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356 Cards in this Set

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  • Back
In general, what is the cause of primary congenital immunodeficiencies?
due to genetic changes in DNA v.s aquired (AIDS)
The recurrent sinopulmonary infxns associated with B cell deficiency are the cause of what?
extracellular bacteria--the affected cant fight extracellular bacteria but they handle intracellular pathogens fine
Characteristics of B cell deficiency?
can't activate C' properly
can't fight encapsulated bacteria
greater incidence of pneumonia, staph, strep
What is another name for XLA?
What type of def. is XLA?
primary humoral deficiency
When do manifestastions for XLA start?
at 5-6months old when maternal IgG is reduced and they can't produce their own
What is the inheritance of XLA?
What are some characteristics of XLA?
recurrent staph pneumonia by 2-3yo
X linked-males affected
recurrent sinusitis, bronchitis, otitis, pnuemonia
handle viral infxns but not extracellular pathogens
What condition exhibits missing tonsils and no lymphedenophathy?
Boys with XLA
(B cell rich areas not there, no follicular structures in lymphoid biopsy)
What is the defect in XLA?
mutation in Bruton tyrosine kinase encoded on X chromosome. It is reqd for progression to pre B to immature B
What is missing in XLA?
no movement from BM
no plasma cells
no Ab isotypes (not even IgM)
no CD19 cells
no BCR
What is the Tx for XLA?
Intravenous Gamma Globulin (IVIG) : purify then concentrate serum IgG and inject intramuscularly. Used for Ab replacement in humoral immunodeficiencies
What type of def is X linked Hyper IgM?
primary humoral immunodeficiency
What is the diagnostic clue for X linked Hyper IgM?
increased serum levels of IgM, absent of extremely low IgG, A, E
normal CD19
B cell maturation and activation normal
What is the defect in Hyper IgM def?
mutation in gene encoding CD40L (CD145) which is expressed on T cells and normally triggers isotype switching
No isotype switchin can occur so IgM still secreted and can still activate C' but not enough to protect you. Also mucosal surfaces unprotected b/c missing IgA and IgE
What type of def is transient hypogammaglobulinemia of infancy?
primay humoral immunodef
When does hypogammaglobulinemia of infancy resolve?
it is transient so resolves by 2-3 yrs
What is the problem with transient hypogammaglob of infancy?
failure of infants immune system to mature at right time b/c defect in number and fxn of Th is noticed after 5-6mo when maternal IgG catabolized and not adequately replaced by baby immune system
Describe the serum levels of transient hypogammaglob of infancy.
serum IgM and IgA are normal
IgG levels low leading to failure of opsonization and phagocytosis
What type of def is common variable immunodef (CVID)?
primary humoral...but acquired!
What is the most common cause of hypogammaglobulinemia in adults?
CVID (adult onset at 15-35yr)
What is the hallmark of CVID?
increased susceptibility to freq recurrent sinopulmonary infxns b/c encapsulated bacteria
*GI disorders b/c low IgA
*decreased levels of IgG
*as disease progresses all isotypes decrease
What are the serum levels of CVID like?
as disease progresses all isotypes decrease
decreased production of IL-2, 4, 5
T cells dont prolif b/c lack IL-2
What phyisical symptoms will you see in CVID patient?
enlarged lymph nodes with NO plasma cells
noncaseating granulomas in liver and spleen
increased risk of developing lymphoma, skin cancer
biopsy shows lack of plasma cells in B rich germinal centers
What is the problem with MGUS (monoclonal gammopathy of uncertain signif)?
-M protein spike (serum monoclonal Ab of IgG class)
-decreasing # plasma cells in BM and lymph nodes
What are the symptoms associated with MGUS?
no symptoms or signs only show protein spike and decresaeing number plasma cells in BM and lymph nodes
What is the most common selective immunoglob def?
selective IgA
What is the problem with selective immunoglob def?
1 Ab isotype not produced or isotype subclass
What is the most common immunodef disorder?
selective IgA: low serum AND secretory IgA
How is selective IgA diagnosed?
serum IgA below 15mg/dL
# mIgA B cells normal, but blocked from becoming IgA secreting plasma cells
Why do we care about selective IgA if it is asymptomatic?
pts that have anti-IgA Abs so when you give them IgA transfusion they will have rxn (anaphylactic transfusion rxns)
What organisms cause T cell med Immunodef?
intracellular pathogens, fungi, viral infxns *most common fungal pathogen Pneumocystis jeroveki
What is the defect with DiGeorge syndrome?
malformation of 3rd and 4th pharyngeal/branchial pouches during fetal development b/c of deletion of 22q11: abnormal migration therefore all organs that arise from these structures disfxnl
What will you typically see in Di George kids?
hypoplasia or aplasia of thymus and parathyroids
truncal CV malformations
abnormal facies
recurrent or chronic infxn to viral bacterial organisms
seizures b/c hypocalcemic (no PTH)
What is the serum like in Di George?
no T (low CD3): no CMI, no primary selection
CD19 normal, but low Ab response
describe the distinquishable face of Di George.
absence of philtrum
small chin
wide spread eyes
notched low set ears
Xray: absence of thymic shadow
How can you detect Di George?
with FISH b/c microdeletion of 22q11
What are SCIDS
severe impairment of T and B cell fxns
What is the same about all SCIDS?
T cells not fxning therefore no B-T tango, no memory (humoral immunity impaired secondary to defect)
When do T cell defects occur in SCIDS pts?
at ANY stage in T cell development
What SCIDS are T-B-NK-?
What SCIDS are T-B+NK-
gamma common chain
JAK3 def
What SCIDS are T-B+NK+?
MHC I def
MHC II def
What SCIDS are T-B-NK+?
Omenn syndrome
What are the features of neonates with SCIDS?
no humoral or CMI
vaccines don't work
no thymic shadow
small dysplastic thymus
hypoplastic lymph nodes w/ marked depletion of T rich areas
Why won't vaccines work in SCIDS?
b/c T cells unresponsive to mitogens and antigens
What immunodef is almost alsways fatal w/o BM transplant?
What are the symptomes of SCIDS?
seen by 3-6 mo age
oral candidasis (prominent thrush)
diaper rash
failure to thrive
morbilliform rash
recurrent infxns
What is the classic clinical triad of Wiskott-Aldrich Syndrome (WAS)?
thrombocytopenia (at birth)
severe eczemea by age 1
recurrent pyogenic infxns by encap bacteria
What is the inheritance of WAS?
X linked recessive
What does the serum of WAS patient look like?
IgM low
IgG normal--high turnover
IgA and E high
Do WAS patients exhibit responses to thymus independent and dependent antigens?
no TI responses, poor TD responses
What are the names for Types1-4 HSRs?
I: immediate HS
II: antibody-mediated HS
III: Immune complex mediated HS
IV: T lymphocyte HS/DTH
When does Type I HS start and end?
starts w/n seconds
resolves w/n 2 hours
In Type I what happens to elicit reponse?
Ag cross linking of IgE on surface of mast cells induces release of vasoactive mediators
*signal transdxn via FcR resulting in degran of mast
Manifestations of Type I HS?
systemic anaphylaxis (hives, eczema) or local anaphylaxis (at site of injury) such as hay fever, asthma, hives, food allergies, and eczema
What is an allergen?
immunogen that induces an allergic response
- low molecular wt protein; diffusible, soluble and stable and must contain peptides that bind to host MHC class II molecules
What is an allergic response?
undesirable physical rxn or anaphylaxis- a state of HS
synonymous with Type IHS
What is anayphylaxis?
occurs when pt. w/ immediate HS is exposed to the relevant allergen entering the circulation rapdily: bee sting, injection of penicillin, ingestion of allergen
Response can be local or become generalized leading to urticaria and or bronchospasm
What is atopy?
familial predisposition of certain individuals to react against common foreign substances in an uncommonly excessive way
*circulating levels of IgE
What is the sensitization phase?
initial exposure to immunogen which results in production of reactive B or T(CD4) cells
What is the eliciataion phase?
subsequent re-exposure to SAME immunogen (allergen in atopic individual) results in allergic rxn
What property of allergens determines when rxn will occur?
MW of allergen
ex: small particles will present in lower respiratory (asthma) while large particles(mite poop) will tend to trap in airway
Describe phase I of Type I HS
1. IgG picks up allergen on BCR
2. B-T tango
3. Stimultion of IgE class switch in B by IL-4, 5, 13 to produce IgE that is allergen specific
4. IgE then binds to FceR1 on mast cells
Describe phase II of Type I HS
after IgE that is allergen specific from phase I is bound to FceRI of mast cell, a repeat exposure to antigen elicits mast cell degran w/n minutes after reexposure
What 3 classes of cmpds are released immediately in Type I HS?
1. membrane-derivd lipid mediators: IP3
2. cytokines (TNF)
3.biogenic amines:histamine and serotonin
Describe the order of compound release following elicitation phase of Type I
antigen cross linking of mast cell IgE resultes in IP3 and Ca into cytoplasm, the release of PREFORMED histamin and seretonin into CT; adjacent capillary endothelial cells retract, increaseing perm, allowing plasma to seep into tissues
In type I what happens after histamine and seretonin release?
plasma seeps into tissues and contains C' proteins resulting in redness (rubor) and swelling (tumor). Histamine then binds to local type c nerve fibers: pain (dolor) and itching resulting in a wheal (fluid filled itchy bump). Stimulation of c nerve fibers results in further capillary dilation: "flare" or increased redness at site (if you itch it it will repeat flare)
The influx of plasma and protein mediators (Ig, C')in Type I HS results in what?
opsonization, phagocytosis, and C' activation to yeild C3a which serves as a feedback regulator to mast cells inhibiting further IgE-mediated degranulation
*visible signs of Type I can reside w/n minutes if you don't scratch!
Why does pain (dolor) occur in Type I?
b/c histamine binds to local type c nerve fibers..the tightness, pressure on nerves causes pain
why does a wheal development during type I?
due to degran of mast cells
What mediators are released in late phase rxn of Type I 6-24 hours after repeat exposure to Ag?
fatty acid derived arachidonic acid pathway cascade releasing vasoactive and chemotactic prostaglandins and leukotrienes. then release of heparin and cytokines TNF, IL-1, 3, 4, 5, 6 GMCSF
the late response mediators of the fatty acid derived arachidonic acid pathway cascade have what action?
Recruite PMN's and eosinophils to local site (2 hours) then mononuclear cells, CD4 over next few hours
*vasoactive and spasmogenic that affect bronchiole artery walls-bronchoconstrict
Which mediators are preformed?
the phospholipids are not premade, they are synthesized from cell membrane
The release of heparin in late response of Type I has what effect?
activation of kinin pathway; bradykinin (vasoactive peptide) formation further increases vascular perm at site of injury and further
activates C'
What are the actions of the cytokines released during late response of Type I?
stimulate mast cells
induce B cell class switch
drive growth of eosinophils
chemotactily attract monocytes and macs
give time course for mediator release of Type I
1. immediate: biogenic amines (histamine, seretonin)
2. over minutes: prostaglandins, leukotrienes, PAF, bradykinin (all increase vascular perm)
3. over hours: cytokines (IL1,3, 4, 5, TGFb, TNFa)
what are the important cells participating in Type I HSR?
mast cells : tissue resident
basophils: BM resident
eosinophils: BM resident
Diff b/n mast cells and basophils?
mast cells are not circulatin.they are tissue resident therefore they aren't attracted to site of infxn they are already there. Basophils are circulating thus a secondary effector. Mast cells can prolif and basophils can't
*both contain histamine granules
What are the majore cytokines for developemnt of the 3 important cells of Type I?
mast cell: stem cell factor
basophil: IL-3
eosinophil: IL-5
** all express FceRI
the late response mediators of the fatty acid derived arachidonic acid pathway cascade have what action?
Recruite PMN's and eosinophils to local site (2 hours) then mononuclear cells, CD4 over next few hours
*vasoactive and spasmogenic that affect bronchiole artery walls-bronchoconstrict
Which mediators are preformed?
the phospholipids are not premade, they are synthesized from cell membrane
The release of heparin in late response of Type I has what effect?
activation of kinin pathway; bradykinin (vasoactive peptide) formation further increases vascular perm at site of injury and further
activates C'
What are the actions of the cytokines released during late response of Type I?
stimulate mast cells
induce B cell class switch
drive growth of eosinophils
chemotactily attract monocytes and macs
give time course for mediator release of Type I
1. immediate: biogenic amines (histamine, seretonin)
2. over minutes: prostaglandins, leukotrienes, PAF, bradykinin (all increase vascular perm)
3. over hours: cytokines (IL1,3, 4, 5, TGFb, TNFa)
what are the important cells participating in Type I HSR?
mast cells : tissue resident
basophils: BM resident
eosinophils: BM resident
Diff b/n mast cells and basophils?
mast cells are not circulatin.they are tissue resident therefore they aren't attracted to site of infxn they are already there. Basophils are circulating thus a secondary effector. Mast cells can prolif and basophils can't
*both contain histamine granules
What are the majore cytokines for developemnt of the 3 important cells of Type I?
mast cell: stem cell factor
basophil: IL-3
eosinophil: IL-5
** all express FceRI
preformed histamine in mast cells and basophils has what effect?
increases vascular perm; stimultes smooth muscle cell contraction
What major lipid mediators are produced on activation in mast cells and basophils?
prostaglandins (vasodilation, bronchoconstriction, neutrophil chemotaxis)
leukotrienes(prolonged bronchoconstriction, incresed vasc perm)
platelet activating factor (chemotaxis)
what do eosinophils are preformed in granules?
major basic protein, eosinophil cationic protein, eosinophilic peroxidase, lysosomal hydrolases
What are the 2 types of mast cells? differences?
mucosal mast cells (gut, lung)-MMC : T cell dependent, less trptase and chymase enzyme

2. CT mast cells (skin, blood vessls) (CTMC): NOT T cell dependent, more histamine content, more tryptase
What happens in nasal mucosa to mast cells and basophils during HSR?
mast cells moves from subepithlium to epithelium
basophils appear in nasal mucus
*this is done to localize histamine containing cells to allergen entry site..way of increasing the hypersensitiviy of the atopic individual
Describe the differences of IgE on plasma cells vs. mast and basophils
plasma: IgE expressed as a transmembrane BCR with single specificity
mast and basophils: Fc region of IgE has a high affinity for FceR; these cells can bind different IgE molecules specific for thousands of different allergens: homing results in localized effector intensity (mast cells in intestine more likely to bear IgE specific for peanut proteins)
Mast cells and basophils have preformed granules of ? what do they newly generate?
preformed: histamine, heparin, tryptase
newly made: arachidonic acid, leukotrienes, prostaglandin, cytokines
What are the 2 different types of Fc R's on mast cells?
FceR1: bound by IgE from B that induces degranulation
FcgRI: bound by aggregated IgG1 and 3 that induces cytokine release
What are some examples in which sytoms of Type I reflect the site of allergen introduction?
upper resp tract: inhaled allergens induce rhinitis, hay fever
lower airway: asthma
food allergies: vomiting, diarrhea, can lodge in skin capillaries causing rashes
allergic rhinitis (sinusitis, hay fever) has what clinical and pathologic manifestations?
increased mucus production
inflammation in upper airways, sinuses
bronchial ashthma of Type I has what clinical and pathologic manifestations?
bronchial hyperresponsiveness caused by smooth muscle contraction and inflammation
atopic urticaria (hives) and dermatitis of Type I has what clinical and pathologic manifestations?
inflammatory skin response; either transient or chronic
food allergies of type I has what clinical and pathologic manifestations?
increased peristalsis due to contraction of intestinal mm; possibilty of urticarial and eczematous response
anaphylaxis initiated by any allergens: drugs, venom, food of type I has what clinical and pathologic manifestations?
fall in BP (shock) caused by vascular dilatation; airway obstruction due to laryngeal edema
is extrinsic or intrinsic asthma considered type I hsr?
extrinsic b/c involves IgE crosslinking
What is asthma?
inflam disease of airways of lung characterized by intermittent airway narrowing and variable symptoms of chest tightness, wheeze and shortness of breath
what causes extrinic and intrinsic asthma?
extrinsic: common allergens: pollen, dust, food

intrinsic: stress, exercise, cold temps, drug induced
what are the primary causal agents in hay fever, chronic rhinitis, and asthma?
inhalant allergens
Large particles (pollen, mite poop) are limited to upper airway and associated with hay fever
Smaller particles (dander, spores) can travel to alveolar air spaces and are associated with asthma
what type of T cell response occurs following antigen presentation that causes allergic rhinitis and asthma?
Ag presentation to Eosinophils leading to stimulation of T cells creating Th2 response with IL-4, 5, and 13 driving IgE production
what cell, classically considered only an effector cell, is now considred an important component of the response to inhaled allergens?
How do large allergens such as pollen stimulate an immune response?
damaged surface epithelial cells secrete eosinophil chemotaxins RANTES, IL16, and eotaxin.
Mast cells aslo release eosinophil chemotaxins IL-5 and ECF-A
gammadelta T cells lining the subcutaneous and mucosal surfaces secrete IL-5 to drive eosinophil prolif
when recruited eosinophils in response to inhaled allergens scavenge allergens in the alveoli of lung, where do they transport the allergen?
to paratracheal lymph nodes
** Eosinophls fxn as APC b/c express MHC II and CD80/86
What happens to the airways in the early response w/n minutes?
vasodilation by histamine
increased mucus secretion by leukotrienes
bronchoconstriction by prostaglandins
What happens to the airways in the late response w/n hours:
worsening bronchoconstriction
remodeling of airways w/ thickened lamina propria packed with eosinophils and lymphocytes *recruitement of inflammatory cells
describe atopic urticaria
mediated by IgE response to allergens that either enter the skin from outside or travel through the circulation and manifest the allergic response in skin
*allergen results in itchy raised welts w/n minutes or hours. Lesions have raised edge but upon resolution leave no trace (with antihistamines or steroids)
what is the epidermal equivalent of chronic asthma?
atopic dermatitis (eczema) from food and inhalant allergens, microbial infxn, autoantigens
Describe atopic dermatitis.
genetic component
eczema in patches in same place every time
*almost always itchy (atopic urticaria not always itchy) damaging skin--itchy, red, painful
*Lichenification (thickening of skin) occurs follwoing scratching
*during flares, epidermis swells (spongiosis) and activated CD4 memory Th cells found in dermis with eleveated serum IgE
What are the key effector cells of atopic dermatitis?
T cells
FceRI+/IgE Dendritic cells
How do you look for atopic dermatitis?
stain for eosinophil products: Ab to eosinophil major basic protein (MBP) that reveal extensive deposition of MBP in the dermis, where eosinophils have degranulated
Onset of atopic dermatitis?
adult..never episodes as a child (rare)
What T cells are involved in acute phase of atopic dermatitis? chronic?
acute: allergens stimulate Th0 to become Th2 secreting IL13, 4 and 5
chronic: scratching activates cytokines IL-12 from Th0 that activate Th1 to release IFN-gama
What type of HSR is the most frequent in food allergies?
type I: IgE mediated immediate HSR
What are the local symptoms of food allergies? systemic?
local: nausea, vomiting, lip swelling, itching of throat all b/c of smooth mm contraction-kinin cascade
systemic:dermal (itching and rash), diffuse swelling (angioedema) upper and lower resp tract, dypsnea, anaphylactic shock
What is epitope spreading?
ex: adult develops allergy to shellfish. the immune response the spreads from 1 epitope to another and b/c common proteins share similary epitopes the person is now allergic to mussels as well
what is useful in identifying recent anaphylactic rxns?
elevated serum tryptase released from MCT cells w/n 0.5-1.5 hrs after anaphylaxis
what is the PRIMARY method for diagnosing Type I HSR ?
skin testing
characteristic response: wheal and flare rxn
wheal: extravasation of serum from capillaries (histamine release)
flare: mediated by axon reflex..flush due to edema..on either side of wheal
response takes 5-15 minutes and may persist for 30 min
*dimater of wheal determines pos or neg rexn
What is the RAST test?
radioallergosorbent test that detects allergen specific IgE in SERUM
*take allergen coated dip stick and dip into tube w/ patient's serum then develop with radiolabeled 2ndary Ab to determine if complexes made
How do you desensitize (hyposensitize) a person with allergic disease?
give pt. progressively increasing doses of allergen which results in increase in serum IgG(most IgG4) Ab ,increase in IL-10 (blocks Th2) decresae in responsiv T cells and decreased in IgE in serum and skin
*want to constantly increase amts. of Ag to supprses immune response
Why do you want to incresae IgG4 when desensitizing an allergic person?
b/c IgG's don't bind mast want to decrease IgE b/c it binds mast cells and elicits rxn
why do atopic people have an incresae in IgE?
b/c they are deficient in IL-10
What are teh 2 contributing factors to increasing atopy?
genetics and exposure
Explain how exposure has a role in increasing atopy.
when born whe have a predelection towards Th2 arm. Then through Ag exposure in day cares etc we move to Th1 or tolerance. Those kids that are overprotected from allergens stay Th2 and develop allergies and asthma
when do Type II and III HSR start and end?
start w/n hours may resolve w/n 24 hrs
Manifestations of Type II?
blood transfusion rxns, erythroblastosis fetalis and autoimmune hemolytic anemia
all caused by IgG binding target Ag and cell damage with NK involvement
How do Type II HSR's differ from Type I?
1. they result from the action of IgG rather than IgE
2. they can represent an attack by the immune system on the body's own tissues by direct Ab mediation (inducing Ag can be self)
What are the 3 mechanisms in which Ab can cause Type II HSR?
1. bound IgG1and3 activate classical pathway and produce acute inflammatory response (c5a and c3a)
2.opsonization and phagocytosis with generation of an inflammtory reponse.phagocyte directly binds C' on target cell
3.production of abnormal physiologic response w/o an inflammatory response (Grave's disease and myasthenia gravis)
when can the phagocytosis mechanism of Type II not occur? causes what?
whne the Ag is a structural part of a tissue.. leading to frustrated phagocytosis resulting in release of granule contents onto the tissue causing bistandard damage
Why is Graves disease an Type II HSR?
b/c it involves Ab against TSH receptor that bind to the TSH R and cause chronic stimulation and release of thyroid hormones (no inflammatory response generated)
*Ab stimulates R w/o hormone
Why is Myasthenia gravis a Type II HSR?
*Ab inhibits binding of NT to R
Ab to ACh R binds ACh R and now ACh can't bind (no inflammatory response involved)
What type of circumstances lead to Type II HSR?
1. person receives Ab from another individual
2. person has AB reactive w/ cells they received from another individual (transfusion)
3. a person has an Ab response to a foreign substance that has adhered to self cells (penicillin )
4.person makes Ab to his or her own tissues (autoimmune)
explain situation in erythroblastosis fetalis (happens to fetus in utero);hemolytic disease of newborn
1st pregnancy: fetus Rh+ and mom Rh-. entry of Rh+ RBC during labor and mom produces IgM Ab against D Ag
2nd pregancy: new Rh+ fetus. mom reexposed and now IgG anti-Rh+(D) Ab cross placenta and cause lysis of fetal RBC
What is the D antigen?
determination of Rh positivity
**polypepide--a protein!
What is L-fucosyltransferase?
puts fructose on galactose to create in 99.9% of population
What sugar is put on the terminal carb of Blood Type O? is H substance (silent allele)
What sugar is put on the terminal carb of Blood Type A?
galactosaminyl transferase places N-acetyl galactosaminyltransferase on terminal sugar
What sugar is put on the terminal carb of Blood Type B?
galactosyl transferase places galactose on terminal sugar
What sugar is put on the terminal carb of Blood Type AB?
both sugars present in A and B: N-acetyl galactosamine and galactose b/c both A and B Ag
What Ab does a person with O have? A? B? AB?
O: anti-A and anti-B AB
A: anti-B
B: anti-A
AB: no Ab
describe an immediate transfusion rxn if person with type O given A
first transfusion: activation of Anti-A IgM (aglutination) and blood group Ag-specific memory B cell made
delayed transfusion rxn: memory cell secretes blood group Ag specific IgG
What happens in some individuals after penicillin injection?
Ab response to foreign substance that has adhered to self cells: nucleophilic amino or hydroxyl groups on proteins form covalent linkages w/ penicilin producing a drug-protein adduct that is capable of eliciting an immune response (isomerization causes response)
What are the 2 ways that drug Tx can cause damage?
1. drug absorbs to cell membranes; Ab made, to the immunogenic drug epitope on carrier cell, bind and cause C' lysis
2. immune complexes of drugs and Ab with C3b attached are absorbed to the red cell via C3b R CR1 and C' lysis occurs
Are the Ag evoking autoimmune Type II HSR extracellular or intracellular?
extracellular, and may be expressed on cell surfaces, structural proteins or membranes
What are the manifestations of Type III HSRs?
localized Arthus rxns and generalized rxns such as serum sickness, necrotizing vasculitis, glomerulonephritis, rheumatoid arthritis and SLE
*action of PMN causes disease
How do Type III differ from Type II?
in Type II, tissue is damaged by direct Ab binding and initiation of C' and other cascades
in type III, damaged tissues are innocent bystanders to destruction when a soluble immune complex becomes deposited in the tissues
**both types don't involve IgE
In Type III where do immune complexes of circulating Ag and IgM or IgG Ab deposit?
in vascular BM
tissue injury, pathology and disease of Type III is caused by?
complement and FcgR's (IgG) that cause an inflammatory reponse mediated by massive infiltration of neutrophils
what type of antigens are Type III directed against?
soluble antigens
what is the normal response of immune complex clearing?
they are carried to the liver and spleen and endocytosed by histiocytes and kupfer cells..but in Type III they trigger increased perm b/c they are deposited in vessels and not properly removed from circulation
what effect does size have on immune complex pathogenicity?
smaller complexes cleared less readily than large
what effect does charge have on immune complex pathogenicity?
positively charged immune complexes "stick" to negatively charged BM
what affect dose dose and route of antigen administration have on the pathology observed in Type III HSR?
intravenous (high dose) resutls in vasculitis, nephritis and arthritis by depositing in blood vessel walls, renal glomeruli and joint spaces
Subcutaneous dose results in Arthrus rxn when
deposits in perivascular area
Inhaled dose: results in Farmer's lung by deposition in alveolar/capillary interface
what are the hemodynamic factors affecting complex deposition?
filtration (renal glomerulus) and high blood pressure (arteries and renal glomerulus)
what happens when immune complexes produced bind to vascular endothelium and kideny glomeruli?
activate C' (MAC generation)
initiate acute inflammatory response that destroys the vessel walls or glomeruli and leads to thrombosis, ischemic damage to tissues and scarring
deposition of immune complexes in blood vessel walls produces wht?
vasculitis by activation of C' by complexes that attracts PMN's and macrophages to site. these cells then exocytose their granule contents and release reactive oxygen and nitrogen intermediates to cause local tissue damage
what is the classic example of a transient syndrome mediated by immune complexes?
serum sickness caused by injection of foreign serum that leads to Ab response and formation of circulating immune complexes which activate C' and phagocytes, inducing fever. they then deposit in small blood vssls induce symptoms of vasculitis, nephritis, arthritis ** all effects are transient and resolve when foreign protein is cleared from the system w/n 20-30 days
Serum sickness is seen as a rxn to what?
1. drugs mainly penicillin and its derivatives, which act as haptens. the drugs bind to host PROTEINS and serve as carriers eliciting stong IgG response and formation and deposition of immune complexes
*when hapten is bound to cell surface-type II is induced
2. antitoxins to snake venom
3. monoclonal Ab for immunotherapy
physical symptoms of serum sickness?
urticarial rash, hemorrhaging in the skin
immune complexes in SLE (type III) give what classic histological portrayal?
"lumpy bumpy" deposits as seen in SLE when immune complexes form in blood and deposit in kidney
immune complexes in Goodpasture Disease (type II) give what classic histological portrayal?
linear deposition on BM that tells you where BM is b/c anti-BM Ab binds directly to glomerular BM in an even pattern
what is hypersensitivy pneumonitis?
when fungal antigen is inhaled into the lung of a sensitized person immune complexes form in alveoli. C' fixation leads to cell accumulation, inflammation and fibrosis
How do you test for Type III?
the arthrus rxn by skin test: injected Ag + specific Ab form complex that act on platelets and mast cells which release vasoactive amines and induce mac to release TNF and IL-1. Histamine and leukotriens from mast incrsae blood flow. PMN's release lysosomal enzymes
Differnce b/n Type I skin tests and Type III?
type I: raised wheal 5-7mm with well defined edge after 15 min
type III (arthus):greater than 50mm wheal with less well defined edge after 5-12 hrs
when do Type IV rxns start?
start 48 hrs after Ag exposure
briefly what happens in Type IV HSR?
T cells release cytokines that activate macrophages resulting in cell damage
Manifestations of Type IV ?
contact dermatitis, rxns to Mycobacterium tuberculosis and graft rejection
What are the 3 types of DTH/Type IV? rxn times?
contact: 48-72 hrs
tuberculin: 48-72 hrs
granuloma: 21-28 days
clinical appearances of 3 types of DTH?
contact: eczema
tuberculin: local induration
granuloma: hardening (skin or lung)
What are the antigens for the 3 types of DTH?
contact: epidermal Ag like nickel, poison ivy
tuberculin: intradermal
granuloma: persistent Ag or Ag/Ab complexes..insoluble Ag
What is the classic diagnostic test for tuberculin type DTH?
tuberculin skin test first developed for tuberculosis. If there is a continous antigenic stimulation, rather than a single test jab, a granulomatous rxn or contact hypersensitivity will occur.
*the test is an example of recall response to soluble Ag PREVIOSLY encountered during infexn
Describe what happens in tuberculin type hypersensitiivy.
hapten is injected into subcutaneous tissue and processed by local mac or DC. Mac or DC activates a Th1 cell which secretes TNF. w/n 1-2 hours there is expression of E-selectin on cqapillary endothelium causing brief influx of neutrophils. By 12 hours, ICAM and VCAM on endothelium bind the integrins LFA and VLA on monocytes and lymphocytes, leading to accumulation of them in dermis. Peaks at 48 hrs and followed by expression of MHC II on keratinocytes..NO EDEMA in EPIDERMIS
list some contact hypersensitivity antigens?
**food that is transported by blood and deposited in skin
insect venom
dust mite
describe the sensitization phase of contact hypersensitivity.
1. hapten forms hapten/carrier complex in epidermis
2. complex internalized by Langerhans cells
3. LC migrate (now veil cells) to afferent lymphatics to the paracortical region of lymph node veil cell is an interdigitating cell and presents Ag to CD4+ cell
what happens when LC present hapten complex to CD4 cells during elicitation phase of contact hypersensitivity?
Landerhans cells secretes IL-1 to cause T cells to proliferate. Activated T cells also release IFNg and IL-2 to proliferate T and
causing the expression of ICAM and MHC II on keratinocytes and endothelial cells as well as macrophage activation and recruitment (IFNg)
What unique cell expresses MHC II upon cytokine stimulation in contact hypersensitivity?
keratinocytes..only express MHC II under special act as immune stimulators
During elicitation phase of contact Type IV, what do keratinocytes do after IFNg stimulates them to express MHC II?
the release proinflammatory cytokines IL1, IL6 and GM-CSF. Then non-antigen specific T cells enter followed by activated macrophages
Histologically, what is seen in the appearance of a lesion in contact hypersensitivity?
mononuclear cells infiltrate both dermis and epidermis. The epidermis is pushed outwards and microvesicles form w/n it due to edema
During contact hypersensitivy, what does the keratinocyte and macrophage secrete to suppress the reaction?
the keratinocyte and mac secrete prostaglandins to inhibit IL-1 and IL-2 production, inhibit Ag presentation by LC and mast cell degran to down regulate the rxn
What mediates the development of contact dermatitis after second exposure to poison ivy?
Tdth cells secrete IFNg and chemokines MCF (mac chemotactic factor) and MIF (mac inhibition factor)mediate the rxn. Tissue damage results from lytic enzymes released by activated macrophages
why do blistering lesions develop from posion ivy?
b/c of formation of lytic enzymes
What is the most common eruption of the eyelid from preservtives in eye medications?
contact dermatitis
Sarcoidosis, leprosy, tuberculosis, schistosomiasis, and Chrohn's disease are examples of what types of rxns?
granuloma type DTH rxns
Describe what happens in the sensitization phase of granulomatous response.
first exposure to Ag
hapten-carrier formation
DC processing
presentation to CD4 Th cell in draining lymph nodes
production of IL-12
diff to Tdth cells (Th1 most)
homing and memory production
Describe what happens in the elicitation phase of granulomatous response.
immediate indxn of IgM which activates C'
C5a recruits PMNs and mast
mast produce TNFa
promotes arrival of previousy sensitized Tdth cell which secrete TNFb, IL-2 and GM-CSF upon restim.
Monocytes synthesize fibrinogen leading to form of fibrin wall..nodule in 2-3 days
which cells are involved with walling off an antigen in granulomatous rxn?
monocytic lineage: epitheloiod histiocytes, mac, and multinucleated giant cells
what does IFNg activate?
What is sarcoidosis?
chronic, systemic disease: Type IV granulomatous
association w/ HLA-A1 and HLA-B8
seen in African Americans
activated mac and noncaseating granulomas accumulate in many tissues accompained w/ fibrosis
accumulation of CD4: TH1
What is the presentation of sarcoidosis patient?
angiotensin converting enzyme (ACE) and serum calcium frequently elevated (mac products)
*anergic when testing w/ tuberculin but responsd with cortisone
-chest radiograph: enlargement of lymph nodes
*nodular, papular or plaque sarcoid lesions: facial granulomas
How do the 2 different forms of leprosy correlate with the Th polarity of the immune response?
Th1: tuberculoid response-properly contained infxn
Th2: ineffective response leading to lepromatous leprosy
What is Chrohns' disease?
Type IV granuloma diesase
chronic inflammatory diease of the ileum and colon caused by accumulation of lymphocytes and macrphages
Describe what Ab penicillin can induce in HSR.
Type I: IgE
Type II: IgM, IgG
Type III: IgG
Type IV: Tdth cells
*but mostly induces Type I HSR
Explain the 3 main type of skin test rxns of hypersensitivity.
Immediate: wheal and flare after 15 min
Immune-complex mediated: Arthus rxn-large wheal after 5-12 hours
T- cell mediated: red indurated lesion after 24-48 hrs
initiating Ag of Autoimmune hemolytic anemia?
freq. unknown
bacterial or viral Ag mimicry of RBC antigens
Mechanism of autoimmune hemolytic anemia?
results in effective Ab response to Ag on RBC: IgG-autoantibody-red cell membrane complexes are bound by FcgR via CR1 on macrophages in the spleen and liver
*C3b opsonization results in extravascular hemolysis
Clinical features of autoimmune hemolytic anemia?
co-existing thrombocytopenia
marked anisocytosis (very irregular cell shapes )
Diagnosis of autoimmune hemolytic anemia?
direct coombs test is positive
if indirect positive: large amts of autoAb are present
initiating ag of autoimmune thrombocytopenia purpora?
platelet membrane proteins gpIIIa, gpIIb usually following viral infection
*Ab mediated disease: Type II HSR
mechanism of autoimmune thrombocytopenia purpora?
opsonization and phagocytosis of platelets via IgG autoantibodies
presenting feautures of autoimmune thrombocytopenia purpora?
*petechial hemorrhages b/c platelets not working
increased prolif of megakaryoctyes in BM
decreased platelet count
Genetics of Pemphigus vulgaris?
dermatologic Type II HSR condition
strong linkage to DRB1-0402 and DQB1-0503 which present immunogenic peptide (PVA) in a negatively charged P4 pocket
*high freq in Ashkenaski Jews
Initiating Ag of pemphigus vularis?
peptide PVA that is common in desmosomal adhesion molecules
in which disease is the initiating antigen a peptide common to desmoglein I and 3 that form desmosomes?
pemphigus vulgaris
what is the mech. of action of pemphigus vulgaris?
Ab-mediated (IgG1 and IgG4) activation of proteases, disruption of intercellular adhesions
presenting features of pemphigus vulgaris?
oral and dermal blisters as a result of intraepidermal splitting (acanthylosis) and erosion. large blisters result in loss of fluids, proteins and electrolytes
what disease is the clinical constellation of glomerulonephritis and pulmonary hemorrhage?
goodpastures' syndrome
what is the incidence of Goodpasture syn?
in males 6x that in females
most freq in patients 20-30 years
initiating Ag of goodpasture?
alpha3 domain of type III collagen
Mechanism of Goodpasture?
C' and FcR mediated inflammation: Anti-glomerular BM Ab activate C' inviting C3 mediated opsonization by neutrophils
presenting features of goodpasture?
previous upper resp. tract infxn in up to 60% of cases
hemoptysis (spitting up bld)
possible respiratory failure
Diagnosis for goodpature?
diffuse, linear deposition of IgG, and co-localization of C3 along the glomerular BM
what Type II HR is a progressive neuromuscular disease w/ weakness and premature fatigue of voluntary mm?
myasthenia gravis
incidence of myasthenia gravis?
predominance in females
adolescence to old age
genetics of myathenia gravis?
strong association with HLA B8 and HLA DR3
*not in Asian populations
initiating Ag of myasthenia gravis?
postsynaptic Ach R
mechanism of myasthenia gravis?
IgG, C3 and C9 inhibits Ach binding and C' mediated lysis
*Ab recognize embryonic AchR in thymus and eye mm
presenting features of myasthenia gravis?
ocular mm weakness resulting in ptosis (loss of ability keep eyelids raised when looking up)
can progress to inability to chew, swallow and speak and may spread to extremities
diagnosis of myasthenia gravis?
Anti-AchR Ab w/ ELISA
monitor repetitive muscle stimulation that improves following admin of an Ach esterase inhibitor (transiently increases Ach bound)
incidence of graves disease?
predominance in females
age of onset: 20-40 yrs
initiating Ag of graves disease?
TSH R; mimicry w/ viral Ag
mechanism of graves disease?
AutoAb acting as agonists bind to TSHR, stimulating hormone production (hyperthyroidism) resulting in high T3 and T4
autoAb that inhibit TSHR can indcue hypothyroidism
presentation of graves?
diffuse enlargement of thyroid (soft goiter)
protrusion of eyeballs (exopthalmos) due to edema of ocular mm
What autoimmune Type II rexns can be passively transferred to infants?
thyroiditis (transient hypothyroidism)
myasthenia gravis
Grave's disease (transient hyperthyroidism)
ITP: popura: platelet aggregation..tiny hemorrhage throughout body (anti-platelet Ab)
Explain male immune mediated infertility.
development of autoAb to spermatozoa-specific acrosomal Ag or membrane peptide Ag that immobilize the sperm
Explain female immune mediated infertility.
may occur as a result of isoantibodies to sperm or autoAb to zone pellucida Ag that inhibit the accumulation and penetration of the sperm into the egg cell
SLE and Wegener's Granulomatosis are autoimmune diseases charachterized by what type of HSR?
Type III
What type of HSR involves Ag-Ab with soluble Ag which form immune complexes that deposit mainly in blood vessels and in kidney glomeruli?
incidence rate of SLE?
10:1 females
onset post-pubertal
what is SLE?
autoimmune Type III
multi-organ system inflammatory disease
initiating Ag of SLE?
multiple SELF nuclear Ag
mechanism of SLE?
Ab directed against nuclear Ag (ANA)
-tissue lesions release of TNFa leading to aberrant expression of autoantigens on the cell surface. Presentation of autoAg to Th cells. B cell help occurs thereby allowing the Bs to present antigens to autoreactive T cells..epitope spreading. Development of Ab against subcellular Ag leads to accumulation of too many immune complexes that can't be phagocytosed and eliminated so they accumulate in vessel walls and cause vasculitis and in glomeruli causing glomerulonephritis
what is the key event in the pathogenesis of SLE?
the FcgR-mediated delivery of nucleid acid containing immune complexes to TLR7 or 9 in the plasmacytoid DC, which causes copius secretions of IFN-a
Clinical features of SLE?
Malar rash
Discoid rash (appear on scalp)
Oral Ulcers
Renal disorder
Neurological disorder
Hemotological disorder
Immunological disorder
Antinuclear Ab
(4 of these 11 is considered SLE)
Diagnosis of SLe?
demonstration of Anti-nuclear Ab; anti-double stranded DNA
Presence of anti-Smith Ab is indicative of what disease?
anti-smith is Ab against histones
What is Wegener's granulomatosis?
granulomatous inflammation of the resp. tract, glomerulonephritis and vasculitis
Type III autoimmune
initiating Ag of Wegener's granulomatosis?
proteinase 3 the target antigen of anti-neutrophil cytoplasmic antibodies (cANCA)
mechanism of wegeners?
inflammatory cytokines, TNFa, causes expression of PR3 (proteinase 3) on PMN. Now PMN binds to endothelial cells via LFA-ICAM. ANCA Ab now bind PR3 on PMN cuasing degranulation of PMN..end result: endothelial cell lysis and necrotizing vasculitis
diagnosis of wegener's?
detection of serum Ab against PR3
Clinical triad of Wegener's?
upper resp. tract granulomas w/ inflammation leading progressive destruction and deformity of cartilage (saddle nose),
fleeting lung shadows, and
necrotizing glomerulonephritis
** anywhere you can get vasculitis
Hashimoto's Thyroiditis
Spondyloarthropathies are what type of autoimmune HSR?
Type IV
incidence of Hashimoto's Thyroiditis?
female: male 2:1
later decades
mechanism of Hashimoto's Thyroiditis?
Th1 cells release TNF, IL2 and IFNg stimulating CD8 which damage cells releasing autoAg that triggers further lymphocyte infiltration and formation of germinal centers in the thyroid w/ local Ab production to TPO or thyroglobulin
clinical features of Hashimoto's Thyroiditis?
cold intolerance
wt. gain
small hard goiter
diagnosis of Hashimoto's Thyroiditis?
thyroid histology shows germinal centers with Ab to TPO and thyroglobulin
incidence of MS?
3:1 female
primarily N. American and European caucasians
initiating Ag of MS?
myelin Ag: myelin basic protein of myelin sheath by oligodendrocytes
mechanism of MS?
primarily T cell: Th1 secretes IL2, TNFa, and IFNg to activate mac and CTL killing of oligodendrocytes (form myelin)causing demyelination
Th2 induce B activation and production of myelin-reactive autoAb
clinical features of MS?
axonal demyelination
if stimulatory neurons are damaged: reduced signal transduction
limb weakness
impaired vision
If damaged to inhibitory neurons: enhancement of signal transmission leads to tonic contractures, and Lhermitte's sign (the occurence of electric like shocks that spread from the neck down to the legs upon flexion of the head
incidency of IDDM?
primarily younger patients
following viral infxn
initiating Ag of IDDM?
autoAb to various islet cell autoAg such as insulin,and most importantly glutamate decarboxylase 65 (GAD65)
mech of IDDM?
peri-insulitis (Ab cause inflammation outside pancreatic beta islet cells)which results in recruitement of APC. These can capture Ag from the damaged islet cells and induce cytotoxic Th1 response w/n the beta islat cells (intra-insulitis)
epitope spreading then occurs)
what is IDDM?
Type I diabetes: insulin def.
inability to incorporate glucose into the cells results in increased blood glucose levels and increased plasma osmolarity
clinical features of IDDM?
increased appetite (polyphagia)but patients lose wt. bc the body is unable to use glucose
increased thirst (polydipsia)
kidney failure
genetics of IDDM?
diabetes associated DQB1 0302
*presence of HLA-DQ and DR alleles that contain a ser, ala, or val at post 57 increases risk of IDDM while the presence of apartate at this position is associated with decreased risk.
"diabetogenic" alleles bind peptides w/ a - charge at pos 9 while diabetes resistant allelels bind peptides with a post. charge
Diabetogenic: Th1 response
Diabetes res: Th2 response
explain the role of molecular mimicry in IDDM.
highly conserved aa seq of p2C and GAD65 motif has proven to bind HLA-DR3; both p2C and GAD56 peptides bind in the same position in the peptide binding groove of the -DR3 molecule, which is essential for T cell reactivity
Which disease has a strong association with HLA-B27 (90-95%)?
incidence of spondyloarthropathies?
predom males betwn 15-30 yrs
mechanism for spondyloarthropathies
presumably an HLA-B27 restricted CTL mediated inflammatory process in joints
presentation of spondyloarthropathies?
low back pain
fracture of the spine
affects jts and fibrocartilaginous structures
clinical triad of Reiters syndrome?
Describe the molecular mimicry model of HLA-B27
b/c there is structural similarity b/n polymorphic regions of HLA-B27 Ag and bacterial pathogens, HLA-B27 can be mistaken as foreign leading to cell damage
Describe the tolerance model of HLA-B27.
structural similarity b/n HLA-B27 and microbial Ag does not lead to autoaggressive process, but to incorrect tolerance of bacterial Ag resulting in cell damage
Describe the promiscuous model of HLA-B27.
acts as an autoantigen that INDIRECTLY sets off inflammatory cascade via CD4. HLA broken down into tiny fragments and enter peptide binding site of HLA-DR Ag and presented to CD4 causing arthritis
Rheumatoid arthritis
Autoimmune CT diseases are what type of autoimmune rxns?
mixed HSR
What is the most common disease of joints?
Rheumatoid arthritis
incidence of rheumatoid arthritis?
3:1 females
usually begins after age 40
clinical features of RA?
extensive lymphocyte infiltration (virtually all cells)
activated cells which induce formation of a pannus (penetrates into bone, covers the cartilage and destroys both structures)
diagnosis of Rheumatoid arthritis.
detection of IgM Rheumatoid factor
Where are Rheumatoid factors found?
where extra-articular manifestations occur
What is the shared epitope hypothesis of RA?
disease is not only associated w/ a certain HLA-DR specificty but also w/ common eptitopes on various DR molecules: exchange of neutral for acidic aa leads to loss of diease association
Where are the effector cells in the arthritic joint?
all cells located in synnovial membrane..synovium assumes features of lymphoid organ: B cells, T cells, plasma cells, NK cells, DC cells
what is the lining like in the arthritic joint?
hypertrophied lining layer of cells that contains macrophages, fibroblasts, and lymphocytic infiltrates
immunopathogenesis of RA.
antigen activates CD4 T cells which activate B cells to form rheumatoid factor and deposit immune complexes into joints leading to pannus formation. The activated CD4 release TNF and IL-1 activating macs and leading to pannus formation
what are some criteria for RA?
morning stiffness
arthritis in 3 or more jts
arthritis in the jts of hands
symmetrical swelling (arthritis)
rheumatoid nodules
rheumatoid factor in serum
what disease exhibits an abnormal accumulation of fibrous tissue in the skin and multiple organs?
scleroderma: progressive systemic sclerosis
incidence of scleroderma?
females 3:1
50-60 yrs age
mechanism of scleroderma?
CD4 cells accumulate in skin and release cytokines (IL1, 2, 3, 13, TNF, TGF) that recruit and activate inflammatory cells and stimulate collagen syn by fibroblasts leading to fibrosis
clinical features of diffuse scleroderma?
microvascular disease
Raynaud's syndrome
digital edema progressing to sclerodactyly
telangiectasias of skin and mucosa
diagnosis of scleroderma?
detection of anti-centromere Ab, anti-Scl70 (topoisomerase I) and IgM rheumatoid factor
another name for scleroderma limited?
Crest syndrome
Raynauld's syndrome
Esophoageal dysmobility
what syndrome is characterized by dry eyes and dry mouth (xerostomia) due to destruction of lacrimal and salivary glands?
sjogren's syndrome
mechanism of Sjogren's syndrome?
epi cells in infected gland present viral Ag that attract T cells which infiltrate the tissue and cause a local inflammatory response
activated Cd4 T and B with local antibody secretion of anti-ss-A (Ro) and SS-B (La)
clinical features of Sjogrens' syndrome?
decrease in tears
descrease in saliva
enlarged parotid gland infiltrated with plasma cells
Diagnosis of Sjogren's syndrome?
anti-Ro and La antibodies
lip biopsy
what characterizes proximal muscle weakness, especially in the shoulders, upper arms and thighs?
dermatomyositis and polymyositis
What is happening in polymyositis?
aberrant expression of MHC I on muscle cells due to either genetic or viral infxn factors which alters their cell surface. cytotoxic T cells then recognize the altered myocytes as foreign and destroy them
AutoAb of SLE?
AutoAb of MCTD?
U1-RNP (auto Ab against ribonuclease P)
AutoAb of scleroderma?
scl 70
AutoAb of Sjogrene's syndrome?
What was the 1st iatrogenic transplant?
blood transfusion
What is an ex of transplant in nature?
fetus (allogenic graft)--only naturally occuring graft
from one part of body to another (self)
no immunesuppression req
b/n different members of same species
*most common
*match phenotypes as closely as possible
*immune suppression always reqd
b/n genetically identical individuals (twins)
b/n members of different species (monkey to man)
the capacity to reject a graft is mediated by ?
NOT serum!
what is the evidence that graft rejection is an immulne phenomenon?
graft rejection shows memory and specificity (featues of adaptive immunity)
graft rejection is mediated by lymphocytes
What happens when a strain C graft is repeated in a person who already received a strain C graft?
rejection occurs at day 5 instead of day 12 indicating memory specific to strain C
Type of graft rejection by host is defined by?
time: immediate, intermediate or delayed graft rejections
what is a hyperacute rejection?
PREFORMED anti-donor Ab and C' destroy the graft in minutse to hours (mediated in vasculature)
*when donor and recipient are incompatitible for Ags found on endothelial cells
What is accelerated rejection?
SENSITIZED T cels are reactivated to destroy graf in DAYS (seen in prevous transplant recipients or multipara)
What is acute rejection?
PRIMARY activation of T cells destroying the graft in DAYS to WEEKs (most typical)
What is chronic rejection?
antibodies, immune complexes, or cytotoxic cells destroy the graft over MONTHS and YEARS
What typing should be done for organ transplantation?
when is the full battery of typing (mixed lymphocyte rxn) performed?
when organ and recipient are identified and both can remain viable for some time (renal, BM) NOT heart/lung
why hyperacute rejections immediate?
due to ABO incompatibility: preformed Ab
NO T cell involvement
What are the steps of hyperacute rejection?
1. incompatible blood group Ag on endothelium
2.Ab bind Ag and bind C'
3. formation of MAC, damage endothelial
4. release of c5a and c3a anaphylatoxins
5. PMN migration
6. activation of clotting, blockage of blood vessels
7. failure of graft
What type of rejection exhibits secondary response kinetics?
acclerated rejection
mediated by sensitized T cells
rare group pts: previous transplant, multiple blood transfusion recipients, multipara
Which rejection is induction of primary response?
acute rejection
What is direct allorecognition?
direct presentation of Ags from graft by donor's APCs to alloreactive T cell of recipient (our T have been taught to recog our MHC by CDR1 and 2..recog donor MHC based on general shape)
*T cell recog UNprocessed allogenic MHC on graft APC
What is indirect allorecognition?
T cell recog processed peptide of allogenic MHC molecule bound to self MHC on host APC
*happens when place graft in pt. killing cells in process. now MHC presents this Ag (foreign)
steps of acute rejection?
1. CD8 T cells attack paranchyma ..any cells in graft bearing Ag inducting induction of B cell response. Now have reactive Ab that attack vasculature (endothelial damage)
*parenhymal cell damage and endothelialitis (inflam of endothelial cells)
chronic rejection is characterized by?
widespread and diffuse narrowing of the vascular lumen as a result in intimal proliferation of smooth muscle cells and fibroblasts (prolif of adventitia-narrowing of lumen)
What type of rejection involves de novo secondary unencapsulated lymphoid organ structure producing alloantibodies (anti-graft MHC1 molecules)?
chronic rejection shows the appearance of germinal centers : w/n 10 days of graft at these sites: 50% CD4, 50% CD8 secreting IFNg, promoting IFNg
after 30 days: downreg of CMI, increase CD4 Th2 and IgM B
which MHC is more important in mediating graft rejection?
difference b/n direct and indirect pathway of rejection of allograft?
direct: donor APC presents Ag to recipient CD8 and CD4
indirect: donor cells present Ag to recipient APC who processes Ag and presents to selft APC. APC then presents Ag to CD8 and CD4
elicitation of CTL in indirect and direct allogenic rejection does what?
1. attack endothelial cells that express MHC II
2 attack parencyma of graft
what is accomodation? when does it occur in terms of days of rejection in accepted graft?
complete inhibition of C'
day 14
in acute rejection(primary rejection), how long does it take for a full response with Ab, ADCC and cytokines?
14 days
in accelerated rejection (secondary response) how long does it take for full response with Ab, ADCC and cytokines?
6 days
what are the historically sited areas of immunoprivilege?
Anterior chamber of eye
Testes, ovaries
partial immunoprivilege: gravid uterus
why is the concept of immunoprivilege bunk?
b/c afferent and efferent sensitization does occr and immune rxns do occur as seen in rejection of corneas, reactive orchitis, hemolytic disease of newborn
What do corneal cells express that debunks the myth of immunoprivelge?
HLA-A and B
DR-positive dendritic cells
therefore w/ cornal rejection is has been shown that immunosupprssion is needed b/c HLA is exprssed (local steroid drops as anti-rejection therapy)
How is the fetus an allograft?
the placenta is comprised of tissue from 2 genetically disparate individuals where maternal (decidua basalis) and fetal (trophoblast) tissues interface..trophoblast fuses with endometrium (maternal) forming chorion
what is HLA-G?
MHC-I Like on trophoblast cell..not MHC I or II therefore can't be killed by CTL, but can by NK
looks like MHC-1 so it fools maternal NK cells to not kill the cells of trophoblast
what does the trophoblast produce to suppress prolif of NK and inhibit TNFa (divert to TH2)?
progesterone to progesterone inhibiting factor
what does trophoblast express that causes apoptosis of cells?
FasL that binds to Fas on T causing apoptosis
what is the suppresion of immune effector mech. in the placenta?
trophoblast-exprssed indoleamine (IDO) which catabolized Tryp starving maternal lymphocytes of Tryp inhibiting their prolif
placenta constitutively expresses C' regulatory protein (Crry) that prevents the formation of C3 convertase
How is the percent of surviving grafts related to discrepancies in MHC matching?
3-4 discrepancices in MHC I will cause decrease in % surviving
only 1-2 discrepancies in MHC II will cause greater descrease in % surviving
with which MHC class can you have more discrepancies and stil have high survival of graft?
explain microcytotoxicity for MHC typing
take lymphocyte with MHC I allele add specific Ab for allele and add C'. there will be MAC formation and lysis if Ab recog Ag. Then add typan blue dye a positive test indicates Ab recognition of Ag if lymphocyte excludes the dye its a negative rxn
what detects MHC stimulation?
mixed lymphocyte rxn
if MLR > 2 not good for match
MLR < 2 do-able match
acute allograft rejection is primarily mediated by what?
T cells
What is the action of Azothioprine, Mycophenoloate mofetil?
cytotoxic prodrugs
shut down everything in nucleaus thus suppressing allograft rejection
-block lymphocyte prolif by inhibiting guanine nucleotide syn in lymphocytes
action of corticosteroids in suppressing allograft rejection?
reduce inflammation by inhibiting macrophage cytokine secretion
-drive cells to Th2 response
Action of Cyclosporin A and Tacrolimus in allograft rejection suppression?
calcineurin inhibitors that blocks T cell cytokine production by inhibiting activation of the NFAT TF
Action of anti-IL-2R Ab in suppression of allograft rejection?
inhibits T cell prolif by blocking IL-2 binding. May also help opsonize and help eliminate activated IL-2R expressing T cells
**only transient in preventing IL-2 to bind R
*can't be used constantly b/c don't want to wipe out IL-2R forever
Action of Sirolimus in allograft suppression?
inhibits IP3 DAG pathway
Action of Anti-CD3 monoclonal Ab in suppression of allograft rejection?
depletes T cells by binding to CD3 and promoting phagocytosis or C' mediated lysis (used to treat acute rejection)
action of Rapamycin in acute allograft rejection suppression?
blocks lymphocyte prolif by blocking IL-2 signalling
action of tacrolimus drug?
inhibits gene expression in lymphocytes, inactivates calceurin
Administering ALS (anti lymphocyte serum) and ALG for selective immunosuppression can cuase what side effects?
production of HAMA (human anti mouse), cytokine cascade
criteria for organ transplantation in donor besides kidney and liver donation (they can be alive)?
irreversible areflexia (pupils)
irreversible absence of spontaneous breathing
isoelectric EKG
absence of cerebral blood flow
what is a discordant graft?
species combos in which hyperacute rejection occurs: anti-Gal Ab
why are pigs most sutiable for xenotransplant?
organs are similar in size and fxn
unlimited availability
derivation of mini swine (custom size and defined MHC for tolerance induction)
where is gal gal alpha found?
in new world monkeys and lower -order mammals, not in humans and higer order primates
Why can't we use higher order primates for xenograft?
they have natural Ab to gal gal on vascular endothelium (anti-Gal)
how can we prvent hyperacute rejection from occuring with pig transplants?
normally our anti-gal will bind to gal in pig and cause hyperacute rejection. to prvent this, create gal pig that doesn't produce gal gal get rid of rejection then genetically manipulate the embryo to express HLA 1 and 2 then tolerize yourself to Ag of pig