Allergy, hypersensitivity Flashcards
Hypersensitivity
are exaggerated or inappropriate immunologic responses occurring in response to an antigen or allergen. Type I, II and III hypersensitivity reactions are known as immediate hypersensitivity reactions because they occur within 24 hours of exposure to the antigen or allergen.
Type I hypersensitivity
IgE antibodies are responsible
- Allergies are initiated by an interaction between an IgE antibody and a multivalent antigen
– Free circulating IgE is usually very, very low in concentration in blood serum
Type I hypersensitivity is also known as an immediate reaction and involves immunoglobulin E (IgE) mediated release of antibodies against the soluble antigen. This results in mast cell degranulation and release of histamine and other inflammatory mediators.
Atopy
a predisposition to an immune response against diverse antigens and allergens leading to CD4+ Th2 differentiation and overproduction of immunoglobulin E (IgE). The clinical consequence is an increased propensity to hypersensitivity reactions.
Allergens (Ags)
Most Ags are proteins or glycoproteins
* Most Ags possess many antigenic sites (epitopes) per molecule
– Often intrinsic enzymatic properties
– May contain PAMPs, stimulating innate immunity
– Might be polysaccharides (parasitic)
– May enter mucosal tissues at very low concentrations, inducing IgE-stimulating TH2 responses
Sensitized mast cells
The binding of antigen-specific IgE to FcεRI sensitizes mast cells and other effector cells to release mediators in response to subsequent encounters with that specific antigen or with crossreactive antigens
Sensitized mast cells and basophiles
IgEpre-boundtohigh-affinityreceptorFCƐR
– Cross-linkingofreceptorsbybindingofantigen
– Granulecontentsreleasedincludehistamine, heparin, proteases, leukotrienes, prostaglandins, chemokines
FcεRI and FcεRII
IgE antibodies act by cross-linking Fcε receptors on the surfaces of innate immune cells
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– The high-affinity IgE receptor, FcεRI
* Responsible for most allergy
symptoms
* Mast cells and basophils constitutively express
– The low-affinity IgE receptor, FcεRII
* Regulates production of IgE by B cells (FcεRIIB and inhibitory ITIM)
IgE antibodies act by cross- linking Fcε receptors on the surfaces of innate immune cells
– The high-affinity IgE receptor, FcεRI
* Linking receptors trigger Lyn- mediated phosphorylation of ITAMs
* Triggers PKC and MAPK pathways, leading to allergic effects
Coclustering with inhibitory receptors
Mast cells express both FcεR1 (activating) and FcγRIIB (inhibiting) Ig receptors
– If a cell binds IgE and IgG, the inhibiting signal induced by IgG binding wins
– In part why inducing IgG in atopic individuals (“allergy shots”) is effective
Inhibition of downstream signaling molecules
Lyn can also phosphorylate ITIMs on FcγRIIB, inhibiting signaling
* Signaling through FcεR1 activates E3 ubiquitin c-Cbl
– This targets Lyn, Syk, and even FcεR1 for degradation by proteasomes
Early responses
occur within minutes of allergen exposure
* Mediated by mast cell granule release of histamine, leukotrienes, and
prostaglandins
Late responses,
hours later, a result of recruited cells
* Cytokines released from mast cells increase expression of chemokines and CAMs
on endothelium facilitating influx of neutrophils, eosinophils, and TH2 cells
* Eosinophils play a large role in late-phase recruiting neutrophils and degranulation
Histamin
Binds to one of four possible histamine receptors(H1-H4)
Histamine is a signaling chemical your immune system releases to send messages between different cells. Histamine has several functions, but it’s mainly known for its role in causing allergic and anaphylactic symptoms.
H1
binding induces contraction of intestinal and bronchial smooth muscles, increased permeability of venules, and mucous secretion
H2
binding increases vasopermeability and vasodilation, stimulates exocrine glands, and increases stomach acid; also suppresses degranulation of mast cells/basophils in a negative feedback loop
H3
less involved in type 1; modulates neurotransmitter activity in CNS
H4
mediates mast cell chemotaxis
Secondary mediators
formed when membrane
phospholipids are enzymatically cleaved
Leukotrienes
are a family of biologically active compounds that are produced from arachidonic acid in a multistep process via activation of the 5-lipoxygenase pathway.
Prostaglandins
Prostaglandins are a group of lipids with hormone-like actions that your body makes primarily at sites of tissue damage or infection. There are several different types of prostaglandins, and they play several essential roles in regulating bodily processes, including:
Blood clot formation at the site of an injury.
Blood flow.
Healing.
Inflammation.
Labor induction in pregnancy.
Menstruation.
Ovulation.
Cytokines
are signaling proteins that help control inflammation in your body. They allow your immune system to mount a defense if germs or other substances that can make you sick enter your body. Too many cytokines can lead to excess inflammation and conditions like autoimmune diseases.
chemokines
re a large family of small, secreted proteins that signal through cell surface G protein‐coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes).
Cytokines and chemokines
Mast cells and basophils release several of these signaling molecules
IL-4 and IL-13
stimulate TH2 responses to increase IgE production by B cells
IL-5
recruits and activates eosinophils
TNF-α
may contribute to shock in systemic anaphylaxis
CXCL-8
acts as a chemotactic factor, attracting other cells
GM-CSF
stimulates production and activation of myeloid cells, e.g., granulocytes
Type I hypersensitivity reactions:
systemic or localized
systemic anaphylaxis
Often initiated by an injected or gut-absorbed allergen, e.g., bee sting venom,
penicillin, seafood, nuts
* Severe symptoms
localized anaphylaxis
Pathology is limited to a specific tissue or organ
* Includes allergic rhinitis (hay fever), allergic conjunctivitis, asthma, atopic dermatitis (eczema), atopic urticaria (hives), and food allergies
* Symptoms result from release of mediators in immediate exposure area
Asthma
a chronic lung disease affecting people of all ages. It is caused by inflammation and muscle tightening around the airways, which makes it harder to breathe. Symptoms can include coughing, wheezing, shortness of breath and chest tightness. These symptoms can be mild or severe and can come and go over time.
Skin barrier
Skin barrier disruption might cause development of high IgE
Results in food allergies and secondary infections
Barrier immunity – allergic induction
Food allergy initial sensitization takes place through the skin
* Infants with eczema and children deficient in filaggrin support the hypothesis
– Skin epithelial cells produce innate cytokines that affect DCs and induce allergen- specific TH2 cells, which trigger B-cell isotype switch to IgE
– Circulating IgE Ab carried in blood to intestinal tissue
– Intestinal epithelial, ILC2, TH2, and TH9 cells are activated by binding IgE to produce cytokines that recruit, support, activate mast cells and basophils
– Mediators released that cause symptoms of food allergies
Desensitization immunotherapy
Repeated low-dose exposures may induce a TREG cell increase and their cytokines
* May also induce TH1 and TREG cells where TH1 cytokines induce competitive IgG subtypes switching from IgE to IgG4
* TREG cytokines downregulate TH2 response inhibiting recruitment of basophils and eosinophils
* Oral immunotherapy consists of feeding children increasing amounts of the food allergen(s)
* Anti-IgE antibodies that bind and inhibit the allergen-specific IgE from binding to mast cell FcεR molecules
Type II hypersensitivity reactions
refers to an antibody-mediated immune reaction in which antibodies (IgG or IgM) are directed against cellular or extracellular matrix antigens, resulting in cellular destruction, functional loss, or damage to tissues. Damage can occur through multiple mechanisms.
Transfusion reactions
nvolve Ab-mediated destruction of cells by non-IgE Ab
* Blood group Ag are carbohydrates
– Adults possess antibodies to the blood type they do NOT have
– If they receive a transfusion of the “wrong” type of blood, their antibodies will quickly attach to the donor blood cells and trigger complement proteins
» The degraded RBC components can build to toxic levels
Hemolytic disease of newborn
is a blood disorder that occurs when the blood types of a mother and baby are incompatible. HDN is relatively uncommon in the United States due to advances in early detection and treatment, limiting it to approximately 4,000 cases a year.
Immune complex-mediated (type III) hypersensitivity
an abnormal immune response is mediated by the formation of antigen-antibody aggregates called “immune complexes.”[1] They can precipitate in various tissues such as skin, joints, vessels, or glomeruli and trigger the classical complement pathway.
Immune complexes
If immune complexes aren’t cleared effectively, they may deposit in tissues
* May trigger release of inflammatory mediators and vasoactive mediators
– Proteases released may damage connective tissues
– Clots may form as complexes activate platelets
* Symptoms include fever, rashes, joint pain, lymph node enlargement, and proteinuria
– Vasculitis if in blood vessel
– Glomerulonephritis if in kidney
– Arthritis if in joints
Autoantigens
An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease.
Arthus reaction
an acute, localized inflammatory response that typically occurs after vaccination. It is classified as a type III hypersensitivity reaction, which is when antigen-antibody clusters, also known as immune complexes, are formed due to an abnormal immune system response.
Hypersensitivity pneumonitis
Hypersensitivity pneumonitis is an immune system disorder in which your lungs become inflamed as an allergic reaction to inhaled microorganisms, plant and animal proteins or chemicals.
Delayed-type (type IV) hypersensitivity (DTH)
Cell-mediated response
Purely cell mediated rather than Ab mediated
Initiated by T cells
Requires a delay for the reaction to develop
Characterized by recruitment of macrophages at inflammation site
Type IV hypersensitivity
The Type IV hypersensitivity (also called delayed-type hypersensitivity, DTH) involves T cell–antigen interactions that cause activation and cytokine secretion (Figure 8.4). This type of hypersensitivity requires sensitized lymphocytes that respond 24–48 h after exposure to soluble antigen.
Inititiation – sensitization by an antigen
Initial exposure triggers production of a T-cell response
* Often of the CD4+ TH1 subset
* Takes 1–2 weeks of time
Effector phase – second exposure to Ag
Second exposure induces production of TH1 inflammatory cytokines
* These recruit and help activate macrophages
– A prolonged activation of macrophages leads to granuloma formation
Turberculosis
A prolonged inability to clear Ag can result in formation of destructive multinucleate giant cell and granulomas
Contact dermatitis (contact hypersensitivity)
– Sensitization can occur if a reactive chemical compound binds to skin proteins
* Modified proteins are then presented to T cells
* Could be induced by cosmetics, pharmaceuticals, industrial chemicals, metal ions, poison ivy, poison oak
– Can cause strong cell-mediated responses against skin cells, inducing blisterlike lesions and rashes
Celiac disease
- Food protein α-gliadin – Wheatgluten
– Oat gluten
– Barley gluten - Infiltration lamina propria
- CD4 T-cells, plasma cells, macrophages
