15 - Allergy, Hypersensitivities, and Chronic Inflammation

Question 1

Immediate vs delayed hypersinsitivities

Answer 1

Immediate = rapid symptoms, from Ab/Ag-reactions

delayed = 1-3 days later, caused by T cell reactions.

Question 2

Overview Type I hypersensitivity

Answer 2

Allergy and Atopy

immune mediator: IgE

Mechanism: Ag induces cross-linking of IgE bound to mast cells and basophils with release of vasoactive mediators.

Typical manifestations: Includes systemic anaphylaxis and localized anaphylaxis such as hay fever, asthma, hives, food allergies, and eczema

Question 3

Overview Type II hypersensitivity

Answer 3

Ab-mediated hypersentitivity

Immune mediator: IgG or IgM

Mechanism: Ab directed against cell surface Ags mediates cell destruction via complement activation or ADCC. Red blood cells are common targets.

Typical manifestations: Includes blood transfusion reactions, erytroblastosis fetalis, and autoimmune hemolytic anemia.

Question 4

Overview Type III hypersensitivity

Answer 4

Immune complex-mediated hypersensitivity

Immune mediator: Immune complexes

Mechanism: Ag-Ab complexes deposited in various tissues induce complement activation and an ensuing inflammatory response mediated by massive infiltration of neutrophils

Typical manifestations: Includes localized Arthus reaction and generalized reactions such as serum sickness, necrotizing vasculitis, glomerulonephritis, rheumatois arthritis, and systemic lupus erythematosus.

Question 5

Overview Type IV hypersensitivity

Answer 5

Delayed-type hypersensitivity (DTH)

Immune mediators: T cells

Mechanism: Sensitizes T cells (TH1, TH2, and others) release cytokines that activate macrophages or TC cells which mediate direct cellular damage

Typical manifestations: includes contact dermatitis, tubercular lesions, and graft rejections.

Question 6

atopy

Answer 6

condition, people who are genetically highly susceptible to allergies.

Question 7

Allergens

Answer 7

Allergens are highly soluble proteins or glycoproteins, usually with multiple epitopes

Many allergens are proteases and/or contain PAMPs, which result in stimulation of the immune system

Some allergens activate TH2 cells, which induce the heavy-chain class switching to IgE (responsible for allergy).

Many allergens can elicit a type I response.

Question 8

Fcε receptors

Answer 8

IgEs bind to Ags via their variable regions, and to one of two types Fc receptor via their constant regions.

Mast cells, basophils, and to a lesser extent eosinophils, express the high-affinity FcεRI, and are the main mediators of allergy symtpoms.

Cross-linking of FcεRI receptors by Ag-IgE complexes initiates multiple signaling cascades that resemble those initiated by Ag receptors.

Mast cells, basophils, and eosinophils that are stimulated by FcεRI cross-linking release their granular contents (including histamine and proteases) in a process called degranulation. They also generate and secrete inflammatory cytokines and lipid inflammatory molecules (leukotrienes and prostaglandins).

The second IgE receptor, the low-affinity FcεRII (aka CD23) is found on IgE-expressing B cells and on other cells; it helps regulate IgE responses, transports IgE across the intestinal epithelium, and induces inflammatory cytokine production by macrophages.

Question 9

Regulation of Fcε receptors

Answer 9

Mast cell and basophil activation by FcεRI signaling can be down-regulated by inhibitory signals (incl inhibitory FcγRIIB signaling) phosphatases (SHP, SHIP, PTEN) that remove key phosphate residues from signaling intermediates, and uniquitinylation and degradation of signaling molecules.

Question 10

Primary and secondary mediators Type I

Answer 10

primary mediators = preformed, stored in granules.
secondary mediators = synthetized after target-cell activation or released by the breakdown of membrane phospholipids during the degranulation process.

Most significant primary mediators: histamine, proteases, eosinophil chemotactic factor (ECF), neutrophil chemotactic factor (NCF) and heparin.

Secondary mediators:
platelet-activating factor (PAF), leukotrienes, prostaglandins, bradykinin, various cytokines/chemokines.

Question 11

primary molecules Type I effects

Answer 11

histamine, heparin: increased vascular permeability; smooth muscle contraction.

Eosinophil chemotactic factor (ECF-A): eosinophil chemotaxis

Neutrophil chemotactic factor (NCF-A): neutrophil chemotaxis

proteases (tryptase, chymase): bronchial mucus secretion; degradation of blood vessel basement membrane; generation of complement split products.

Question 12

secondary molecules Type I effects

Answer 12

Platelet-activating factor: platelet aggregation and degranulation; contraction of pulmonary smooth muscles.

Leukotriens (slow reactive substance of anaphylaxis, SRS-A): increased vascular permeability; contraction of pulmonary smooth muscles.

Prostaglandins: Vasodilation; contraction of pulmonary smooth muscles, platelet aggregation.

Bradykinin: Increased vascular permeability; smooth muscle contraction

Cytokines:
- IL-1 and TNF-α: systemic anaphylaxis; increased expression of adhesion molecules on venous endothelial cells

• IL-4 and IL-13 induction of TH2 cells, incerased IgE production
• IL-5: important in the recruitment and activation of eosinophils
• IL-8: attracts additional neutrophils, monocytes, mast cells, basophils, and various subsets of T cells

Question 13

Type I early and late responses

Answer 13

early response: within minutes of allergen exposure, and results from the release of histamine, elukotrienes, and prostaflandins from local mast cells.

late-phase: hours after the early response begins to subside, mediators from the reaction can induce local inflammation. Cytokines from mast cells (esp TNF-α and IL-1) increase the expression of chemokines and cell adhesion molecules on venous epithelial cells, thus facillitating the influx of neutrophils, eosinophils, and TH2 cells.

Eosinophils play a major role in the late-ohase response, incl recruitment of neutrophils. Degranulation by both cell types induces further inflammation and tissue damage.

A third phase of response has been identified at some sites, including the skin, involving basophils and fibroblasts, which then recruit other cells that promote continued inflammation

Question 14

Systemic anaphylaxis

Answer 14

most severe allergy response.

systemic, often fatal state that occurs within minutes of exposure.

usually initiated by an allergen directly in the bloodstream.

symptoms: drop in blood pressure (leading to analyptic shock), followed by contraction of smooth muscles, leading to defecation, urination, and bronchiolar constriction (causing labored respiration).

asphyxiation, can cause death in 2-4 mins.

Symptoms are due to rapid and wide-spread IgE-mediated degranulation of mast cells and basophils and the systemic effects of their contents.

Adrenaline can counteract some of the effects, avoiding death.

Question 15

Localized hypersensitivity reactions

Answer 15

the effects are limiteed to a specific target site in tissue or organ.

incl: hay fever, asthma, eczema, hives, food allergies. All from IgE-mediated reactions.

Food allergies may cause local (mouth and throat, GI tract, ++) responses, as well as anaphylaxis.

Question 16

Environmental factors that can influence susceptibility to Type I hypersensitivity reactions:

Answer 16

environmental:
- air pollution
smoke from factories. associated with
early atopic dermatitis, which can lead
to asthma.
- farm animals and bacteria
exposure to farm animals and their
bacteria can protect against allergies
and asthma. Having pets might also
help.
- diet
the diet of a pregnant woman can
affect the predisposition for allergies.
-hygiene hypothesis
Proposes that exposure to some
pathogens during infancy and
childhood benefits the individual by
stimulating immune responses other
than the type 2 responses that induce
IgE responses and allergies.

Question 17

genetic factors that can affect allergies

Answer 17

among the genes that have variants associated with presdisposition to allergies and asthma are genes that affect the integrety of the epithelial barrier, cytokines and chemokines, proteins controlling regulatory T cells, TFs and receptors and signalling proteins.

Question 18

tests and treatments for allergies

Answer 18

skin tests are effective in determining/diagnosing allergies.

allergic reactions can be treated with pharmacological inhibitors of cellular and tissue responses and inflammation, including antihistamines, leukotriene inhibitors, and corticosteroids. An anti-IgE Ab can also be effective, though expensive and difficult to administer.

Immunotherapeutic approaches include attempts to desensitize allergic individuals by exposing them to increasing levels of their allergen. Immunotherapy by injection or sublingual administration of airborne allergens such as pollen, dust, insect venom, and animal dander proteins has been successful in preventing allergic rhitinitis. Clinical trials are underway to desensitize children with food allergies by feeding increasing doses of the allergen, which might work by inducing Tregs and TH1 instead of TH2 cells, tha the production of IgG4 instead of IgE Abs.

Question 19

ABH

Answer 19

(Type II hypersensitivity)
A = surface antigens for blood type A

B = B

H = O

carbs, not proteins.

occur on red blood cells, and on the surface of other cells as well as in bodily secretions.

Abs directed towards ABH = isohemagglutinins.

people are tolerant of their own Ags, but generate Abs against the Ag (A or B) that they do not express. All individuals express H (no Abs for this)

Transfusion of different blood-group Ags stimulate the production of IgG Abs, which cause delayed and less severe reactions.

Question 20

Hemolytic disease of Newborns :(

Answer 20

five alleles for Rhesus Ag. expression of D allele elicits the strongest immune response (Rh+). The others are Rh-.

Rh- mother + Rh+ father = danger for development of a response to the Rh Ag that the fetus may have inherited from the father, causing rejection of the Rh+ fetus. As red blood cells of the fetus enter the maternal circulation during pregnancy, the mother will develop Rh Abs that can cause hemolytic disease in subsequent pregnancies. This can be prevented by several approaches to eliminate fetal red blood cells or the meternal Abs.

Similar immunization of the mother against A or B blood-group Ags of the fetus may also occur; blood-group Ag Abs cause les severe hemolytic disease for the newborn.

Question 21

Type III

Answer 21

uncleared immune complexes can induce degranulation of mast cells and inflammation, and can be deposited in tissues and capillary beds where they induce more innate immune activity, blood vessel inflammation (vasculitis), and tissue damage, such as glomerulonephritis in the kidneys or arthritis in the joints.

Immune comples-mediated hypersensitivity can resolve spontaneously. If Abs are present, a single bolus of the Ag may produce immune complexes that may be cleared without protblems, but repeated exposure (e.g., injection with Ab from different species) can cause serum sickness.

Autoanigens can be involved in immune complex-mediated reactions. Chronic exposure to immune complexes against auto-antigens can leas to chronic type III hypersensitivity.

Arthus reactions are localized type III hypersensitivity reactions. They are examples of immune complex (type III) hypersensitivity reactions and can be induced by insect bites, as well as by inhalation of fungal or animal protein in individuals with Abs to those Ags. Depositions of immune complexes in blood vessels can cause local and sometimes severe inflammation of blood vessels in the skin and other tissues.

Question 22

Type IV (DTH)

Answer 22

initiation: T cells are activated by APCs. The T cells are primarily of the TH1 subtypes, but can also be TH17, TH2, and CD8+ cells. After sensitization, T cells are developed ofr 1-2 weeks.

effector phase: induced by second exposure to a sensitizing Ag. in the effector phase, sensitized TH1 cells are re-activated by an APC, which produces cytokines like IFN-γ, which activates macrophages. Other cytokines that are secreted include TNF-α, and -β (also affect macrophages). Activated macrophages are better at killing, and they secrete TNF-α and IL-1β, and chemokines that lead to the recruitment of more monocytes and neutrophils, and enhance the activity of TH1, amplifying the response.

DTH reaction can be detected by a skin test. Prior sensitazion to M. turberculosis can be detected by skin test, in which a small amount of M. tuberculosis protein is injected into the skin. If sensitized T cells are present, a localized hypersensitivity response occurs, assessed after 48 h.

Contact dermatitis is a Type IV Hypersensitivity response. Contact dermatitis is a skin DTH response. Sensitizing molecules, including metals such as nickel, bind to skin proteins and create modified peptides that can be rec by T cells.

The plant lipid toxin urushiol induces contact dermatitis by activating three types of effector T cells. It binds to extracellular and intracellular proteins in the skin and activates TH1 and CD8+ cells specific for urushiol-modified peptides. It also binds to the CD1a protein on skin Langerhans cells and activates urushiol-specific TH17 cells.

Question 23

Chronic inflammations - causes and consequences

Answer 23

causes:
- infecious causes:
* unresolved infection
* intestinal microbes
- noninfectious causes:
* hyperglycemia/obecity
* Autoimmune responses
* allergic responses
* Organ transplantation
* Cancer

DAMPs released by damaged tissue induce the secretion of inflammatory cytokines and other mediators, and can lead to chronic inflammation if tissue damage persists.
Obesity can result in chronic inflamation in part because adipocytes can be stimulated to produce proinflammatory cytokines directly. Other inflammatory cytokine-producing cells (incl macrophages) are also found in adipose tissue.

Consequences: 
- Tissue changes:
           * Cell death
           * Scarring (fibrosis)
           * Blood vessel growth (angiogenesis)
           * Cell proliferation
- metabolic changes:
           * Impaired insulin signaling 
           * Obesity
Metabolic changes can lead to Type 2 diabetis

• Other systemic conditions:
  * Heart disease and atherosclerosis
  * Organ failure (kidney, heart, liver)
  * Cancer
  * Alzheimer’s
  * Autoimmune diseases
  * Autoinflammatory diseases
  * Inflammatory bowel diseases
  * Allergic conditions, asthma
  * Organ transplant rejection

Inflammatory cytokines associated with chronic inflammation contribute to insulin resistance (type 2 diabetes) by interfering with the activity of enzymes downstream of the insulin receptor.
tissue scarring can lead to organ dysfunction and may contribute to tumors