L15: Hypersensitivities Flashcards Preview

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Flashcards in L15: Hypersensitivities Deck (52)

What are the 4 types of hypersensitivities mediated by?

Type I - IgE

Type II - IgM, IgG, complement

Type III - IgG, complement (immune complex-mediated)

Type IV - T cells


In Type I hypersensitivity, what is immune reactant, antigen, effector mechanism, and examples of hypersensitvity reaction

Immune reactant - IgE

Antigen - soluble antigen

Effector mechanism - Mast-cell activation

Examples of hypersensitivity reactions - Allergic rhinitis, asthma, systemic anaphylaxis


Describe general mechanism underlying type I hypersensitive reaction

If immune system recognizes allergen, B cell gets activated w/ help from Th cells → Plasma cell secretes IgE and memory cell is formed → allergen-specific IgE is secreted → mast cells (which have Fc-epsilon receptors that specifically recognize the Fc portion of IgE antibody) become sensitized → if this mast cell is exposed to the same allergen a 2nd time → allergen will bind to the Fab portion of the antibody stuck to the Fc receptor on mast cell → allergen will crosslink 2 antibodies → downstream signaling occurs → mast cells (which contain vasoactive amines such as histamine) degranulate → leads to pathology of type I hypersensitivity: vasodilation, smooth muscle cell contraciton


What is the effect of mass-cell activation on GI tract?

Increased fluid secretion, increased peristalsis → expulsion of GI tract contents (diarrhea, vomiting)


What is the effect of mast cell activation on eyes, nasal passages, and airways?

Decreased airway diameter, increased mucus secretion → congestion and blockage of airways (wheezing, coughing, phlegm); swelling and mucus secretion in nasal passages; ocular itching; sneezing


What is the effect of mast cell activation on blood vessels?

Increased blood flow, increased permeability → increased fluid in tissues causing increased flow lymph to lymph nodes, increased cells and proteins in tissues, increased effector response in tissues; hypotension potentially leading to anaphylactic shock


What are the biochemical events in mast cell activation in addition to granular exocytosis?

Granule exocytosis → vascular dilation, smooth muscle contraction

Enzymatic modification of arachidonic acid → secretion of prostaglandins and leukotrienes → vascular dilation and smooth muscle contraction (respectively)

Transcriptional activation of cytokine genes → cytokine secretion → Cytokines, e.g. TNF → inflammation (leukocyte recruitment)


What are consequences of type I reactions?

Systemic anaphylaxis: shock-like and often fatal; systemic vasodilation and smooth muscle contraction; loss of BP, airway constriction

Localized anaphylaxis: reaction is limited to a specific target tissue or organ, often involving epithelial surfaces at the site of allergen entry



The tendency to manifest localized anaphylactic reactions

This tendency is inherited


What about allergen administration determines the type of IgE-mediated allergic reaction that results?

Dose and route


What route of allergen administration leads to anaphylactic shock?

Intavenously to connective tissue mast cells

Either directly or following absorption into the blood after oral intake


What is the appearance of type I hypersensitivity?

Wheal and flare

Wheal: increased vascular permeability leads to extravasation of fluid and swelling

Flare: vasodilation of surrounding cutaneous blood vessels leading to redness of the surrounding skin


What are features of inhaled allergens that may promote the priming of Th2 cells that drive IgE responses?


Often are proteases, which allows them access to the tissues

In low doses, can induce a very strong IL-4 activating Th2 response which favors isotype switching to IgE antibody

Highly soluble

Very stable

Contain peptides that can bind MHC class II and induce T cell priming


What is Der p 1? How does it work?

Der p 1 is a protealytic enzyme found in fecal pellets from house dust mites that acts as an allergen

Der p 1 is a cysteine protease

Der p 1 cleaves occludin in tight junctions and enters mucosa → Der p 1 is taken up by dendritic cells for antigen presentation and Th2 priming → dendritic cell primes T cell in lymph node → Th2 cell induces B-cell switching to IgE production→ plasma cells travel back to mucosa and produces Der p 1-specific antibodies → IgE binds to FcRI receptor on mast cell → Der p 1-specific IgE binds to mast cell; Der p 1 triggers mast-cell degranulation → mast-cell granule contents cause allergic symptoms


Netherton's syndrom

Caused by a deficiency in the protease inhibitor SPINK5

Persistent erythroderma (redness of skin), recurrent infections of the skin and other tissues, and multiple food allergies associated w/ high serum IgE levels

These individuals have a lot of enzymes that are secreted by various bacteria; prevention of breakdown of these proteins causes accumulation of these proteases to act as an allergen → induces a strong IgE-mediated allergic reaction


Early and late inflammatory responses in asthma

Initial reaction is a true IgE-mediate hypersensitivity reaction where allergen induces activation of mast cells

This early response turns into a chronic response caused by products that are secreted in the early response which further activates Th2 cells → a lot of Th2 cells are recruited to respiratory tract → these Th2 cells secrete a lot of factors that recruit a lot of inflammatory cells to the site to cause chronic infection → products that released by recruited inflammatory cells cause damage to epithelial cell and thickened basement membrane

Chronic infection is more like a type IV hypersensitivity reaction, but initiation is type I


What is morphological evidence of chronic inflammation in the airways of asthmatic patients?

Total occlusion of the airway by mucous plug

Dense inflammatory infiltrates


What leads to atopic allergic diseases?

There is both genetic susceptibility and environmental factors

People w/ genetic susceptibility that are living in a hygienic environment are most likely to have
allergic reactions

This is sometimes called the hygiene hypothesis


What cytokine is pivotal in regulating the type I response?

IL-4, which is made by Th2 bc it is necessary for inducing IgE synthesis


Skin testing for detection of type I hypersensitvity

Inject a small amount of allergen subcutaneously and look for wheal and flare response at the site of inection



Radioallergoabsorbent test

Detects the serum level of IgE specific for a given allergen

Allergen coupled to solid phase + patient IgE → non-specific IgE is washed away → left w/ bound allergen-specific IgE → add radiolabeled anti-IgE → wash again → count bound label


Hyposensitization treatment of Type I allergy

Inject very small amounts of antigen over a long period of time

Can push the immune system to make a lot of IgG antibody to the allergen

This is referred to as blocking antibody bc IgG will mop up the allergen and prevent it from binding to the IgE that is on the mast cells

Doesn't work for all allergens and all individuals



Used to treat type I hypersensitivity

Blocks H1 and H2 receptors on target cell


Cromolyn sodium

Used to treat type I hypersensitivity

Blocks Ca2+ influx into mast cells → mast cells cannot degranulate



Used to treat type I hypersensitivity

Prolongs high cAMP levels in mast cells by inhibiting phosphodiesterase, which cleaves cAMP to 5'-AMP → inhibits mast cell degranulation



Used to treat type I hypersensitivity

Stimulates cAMP production by binding to beta-adrenergic receptors on mast cells

Relaxes smooth muscle cells and reduces vascular permeability



Used to treat type I hypersensitivity

Reduces histamine levels by blocking conversion of histidine to histamine and stimulates mast-cell production of cAMP


In Type II hypersensitivity, what is immune reactant, antigen, effector mechanism, and examples of hypersensitvity reaction

Immune reactant: IgG

Antigen: Cell- or matrix associated antigen

Effector mechanism: Complement, FcR+ cells (phagocytes, NK cells)

Example of hypersensitivity reaction: some drug allergies (e.g. penicillin)


What is type II hypersensitvity primarily mediated by?




Phagocytes and NK cells may also be involved (ADCC)


What kind is transfusion reactions?

Type II hypersensitivity


What itype of hypersesnsitivity reaction is hemolytic disease of the newborn (Rh)?

Type II


What occurs in first pregnancy of RhD- mother carrying RhD+ fetus?

During the deliver, the fetal RBCs get into the mother's circulation → primary immune response, IgM plus low amounts of low-affinity IgG → healthy newborn baby


What occurs in second and subsequent pregnancies of RhD- mother carrying a RhD+ fetus?

Secondary immune response, abundant, high-affinity IgG transcytosed to fetal circulation → massive destruction of fetal erythrocytes triggered by anti-RhD IgG → anemic newborn babies



Anti-RhD IgG

Used to treat RhD- mother

Blocks the Rh factor → prevents B-cell activation and memory cell formation → in 2nd pregnancy, there are no memory B cells specific for Rh and no destruction of fetal RBCs


What are diagnostic tests for type II hypersensitivities?

Detection of circulating antibodies against the tissues involved

Presence of antibody and complement in the lesions - immunofluorescence


What is treatment for type II hypersensitivities?

Anti-inflammatory agents and immunosuppressive drugs


In Type III hypersensitivity, what is immune reactant, antigen, effector mechanism, and examples of hypersensitvity reaction

Immune reactant: IgG

Antigen: soluble antigen

Effector mechanism: Complement, phagocytes

Example of hypersensitivity reaction: Serum sickness, arthus reaction


What is type III hypersensitivity also known as?

Immune complex hypersensitivity


How do reactions develop in type III hypersensitivity?

When immune complexes activate complement

Deposit in vascular walls or other tissues - inflammation


What is tissue damage caused by in type III hypersensitivity?

Caused by platelets and neutrophils


Pigeon breeder's lung

Type III hypersensitivity

Individuals take up a lot of spores → make antibodies to the spores → immune complex deposition in alveoili → in the presence of complement, will activate mast cells → neutrophils are recruited → lytic activity of neutrophil causes pathology associated w/ type III hypersensitivity


What contributes to the pathogenesis of SLE and RA?

Formation of circulating immune complexes (type III hypersensitivity)


What are the diagnostic tests and treatment for type III hypersensitivities?

Diagnostic tests: the presence of immune complex in serum

Treatment: anti-inflammatory agents


In Type IV hypersensitivity, what is immune reactant, antigen, effector mechanism, and examples of hypersensitvity reaction

Immune reactant: CTL

Antigen: cell-asociated antigen

Effector mechanism: cytotoxicity

Example of hypersensitivity reaction: graft rejection


What is type IV hypersensitivity also known as?

Cell-mediated or delayed-type hypersensitivity (DTH) reaction


What cells does type IV involve?

Mainly monocytes and few T cells


What is the appearance of Type IV hypersensitivity?

Erythema and induration


Describe the development of DTH reaction following exposure to poison oak

Poison oak → pentadecacatechol → binds to self-proteins in skin → can now be taken up by dendritic cells → Th1 cells become activated → release IFN-γ → macrophages are further activated and release a lot of lytic enzymes → pathology seen due to activated macrophages


What type of hypersensitivity is celiac disease?

Type IV


Describe the molecular basis of immune recognition of gluten in celiac disease

Peptides naturally produced by gluten do not bind to MHC class II molecules → and enzyme, tissue trasnglutaminase (TF), modifies the peptides so they can now be processed and bind to the MHC class II molecules → the bound peptide activates gluten-specific CD4 T cells → activated T cells can kill mucosal epithelial cells by binding Fas; they also secrete IFN-γ which activates the epithelial cell to produce cytokines and chemokines that recruit other inflammatory cells


What is a defining pathological feature of celiac disease?

Jejunem's epithelial layer is completely destroyed


What are diagnostic tests for type IV hypersensitivity? What is treatment?

Diagnostic tests: detection of IgA anti-tissue transglutaminase antibody, endoscopy, pathology

Treatment: diet, corticosteroids and other immunosuppressive agents