BSCI422 - 18. Immediate hypersensitivity and allergy

Hypersensitivity

is an exaggerated immune response to an antigen, leading to tissue damage and inflammation. It encompasses various reactions, including allergic responses.

Type 1

Hypersensitivity that gives rise to allergic reactions

• Response

  • First Exposure

  • Cytophilic antibodies

  • Sensitized mast cell

  • Second exposure

  • Degranulation of mast cells

First Exposure

• type 1 hypersensitivity response

• Antigen activation; B cells get exposed to the allergen

  • Allergen-specific B cells clonally expand → produce Ig

  • Allergen also recruits TH2 immune response

    • Makes IL-4, so B cell class switches to IgE

Cytophilic antibodies

• type 1 hypersensitivity response

• IgE molecules that bind to Fc epsilon receptors

• ITAM - for signaling

Fc Epsilon Receptors

• high affinity receptors that will bind IgE antibodies that are waiting for allergens to cross link it

  • Affinity for IgE

  • Can measure atopic individuals by seeing how many IgE’s there are

Sensitized mast cell

• type 1 hypersensitivity response

• Mast cell with IgE molecules bound to Fc epsilon receptors

mast cell

A type of immune cell that contains granules rich in histamine and other mediators, playing a crucial role in allergy and anaphylaxis

Degranulation

• type 1 hypersensitivity response

• of mast cells

• release of granules that have vasoactive amines

ex.

• Histamine

• Serotonin

• Cytokines

immediate reaction

degranulation

• histamine and serotonin release

  • vascular permeability/smooth muscle response

  • feeling of not being able to breathe

late phase reaction

degranulation

• cytokine release

  • inflammation

PLC activation

• fast kinetic mechanism for degranulation

• Receptor activation → Phospholipase C (PLC) activated

• PLC cleaves membrane lipid → makes:

  • IP₃ (inositol triphosphate)

  • DAG

• IP₃ → releases Ca²⁺ from ER

• ↑ Ca²⁺ → histamine release (degranulation)

Adenylate cyclase activation

• fast kinetic mechanism for degranulation

• Adenylate cyclase → ↑ cAMP (initially)

• Then:

  • cAMP levels drop

• This drop is important because:

  • Low cAMP → allows Ca²⁺ influx

• ↑ Ca²⁺ → degranulation

PMT activation

• fast kinetic mechanism for degranulation

• Phospholipid methyltransferases (PMT) activated

• Causes methylation of membrane phospholipids

• This changes membrane properties:

  • Makes membrane more fluid/permeable

• Leads to:

  • ↑ Ca²⁺ entry into the cell

• ↑ Ca²⁺ → histamine release (degranulation)

common allergens

• Ragweed

• Pollen

• Nuts

• Dust mites

• latex

dust mites

• common allergen

• Creatures that live on pillow cases and pillows

• Each skin and oil

• Defecate in pillow

  • Feces pellets contain Der p1 protease—ppl are allergic to this

biological effects to allergy

• Vascular leak

• Bronchoconstriction

• Intestinal hypermotility

• Inflammation

• Tissue remodeling

• TH2 response

  • killing of parasites and host cells

  • tissue remodeling

  • IL-4 signals through IL4R → Stat6 activation

TH2 response

• killing of parasites and host cells

• tissue remodeling

• IL-4 signals through IL4R → Stat6 activation

TH1 response

• Involves the activation of macrophages and cytotoxic T cells

• IL-12 signals through IL-12R → Stat4 activation

Stat6+/+

• Moderate levels of IFNy

• High levels of 

  • IL4, IL5, IL13

Stat6-/-

• knockout

• High levels of IFNy

• Low levels of IL4, IL5, IL10

• Don't make TH2 response → default to TH1 response

Stat4-/-

• knockout

• Moderate levels of IFNy

• High levels of 

  • IL4, IL5, IL13

Tbet+/+

• Normal in general

  • Normal levels of IFNy

  • Low levels of IL4, IL5, IL13

Tbet-/-

• knockout

• Cannot make IFNy

• Defaults to TH2 allergic response

  • over activation

    • Airway inflammation with lymphocytes and eosinophils

    • Airway remodeling with increased collagen deposited around airway

Antihistamines

• drug for allergy

• Block H1, and H2 receptors on target cells

Cromolyn sodium

• drug for allergy

• Blocks Ca2+ influx into mast cells

Theophyline

• drug for allergy

• Prolongs high cAMP levels in mast cels by inhibiting phosphodiesterase

  Cleaves cAMP to 5’-AMP

Although cAMP rises transiently during mast cell activation, degranulation is prevented if cMAP levels remain high**

Epinephrine (adrenaline)

• drug for allergy

• stimulates cAMP production by binding to adrenergic receptors in mast cells

Although cAMP rises transiently during mast cell activation, degranulation is prevented if cMAP levels remain high**

Cortisone

• drug for allergy

• reduces histamine levels by blocking conversion of histidine to histamine and stimulates mast cell production of cAMP

Although cAMP rises transiently during mast cell activation, degranulation is prevented if cMAP levels remain high**

Adjuvants

• stimulate TH1 response instead of TH2 response

  • Retrain immune response

  • Targets TH2 activation

wheal and flare reaction

• an immediate hypersensitivity reaction characterized by

  • localized swelling (wheal)

    • serum accumulation

  • redness (flare)

• at the site of allergen exposure, mediated by mast cells releasing histamine

Type 2

• hypersensitivity response

• IgG or IgM mediated cytotoxic Hypersensitivity

• Immune complexes to cellular antigens (Antigens on the cell surface)

• ex. Blood group antigen

Blood group antigen

• We make IgM antibodies to the ABO blood group antigens

  • Carbohydrates can’t fit into MHC

  • T cells cannot provide B cell help

• Make IgM antibody →  carbohydrate

• IgM does not cross the placenta

A antigen

• a carbohydrate structure found on red blood cells that, in the presence of anti-A antibodies, can trigger an immune response in individuals with type B or O blood.

• Add one galactosamine sugar

B antigen

• a carbohydrate structure present on red blood cells that can provoke an immune response when mixed with anti-B antibodies in individuals with type A or O blood.

• Add galactose sugar

Rh factor

a protein that can be present on the surface of red blood cells, which can lead to an immune reaction if Rh-negative individuals are exposed to Rh-positive blood.

Erythroblastosis fetalis

• we produce IgG antibodies to Rh factor

• First birth: Rh- mother with Rh+ fetus

  • Mom becomes exposed to IgG, and develops Ab to it

• Second birth: Mom has Ab for Rh factor, which can cause complications when IgG is passed through the placenta from Rh+ fetus

Rhogam

passive immunization method to prevent Erythroblastosis fetalis

• Prevents B cell activation and memory cell formation against Rh factor

Type 3

• hypersensitivity reaction

• caused by immune complex formation that leads to tissue damage

• Soluble antigens, rather than cellular antigens

• Ag-Ab complexes

• Arthus reaction

  • If we are exposed to foreign proteins in serum, there will be antibody response to the harmless antigens

Type 4

• hypersensitivity reaction

• mediated by T cells and macrophages, leading to delayed allergic responses

• Cell mediated hypersensitivity

• TH1 response, that happens more quickly