage

49
Q

Where are antigens located for all 4 types of hypersensitivity reactions?

A

Type I & III, soluble antigens, type II - on the cell surface or in the matrix, type IV - either soluble or cell-associated

50
Q

What are the immune reactants for each of the 4 hypersensitivity reactions?

A

Type I, II, III - antibody mediated (Type I, IgE; type II, IgG, IgM; type III, IgG, IgM)
Type IV - T-cell mediated

51
Q

What are the mechanisms of each type of hypersensitivity reaction?

A

Type I: antigen bind to IgE antibodies on mast cells, trigger mast cell activation which release mediators that cause inflammation & tissue damage
Type II: Antibody dependent cell mediated cytotoxicity - phagocytic cells recognize antigen (IgG binds to antigen on cell surface)
Type III: antigen/antibody binding causes immune complex, that complex causes neutrophil & macrophage activation & inflammation
Type IV: cytotoxic T-cell & macrophage mediated response - two types of cells produce chemokines, cytokines & tissue damaging cytotoxic mediators

52
Q

What kind of antibodies do we make during sensitization, and what happens to them?

A

IgE antibodies
antigens bind to mast cell surface (have epsilon receptor)
re-exposure - antigens bind to antibodies on mast cell surface - causes cross linking & mast cells get activated

53
Q

What does each B cell do?

A

make 1 type of antibody - that recognizes a specific antigen
that one antibody can have 5 different flavors : IgE, IgM, IgA, IgG, IgD
IgE is one isotype of antibodies that bind to Fcepsilon receptor

54
Q

What kind of cell does IgE bind to?

A

Mast cells - when Mast cells get activated, the kind of molecules they release & make cause allergic reaction, that’s why IgE is important in allergic reactions

55
Q

What causes IgE production?

A

Th2 t-cell activation - make IL-4 and IL-13 - important for B-cell activation & switching to make IgE antibody

56
Q

How is IgE antibody made?

A

activated t-cell becomes plasma cell. All plasma cells do is make antibodies. IgE is made by activated b-cells. b-cell activation is triggered by Th2- t-cells (type 2 helper cells) which make IL-4 and IL-13. Naive t-cells become TH-2 - allergen exposure gets through epithelium in the skin - taken up by antigen presenting cells (dendritic cell) will present allergen derived antigen to t-cell and t=cell becomes TH-2

57
Q

what makes a t-cell become TH-1 or TH-2?

A

decision is made during synapt interaction between t-cell and antigen presenting cell
this synpat is critical for a lot of our immune responses: signal 1 (antigen recognition by receptor)
signal 2 (costimulation B7-1 B7-2 and CD-40) 1 & 2 can cause full t-cell activation
there’s another signal - signal 3 - determines what kind of t-cells it differentiates into: type 1 or type 2
that signal is cytokine
tH 2 response cytokine is IL-4 (not clear what cell is making IL-4)
TNF alpha and IL-12 - it becomes TH-1
in allergic reaction, it’s IL-4 that drives TH-2 differentiation which makes more IL-4 and IL-13 which causes B-cell to make IgE

58
Q

Mast cells - what about them?

A

most important cell in causing allergic reaction: derived from myeloid progenitors in bone marrow (don’t see them in the blood) but near blood vessels, nerves & beneath epithelium - why IgE population in blood is very low, once they are made they are bound to mast cells

59
Q

What about mast cell granules?

A

granules contain proteins and mediators that are pre made so they can be released very quickly - that’s why allergic reaction starts very quickly
pathway is there to fight against parasite infections

60
Q

during sensitization and mast cell binding stage are there symptoms?

A

nope

61
Q

when do we get allergic response symptoms?

A

when we’re exposed to the same allergen subsequent times
antigens (the 3 antigens can be the same or different) bind to antibody on surface of mast cell - cause cross linking of several antibodies together on mast cell surface - leads to activation. once mast cells are activated, they release their granule contact, including histamine & start to synthesize cytokines & lipid mediators - these are factors that cause tissue damage & symptoms we experience when we have allergic reactions

62
Q

What are substances in the granules of mast cells?

A

proteases: tryptase & chymase. tryptase is only found in mast cells & all mast cells have tryptase in their granules (if patient has high level of tryptase in serum, that means they have mast cell activation). tryptase & chymase cause break down of tissue matrix proteins, causes tissue destruction & stimulates mucus secretion. chymase is expressed in certain connective tissue mast cells
biogenic amines: histamine - only biogenic amine that is expressed in human mast cells in a large amount Non-lipid molecules that have an amine group on it.
histamine lasts only a little while - action is very short- causes vasodilation smooth muscle constriction - hives, difficulty in breathing

63
Q

What are the biological effects of histamine?

A

can act on intestinal and bronchial smooth muscles -> increased peristalsis & bronchospasm. Food allergy gives vomiting & diarrhea
can bind to receptors on endothelial cells that line the blood vessels - leads to vasodilation, decrease in blood pressure (septic shock) and capillary permeability increase (leads to hives)
can also bind to endothelial cells, cause contraction of cells and up regulation of adhesion molecules, so gaps between cells lining the blood vessels so leukocytes can come in, increase tethering of leukocytes onto the blood vessel - mechanism of causing inflammation

64
Q

how does anti-histamine treatment work?

A

all actions of histamine are mediated through histamine receptor
most antihistamine therapy is H1 antagonist (like benadryl) - most useful in relieving symptoms of acute allergic reaction: sneezing, rhinorrhea , itching of eyes, nose & throat = very effective during early season of pollen release, when pollen becomes abundant, mast cells are already activated, anti-histamine is not that helpful anymore
limitation in treating asthma: bronchoconstriction & chronic inflammation are not mediated by histamine, so anti-histmamine doesn’t help much

65
Q

What causes the symptoms of asthma?

A

not histamines
lipid mediators- produced by mast cells - especially leukotriene C-4 & it’s metabolites D4 and E4
Other lipid mediators mast cells made are prostaglandin D2 and platelet activating factor
all of these mediators can bind to their respective receptors on endothelial cells & smooth muscle cells causes vasodilation, bronchoconstriction,
some of these mediators are also chemokines
can attract neutrophils & other leukocytes

66
Q

What are leukotrienes also called?

A

slow reacting substance
histamine action is very quick
these factors are released much later after mast cell activation ‘ takes 8-12 hours for mast cells to make these factors
also make cytokines & chemokines (IL-4 & IL-13) important in B-cell producing IgE - positive feedback, mast cells are activated because of IgE binding, once they are activated they make more Il4 & IL13 for bcells to make more IgE - stimulate and amplifies the response
also make IL3 and IL5 - growth factors for eosinophils

Mechanism of Disease (4 decks)

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