Tuesday, September 7, 2010

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
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

Monday, September 6, 2010

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