L15: Hypersensitivities Flashcards
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
Atopy
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?
Proteins
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
