5. Introduction to Immunopathology Flashcards
SKIPPED ALL REVIEW OF IMMUNE SYSTEM - MAKE SURE YOU REVIEW!
YAS
Hypersensitivity disease classification
• Classification based on principle immune mechanism responsible for injury (3-Ab, 1 T-cells)
• Mechanism of injury often good predictor of ____ and ____ changes
• Type I hypersensitivity:
– Etiology: allergens activate ____ cells and
promote hyper ____ production
– Pathogenesis: allergen-IgE-mediated ____ activation
– Risk factors:
• ____ predisposition
• Route of allergen ____; dose; chronicity of exposure
• Exposure to environmental ____
• Decreased infections ____ in life
Perturbation of a host response designed to respond to ____
• Hypersensitivity - how immune system in response to foreign antigen creates tissue disease, etc. ○ AID - immune reaction to an autoantigen that causes disease, additional requirements are needed ○ Do not apply autoimmunity answers to hypersensitivity questions! • Classification is based on underlying immune mechanisms that contribtues to pathogenesis ○ I-III - \_\_\_\_ mediated; IV mediated by \_\_\_\_ cells • \_\_\_\_ hypersensitivity = Type I • It's due to antigens - referred to as allergens (only time used) - activate T cells after processed, and activate Th2 cells • When exposed to allergens, overproduce IgE - \_\_\_\_ individuals: ○ This example is truly a hyperresponse • IgE - can bind to mast cells > sensitizes the mast cells, and activated but in an abnormal way (same result, but expolsive) • May have \_\_\_\_ involvement • \_\_\_\_ hypothesis - contributed to higher incidence of atopic disease
morphologic (histopathology)
functional (clinical manifestations)
Th2
IgE
mast cell
genetic
entry
pollutants
early
parasites
ab
T
anaphylactic
atopic
MHC
hygiene
Overview of Type I hypersensitivity
• Left: normal immune response • \_\_\_\_-fold higher levels of IgE • IgE have Fc that allow it to bind to a receptor on mast cells - \_\_\_\_ ○ When produce IgE > blood column > tissue > sensitizes mast cells in tissues, and basophils • Most hypersensitivity happens in two steps: \_\_\_\_ and \_\_\_\_ • At end of sensi > overproduce IgE > mast cells sensi, not damaged > however, the binding of Ab makes it \_\_\_\_ specific; in non-atopic, perhaps 10,000 are occupied in IgE, in atopic 1-20,0000 receptors are occupied; IgE can be replaced and fall off, and all the receptors don't contain the same IgE > contain the IgE you're currently producing at that time (\_\_\_\_ allergies, etc), and the mast cells contain an array of \_\_\_\_ • Atopic disease occurs upon \_\_\_\_ exposure, as a result of sensitization • Requires that multiple IgE molecules are \_\_\_\_ - if atopic, you have lots of receptors clustered - more likely to be \_\_\_\_ > signal transduction > signals to mast cell that causes it to degranulate ○ IgE not involved in acute inflammation [???] ○ Much greater degranulation - more histamine • \_\_\_\_, PG are also all created following degranulation • Late phase where \_\_\_\_ may be produced - most of the pathologic reactions that occur are due to the immediate release of \_\_\_\_ and \_\_\_\_
1,000-10,000
FcERI
sensitization
reactive
antigen
seasonal
specificities
repeat
crosslinked
activated
leukotriene
cytokine
histamine
PG
Overview of Type I hypersensitivity- continued
• Consequence of release depends on what tissue it occurs in: ○ Bronchial, intestine - \_\_\_\_ contraction ○ Lung, mucus producing cells - activated, more \_\_\_\_ ○ Platelets activated - produce \_\_\_\_ ○ Sensory nerve endings may be stimulated, along with kinins - \_\_\_\_ with these reactions ○ Do not see the presence of inflammatory cells - only see the \_\_\_\_ in the acute phase
smooth muscle mucous serotonin itching (peritis) eosinophil
Primary Mediators Produced by Mast Cells and Basophils
- Biogenic amines (histamine)
- ____ contraction
- Increased ____ permeability
- Increased secretion by nasal, bronchial and gastric ____
- Enzymes (proteases, hydrolases)
- Cause tissue damage
- Generate ____ and activate complement
- Proteoglycans (____)
- Serve to package and store other mediators
Secondary Mediators Produced by Mast Cells and Basophils
• Lipid-derived mediators:
• ____- increase vascular permeability and bronchial smooth muscle contraction; also chemotactic for eosinophils
• Prostaglandin- ____ and increased mucus secretion
• ____- platelet agregation, release of serotinin, chemotactic for eosinophils
- Cytokines:
- Participate in late phase response
- Tissue damage is not a hallmark of type I reactions
- Lipid mediators - minutes to hours
- PAF - serotonin > vasodilation
smooth muscle vascular glands kinins heparin
leukotrienes
bronchospasms
PAF
Type I hypersensitivity
• Immune mechanism: ____ production > mast cells > ____ release
- Lesion/Clinical manfestations:
- Route of exposure determines nature of reaction/lesion
- vascular ____
- Vascular permeability— ____
- smooth muscle contraction
- mucus production• Sensitized mast cell > upon exposure to antigen, activated resulting signal transduction > increase intra ____> cell degranulates, releasing histamine, heparin and enzymes; later: LT, PG; hours: cytokines
• Clinical manifestations depend on where you encounter ____ in secondary response and the subsequent reaction
○ No consequence to the production of IgE
○ Edema is due to ____, but low in protein cxn (more serous)
IgE mediator dilation edema Ca++ antigen exudate
Kinetics of Type I hypersensitivity
• Immediate: \_\_\_\_, and AA metabolites • Hours-days: can be recycling of early events, but involves \_\_\_\_ • B: dilated \_\_\_\_, edema (in skin - clear spaces bt collagen bundles); cells are \_\_\_\_ ○ Eosinophils - \_\_\_\_ response, IgE in highly contaminated areas - parasites induce IgE response > eosinophils play a role that facilitate killing of parasite ○ Where parasites are endemic, it's protective; but in atopic individuals, they're mounting and resulting… [NOTES]
histmine cytokines BV eosinophils vestige
Clinical examples of Type I hypersensitivity disease
• Pathogenesis:
– antigen-IgE mediated mast cell ____
• Morphologic and functional changes:
– Result of action of mediators; depends on ____,
i.e., route of exposure to allergen
• Local disease: (local antigen) challenge
– Atopic ____: hives, urticaria, ____
– Allergic ____ (hay fever) and conjunctivitis
– Allergic gastroenteritis
– ____
• Systemic disease: ____
• Penicillin - 100-500 deaths/year from prescribed medications • \_\_\_\_ - hay fever • \_\_\_\_ - GI tract • \_\_\_\_ - involving lower respiratory tract - asthma ○ Type I not only cause, but prominent
degranulation
location
dermatitis
angioedema
rhinitis
asthma
anaphylaxis
inhalation
ingestion
inhalation
Urticaria and Angioedema
• Common disorder
• Antigens: ____, foods, drugs, insect venom
• Pruritic slightly elevated areas on the skin which are redder or paler than the surrounding skin (____; hives)
– Edema of ____ dermis
• Lesions appear rapidly and fade with in hrs
– Episodes may last for ____
• Angioedema: closely related; deeper edema of both ____ and ____ (lips, tongue and eyes)
– Don’t confuse with hereditary angioneurotic edema (____ deficiency)
* ATOPIC DERMATITIS * Pruiritic - itch * Develops bc of mediators (vasodilation, permeability) > edema formation > occurs in superficial dermis (right below the epidermis) * HAE has nothing to do with angioedema, has to do with a deficiency in a complement inhibitor
pollens wheals superficial days dermis subcutaneous fat
C1 inhibitor
- Can be ____
* More ____
small
ring-like
• Left: ____ - first thing you want to know what thing you’re allergic to (usually multiple things); can block, but one antigen at a time
○ Injected ____ - reaction = ____ (erethymetous)
• Right: dilated BV (sensitized ____ cells > IgE > degranulate); edema (collagen bundles are pushed apart)
○ Taken early in lesion; if gone on longer > would only see ____
skin test subcutaneously hives mast eosinohpils
- Left: hives, urticaria
- Middle: LP, dots are mostly ____
- Right: eosinophils - taking up a lot of eosin in cytoplasm bc of granules
- Hallmark of Type I: ____, presence of ____, presence of ____
eosinohpils
vasodilation
edema
eosinophils
- Related disorder - how we’re exposed to antigen
- Same reaction - involves deeper ____ (lips); transient, but can last a while - occurs in ____ individuals (____)
- ____ are a potent inducer of this reaction
- Life threatening when it affects the ____ - deeper ____
cutaneous tissue
sensitized
ingestion
nuts
tongue
submucosa
Allergic Rhinitis/allergic conjunctivitis (hay fever)
• Affects ____ of population
• Antigens: ____, fungi, animal allergens, dust mites
• Morphologic changes:
– ____ edema, redness and ____ secretion
– Secretions and mucosa contain numerous ____
* Can develop atopy later in life, or can \_\_\_\_ out of it * \_\_\_\_ and \_\_\_\_ component to this - never know when you received the first dose * Doesn't matter how the primary exposure to antigen takes place > how it gets \_\_\_\_ * The manifestations are a result of \_\_\_\_ infection
20% pollen mucosal mucous eosinohpils
grow environmental familial sensitized secondary
- Increased ____ duct secretion, increased ____ secretion
* Histo: from ocular area > many ____ and evidence of edema
tear
mucous
eosinophils
Atopic Asthma (extrinsic)
• Most ____ type of asthma
• Antigens: ____ antigens, dusts, pollens, animal dander, foods
– Stimulate Hyper IgE production leading to ____ hypersensitivity reaction
• Acute and intermittent, but eventually becomes ____ inflammatory disorder of airways; with recurrent episodes of wheezing, ____, chest tightness and cough
* Route of exposure - inhalation involving \_\_\_\_ airways * Diff types of asthma; \_\_\_\_ asthma is extrinsic asthma
common environmental Type I chronic breathlessness
deeper
atopic
Asthma: immediate phase (acute) • Triggered by \_\_\_\_ (1,2) • Mast cell \_\_\_\_ (3) • Mediators (\_\_\_\_ or via \_\_\_\_ reflex (4): – Bronchoconstriction (\_\_\_\_) – Vascular: \_\_\_\_ and edema – mucus production – recruitment of inflammatory cells, in particular \_\_\_\_
* Same mediators, but bc of presence of \_\_\_\_ > bronchoconstriction and spasm; can breath in but cannot \_\_\_\_ (exhalation requires muscle \_\_\_\_) * Mucus further interferes with presence of mucus [???]
antigen degranulation direct neuronal bronchospasm dilation eosinophils
smooth muscle
exhale
relaxation
Asthma: late phase
- ____ release by eosinophils, basophils, neutrophils, monocytes, lymphocytes
- Damage to ____ (e.g., ____ from eosinophils)
- Additional ____ reflex
- Smooth muscle ____
- Produced by a ____ lung
- ____ inflammation in the late phase - driven initially by allergenic stimulation > damage epithelium > detected and leads to ____ nerve discharge > bronchoconstriction and mucus secretion not only being driven by mediators, but also by ____ discharge
- SM contracts and undergoes hypertrophy
mediator epithelium major basic protein neuronal hypertrophy
hyperactive
chronic
afferent
efferent/afferent
• Hallmarks:
– Intermittent and ____ airway obstruction
– Hyper-reactive airways leading to bronchoconstriction due to bronchial ____ hyper-reactivity
– Increased ____ secretion
– Chronic inflammation with ____
• Morphologic changes:
– ____ lungs, occlusion of bronchioles with mucous plugs
– Edema, increased ____ glands, ____ of bronchial wall muscle, eosinophils
• Increased incidence: ____hypothesis
* Airway is reduced due to presence of mucus secretion, hypertrophy of SM, and bronchoconstriction * Wall of bronchial - normally thin wall of mucus, thin band of SM, and glandular elements below that > hypereactive airway, lots of \_\_\_\_ interfering with respiration - BM has thickened, LP is full of inflam cells and cytokines, SM is hypertrophied, and underlying glandular elements expanded > lungs are chronically inflamed * Lungs become overextended - can breathe in but can't \_\_\_\_
reversible
smooth muscle
mucous
eosinohpils
over-distended
submucosal
hypertrophy
“hygiene”
mucous
exhale
Asthma and Mast Cell Mediators
• Smooth muscle spasm – Leukotrienes \_\_\_\_, \_\_\_\_, \_\_\_\_ – Histamine – \_\_\_\_ – PAF
• Cellular infiltration: – Cytokines (e.g. \_\_\_\_) – Leukotriene B4 – \_\_\_\_ – PAF
• Vasoactive (dilation, permeability): –\_\_\_\_ – PAF – Leukotrines \_\_\_\_, \_\_\_\_, \_\_\_\_ – Prostaglandin \_\_\_\_ – \_\_\_\_ proteases • activation of \_\_\_\_ and kinins
C4
D4
E4
prostaglandins
TNF
ECF
histamine C4 D4 E4 D2 neutral complement
Cast of ____ formed of inspissated mucus coughed
up by a patient during an asthma attack
bronchial tree
Anaphylaxis
Systemic Type I Hypersensitivity reaction
* Still \_\_\_\_-mediated * Eggs, peanuts, bee stings, \_\_\_\_, drugs (\_\_\_\_)
IgE
shellfish
penicillin
Systemic anaphylaxis
• All components of type I reactions - individual is \_\_\_\_ to begin with, exposed to antigen; the following exposure is what is deadly ○ Giving something that is \_\_\_\_ distributed (giving penicillin [inject, ingest], allows it to encounter mast cells throughout the body rapidly • Involves many regions of the body almost \_\_\_\_ • Wide distribution [???]- most rapid spread > allergen into \_\_\_\_ ○ Bee sting - some of allergen will make its way into the local \_\_\_\_ and rapidly distributed ○ \_\_\_\_ of drugs (penicillin)
atopic widely simultaneously blood BS injection
Systemic Anaphylaxis
• Characterized by widespread edema, respiratory distress and vascular shock,
• Skin: ____, hives, ____ erythema
• Lungs: Contraction of respiratory
bronchioles and ____
• Laryngeal edema results in ____ and possibly obstruction
• GI:____, abdominal cramps, ____
• Vascular: Patient may go into shock within 1 hr due to severe ____
* Respiratory distress due to mucus, bronchoconstriction * Shock - septic, hypovolemic, \_\_\_\_ shock also results in vascular collapse * At level of skin you see everything you see with \_\_\_\_ manifestations * Lungs has similar manifestations to asthma * Upper airway - \_\_\_\_ edema * GI - mediators increase \_\_\_\_ * Lethality - vascular \_\_\_\_ > rapid * Allergic \_\_\_\_, uriticaria, angioedema
itching skin respiratory distress hoarseness vomiting diarrhea hypotension
anaphylactic laryngeal motility collpase rhinitis
• Five major categories of clinical manifestations with systemic anaphylaxis
○ Cannot ____ which is going to predominate within one patient
○ Swelling, hives, uritcaria in patients - swelling due to ____ edema
• Bottom left - child, angioedema of lips
• Swollen airway
• Skin reactions, respiratory problems (heavy breathing, wheezing, tightness of chest, hoarse voice, eyes tearing, nose running/sneezing)
• Inject penicillin - takes a ____; given orally - GI problems within ____, but in order to be this severe it’ll take ____
• Time of onset - depends on ____ sensitized, number of ____ that are occupied to IgE to that specificity (involves cross-linking) leading to greater chance of encounter and cross-linking
• All of these manifestations will not occur; depends on ____ of the allergen and how it spreads, if it remains ____ it will only remain there
predict laryngeal minute GI longer mast cells receptors location locally
- The representation of anaphylaxis is ____
- ____ abnormalities
- ____abnormalities
- > ____ circulatory problems
- If left untreated, all the manifestations will arise
- Do not memorize these! But know that they do occur!
unpredicable
subcutaneous
respiratory
1/3
• Individual could inhale but couldn’t ____ - increase ____ and air - did not collapse
• Histologic section - ____ of cells, the alveoli are spread and large, alveolar ____ that are broken, dilated BV, no ____ or ____
○ Not very striking histopathology, but ____
exhale fluid absence septa inflammation eosinophils consistent
Summary of Clinical Manifestations of Anaphylaxis
- ____ and ____
- Laryngeal edema
- ____ and wheezing
- Dizziness and hypotension
- ____ symptoms
- Rhinitis
• Cardiovascular: – \_\_\_\_ – \_\_\_\_ – Hypotension/shock – \_\_\_\_ – Chest pain
* Laryngeal edema - \_\_\_\_, and before they will sound \_\_\_\_ * Cardiovascular reactions as try to compensate for loss of hypotensive shock
uritcaria
angioedema
dyspnea
GI
tachycardia
bradycardia
arrhythmias
respiratory distress
hoarse
• First: take patient ____, and ____ allergies
• Then, if you don’t have to ____ then don’t!
○ Given orally, the GI symptoms will be early, but life-threatening will have later onset
• Do not leave the patient ____; and if given prescription, give them a list of ____
• Upon development of symptoms - stop procedure, immediately seek help
• Get patient in position ____ on back, slightly elevated
○ Antihistamine - stoichiometric activity, block the histamine receptors
○ Drug of choice is ____ (alpha1, beta1, beta2) > works on mast cell > stops degranulation; on shock organs > relaxation of organs, and ____ of BV
○ Given ____ (not intravenous)
• Establish a line with O2 under ____ pressure (may not work due to ____ edema), give patient ____, and ____ compressions
history
parent/sibling
inject
alone
warnings
flat epinephrine vasoconstriction intramuscular high laryngeal saline chest
Treatment
• Acute emergency: ABC
• ____
• Pharmacologic – \_\_\_\_ (drug of choice for acute-emergency Tx) • Vasoconstriction (\_\_\_\_) • \_\_\_\_ and blocks degranulation (β2) – \_\_\_\_ – Corticosteroids (??-recurrent) – Antihistamines (after pt is \_\_\_\_)
• Prevention:
– Avoid antigen (take complete ____)
– ____ sodium
– hyposensitization
• Establish airway - \_\_\_\_ pressure O2 • Theophylline - present in \_\_\_\_ (caffeine) ○ Adenylate cyclase takes ATP and converts to cAMP; upon mast cell activation, cAMP levels go down > triggers Ca++ influx into cell • Mast cells activation - part of signaling process is to lower cAMP levels; in order to keep cell from degranulating you want to keep \_\_\_\_ high ○ Two drugs to keep cAMP levels high: § Anything that activates \_\_\_\_ (epinephrine can act on this) § Inhibiting the \_\_\_\_ of cAMP (via \_\_\_\_, making it a 5' AMP) (theophylline blocks this enzyme, caffeine also does this as well) • \_\_\_\_ used in sensitive individuals - anti-inflam and immunosuppressive (non-specific effect) • Antihistamines - used well after the patient is stabilized; not the drug of choice for the \_\_\_\_ phase • Of the choices, epinephrine is the best for the anaphylaxis • Cromolyn sodium - given to stabilize \_\_\_\_ so they don't readily degranulate • Hyposensitization therapy ○ Two ways to control immune - hit immune system and shut it down entirely (susceptible to infection and even cancer) (\_\_\_\_ does this); but make nonresponsive to certain \_\_\_\_: requires that you know what the person is allergic to, done via scratch test (next slide) ○ Once antigens found, can be used in therapy - given in a regiment in \_\_\_\_ doses that doesn't trigger a reaction and overtime instead of IgE the patient will produce \_\_\_\_ > not lowering IgE, but producing \_\_\_\_ and it interacts with allergen before the \_\_\_\_ can interact with allergen on mast cell
cricotyroidotomy epinephrine alpha1 bronchodilation theophylline stabilized
history
cromolyn
high
coffee cAMP adenylate cyclase degradation phosphodiesterase
corticosteroids
acute
mast cells
cortico’s
antigens
low
IgM
IgG
IgE
Scratch Test
Also referred to as a puncture or skin prick test
- A solution containing a very ____ amount of a potential is placed on the skin and a small needle is used to prick the substance into the skin
- Responses are evaluated ____ minutes after exposure
small
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