Lecture 21: Hypersensitivity Disorders Flashcards
What is an exaggerated IR thats harmful to the organism itself?
Hypersensitivity (or allergy)
- it produces collateral to body
- What type of effector mechanism corresponds defenses against extracellular pathogens?
* which hypersensitivities would these include? - What type of effector mechanism corresponds defenses against intracellular pathogens?
* which hypersensitivities would these include?
- Ab-mediated
* Type I, II, III - Cell-mediated (CD4+, CD8+ and MΦ)
* Type IV
- What type of hypersensitivity produces immediate rxns and are mediated by allergens and IgE Abs?
- What cell types do IgE Abs activate and what do they release?
- What term describes ppl w/ strong propensity to develop allergic rxns?
- Which Th cell and their cytokine are impt for IgE production?
- Immediate type I
- Mast cells and eosinophils –> release inflammatory mediators
- Atopic
- Th2 produce IL-4 –> switch isotype to IgE Abs
(also follicular Th cells help with this)
Type 1 Hypersensitivity:
- Describe the 1° Allergen encounter (priming)
- Describe the 2° allergen encounter
- Allergen injested/inhaled/skin contact –> APC activates T cells (Th2) —> allergen delivered to LN where BCR specific for those allergens activates B cell –> IgE enters circulation and is bound rapidly by FcRε (CD23) on mast cells in tissue
- Upon 2° exposure to same allergen immediately bound to IgE on the mast cell –> cross-linking causes mast cell degranulation releasing –> vasoactive amines, cytokines/chemokines, lipids –> 3 primary repsonses
- What are the hallmarks for Type 1 hypersensitivity?
- What causes dilation of small vessels, increaes vascular permeability, and sm. m contraction? (granule exocytosis prod)
- What causes local tissue damage? (granule exocytosis prod)
- What is a lipid mediator stimulates prolonged sm. m contraction?
- What is a lipid mediator that causes vascular dilation?
- What causes local inflammation? What phase is this?
- Acute rxns and inflammation (caused by mast cell mediators)
- Histamine
- Proteases
- Prostaglandins
- Leukotrienes
- Cytokines –> TNF and IL-1
Type 1 Hypersensitivity Synopsis:
- When would no clinical signs be seen?
- When does allergic dz result?
- Primary exposure
* Allergen exposure –> Ag activaiton of Th2 cells –> stim of IgE class switching –> production of IgE –> binding of IgE to FcεR1 on mast cells - Secondary exposure
- repeat allergen exposure
- allergens bind and cross-link memb-bound IgE –> Mast cell activaiton causes release of:
- vasoactive amines –> IMMEDIATE rxn = w/in second to minutes
- cytokines (TNF and IL-1) –> LATE PHASE rxn = w/in 6-24 hrs
What are the events in IMMEDIATE reaction vs Late-phase rxn in Type 1 hyerpsensitivity?
What are some examples of Type 1 hypersenstivity?
- Immediate: w/in minutes
- immediate vascular and sm. m reaction to allergen
- vasodilation, congestion, edema
- Late-phase: w/in 2-24 hrs
* inflammatory infiltrate rich in eosinophils, neutrophils, and T cells - Systemic anaphylaxis, acute urticaria, allergic rhinitis, asthma, food allergy
- What is a major example of a local type 1 hypersensitivity rxn that causes reversible airway obstruction due to release of inflammatory mediateors from mast cells upon allergen encounter?
- What occurs when an allergen causes systemic release of vasoactive amines from mast cells and a flood of cytokines after absorbed allergen is distributed thru body via circulation?
-
Asthma
* mediators cause loosening of tight jxns –> inc. cap permeability –> spasmatic contraciton of sm. m surrounding bronchi –> dec size of bronchial lumen –> SOB - Anaphylaxis (systemic)
- sm. m contraction, vasodilation cap endothelium
- blood retention in tissues –> BP drom –> vascular shock
- inc contraciton of sm. m surrounding bronchi –> breathing difficult
- What is a primary property that is unique to all allergens?
- What is the key mechanism of allergen-specific immunotherapy (SIT)?
- What are the 3 aims of allergen-SIT?
- Produce IR at very low []
- Generation of induced regulatory FOXP3+CD4+CD25+ Treg cells
- Induce peripheral T cell tolerance
- inc threshold for mast cell and basophil activaiton via allergens
- dec. IgE-mediated histamine release
- What type of hypersensitivity is mediated by non-IgE Abs that bind cell surface and tissue Ags (SOLID Ag) causing inflammation in a complement-dependent manner?
- Which complement pathway is activated and what are the complement byproducts that recruit leukocytes and induce inflammation?
- Abs opsonize (via C3b) leading to phagocytosis of cells via what 2 receptors, corresponding to what 2 cells?
- What are the inflammatory mediators of these 2 cells types?
- Type II Hypersensitivity
* IgG and IgM abs activate complement - Classical pathway; C3a and C5a
- FcRγ –> on neutrophil and CR1 –> on macrogphage
- ROS and lysosomal enz –> damage adj tissues and cause inflammation
*** Ags are bound to cell or tissue surface*** (they are not soluble)
Type II Hypersenstivity also has an Ab-dependent cellular cytotoxicity (ADCC) mechanism that is mediated by what cell type?
NK cells
- via FcγRIII –> low affinity
1. Autoimmune hemolytic anemia is an example of what type of hypersensitvity?
- When does hemolytic dz of newborn occur?
- Type II hypersensitivity
- target Ag = erythrocyte memb prtns (Rh blood group Ags)
- causes opsonization and phagocytosis of RBC
- When mom is Rh-neg and fetus is Rh-pos
- mom makes anti-Rh Abs and complement from fetus
- only affects subsequent pregnancies
- Grave’s dz and myasthenia gravis are what type of hypersensitivity?
- During their MOA is there cell tissue/injury?
- Which dz is where the abs stimulate TSH receptors even in the absence of TSH causing ______?
- Which dz is where Abs inhibit binding of Ach to Ach receptors?
- Type II
- No cell/tissue injury (abs are either blocking or activating the receptors)
- Grave’s dz; hyperthyroidism
* anxiety/irritability, tremor hands/fingers, heat sensitivity - Myasthenia gravis
* m. weakness, drooping of 1 or both eyelids, impaired speaking
What type of hypersensitivity is seen when mismatched ABO blood transfusion rxn occurs?
Type II
ex) donated type A blood w/ type A Ags enters bloodstream of type B recipient
Anti-A abs in plasma of type B recipient bind to the donated type A RBCs
Bound anti-A Abs activate complement –> hemolysis and release of Hb
What are the 3 drugs cause in Drug-induced hemolytic anemia (DIIHA) via Type II hypersensitivity rxn?
- Penicillin –> directly binds RBC surface –> anti-drug Ab
- Quinidine –> autoAbs form immune complexes w/ drug –> these bind to RBC via CR1
- Methyldopa –> antidrug Abs cross reactis w/ Rh Ag
- What Type II hypersensitivity condition, is a rare autoimmune dz that involves both lungs and kidneys?
- Its characterized by the destruction of what type of collagen found in the basement memb of renal glomeruli and pulm. alveoli?
- It manifests rapidly as what 2 clinical manifestations? (1 for kidney, 1 for lung?
- Goodpasture’s Syndrome
- Type IV
- Glomerulonephritis and necrotizing hemorrhagic pneumonitis
Rheumatic fever is classified as what type of hypersensitivity rxn?
Type II
- target Ag = streptococall pyogenes cell wall Ag
- ab cross reacts w/ myocardial Ag
- Inflammation and MΦ activation
- mycarditis and arthritis
- What type of hypersensitvity is mediated by Ab-Ag immune complexes?
- Are the Ags soluble or bound to tissue?
- _____ Ab-Ag immune complexes are may be formed in the ____ then deposited in BVs and tissues (primarily _____ and _____).
- What is activated as a result of the deposition of Ag-Ab immune complexes? (ie what is the major mechanism of tissue damage?)
- Type III
- Soluble **** (major difference b/w type II and III)
- Soluble; circulation; lungs and kidneys
- Complement (large amounts and via CP) which causes the release of C3a and C5a
- inflammatory cells (NEUTROPHILS, mast cells and basophils) release vasoactive amines
- inflammation caused by activated immune ceels
- What type of hypersensitivity is Systemic Lupus Erythematosus (SLE)
- What are the most frequent type of auto-Abs are found in SLE?
- What are the clinical manifestations of SLE, these are caused by what?
- Which Ab is involved?
- Environmental triggers (ie. viral infection or DNA damage via UV radiation) activate what? Contributing to the secretion of IFN-1 and other cytokines, supporting lymphocyte autoreactivity
- Type III
- Anti-DNA Abs (testing for anti-nuclear Abs = diagnositc test)
- Rashes, arthritis, glomerulonephritis, and vasculitis
* due to formation of immune complexes - IgG
- TLR 7/9
- What type III hypersensitivity dz is a SYSTEMIC necrotizing vasculitis affecting medium-sized MUSCULAR arteries?
- What virus may be associated?
- What do the immune complexes form b/w?
- What clinical manifestation is often seen?
- Polyarteririts nodosa (PAN)
- Hep B virus
- HBV surface Ag and host IgG –> deposit in BVs –> vasculitis
* Tissue injury mediated by complement activation and accumulation of inflammatory cells in tissue - Aneurysms in weakened vessel –> risk for rupture and hemorrhage
- What dz is assoc. w/ glomerular trapping of circulating immune complexes made of nephritogenic bacterial Ags and IgG?
- Activation of complement via what pathway?
- Activation of what cell releases oxidants, proteases, and pro-inflammatory cytokines?
- Acute Post-Streoptococcal Glomerulonephritis (APSGN)
- this is primarily Type III Hypersensitivity
- (type II can be involved if there are nephritogenic bacterial Ags are already planted in kidney tissue then IgG will come bind forming the immune complex)
- Classical
- Neutrophils
* complement + inflammatory prod –> glomerular tissue damage
Which type III hypersensitivity dz is systemic vs local?
- serum sickness
- arthus reaction
Serum sickness = SYSTEMIC
- injection of anti-serum/anti-toxin into pt
- Fc receptors on endothel. bind antitoxin (Ab) that has reacted w/ toxoid
- additional antitoxin and toxoid bind forming larger complex
- CP activated –> C5a, C3a released attracting macrophages and neutrophils
- involves kidneys, lungs and skin (but spreads throughout circulation
Arthus rxn = LOCAL
- subcut. admin of prtn Ag to previously immunized pt –> immune complexes form at site of Ag injection –> local vasculitis
- Type IV hypersensitivity is mediated by what?
- Type IV hypersensitivity and tissue injury can also be caused by T cell responses to _____
- Tissue injury/inflammation induced by cytokines produced by what two types cells?
- OR by direct killing of host cells via _____.
- T - cell mediated
- Microbes –> Mycobacterium tuberculosis
- Th1 and Th17 (CD4+ = cytokine-mediated inflammation)
- CD8+ CTLs
- Type IV hypersensitivity is also known as what?
* what is the time frame of activation? - Th1 recruits _____. Th17 recruits _____.
* what products do these two cell types release resulting in tissue injury - Many AUTOIMMUNE dz’s caused by intercation of autoreactive T cells with ______ leading to cytokine releae and inflammaiton.
- Delayed typed hypersensitivity (DTH)
- macrophages; neutrophils
- MΦ release –> NO and pro-inflammatory cytokines (IL-1 and 6)
- Neutrophils –> lysosomal enz, ROS
- self-Ags
- What are the 3 primary autoimmune dz’s mediated by type IV hypersensitivity?
- What are 2 inflammatory dz’s w/ microbial component?
- MS, RA, and type 1 DM
-
Crohn’s dz (IBD and ulcerative colitis)
* due to abberant rxns to intestine microflora which has autoimmunity component
Tuberculosis (due to rxns w/ microbial Ags)
- MS is a result of ____ type of autoimmunity causing dz affecting brain.
- What must occur during primary exposure for MS to develop?
- Excess glutamate causes what?
- Th1
- Damage to BBB
- demyelination of neurons (bc oligodendrocytes are extremely sensitive to inc. glutamate)
- RA, an inflammatory dz of small and large joints is a result of what type of hypersensitivities?
- What are all the cells involved?
- RA patients have circulating ______ that reacts w/ Fc portion of IgG mlcls?
- Mixed –> Type III/IV hypersensitivity (but primarily Type IV bc Th1 and Th17 are major contributers)
- Th1, Th17, activated B cells, plasma cells –> IgG, and MΦ
- Rheumatoid factors (auto-Abs)
Lymphocytes, Abs and immune complexes enter joints –> inflammation of synovium assoc w/ destruciton cartilage and bone
- Type 1 DM is what hypersensitivity?
- Local APCs present Ag via ____ MHC and secrete _____ activating Th1 cells and CD8 T cells which further stimulate what cytokine?
- CD4 and CD8 T cells act against β-cell autoAgs via what type of autoantibodies?
- These β-cell autoAgs would be classified as ____ bc they are hidden inside the β-cell.
- Type IV
- Class II; IL-12; IFN-γ
- Islet cell autoAbs
- cryptic
** once activated islet specific T cells traffic to pancrease where they proliferate and accumulate causing inflammation and destruction of β-cells
Contact dermatitis with poison ivy is what type of hypersensitivty reaction?
Type IV –> DTH
- Haptens (small pentadecacatechol mlcls) interact w/ skin proteins –> w/in 7-10 days T cells sensitized and T memory cells formed
- this is primary contact –> no sx
- secondary contact –> w/in 1-2 days T memory cells develop into many active T cells –> dermatitis
DTH can be used to confirm dx.
- They are ____ - mediated inflammatory rxn resulting from activation of CD4+ T cells.
- How long does this rxn typically take to develop?
- Humans can be sensitized for DTH rxns by TB (microbial infection), Poison ivy (contact sensitization) or diptheria toxin/tetanus toxin (immunizaiton).
- Wht prtn Ag of mycobacterium tuberculosis elicits a DTH rxn called tuberuclin rxn?
- cytokine
- 24-48 hrs
- PPD = purified protein derivative