4.7 Hypersensitivities Flashcards
What types of hypersensitivities are there
I, II, III, IV
Type I hypersensitivity
rapidly developing reaction occuring with minutes of exposure, IgE and mas cell mediated, Complement (C3a, C5a) and cytokines (IL1 and TNF) later mediators
With allergen exposure
there is a rapid immediate response, don’t need a second exposure. There is also a late-phase reaction.
Mast cells are full of
mediators, like histamine
Local type I reactions
hay fever or allergic reactions depending on portal of entry
Systemic type I reactions
anaphylaxis and possible shock. When there is bronchoconstriction that is really bad.
A combination of you and the thing you react to leads to
ag presented by APC to CD4 T cell can mediate a Th1 response. Macs secrete IL1 and IL12. CD4 secretes IFN gamma and IL2. Cellular immune response. BUTTT when in contact with an alergen, CD4 cells instead secrete IL3, 4, 5, 13 and GMCSF mediating a TH2 response, leading to B-cell production of IgE
CD4 Th1 secretes
Il2 IFN gamma
CD4 Th2 secretes
IL3, 4, 5, 13, GMCSF
CD4 Th17 secretes
IL17, 22
Th2 can go in different directions
IL4 –> IgE, IL4 + IL10 –> IgG
IL4
induces IgE and sustains Th2 cells
IL3
eosinophil survival
IL5
activates eosinophils
IL 13
promotes IgE and stimulates epithelial cells to produce mucin
GMCSF
eosinophil support and survival
Th1 or Th2 depends on
both host and ag characteristics
allergens
certain substances (like pollens and bee venom) that elicit allergic responses more than others, hence are often called allergens. There is a strong familial link in allergic individuals (atopy). 50% + history. Atopic individuals have higher circulating IgE levels.
Mast cells
bone marrow derived cells containing metachromatic granules.
Where do mast cells live
in tissues especially around blood vessels, nerves, and epithelial surfaces
What do mast cells have on their surfaces
Fc receptors for IgE. When the bound IgE bind ag, the receptors dimerize and crosslink triggereing secretion.
other stimuli that cause mast cell degranulation
C3a, C4a, IL8, codeine, morphine, mellitin (bee venom), heat, cold, sunlight
What is released from mast cell granules
Histamine, LTC4, LTD4, PGD2, IL1, TNF
Primary mediators
very rapid and preformed in mast cell granules: include histamine, adenosine, chemotactic factors for neutrophils and eosinophils, and proteases (kinin and complement activation)
What are some primary lipid mediators
LTC4, LTB4, LTD4
Secondary mediators
includes a virtual soup of lipid and cytokine mediators secreted by both mast cells and infiltrating leukocytes
What are some secondary mediators leading to bronchospasm
leukotrienes C4, D4 and PGD2
what are does PAF do
secondary mediator – release of histamine, increased vascular permiablity and dialation, bronchospasm, leukocyte activation
What are some cytokines that are secondary mediators
TNF (proinflammatory) and GMCSF (enhances survival of eosinophils)
Systemic Anaphylaxis
life threatening reaction including shock, anasarca, and difficulty in breathing. Can be caused by sensitization to proteins, sugars, hormones, enzymes and DRUGS (penicillin), severity depeinds on level of sensitization, very small amounts of exposure can trigger response. Response only takes minutes – itching, hives and erythema, closely followed by bronchoconstriction. Laryngeal edema leads to hoarsness. Vomiting, diarrhea, cramps, laryngeal obstruction, vascular shock and death
Type II hypersensitivity
humoral autoimmunity to cells, membranes, and other solid body structurs (self or coated ag), activation of complement and cytolysis, ab dependent cell-mediated cytotoxicity (ADCC), Ab mediated cellular dysfunction. When these ab bind they activate complement and complement can kill, or fragments that are cehmotactic activated inflammatory cells to come in and cause damage, or we get ab to receptors on cells so they act as a ligand that can be an agonist or antagonist, so type 2 spans a wide range of sypmptoms and disease
Goodpasteur Syndrome
involves basement membrane of the capillary bed of glomeruli and alveoli – anti basment membrane antibodies – involves the non collagenous domain of alpha 3 chain of type 4 collagen – usually folded away from exposure
Good pasture affects
males in their 20somethings most commonly, in some studies 89% of pts are smokers
what HLA is overrepresented in Good pasteur syndorme
HLA-DRB1*1501 and 1502
Goodpasteur clinical presentation
respiratory symptoms first (hemoptysis), then rapidly progressive acute glomerulonephritis (with crescents) leading to rapide renal failure
What does immuno fluorescence of good pasteur’s look like
smooth coating of basement membranes of lungs and kidneys with antibody mostly IgG and complement seen on immunofluorescence (“painted” for type 2)
Myasthenia Gravis clinical presentations
ptosis and double vision usually presenting symptoms, then generalized flucturating muscle weakness
Myasthenia gravis affects
3/100,000 ppl, onset begins before 40, females predominate
Myasthenia gravis pts have a history of
thymic hyperplasia ro thymoma commonly associated
Myasthenia gravis
decreased numbers of acetylcholine receptors bc of anti-AChR ab – antagonism/inhibition of the receptor
Myasthenia gravis symptoms caused by
- fixation of complement and injury to synaptic membrane 2. increased internalization and degredation and competitive inhibition of binding of acetylcholine
Anticholinesterase durgs improve myasthenia gravis
symptoms but death occurs eventually from respiratory failure
survival rate of Myasthenia gravis
95% 5-year survival with steroids and plasmaphoresis, anticholinesterase drugs, thymectomy can also improve symptoms—-morning is better night is worse
Myasthenia
agonism of the TSH receptor leading to hyperthyroidism.
Hyperthyroidism
enlargement of gland, sympathetic over activity, cardiac hypertrophy and ischemic changes, Temp intolerance, emotional liability
Graves disease affects
females 20-40 (ratio female:male = 7-10:1) –>10 % of your pts will be male
Graves disease and MHC associations
HLA-B8 and DR3
Graves disease symptoms
exphotalmia, orbital edema, fibrosis (ophthalmopathy) due to autoimmunity not thyrotoxicosis, Pre-timibal myxedema (non-pitting bc of glycoaminoglycans) in minority of pts, dec TSH, inc T3 and T4
Graves disease genetics
30-40% concordance in monozygotic twins.
What are features specific to graves
Ophthalopathy specific to graves_vacant stare due to hyperthyrodism (sympathetic overactivity), Autoimmunity, secretion of glycosaminoglycans, and stimulation of fibroblasts in the orbit and other places
Type III hypersensitivity
Ag-Ab comlex mediated, complement activation, inflammatory cell induced tissue damage — deposition of complexes that percipitate out, they love to go deposit in capillary bets under endothelium and where they deposit is the site of disease.
Proximate cause of type III hypersensitivity
Proximate cause, when they accumulate somewhere they activate complement and you ave accute inflammation in delicate capillaries – neutrophils come in and release O2-, H2O2, OHCl, proteases
Is complex formation normal
yes, you make them all the time_.think of the achy joint feeling with the flue due to deposition and inflammation
steps of Type III HSR
complex formation, complex deposition in vessels, complement activation and infalmmatory reaction
Post-Streptococcal Acute Proliferative glomerulonephritis
immune complexes in glomeruli.
Post strep is seen in
children 6-10 years old, 1-4 weeks following a strep throat or impetigo
What types of Strep are involved in post-Strep
types 1, 4, and 12, beta hemolytic strep
What do you see in post strep acute proliferative glmerulonephritis
onset of nephr-i-tic syndrome hematurea, proteinura (moderate), and hypertension(as opposed to nephrotic), low complement bc it is used up.
Pathogenesis of Post strep
glomeruli are supposed to filter and retain a lot of large MW proteins by size and charge exclusion (charge is more important and due to BM, size exclusion is due to endothelium) and you have tubules to resorb smaller things. Now if you have neutorphils that are damaging, they begin to leak so bad that they can have red cells come out.
Difference btw nephritic and nephrotic syndrom
nephrotic syndrom is worse bc you damaged the underlying structures and lost the charge barrier so you get wrose proteinuria than nephritic syndrome
Urinalysis of post strep
blood, protein, RBC cast, protein cast (casts are from things that got lodged in tubules)
how you tell the difference btw UTI and post strep
both will have bleeding and proteins but only post strep glomerulonephritis will show RBC casts —cylindrical casts of packed red cell proteins of tubules, so you know its not a UTI
Post strep pt recovery
most pts recover with supportive care but a small percentage go on to rapidly progressive glomerulonephritis and renal failure. Mostly this is found in children bc the first time you see strep it can happen. There is an adult form that happens and it is not as benign so you have to treat aggressively.
what will you see histologically in Post strep
splotches of red in tubules, big glmeruli bc they are hypercellular (you might see lots of glomeruli indicating that it is a child), crecent on glomeruli (also seein in goodpasteur – due to cytokine storm stimulating bowman’s epithelium to grow—crescents mean rapid progression to disease we think bc of higher inflammation), see lots of little blue cells (both acute and chronic cells), splotchy lumpy bumpy flourescence since type III
Factors Affecting Complex Disease
Ag-Ab mix (slight ag excess), charge and structure of complexes, fn of mononuclear phagocyte system***most imp bc normally macs clear these complexes so in these pts there is something wrong, organ - high pressure filtration (kidney, joints)
Immune complexes are present in
arthritis, vasculitis, glomerulonerphritis, serum sickness, arthus reaction
Serum sickness
immunized towards proteins and then you get a massive formation of ab-ag complexes– think of snake bite story
Arthus reaction
localized serum sickness–preformed ab to proteins, it localizes right there and you get a rxn.
what is the difference btw a PPD for TB and an Arthus rxn
time. arthus rxn is immediate bc you have preforemd ab. PPD is delayed type 4 HSR so it will take longer.
Type 4 hypersensitivity
cell mediated, sensitized T cells. CD4 (Th1) in delayed hypersensitivity; CD8 in direct cytotoxicity. Tubercilin reaction, contact dermatitis
Contact dermatitis
type 4 hsr where an ag modifies you and you react to your protien–> nickle for example leehes out of jewlery and modifies your protein ex. Poison ivy, chemical sensitizers like nickle, post viral infection
Delayed type HSR
tubercilin rxn, peak induration/swelling in 24-48hrs, mononuclear cells cuffing vessels, some rxns lead to granuloma formation
T cell mediated cytotoxicity
direct killing of targets by CD8 killer cells, virally infected cells (hepatitis), foreign cells (graft rejection), muscle cells polymyocitis (cd8 killing of mus cells)
CD14 is a marker for
macrophages
Immuno peroxidase stain shows
CD4 T cells
the arthus rxn can be differentated from type 4 hsr by
timing of the rxn
hsr that accouns for most immune mediated disease
type I
most direct form of autoimmunity
type II
HSR caused by sensitization of T cells to cryptic self ag
Type IV
HRS that have common mechanisms of the induction of tissue damage
Type II and III
