Chapter 15: allergy, hypersensitivities, and chronic inflammation

Hypersensitivites:

disorders caused by inappropriately vigorous innate or adaptive immune responses to non-threatening antigens

What are the hypersensitivity categories?

Immediate, which manifest quickly usually due to antibody-antigen reactions and delayed-type which take 1-3 days to manifest and are generally caused by T cell reactions

How are the types of hypersensitivity grouped?

into four types based on the immune components that cause them and how they induce damage

Type I hypersensitivity name, immune mediator, mechanism, and examples

• allergy and atopy

• IgE

• Ag induces cross linking of IgE bound to mast cells and basophils with release of vasoactive mediators

• systemic or localized anaphylaxis such as hay fever, asthma, allergies, and eczema

Type II hypersensitivity name, immune mediator, mechanism, and examples

• antibody-mediated hypersensitivity

• IgG or IgM

• Ab directed against cell surface antigens mediates cell destruction via complement activation or ADCC. RBCs are common targets

• blood transfusion reactions or autoimmune hemolytic anemia

Type III hypersensitivity name, immune mediator, mechanism, and examples

• Immune complex-mediated hypersensitivity

• immune complexes

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

• rheumatoid arthritis, lupus, or serum sickness

Type IV hypersensitivity name, immune mediator, mechanism, and examples

• delayed-type hypersensitivity

• T cells

• sensitized T cells release cytokines that activate macrophages or TC cells which mediate direct cellular damage

• contact dermatitis and graft rejections

Atopic

individuals that produce IgE against common environmental antigens

Mechanism of type I hypersensitivity

IgE antibodies cross link FcεRIs leading to degranulation. Granule contents released include histamine, heparin, proteases, leukotrienes, prostaglandins, and chemokines that act on surrounding tissues and cells causing symptoms.

FcεR I

high affinity IgE receptors on the surface of innate immune cells that are responsible for most allergy symptoms.

How does IgE signal through FcεR I

IgE binding FcεRIs triggersn Lyn to phosphorylate ITAMs and activate Syk. Syk activates PKC and MAPK signaling pathways that lead to allergic effects

IgE receptor signaling regulation

Mast cells express both FcεRI (activating) and FcyRIIB (inhibiting) IG receptors. If a cell binds IgE and IgG, the inhibiting signal from IgG wins.

FcεR II

the low affinity IgE receptor that regulates IgE production by B cells. It may be membrane bound or soluble and can also bind CD21.

Classifications of inflammatory mediators

• primary mediators: performed and stored in granules, includes histamine, proteases, ECF, NCF, and heparin

• secondary mediators: synthesized after target-cell activation or released by membranes phospholipid breakdown during degranulation, includes PAF, leukotrienes, prostaglandins, bradykinin, cytokines, and chemokines

Histamine formation and receptors:

• formed by decarboxylation of histidine amino acid and accounts for approximately 10% of granule weight

• binds to H1, H2, H3, or H4

H1 receptor

binding induces contraction of intestinal and bronchial smooth muscles, increased permeability of venules, and mucous secretion

H2 receptor

binding increases vasopermeability and vasodilation, stimulate exocrine glands, and increases stomach acid. Also suppresses degranulation of mast cells/ basophils in a negative feedback loop

H3 receptor

is less involved in type 1 hypersensitivity and modulates neurotransmitter activity in the CNS

H4 receptor

mediates mast cell chemotaxis

Leukotrienes and protaglandin formation

formed when membranes phospholipids are enzymatically cleaved and are more potent than histamine. Leukotrienes are major causes of asthma symptoms

Cytokines and chemokines formation

release by mast cells and basophils

IL-4 and IL-13

stimulate TH2 responses to increase IGE production by B cells

IL-5

recruits and activates eosinophils

IL-8

acts as a chemotactic factor attracting other immune cels

IL-9

increases mast cell number and activity

TNF-α

may contribute to shock in systemic anaphylaxis

GM-CDF

stimulates production and activation of myeloid cells

Type IV

purely cell mediated, T cell reaction that requires a 1-2 day delay

Most common example of Type IV hypersensitivty reaction?

Poison Ivy contact dermatitis, which affects 50-70% of adults in the US

Initiation of Type IV reaction

the initiation of a type IV response involves sensitization by an antigen. This initial exposure triggers production of a T cell response (TH1)

Effector phase of a type IV response

Second exposure to antigen triggers production of TH1 inflammatory cytokines that recruit and help activate macrophages. This make take 24 hours to appear after secondary exposure.

TB example of type IV reaction

There is a prolonged inability to clear the Ag that results in the formation of destruction multinucleate giant cells and granulomas

DTH reaction detection

DTH reactions are detected by a skin test, which is performed by injecting a small amount of Ag under the skin. Positive- a red slightly swollen/ firm lesion appears within 48-72 hours.

Contact dermatitis

sensitization can occur if a reactive chemical compound (urushiol) binds to the skin proteins. These modified proteins are then presented to the T cells, causing a strong cell-mediated response against the skin cells that creates blister-like lesions and rashes.

Chronic inflammation causes

infectious conditions, physical damage, obesity, and diabetes.

Chronic inflammation consequences

• tissue changes: cell death, scarring

• metabolic changes: impaired insulin signaling, T2DM

• other conditions: organ failure, heart disease, Alzheimers, cancer

Explain chronic inflammation due to infection

Continual microbial invasion can induce chronic inflammation such as gun disease or un-healed wounds.

Explain noninfectious causes of chronic inflammation

physical damage can release DAMPs which can lead to tumors, autoimmune disease, heart disease, or obesity