Hypersensitivity (extended)

• Type I (Anaphylaxis)
• Type II (Antibody-mediated type)
• Type III (Immune-complex mediated)
• Type IV (Cell-mediated hypersensitivity)

 Type I (anaphylaxis)

• A type I hypersensitivity (allergic) reaction between an allergenic antigen and immunoglobulin E (IgE) bound to mast cells, which stimulates the sudden release of immunological mediators locally or throughout the body.
• The first symptoms occur within minutes, and a recurrence may follow hours later (late-stage response). Anaphylaxis can only occur in an individual previously sensitized to an allergen, as it is the initial exposure that causes immunoglobulin E (IgE) to bind to mast cells. It is categorized as local or systemic. Local anaphylactic reactions include hay fever, hives, and allergic gastroenteritis. Systemic anaphylaxis, which produces peripheral vasodilation, bronchospasm, and laryngeal edema, can be life- threatening.
  • 
    ETIOLOGY: IgE antibodies bound to mast cells throughout the body as the result of previous exposure to an allergenic antigen (sensitization) react when the allergen is introduced a second time. The mast cells release packets containing chemical mediators (degranulation) that attract neutrophils and eosinophils and also stimulate urticaria, vasodilation, increased vascular permeability, and smooth muscle spasm, esp. in the bronchi and gastrointestinal tract. Chemical mediators involved in anaphylaxis include histamine, proteases, chemotactic factors, leukotrienes, prostaglandin D, and cytokines (e.g., TNF-aand interleukins 1, 3, 4, 5, and 6). The most common agents triggering anaphylaxis are drugs, food, and insect stings. Local anaphylactic reactions are also commonly triggered by pollens (e.g., hay fever, allergic rhinitis, allergic asthma).
  • SYMPTOMS: Local anaphylaxis causes signs to appear at the site of allergen- antibody interaction including urticaria (hives), edema, warmth, and erythema. In systemic anaphylaxis the respiratory tract, cardiovascular system, skin, and gastrointestinal system are involved. The primary signs are urticaria, angioedema, flushing, wheezing, dyspnea, increased mucous production, nausea and vomiting, and feelings of generalized anxiety. Systemic anaphylaxis may be mild or severe enough to cause shock when massive vasodilation is present.
  • TREATMENT: Local anaphylaxis is treated with antihistamines and occasionally epinephrine, if the reaction is severe. Treatment for systemic anaphylaxis includes protection of the airway and administration of oxygen; antihistamines (e.g., diphenhydramine or cimetidine to block histamine H1 and H2 receptors); IV fluids to support blood pressure) and vasopressors (e.g., epinephrine or dopamine) to prevent or treat shock. Epinephrine also is used to treat bronchospasm. Generally, drugs are given intravenously; drugs may also be given intramuscularly (e.g., diphenhydramine) or endotracheally (e.g., epinephrine). In mild cases they may be given subcutaneously. Corticosteroids may be used to prevent recurrence of bronchospasm and increased vascular permeability.
  • PATIENT CARE: Prevention: A history of allergic reactions, particularly to drugs, blood, or contrast media, is obtained. The at- risk patient is observed for reaction during and immediately after administration of any of these agents. The patient is taught to identify and avoid common allergens and to recognize an allergic reaction.
    Patients also should be taught to wear tags identifying allergies to medications, food, or insect venom at all times to prevent inappropriate treatment during an emergency. Individuals who have had an anaphylactic reaction and are unable to avoid future exposure to allergens should carry a kit containing a syringe of epinephrine and be taught how to administer it. Patients who are allergic to the venom of Hymenoptera insects (bees, wasps, hornets) can receive desensitization.
    • active anaphylaxisAnaphylaxis resulting from injection of an antigen.
    • exercise-induced anaphylaxisanaphylactoid reaction.
    • local anaphylaxis A reaction between IgE antibodies bound to mast cells and an allergen that is limited to a small part of the body.Localized edema and urticaria (hives) result and may vary in intensity.
    • passive anaphylaxis Anaphylaxis induced by injection of serum from a sensitized animal into a normal one. After a few hours the latter becomes sensitized.
    • passive cutaneous anaphylaxis ABBR: PCA.. A laboratory test of antibody levels in which serum from a sensitized individual is injected into the skin. Intravenous injection of an antigen accompanied by Evans blue dye at a later time reacts with the antibodies produced in response to the antigen, creating a wheal and blue spot at the site, indicating local anaphylaxis.
    • systemic anaphylaxis A reaction between IgE antibodies bound to mast cells and an allergen that causes the sudden release of immunological mediators in the skin, respiratory, cardiovascular, and gastrointestinal systems. The consequences may range from mild (e.g., itching, hives) to life- threatening (airway obstruction and shock).

 Type II

Type II Hypersensitivity (Antibody Mediated Type) 

• AKA:  cytotoxic type (although not always cytotoxic)
• Antibodies directed against normal or modified cell surface or tissue components induce cell lysis
• Complement Dependent
  • Two Mechanisms:
    • Direct lysis by complement activation
    • Lysis by opsonization (C3b) - often involves RBCs
  • Examples: 
    • Transfusion reactions
    • Erythroblastosis fetalis
    • Autoimmune hemolytic anemia
    • Autoimmune thrombocytopenia
    • Certain drug reactions
• Antibody-Dependent Cell-Mediated Cytotoxicity
  • Monocytes, neutrophils, eosinophils, or NK cells recognize cells by Fc portion of IgG bound to cell and kill cell without phagocytosis
  • Example:  Goodpasture's syndrome
• Anti-Receptor Antibodies
  • Noncytotoxic
  • Examples:  myasthenia gravis from antibody to acetylcholine receptor

 Type III

• Type III Hypersensitivity (Immune Complex Mediated)
  • Antigen (Ag) + antibody (Ab) complexes produce tissue damage by activation of serum mediators (primarily complement)
• Antibodies are produced by a large dose od administered antigen (~5 days after administration)
• Ag-Ab complexes are deposited in the tissues, (often inducing localized type I hypersensitivity reactions in glomeruli, joints, skin, heart, serosal surfaces, and small blood vessels, where they can activate complement
• An inflammatory reaction ensues (~10 days) with resulting fever, urticaria, arthralgias, lymphadenopathy, and proteinuria
• Inflammation in and around vessels causes an acute necrotizing vasculitis with fibrinoid deposition and acute inflammation (innocent bystander destruction)

Type IV Type IV (Cell Mediated) Hypersensitivity

Type IV hypersensitivity is often called delayed type hypersensitivity as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response.

CD8+ cytotoxic T cells and CD4+ helper T cells recognize antigen in a complex with either type 1 or 2 major histocompatibility complex. The antigen-presenting cells in this case are macrophages which secrete IL-12, which stimulates the proliferation of further CD4+ T cells. CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other Type 1 cytokines, thus mediating the immune response. Activated CD8+ T cells destroy target cells on contact while activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.

 

Disease	Target antigen	Effects
Diabetes mellitus type 1	Pancreatic beta cell proteins (possibly insulin, Glutamate decarboxylase)	Insulitis Beta cell destruction
Multiple sclerosis	Oligodendrocyte proteins (myelin basic protein, proteolipid protein)	Demyelinating disease Perivascular inflammation Paralysis Ocular lesions
Rheumatoid arthritis	Antigen in synovial membrane (possibly type II collagen)	Chronic arthritis Destruction of articular cartilage and bone
Some Peripheral neuropathies	Schwann cell antigen	Neuritis Paralysis
Crohn's disease	Unknown	Chronic inflammation of ileum and colon
Contact dermatitis	Environmental chemicals, e.g. poison ivy, nickel	Dermatitis with usually short-lived itching
Mantoux test* (diagnostic)	Tuberculin	Skin induration indicates TB exposure

 

• the cell or tissue damage done during diseases like tuberculosis, leprosy, smallpox, measles, herpes infections, candidiasis, and histoplasmosis;
• the skin test reactions seen for tuberculosis and other infections;
• contact dermatitis like poison ivy;
• type-1 insulin-dependent diabetes where CTLs destroy insulin-producing cells;
• multiple sclerosis, where T-lymphocytes and macrophages secrete cytokines that destroy the myelin sheath that insulates the nerve fibers of neurons;
• Crohn’s disease and ulcerative colitis; and
• psoriasis. 

Delayed hypersensitivity also plays a major role in chronic transplant rejection as a result of CTL destruction of donor cells (host versus graft rejection) or recipient cells (graft versus host rejection). Immunosuppressive drugs such as cyclosporin A or FK-506 (Tacrolimus) are given in an attempt to prevent rejection. Both of these drugs prevent T-lymphocyte proliferation and differentiation by inhibiting the transcription of IL-2.
  

Comparison of Different Types of hypersensitivity
characteristics	type-I (anaphylactic)	type-II (cytotoxic)	type-III (immune complex)	type-IV (delayed type)
antibody	IgE	IgG, IgM	IgG, IgM	None
antigen	exogenous	cell surface	soluble	tissues & organs
response time	15-30 minutes	minutes-hours	3-8 hours	48-72 hours
appearance	weal & flare	lysis and necrosis	erythema and edema, necrosis	erythema and induration
histology	basophils and eosinophil	antibody and complement	complement and neutrophils	monocytes and lymphocytes
transferred with	antibody	antibody	antibody	T-cells
examples	allergic asthma, hay fever	erythroblastosis fetalis, Goodpasture's nephritis	SLE, farmer's lung disease	tuberculin test, poison ivy, granuloma

Types of hypersensitivity

Hypersentivity disorders refer to excessive or inappropriate activation of the immune system although activation of the immun system normally leads to the production of antibodies and Tcell responses that protect the body against attack by microorganizms, it is also capable of causing tissue injury and disease.

Disorders caused by immune responses are collectively referred as hypersensitivity reactions.

TYPE I Immediate  (allergic or Anaphylaxis):	IgE mediated,  antigen reacts to IgE on ast cells leading to histamine release Examples: seasonal rhinitis, food allergy
TYPE II Antibody mediated (cytotoxic):	IgM or IgG mediated.  IgG’s react with antigen leading to complement activation causing lysis of the cell.  Examples: drug reactions, hemolytic reactions Antibody-Dependent Cell-Mediated Cytotoxicity Good Pastures Noncytotoxic - myasthenia gravis
TYPE III Immune complex mediated (immune complex reaction):	IgM or IgG mediated,  IG’s bind with antigen forming an Ab/Ag complex.  Complex is deposited in tissues and the inflammatory response is initiated Examples:  autoimmune disease such as lupus and Rheumatoid arthritis
TYPE IV Cell mediated (delayed hypersensitivity):	T-lymphocyte mediated,  exposure to previously sensitized antigen, T-cells release lymphokines leading to cell lysis Examples: TB test, contact dermatitis

Mediators

Histamine à  bronchoconstriction, mucus secretion, vasodilatation, vascular permeability

Acetylcholine and kinins àsmooth muscle constriction in airways, vasodilation, Kinins cause of pain, directly

Leukotrienes and prostaglandins à produce the same effects on a prolonged scale, Leukotrienes initate inflammatory response

Cytokines and chemotactic factors à attract more WBCs to contribute to the response

Iatrogenic - adverse effects or complications caused by or resulting from medical treatment

Neutrophils – soldiers first primary phagocyte

Types of inflammation

Local manifestations of inflammation depends on the cause of the particular tissue involved

These manifestations can range from swelling in the formation of the exudates to excess formation or ulceration.

The acute inflammatory response involves production of exudates that vary in term of fluid/ plasma proteins and cellular debris

• Serous
• Hemorrhagic
• Fibronous
• Membranes or purulent exudates

Inflammatory exudates often composed of a combination of these types

Inflammation – capillary dilatation, fluid exudates formation, neutrophil migration

Suppuration – development of suppurative or purulent exudates containing degraded neutrophils and tissue debris

Abscess formation – walling off of the area of purulent (pus) exudates to form an abscess

Acute	Process typically lasts from a few minutes to a few days Usually resolves with little or no scarring Appears with both local and systemic manifestations – 8-10 days
Chronic	May last for weeks, months or years (usually has exacerbations and remission). Low grade persistent irritant produces fewer systemic symptoms. Most symptoms are localized in this case. Granuloma formation is usually associated with a foreign body. A dense membrane of connective tissue encapsulates the lesion. – more than 2 weeks

Chronic Inflammation – Granuloma formation Foreign body giant cell

The numerous nuclei are randomly arranged in the cytoplasm of the cell, a granulomatous lesion is a distinctive form of chronic inflammation, typically a small 1-2 mm lesion in which there are a massing of macrophage surrounded by lymphocytes

Takes place in about the same way mo matter what the stimulus

Area becomes congested causing redness and warmth

Cellular components - Granulocytes, monocytes

All of these leukocytes can carry out phagocytosis

Circulate in the blood stream and are stimulated by inflammation to an area of injury

Basophil – allergy

Monocyte biggest white cells

Response to inflammation

Acute inflammation is the immediate and early response to an introus agent. This response which serves to control and eliminate the source of injury occurs in 2 phases.

1 Vascular phase = leads to an increase in blood flow and changes in the small blood vessels of the microcirculation

2 Cellular phase = leads to immigration of leukocytes from the microcirculation and their activation to eliminate the injurious agent.

Vascular Phase

            Vasoconstriction

                Vasodilation

Cellular Phase

Margination:	The process by which leukocytes slow their movement and accumulate along the endothelial surface. – line up on vessel
Emigration:	Leukocytes change shape and squeeze through interendothelial junctions into the extravascular space. – move thru vessels walls to injury
Chemotaxis:	The process by which migrate in response to a chemical signal. – drawn to injured cells
Phagocytosis :	Elimination of the injurious agents by cell eating – eats up bacteria and cellular debris by digesting it

 Chemical mediators of inflammatory response

Mast cell degranulation – increase capillary permeability, histamine seratonin

Mast cell synthesis – prostaglandins increase cap. perm stimulate pain and produce fever, leukotrienes initiate inflammatory response

Plasma proteases – plasma proteases Fibrinogen stimulates clot formation to seal the injured site Kinins and Complements stimulate pain and increase capillary permeabality

Vascular stage process : acute inflammation= changes in the small blood vessels, begins with the momentary vasoconstriction followed rapidly by vasodilation. Vasodilation involves the arterioles and venules with a resultant increased capillary blood flow causing heat and redness. (Two of the cardinal signs of inflammation.)

This is accompanied by an increase in vascular permeability with outpouring of protein rich fluid, termed exudate into the extravascular spaces. The loss of proteins reduces the capillary osmotic pressure and increase the intrastitial osmotic pressure. This coupled with an increase in capillary pressure causes the marked outflow of fluid and its accumulation of fluid in the tissue spaces producing swelling, pain and impaired function.  (Other cardinal signs of inflammation)

As fluid moves out of the vessels stagnation of flow and clotting of blood occurs, this aids in localizing the spread of infectious microorganisms.

Cellular stage

Cells involved with inflammation stimulate other cells They do this by secreting -          Lymphokines -          Interferon -          Interleukins

Movement of white blood cells or leukocytes into the area of injury 2 types of leukocytes participate in the acute inflammatory response: granulocytes and monocytes. Rapid response also requires the release of chemical mediators from tissue cells such as mast cells and microphages that are prepositioned in the tissues. - white blood cells enter the injured tissue à destroying infective organisms à removing damaged cells àreleasing more inflammatory mediators to control further inflammation and healing. Leukocytes enter the injured area (mainly neutrophils) à leukocytes express adhesive proteins à attach to the blood vessel lining à squeeze between the cells à follow the inflammatory mediators to the injured area.

Physiologic response

Local	Systemic
Redness Edema Heat Pain	Fever Leukocytosis Malaise (fatigue)

Mechanisms of fever (pyerexia)
1 release of endogenous pyrogen from inflammatory cells
2 resetting of the hypothalamic temperature set point to a higher level (prodome)
3 generation of hypothalamus-mediated responses that raise body temperature (chill)
4 development of fever with elevation of body temperature to new thermostatic set point
5 production of temperature lowering responses (flush and defervescence) and return of body temperature to a lower level.

Interleukin 1-s induce fever

Take temperature and pulse in case high temperature