Chapter 6: Hypersensitivity Flashcards
What does it mean when an individual has been sensitized?
Individuals who have been previously exposed to an antigen are said to be sensitized
What is hypersensitivity?
Sometimes, repeat exposures to the same antigen trigger a pathologic reaction; such reactions
are described as hypersensitivity, implying an excessive response to antigen
MECHANISMS OF HYPERSENSITIVITY REACTIONS
There are several
important general features of hypersensitivity disorders.
- Both exogenous and endogenous antigens may elicit hypersensitivity reactions
- The development of hypersensitivity diseases (both allergic and autoimmune disorders)
is often associated with the inheritance of particular susceptibility genes - general principle that has emerged is that hypersensitivity reflects an imbalance
between the effector mechanisms of immune responses and the control mechanisms
that serve to normally limit such responses.
Give example of exogenous antigens?
Exogenous antigens include those in dust, pollens, foods, drugs, microbes, chemicals, and some blood products that are used in clinical practice.
The immune
responses against such exogenous antigens may take a variety of forms, ranging from
annoying but trivial discomforts, such as itching of the skin, to potentially fatal diseases,
such as bronchial asthma and anaphylaxis.
Injurious immune reactions may also be
evoked by endogenous tissue antigens.
Immune responses against self, or autologous,
antigens, cause the important group of autoimmune diseases.
The development of hypersensitivity diseases (both allergic and autoimmune disorders)
is often associated with the inheritance of particular susceptibility genes.
_______s have been implicated in different diseases; specific examples
will be described in the context of the diseases.
HLA genes
and many non-HLA gene
Hypersensitivity diseases can be classified on the ____________.
basis of the immunologic mechanism that
mediates the disease ( Table 6-2 )
This classification is of value in distinguishing the manner in which the immune response causes tissue injury and disease, and the accompanying
pathologic and clinical manifestations.
However, it is now increasingly recognized that multiple mechanisms may be operative in any one hypersensitivity disease. T
The main types of
hypersensitivity reactions are the following:
- In immediate hypersensitivity (type I hypersensitivity
- antibody-mediated disorders (type II hypersensitivity
- immune complex–mediated disorders (type III hypersensitivity) ,
- cell-mediated immune disorders (type IV hypersensitivity)
In immediate hypersensitivity (type I hypersensitivity) , the immune response is mediated by ___________
- TH2 cells,
- IgE antibodies,
- and mast cells
- and results in the release of mediators that act on vessels and smooth muscle and of pro-inflammatory cytokines that recruit inflammatory cells.
Define the antibody-mediated disorders (type II hypersensitivity)
secreted IgG and IgM
antibodies participate directly in injury to cells by promoting their phagocytosis or lysis
and in injury to tissues by inducing inflammation. Antibodies may also interfere with
cellular functions and cause disease without tissue injury.
What is type III hypersensitivity?
In immune complex–mediated disorders (type III hypersensitivity) ,
- *IgG and IgM**
- *antibodies bind antigens usually in the circulation,** and the antigen-antibody complexes
- *deposit in tissues and induce inflammation.**
The leukocytes that are recruited
(neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes
and generation of toxic free radicals.
What is type IV hypersensitivity?
In cell-mediated immune disorders (type IV hypersensitivity) , sensitized T lymphocytes
(TH1 and TH17 cells and CTLs) are the cause of the cellular and tissue injury.
TH2 cells
induce lesions that are part of immediate hypersensitivity reactions, and are not
considered a form of type IV hypersensitivity.
T or F
True
Immediate (typeI)
hypersensitivity
Prototypic
Disorder
Anaphylaxis;
allergies;
bronchial
asthma (atopic forms)
Immediate (typeI)
hypersensitivity
Immune Mechanisms
Production of IgE antibody ➙
immediate release of vasoactive
amines and other mediators from
mast cells; later recruitment of
inflammatory cells
Immediate (typeI)
hypersensitivity
Pathologic Lesions
- Vascular dilation,
- edema,
- smooth muscle contraction,
- mucus production,
- tissue injury,
- inflammation
Antibodymediated
(type II)
hypersensitivity
Prototypic
Disorder
Autoimmune hemolytic anemia;
Goodpasture syndrome
Antibodymediated
(type II)
hypersensitivity
Immune Mechanisms
Production of IgG, IgM ➙ binds to
antigen on target cell or tissue ➙
phagocytosis or lysis of target cell
by activated complement or Fc
receptors; recruitment of
leukocytes
Antibodymediated
(type II)
hypersensitivity
Pathologic Lesions
Phagocytosis and
lysis of cells;
inflammation;
in some
diseases, functional
derangements
without cell or tissue
injury
Immune
complex–mediated (type
III) hypersensitivity
Prototypic
Disorder
Systemic lupus erythematosus;
some forms of
glomer-ulonephritis;
serum sickness;
Arthus reaction
Immune
complex–mediated (type
III) hypersensitivity
Immune Mechanisms
Deposition of antigen-antibody
complexes ➙ complement
activation ➙ recruitment of
leukocytes by complement
products and Fc receptors ➙
release of enzymes and other toxic
molecules
Immune
complex–mediated (type
III) hypersensitivity
Pathologic Lesions
Inflammation,
necrotizing vasculitis
(fibrinoid necrosis)
Cell-mediated
(type IV)
hypersensitivity
Prototypic
Disorder
Contact dermatitis;
multiple sclerosis;
type I diabetes;
rheumatoid arthritis;
inflammatory bowel disease;
tuberculosis
Cell-mediated
(type IV)
hypersensitivity
Immune Mechanisms
Activated T lymphocytes ➙
(i) release of cytokines
➙ inflammation and
macrophage
activation;
(ii) T cell–mediated
cytotoxicity
Cell-mediated
(type IV)
hypersensitivity
Pathologic Lesions
Perivascular cellular
infiltrates;
edema;
granuloma formation;
cell destruction
Define Type 1 Hypersensitivity
Immediate, or type I, hypersensitivity is a rapid immunologic reaction occurring within minutes
after the combination of an antigen with antibody bound to mast cells in individuals previously
sensitized to the antigen. [26]
These reactions are often called allergy, and the antigens that
elicit them are allergens.
Immediate hypersensitivity may occur as a what kind of reaction?
systemic disorder or as a
local reaction
What happens in the systemic reaction of type 1 hypersensitivity?
The systemic reaction usually follows injection of an antigen into a sensitized individual.
Sometimes, within minutes the patient goes into a state of shock, which may be fatal
What happens in the local phase of Type 1 hypersensitivity?
Local reactions are diverse and vary depending on the portal of entry of the allergen.
They may
- *take the form of localized cutaneous swellings (skin allergy, hives),** nasal and conjunctival discharge (allergic rhinitis and conjunctivitis), hay fever, bronchial asthma, or allergic
- *gastroenteritis (food allergy).**
Many local type I hypersensitivity reactions have two well-defined
phases ( Fig. 6-13 ).
- immediate or initial reaction
- late-phase reaction
What happens in the first phase of Type 1 hypersensitivity local phase reaction?
The immediate or initial reaction is characterized by vasodilation, vascular
leakage, and depending on the location, smooth muscle spasm or glandular secretions.
These
changes usually become evident within 5 to 30 minutes after exposure to an allergen and tend
to subside in 60 minutes.
In many instances (e.g., allergic rhinitis and bronchial asthma),
What happens in the second phase of Type 1 hypersensitivity local phase reaction?
late-phase reaction sets in 2 to 24 hours later without additional exposure to antigen
and may last for several days.
This late-phase reaction is characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue
destruction, typically in the form of mucosal epithelial cell damage
Immediate hypersensitivity.
A, Kinetics of the immediate and late-phase
reactions. .
The immediate vascular and smooth muscle reaction to allergen develops within
minutes after challenge (allergen exposure in a previously sensitized individual), and the
late-phase reaction develops 2 to 24 hours later
Immediate hypersensitivity.
Morphology:
The immediate reaction
(B) is characterized by vasodilation, congestion, and edema, and the late-phase reaction
(C) is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells.
Most immediate hypersensitivity reactions are mediated by ____________
IgE antibody–dependent activation
of mast cells and other leukocytes
WHat cells are central to the development of immediate hypersensitivity?
mast cells are central to the
development of immediate hypersensitivity
From where do mast cells are derived?
Mast cells are bone marrow–derived cells that are widely distributed in the
tissues.
Where are mast cells most abundant?
They are abundant near blood vessels and nerves and in subepithelial tissues, which
explains why local immediate hypersensitivity reactions often occur at these sites.
What are the contents of Mast cells?
Mast cells
have cytoplasmic membrane-bound granules that contain a variety of biologically active
mediators.
The granules also contain acidic proteoglycans that bind basic dyes such as
toluidine blue
What activates mast cells ?
mast cells (and basophils) are activated by the **cross-linking** of **high-affinity IgE Fc receptors**;
in addition, mast cells may also be triggered by several other stimuli, such as complement components C5a and C3a (called anaphylatoxins because they
elicit reactions that mimic anaphylaxis), both of which act by binding to receptors on the mast
cell membrane.
Other mast cell secretagogues include :
some chemokines (e.g., IL-8), drugs
such as codeine and morphine, adenosine, mellitin (present in bee venom), and physical stimuli
(e.g., heat, cold, sunlight)
In what aspects do Basophils have similarities to mast cells?
Basophils are similar to mast cells in many respects, including the
- presence of cell surface IgE Fc receptors
- as well as cytoplasmic granules.
What is the difference of mast cell to basophils?
In contrast to mast cells, however, basophils are not normally present in tissues but rather circulate in the blood in extremely small numbers.
Most allergic reactions occur in tissues, and the role of basophils in these reactions is not as well established as that of mast cells.)
Similar to other granulocytes,
basophils can be recruited to inflammatory sites.
Hypersensitivity & Autoimmune Disorders
374
FIGURE 6-14 Sequence of events in immediate (type I) hypersensitivity.
Immediate
hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates
TH2 responses and IgE production in genetically susceptible individuals. ——–>
- *IgE binds to Fc**
- *receptors (FcεRI) on mast cells,** and subsequent exposure to the allergen activates the mast
- *cells to secrete the mediators that are responsible for the pathologic manifestations of**
- *immediate hypersensitivity.** See text for abbreviations.
FIGURE 6-14 Sequence of events in immediate (type I) hypersensitivity.
Exposure to allergen –> Activation of TH2 cells and IgE class switching in B cells –> Production of IgE –>
Binding of IgE to FcRI on mast cells –> Repeat exposure to allergen –> Repeat exposure to allergen –> Activation of mast cell; release of mediators–> Mediators:
Mediators:
- Vasoactive amines, lipid mediators:
- Immediate hypersensitivity reaction ( min after repeat exposure to allergen)
- Cytokines:
- Late phase reaction ( 2- 24 hours after repeat exposure to allergen)
What plays a central role in the initiation and propagation of immediate hypersensitivity
reactions by stimulating IgE production and promoting inflammation
TH2 cells
What are the steps in the generation of TH2 cells
- presentation of the antigen to naive CD4+ helper T cells, probably by dendritic cells that capture the antigen from its site of entry
- In response to antigen and other stimuli, including cytokines such as IL-4 produced at the local site, the T cells differentiate into TH2 cells.
3, The newly minted TH2 cells produce a number of cytokines upon subsequent encounter with the antigen; as we mentioned earlier, the signature cytokines of this subset are IL-4, IL-5, and IL-13.
4. In addition, TH2 cells (as well as mast cells and epithelial cells) produce chemokines
that attract more TH2 cells, as well as other leukocytes, to the reaction site.
What are the signature cytokines of this
TH2 subset are_____________
IL-4, IL-5, and IL-13.
April 5 2013
Whta does IL-4 do?
IL-4 acts on B cells to stimulate class switching to IgE, and promotes the development of additional TH2 cells.
Whta does IL-5 do?
IL-5 is involved in the development and activation of eosinophils, which, as we discuss subsequently, are important effectors of type I hypersensitivity.
What does IL-13 do?
IL-13 enhances IgE production and acts on epithelial cells to stimulate mucus
secretion.
Mast cells and basophils express a high-affinity receptor, called _________.
FcεRI
What is FcεRI?
t is specific for the Fc portion of IgE, and therefore avidly binds IgE antibodies
When a mast cell, armed with IgE
antibodies, is exposed to the specific allergen, a series of reactions takes place, leading
eventually to the release of an arsenal of powerful mediators responsible for the clinical
expression of immediate hypersensitivity reactions.
What are the steps?
In the first step in this sequence, antigen
(allergen) binds to the IgE antibodies previously attached to the mast cells.
Multivalent antigens
bind to and cross-link adjacent IgE antibodies and the underlying IgE Fc receptors.
The
bridging of the Fcε receptors activates signal transduction pathways from the cytoplasmic
portion of the receptors.
These signals lead to mast cell degranulation with the discharge of preformed (primary) mediators that are stored in the granules, and de novo synthesis and
release of secondary mediators, including lipid products and cytokines ( Fig. 6-15 ).
These
mediators are responsible for the initial, sometimes explosive, symptoms of immediate
hypersensitivity, and they also set into motion the events that lead to the late-phase
reaction.
FIGURE 6-15 Mast cell mediators. Upon activation, mast cells release various classes of
mediators that are responsible for the immediate and late-phase reactions.
- ECF, eosinophil chemotactic factor;
- NCF, neutrophil chemotactic factor (neither of these is biochemically defined);
- PAF, platelet-activating factor.
Preformed Mediators.
Mediators contained within mast cell granules are the first to be released, and can be divided
into three categories:
- Vasoactive amines
- Enzymes
- Proteoglycans.
What is the most important mast cell-derived amine?
Histamine
causes intense smooth muscle contraction, increased vascular permeability, and
increased mucus secretion by nasal, bronchial, and gastric glands.
How do enzymes as act as preformed mediators?
These are contained in the granule matrix and include neutral proteases (chymase, tryptase) and several acid hydrolases.
The enzymes cause tissue damage
- *and lead to the generation of kinins and activated components of complement (e.g.,**
- *C3a) by acting on their precursor proteins**.
Give an example of preformed Proteoglycans.
These include heparin, a well-known anticoagulant, and chondroitin
sulfate. The proteoglycans serve to package and store the amines in the granules.
The major lipid mediators are synthesized by sequential reactions in the mast cell membranes
that lead to activation of phospholipase A2, an enzyme that acts on membrane phospholipids to
yield ___________
arachidonic acid.
This is the parent compound from which leukotrienes and prostaglandins are derived by the 5-lipoxygenase and cyclooxygenase pathways
Lipid Mediators.
- Leukotrienes.
- Prostaglandin D2
- Platelet-activating factor (PAF)
What are are the most potent vasoactive and
spasmogenic agents known.
Leukotrienes C4 and D4 are the most potent vasoactive and spasmogenic agents known.
On a molar basis, they are several thousand times more
- *active than histamine** in increasing vascular permeability and causing bronchial smooth
- *muscle contraction**
What does Leukotrine B4 does?
Leukotriene B4 is highly chemotactic for neutrophils, eosinophils, and monocytes.
This is the most abundant mediator produced in mast cells by the
cyclooxygenase pathway. It causes intense bronchospasm as well as increased mucus
secretion
Prostaglandin D2.
Describe Platelet-activating factor (PAF) .
PAF ( Chapter 2 ) is produced by some mast cell
populations. It causes platelet aggregation, release of histamine, bronchospasm,
increased vascular permeability, and vasodilation. In addition, it is chemotactic for
neutrophils and eosinophils, and at high concentrations it activates the inflammatory
cells, causing them to degranulate. Although the production of PAF is also triggered by
the activation of phospholipase A2, it is not a product of arachidonic acid metabolism.
_________- are sources of many cytokines, which may play an important role at several stages of
immediate hypersensitivity reactions
Mast cells
The cytokines include:
___________-, which
promote leukocyte recruitment (typical of the late-phase reaction);
TNF, IL-1, and chemokines
What IL , which amplifies the TH2
response; and numerous others.
IL-4
What are your addional sources of cytokines?
The inflammatory cells that are recruited by mast cell–derived
TNF and chemokines are additional sources of cytokines and of histamine-releasing factors
that cause further mast cell degranulation.
The development of immediate hypersensitivity reactions is dependent on the coordinated
actions of a variety of _____________
chemotactic, vasoactive, and spasmogenic compounds
Some, such as____________- are released rapidly from sensitized mast cells and
are responsible for the intense immediate reactions characterized by edema, mucus secretion,
and smooth muscle spasm;
histamine and leukotrienes,
others, exemplified by cytokines, set the stage for the late-phase
response by recruiting additional leukocytes.
Not only do these inflammatory cells release
additional waves of mediators (including cytokines), but they also cause epithelial cell damage.
Epithelial cells themselves are not passive bystanders in this reaction; they can also produce
soluble mediators, such as chemokines.
T or F
T
Summary of the Action of Mast Cell Mediators in Immediate (Type I)
Hypersensitivity
Mediators
Vasodilation, increased vascular
permeability
- Histamine
- PAF
- Leukotrienes C4, D4, E4
- Neutral proteases that activate complement and kinins
- Prostaglandin D2
Summary of the Action of Mast Cell Mediators in Immediate (Type I)
Hypersensitivity
Mediators for Smooth muscle spasm
- Leukotrienes C4, D4, E4
- Histamine
- Prostaglandins
- PAF
TABLE 6-3 – Summary of the Action of Mast Cell Mediators in Immediate (Type I)
Hypersensitivity
Mediators for Cellular infiltration
- Cytokines (e.g., chemokines, TNF)
- Leukotriene B4
- Eosinophil and neutrophil chemotactic factors (not defined
- biochemically)
Among the cells that are recruited in the late-phase reaction,_______ are particularly
important. [30]
eosinophils
They are recruited to sites of immediate hypersensitivity reactions by chemokines, such as eotaxin and others, that may be produced by epithelial cells, TH2 cells,
and mast cells.
The survival of eosinophils in tissues is favored by _____________
IL-3, IL-5, and granulocytemacrophage
colony-stimulating factor (GM-CSF), and IL-5
What is the most potent eosinophilactivating
cytokine known
IL-5
