10.1.2 Hypersensitivity diseases
10.1.2.1 Causes of hypersensitivity
Hypersensitivity is caused by uncontrolled or excessive responses against foreign antigens or self- antigen(autoimmune responses).
  • uncontrolled or excessive responses against foreign antigens.The foreign antigens include microbes and noninfectious environmental antigens.
    • immediate hypersensitivity is caused by the uncontrolled and excessive responses to foreign environmental antigens.It is mediated by IgE and leading to activation of mast cells to release a variety of mediators. These mediators collectively cause increased vascular permeability, vasodilation, bronchial and visceral smooth muscle contraction and local inflammaton.
    • DTH reaction is caused by the uncontrolled and excessive responses to the microbe, especailly intracellular microbe.
  • autoimmune response(failure of self-tolerance and response to self- angtigens)
10.1.2.2 Types of hypersensitivity
Four types of hypersensitivty responses areclassified by the responding mechanisms, but not the responding antigens. One type of hypersensitivity could either be responding to the foreign antigens or autoimmune response or both.
  • Type I Hypersensitivity- IgE mediated
  • Type II Hypersensitivity- Antibody mediated
  • Type III Hypersensitivity- Immune complex
  • Type IV Hypersensitivity- Cell mediated
graphic
Type I: IgE antibody mediated Immediate Hypersensitivity (uncontrolled or excessive responses against foreign antigens)
A type I hypersensitive reaction is induced by certain types of antigens referred to as allergens, and has all the hallmarks of a normal humoral response.What distinguishes a type I hypersensitive response from a normal humoral response is that the plasma cells secrete IgE. This class of antibody binds with high affinity to Fc receptors on the surface of tissue mast cells and blood basophils. Mast cells and basophils coated by IgE are said to be sensitized. A later exposure to the same allergen cross-links the membrane-bound IgE on sensitized mast cells and basophils, causing degranulation of these cells to rapidly release a variety of mediators. These mediators collectively cause increased vascular permeability, vasodilation, bronchial and visceral smooth muscle contraction and local inflammation. This effect can be either systemic or localized, depending on the extent of mediator release.
graphic
Components of type I hypersensitivity
Allergens
  • The majority of humans mount significant IgE responses only as a defense against parasitic infections. After an individual has been exposed to a parasite, serum IgE levels increase and remain high until the parasite is successfully cleared from the body. Some persons, however, may have an abnormality called atopy, a hereditary predisposition to the development of immediate hypersensitivity reactions against common environmental antigens.
  • The term allergen refers specifically to nonparasitic antigens capable of stimulating type I hypersensitive responses in allergic individuals.Most allergic IgE responses occur on mucous membrane surfaces in response to allergens that enter the body by either inhalation or ingestion.
graphic
REAGINIC ANTIBODY (IgE)
Serum IgE levels in normal individuals fall within the range of 0.1–0.4 ug/ml; even the most severely allergic individuals rarely have IgE levels greater than 1 ug/ml.
Mast cells, basophils and eosinophile
  • Basophils are granulocytes that circulate in the blood of most vertebrates;in humans, they account for 0.5%–1.0% of the circulatingwhite blood cells.
  • Mast-cell precursors are formed in the bone marrow duringhematopoiesis and are carried to virtually all vascularizedperipheral tissues, where they differentiate into mature cells.
graphicgraphic
graphic
graphic
IgE-BINDING Fc RECEPTORS
Two classes of Fc receptors:
graphic
Sequence of events
graphic
Production of IgE
The nature of allegens:
  • repeated exposure to antigens without stimulation of innate responses - or more likely the stimulation of a different set of innate responses
  • chemical nature of allergens -
    • low molecular weight
    • high glycosylation
    • high solubility in body fluids
    • enzymes - cysteine protease in dust mite
  • history of exposure
Activation of Th2 cells:
Activation of B cells and switching to IgE:
graphic
Binding of IgE to IgE Fc receptor on Mast cells and Basophiles
IgE antibodies bind to a high-affinity Fc receptor specific for e heavey chains, called FceRI, that is expressed on mast cells, basophils and eosinophils.
  • The affinity for IgE is very high.
  • expression is upregulated by IgE.
  • the structure and function of Fc receptor.
graphic
Activation of effector cells
  • IgE Crosslinkage Initiates Degranulation.The binding of IgE to FcRI apparently has no effect on a target cell. It is only after allergen crosslinks the fixed IgE-receptor complex that degranulation proceeds.
  • Experiments have revealed that the essential step in degranulation is crosslinkage of two or more FcRI molecules— with or without bound IgE.
graphic
Activation of Mast cells
Activation of Mast cells:
graphic
  • cross linking of FceRI receptors:
  • in atopic individuals: a large proportion of the IgE bound to mast cells is specific for one antigen. Crosslink to antigen is sufficient for trigger mast cell activation
  • in nonatopic individuals, IgE is specific for many different antigens
  • mast cells can be directly activated by a variety of biologic substances independent of allergen-  mediated cros- linking of FceRI, including polybasic compounds, peptides, chemokines and complement-derived anaphylatoxins.
graphic
Mediators produced by effector cells
graphic
graphic
Regulation of mast cell degranuation
  • FceRI pathway is regulated by the inhibitory Fc receptor FcgRIIb
  • Intracellular Events Also Regulate Mast-Cell Degranulation
graphic
Biological effect
  • Secretion of the preformed granule contents
  • synthesis and secretion of lipid mediators
  • synthesis and secretion of cytokines
graphic
Two effector phases of type I hypersensivity reactions
  • Type I hypersensitivity has two phases:
  • immediate phase: The early response occurs within minutes of allergen exposure and primarily involves histamine, leukotrienes (LTC4), and prostaglandin (PGD2). The effects of these mediators lead to bronchoconstriction, vasodilation, and some buildup of mucus.
  • late phase: The late response occurs hours later and involves additional mediators, including IL-4, IL-5, IL- 16,TNF-, eosinophil chemotactic factor (ECF), and platelet- activating factor (PAF). The overall effects of these mediators is to increase endothelial cell adhesion as well as to recruit inflammatory cells, including eosinophils and neutrophils, into the bronchial tissue.
graphic
  • Example of athma: The early and late phases of inflammatory responses in asthma
graphic
Early phase reaction(immediate)
Immediate: vascular and smooth muscle response to mediators
graphic
  • Wheal and flare
    • vasodilation - reddening
    • swelling – leakage
  • IgE and mast cell involvement:Mast cells at site have discharged
  • Can be mimicked with various cross-linkers of IgE or by C5a,etc.
Late phase reactions(2-4hours)
As a type I hypersensitive reaction begins to subside, mediators released during the course of the reaction often induce localized inflammation called the late-phase reaction. Distinct from the late response seen in asthma, the late-phase reaction begins to develop 4–6 h after the initial type I reaction and persists for 1–2 days. The reaction is characterized by infiltration of neutrophils, eosinophils, macrophages, lymphocytes, and basophils. The localized late-phase response also may be mediated partly by cytokines released from mast cells.
  • Late: leukocyte recruitment and inflammation
    • like the DTH response except Th2 driven
    • delayed 2-4 hours (max by 24 hours)
    • accumulation of inflammatory leukocytes (neutrophils, eosinophils, basophils and Th2 cells)
      • this is a response to cytokines - esp. TNF - to activate endothelium - adhesion molecules E-selectin and ICAM- 1
      • Th2-dominated infiltration is likely due to selective chemokine receptor expression
      • Th2 chemokine production also recruits and activated eosinophils (eotaxin); neutrophils but not many macrophages present
    • Can have chronic late phase response without obvious immediate phase (asthma and eczema – Th2 driven with minimal contribution of mast cells)
Detect Type I Hypersensitivity Reactions
graphic
Type I hypersensitivity diseases and therapies
  • Type I hypersensitivity has some of the protection roles:
    • eradication of parasites and response to bacteria
    • ADCC of helminths
    • expulsion of worms from the gut
  • Type I hypersensitivity caused diseases:
graphic
Systemic/loclized anaphylaxis
SYSTEMIC ANAPHYLAXIS
Systemic anaphylaxis:
  • Systemic immeidate hypersensitivity reaction characterized by edema in many tissues and fall in blood pressure, secondary to vasodilation.Systemic anaphylaxis is a shock-like and often fatal state whose onset occurs within minutes of a type I hypersensitive reaction.
  • Reason: the allergen activates mast cells in many tissures, resulting in the release of mediators that gain access to vascular beds throughout the body.The leakage of plasma caused by the released mediators can lead to a fall in blood pressure or shock, called anaphylactic shock,which is often fatal
LOCALIZED ANAPHYLAXIS (ATOPY)
In localized anaphylaxis, the reaction is limited to a specific target tissue or organ, often involving epithelial surfaces at the site of allergen entry.The tendency to manifest localized anaphylactic reactions is inherited and is called atopy.
ALLERGIC RHINITIS
Allergic rhinitis, commonly known as hay fever. This results from the reaction of airborne allergens with sensitized mast cells in the conjunctivae and nasal mucosa to induce the release of pharmacologically active mediators from mast cells; these mediators then cause localized vasodilation and increased capillary permeability. The symptoms include watery exudation of the conjunctivae, nasal mucosa, and upper respiratory tract, as well as sneezing and coughing.
Bronchial Asthma
Bronchial Asthma:
  • reason:
    • repeated immediate hypersensitivity and late phase reactions in the lung
    • alternative mechanisms of mast cell degranulation
  • Therapy: two major targets
    • prevention and reversal of inflammation:
      • two major class: corticosteroids and sodium cromolyn
      • newer anti-inflammatory therapies: leukotriene receptor antagonists
      • note: antihistamine is not useful in treatment of asthma, because histamine has little role in airway constriction. Asprin is also not useful, because it increase LTC4 mediators by decreasing PDG2.
    • relaxation of airway smooth muscle: by elevating intracellular cAMP
      • epinephrine
      • inhibitors of the phophodiesterase enzyme
graphic
Allergies of skin, upper respiratory and gut
Allergies of skin, upper respiratory and gut
  • Allergic rhinitis (hay fever):
    • immediate hypersensitivity to common allegens - mucosa edema. mucus secretion, eosinophil influx, coughing, etc.
    • treatment: anti-histamines
  • food allergies
    • in gut - mucus secretion - can be followed by hives - easy to become systemic
    • most common allergens are in shellfish and peanuts
  • allergen in the skin
    • urticaria - wheal and flare is histamine mediated - binding to endothelial cells - anti- histamine treated
    • eczema - chronic - treated with corticosteroids
Therapies
immunotherapy
Immunotherapy with repeated injections of increasing doses of allergens (hyposensitization) has been known for some time to reduce the severity of type I reactions, or even eliminate them completely, in a significant number of individuals suffering from allergic rhinitis. Such repeated introduction of allergen by subcutaneous injections appears to cause a shift toward IgG production or to induce T-cell– mediated suppression (possibly by a shift to the TH1 subset and IFN-g production) that turns off the IgE response.In this situation, the IgG antibody is referred to as blocking antibody because it competes for the allergen, binds to it, and forms a complex that can be removed by phagocytosis; as a result, the allergen is not available to crosslink the fixed IgE on the mast-cell membranes, and allergic symptoms decrease.
therapeutic drugs
graphic
Pathogenesis of type I hypersensitivity
Genetic susceptibility
graphic
Hygene hypothesis
In medicine, the hygiene hypothesis says that an excessively hygienic environment in early childhood may predispose some people towards asthma, allergies, and other autoimmune diseases.
graphic
Type II: IgG antibody mediated Cytotoxic Hypersensitivity (immune antibody response against self-antigen)
Type II hypersensitive reactions involve antibody-mediated destruction of cells. Antibody can activate the complement system, creating pores in the membrane of a foreign cell, or it can mediate cell destruction by antibodydependent cell-mediated cytotoxicity (ADCC). In this process,cytotoxic cells with Fc receptors bind to the Fc region of antibodies on target cells and promote killing of the cells.
Blood Transfusion Reactions
If a type A individual is transfused with blood containing type B cells, a transfusion reaction occurs in which the anti-B isohemagglutinins bind to the B blood cells and mediate their destruction by means of complement-mediated lysis. Antibodies to the A, B, and O antigens, called isohemagglutinins, are usually of the IgM class.
graphic
Hemolytic Disease of the Newborn
Hemolytic disease of the newborn develops when maternal IgG antibodies specific for fetal blood- group antigens cross the placenta and destroy fetal red blood cells. The consequences of such transfer can be minor, serious, or lethal. Severe hemolytic disease of the newborn, called erythroblastosis fetalis, most commonly develops when an Rh+ fetus expresses an Rh antigen on its blood cells that the Rh mother does not express.
graphic
Drug-Induced Hemolytic Anemia
Certain antibiotics (e.g., penicillin, cephalosporin, and streptomycin) can adsorb nonspecifically to proteins on RBC membranes, forming a complex similar to a hapten-carrier complex. In some patients, such drug-protein complexes induce formation of antibodies, which then bind to the adsorbed drug on red blood cells, inducing complementmediated lysis and thus progressive anemia.When the drug is withdrawn, the hemolytic anemia disappears. Penicillin is notable in that it can induce all four types of hypersensitivity with various clinical manifestations.
Type III: Antibody-antigen complex mediated Hypersensitivity (self antigens or foreign antigens with bound antibody)
The reaction of antibody with antigen generates immune complexes. Generally this complexing of antigen with antibody facilitates the clearance of antigen by phagocytic cells. In some cases, however, large amounts of immune complexes can lead to tissue-damaging type III hypersensitive reactions.
Effector mechanism:
  • Type III hypersensitive reactions develop when immune complexes activate the complement system’s array of immune effector molecules.The C3a, C4a, and C5a complement split products are anaphylatoxins that cause localized mast-cell degranulation and consequent increase in local vascular permeability. C3a, C5a, and C5b67 are also chemotactic factors for neutrophils, which can accumulate in large numbers at the site of immune-complex deposition.
  • Much of the tissue damage in type III reactions stems from release of lytic enzymes by neutrophils as they attempt to phagocytose immune complexes. The C3b complement component acts as an opsonin, coating immune complexes. A neutrophil binds to a C3b- coated immune complex by means of the type I complement receptor, which is specific for C3b. Because the complex is deposited on the basementmembrane surface, phagocytosis is impeded, so that lytic enzymes are released during the unsuccessful attempts of the neutrophil to ingest the adhering immune complex. Further activation of the membrane-attack mechanism of the complement system can also contribute to the destruction of tissue.
graphic
Type IV: T cell mediated Hypersensitivity(Delayed type hypersensitivity, DTH): autoimmune response or response to foreign antigens
  • Th1 mediated delayed type hypersensitivity(DTH) : When some subpopulations of activated TH cells encounter certain types of antigens, they secrete cytokines that induce a localized inflammatory reaction called delayed-type hypersensitivity (DTH). The reaction is characterized by large influxes of nonspecific inflammatory cells, in particular,macrophages.
  • reactions are delayed by one or more days due to migration of macrophage and T cells to site of foreign antigen
  • reactions are frequently displayed on the skin,itching, redness,swelling,pain.
  • anaphylactic shock may occur
Effector functions
The response plays an important role in defense against intracellular pathogens and contact antigens.The term hypersensitivity is somewhat misleading, for it suggests that a DTH response is always detrimental. Although in some cases a DTH response does cause extensive tissue damage and is in itself pathologic, in many cases tissue damage is limited, and the response plays an important role in defense against intracellular pathogens and contact antigens.
graphic
Phases of reaction
Involve reaction by memory T cells
  • Sensitizaiton phase: The development of the DTH response begins with an initial sensitization phase of 1–2 weeks after primary contact with an antigen.
  • Late effector phase: A subsequent exposure to the antigen induces the effector phase of the DTH response.In the effector phase, TH1 cells secrete a variety of cytokines that recruit and activate macrophages and other nonspecific inflammatory cells. A DTH response normally does not become apparent until an average of 24 h after the second contact with the antigen; the response generally peaks 48–72 h after second contact.
graphic
Detection
The presence of a DTH reaction can be measured experimentally by injecting antigen intradermally into an animal and observing whether a characteristic skin lesion develops at the injection site. A positive skin-test reaction indicates that the individual has a population of sensitized TH1 cells  specific for the test antigen. For example, to determine whether an individual has been exposed to M. tuberculosis, PPD, a protein derived from the cell wall of this mycobacterium, is injected intradermally. Development of a red, slightly swollen, firm lesion at the site between 48 and 72 h later indicates previous exposure.
Diseases
Many contact-dermatitis reactions, including the responses to formaldehyde, trinitrophenol, nickel, turpentine, and active agents in various cosmetics and hair dyes, poison oak, and poison ivy, are mediated by TH1 cells.Most of these substances are small molecules that can complex with skin proteins.This complex is internalized by antigen-presenting cells in the skin (e.g., Langerhans cells), then processed and presented together with class II MHC molecules, causing activation of sensitized TH1 cells.