Chapter 6: Hypersensitivity Flashcards
1
Q
What does it mean when an individual has been sensitized?
A
Individuals who have been previously exposed to an antigen are said to be sensitized
2
Q
What is hypersensitivity?
A
Sometimes, repeat exposures to the same antigen trigger a pathologic reaction; such reactions
are described as hypersensitivity, implying an excessive response to antigen
3
Q
MECHANISMS OF HYPERSENSITIVITY REACTIONS
There are several
important general features of hypersensitivity disorders.
A
- 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.
4
Q
Give example of exogenous antigens?
A
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.
5
Q
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.
A
HLA genes
and many non-HLA gene
6
Q
Hypersensitivity diseases can be classified on the ____________.
A
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
7
Q
The main types of
hypersensitivity reactions are the following:
A
- 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)
8
Q
In immediate hypersensitivity (type I hypersensitivity) , the immune response is mediated by ___________
A
- 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.
9
Q
Define the antibody-mediated disorders (type II hypersensitivity)
A
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.
10
Q
What is type III hypersensitivity?
A
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.
11
Q
What is type IV hypersensitivity?
A
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.
12
Q
TH2 cells
induce lesions that are part of immediate hypersensitivity reactions, and are not
considered a form of type IV hypersensitivity.
T or F
A
True
13
Q
Immediate (typeI)
hypersensitivity
Prototypic
Disorder
A
Anaphylaxis;
allergies;
bronchial
asthma (atopic forms)
14
Q
Immediate (typeI)
hypersensitivity
Immune Mechanisms
A
Production of IgE antibody ➙
immediate release of vasoactive
amines and other mediators from
mast cells; later recruitment of
inflammatory cells
15
Q
Immediate (typeI)
hypersensitivity
Pathologic Lesions
A
- Vascular dilation,
- edema,
- smooth muscle contraction,
- mucus production,
- tissue injury,
- inflammation
16
Q
Antibodymediated
(type II)
hypersensitivity
Prototypic
Disorder
A
Autoimmune hemolytic anemia;
Goodpasture syndrome
17
Q
Antibodymediated
(type II)
hypersensitivity
Immune Mechanisms
A
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
18
Q
Antibodymediated
(type II)
hypersensitivity
Pathologic Lesions
A
Phagocytosis and
lysis of cells;
inflammation;
in some
diseases, functional
derangements
without cell or tissue
injury
19
Q
Immune
complex–mediated (type
III) hypersensitivity
Prototypic
Disorder
A
Systemic lupus erythematosus;
some forms of
glomer-ulonephritis;
serum sickness;
Arthus reaction
20
Q
Immune
complex–mediated (type
III) hypersensitivity
Immune Mechanisms
A
Deposition of antigen-antibody
complexes ➙ complement
activation ➙ recruitment of
leukocytes by complement
products and Fc receptors ➙
release of enzymes and other toxic
molecules
21
Q
Immune
complex–mediated (type
III) hypersensitivity
Pathologic Lesions
A
Inflammation,
necrotizing vasculitis
(fibrinoid necrosis)
22
Q
Cell-mediated
(type IV)
hypersensitivity
Prototypic
Disorder
A
Contact dermatitis;
multiple sclerosis;
type I diabetes;
rheumatoid arthritis;
inflammatory bowel disease;
tuberculosis
23
Q
Cell-mediated
(type IV)
hypersensitivity
Immune Mechanisms
A
Activated T lymphocytes ➙
(i) release of cytokines
➙ inflammation and
macrophage
activation;
(ii) T cell–mediated
cytotoxicity
24
Q
Cell-mediated
(type IV)
hypersensitivity
Pathologic Lesions
A
Perivascular cellular
infiltrates;
edema;
granuloma formation;
cell destruction
25
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.
26
Immediate hypersensitivity may occur as a what kind of reaction?
systemic disorder or as a
local reaction
27
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
28
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).**
29
Many local type I hypersensitivity reactions have two well-defined
phases ( Fig. 6-13 ).
1. immediate or initial reaction
2. late-phase reaction
30
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 minute**s.
In many instances (e.g., allergic rhinitis and bronchial asthma),
31
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
32
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
33
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.
34
Most immediate hypersensitivity reactions are mediated by \_\_\_\_\_\_\_\_\_\_\_\_
IgE antibody–dependent activation
of mast cells and other leukocytes
35
WHat cells are central to the development of immediate hypersensitivity?
mast cells are central to the
development of immediate hypersensitivity
36
From where do mast cells are derived?
Mast cells are **bone marrow–derived** cells that are widely distributed in the
tissues.
37
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.**
38
What are the contents of Mast cells?
Mast cells
have **cytoplasmic membrane-bound granule**s that **contain a variety of biologically active**
**mediators**.
The granules also contain **acidic proteoglycans** that bind basic dyes such as
toluidine blue
39
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.
40
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)**
41
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.
42
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
43
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.
44
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)
45
What plays a central role in the i**nitiation and propagation** of **immediate hypersensitivity**
reactions by stimulating IgE production and promoting inflammation
TH2 cells
46
What are the steps in the generation of **TH2 cells**
1. presentation of the antigen to naive CD4+ helper T cells, probably by dendritic cells that capture the antigen from its site of entry
2. 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.
47
What are the signature cytokines of this
TH2 subset are\_\_\_\_\_\_\_\_\_\_\_\_\_
IL-4, IL-5, and IL-13.
April 5 2013
48
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.**
49
Whta does IL-5 do?
IL-5 is involved in the **development and activation of eosinophils**, which, as we discuss subsequently, are i**mportant effectors of type I hypersensitivity.**
50
What does IL-13 do?
IL-13 **enhances IgE production** and **acts on epithelial cells to stimulate mucus**
**secretion.**
51
Mast cells and basophils express a high-affinity receptor, called \_\_\_\_\_\_\_\_\_.
FcεRI
52
What is FcεRI?
t is specific for the Fc portion of IgE, and therefore **avidly binds IgE antibodies**
53
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.
54
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.
55
Preformed Mediators.
Mediators contained within mast cell granules are the first to be released, and can be divided
into three categories:
1. Vasoactive amines
2. Enzymes
3. Proteoglycans.
56
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.**
57
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**.
58
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.
59
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
60
Lipid Mediators.
* Leukotrienes.
* Prostaglandin D2
* Platelet-activating factor (PAF)
61
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**
62
What does Leukotrine B4 does?
Leukotriene B4 is **highly chemotactic for neutrophils,** eosinophils, and monocytes.
63
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.
64
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.
65
\_\_\_\_\_\_\_\_\_- are **sources of many cytokines**, which may play an important role at several stages of
immediate hypersensitivity reactions
Mast cells
66
The cytokines include:
\_\_\_\_\_\_\_\_\_\_\_-, **which
promote leukocyte recruitment (typical of the late-phase reaction)**;
TNF, IL-1, and chemokines
67
What IL , which amplifies the TH2
response; and numerous others.
IL-4
68
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.
69
The development of immediate hypersensitivity reactions is **dependent on the coordinated**
actions of a variety of \_\_\_\_\_\_\_\_\_\_\_\_\_
chemotactic, vasoactive, and spasmogenic compounds
70
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**,
71
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
72
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
73
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
74
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)
75
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.
76
The survival of eosinophils in tissues is favored by \_\_\_\_\_\_\_\_\_\_\_\_\_
IL-3, IL-5, and granulocytemacrophage
colony-stimulating factor (GM-CSF), and IL-5
77
What is the most potent eosinophilactivating
cytokine known
IL-5
78
Eosinophils liberate proteolytic enzymes as well as two unique
proteins called __________ and \_\_\_\_\_\_\_\_\_\_\_which are toxic to epithelial
cells.
major basic protein and eosinophil cationic protein,
79
Activated eosinophils and other leukocytes also produce leukotriene \_\_\_\_\_\_\_\_and
directly activate mast cells to release mediators.
Thus, the **recruited cells amplify and sustain
the inflammatory response without additional exposure to the triggering antigen**.
It is now
believed that **this late-phase reaction** is a major cause of symptoms in some type I
hypersensitivity disorders, such as **allergic asthma.** Therefore, **treatment of these diseases
requires the use of broad-spectrum anti-inflammatory drugs, such as steroids.**
C4 and PAF
80
**Susceptibility to immediate hypersensitivity reactions is genetically determined**
**T or F**
T
81
What is **atopy?**
The term atopy
**refers to a predisposition** to **develop localized immediate hypersensitivity reactions** to a variety
of **inhaled and ingested allergens.**
82
Atopic individuals tend to have higher serum ____________ compared with the general population.
A positive family history
of allergy is found in **50% of atopic individuals.** The basis of familial predisposition is not clear,
but studies in patients with asthma reveal linkage to several gene loci
IgE levels, and
more IL-4–producing TH2 cells,
83
Candidate genes
have been mapped to\_\_\_\_\_\_, where genes encoding the cytokines **IL-3, IL-4, IL-5, IL-9, IL-13,**
and **GM-CSF** are located.
This locus has attracted great attention because of the known roles
of many of these cytokines in the reaction, but how the disease-associated polymorphisms
influence the biology of the cytokines is not known.
**5q31**
84
Linkage has also been noted to\_\_\_\_\_\_\_\_\_\_\_ close to
the **HLA complex**, suggesting that the inheritance of certain HLA alleles permits reactivity to
certain allergens.
6p,
85
What are your **non-atopic allergy?**
A significant proportion of immediate hypersensitivity reactions are **triggered by temperature
extremes and exercise, and do not involve TH2 cells or IgE;** such reactions are sometimes
called **“non-atopic allergy.**”
It is believed that in these cases mast cells are abnormally sensitive
to activation by various non-immune stimuli.
86
What is the hygiene hypothesis?
A final point that should be mentioned in this general discussion of immediate hypersensitivity
disorders is that the **incidence of many of these diseases is increasing in developed countries,**
and seems to be related to a **decrease in infections during early life**.
These observations have
led to an idea, sometimes called the **hygiene hypothesis**, that **reduced exposure to microbes
resets the immune system in such a way that TH2**responses develop more readily against
common environmental antigens. This hypothesis, however, is controversial, and the underlying
mechanisms are not defined.
87
To summarize, immediate (type I) hypersensitivity is a complex disorder resulting from an IgEmediated
triggering of mast cells and subsequent accumulation of inflammatory cells at sites of
antigen deposition. These events are regulated mainly by the induction of T H2 helper T cells
that stimulate production of IgE (which promotes mast cell activation), cause accumulation of
inflammatory cells (particularly eosinophils), and trigger secretion of mucus. The clinical
features result from release of mast cell mediators as well as the eosinophil-rich inflammation.
88
With this consideration of the basic mechanisms of type I hypersensitivity, we turn to some
conditions that are important examples of IgE-mediated disease.
* Systemic Anaphylaxis
* Local Immediate Hypersensitivity Reactions
89
rWhat is the charteristic of Systemic anaphylaxis?
is characterized by **vascular shock**, **widespread edema,** and **difficulty in**
**breathing.**
It may occur in sensitized individuals in hospital settings after administration of foreign proteins (e.g., antisera), hormones, enzymes, polysaccharides, and drugs (such as the antibiotic penicillin), or in the community setting following exposure to food allergens (e.g. peanuts, shellfish) or insect toxins (e.g. those in bee venom). [32]
Extremely small doses of
antigen may trigger anaphylaxis, for example, the tiny amounts used in skin testing for various
forms of allergies.
Because of the risk of severe allergic reactions to minute quantities of peanuts, the U.S. Congress is considering a bill to ban peanut snacks from the confined quarters of commercial airplanes.
Within minutes after exposure, **itching, hives, and skin**
* *erythema appear,** followed **shortly thereafter by a striking contraction of respiratory bronchioles**
* *and respiratory distress**.
Laryngeal edema results in **hoarseness and further compromises**
**breathing.**
Vomiting, abdominal cramps, diarrhea, and laryngeal obstruction follow, and the patient may go into shock and even die within the hour.
The risk of anaphylaxis must be borne
in mind when certain therapeutic agents are administered. Although patients at risk can
generally be identified by a previous history of some form of allergy, the absence of such a
history does not preclude the possibility of an anaphylactic reaction.
90
Local Immediate Hypersensitivity Reactions
About 10% to 20% of the population suffers from **allergies involving localized reaction**s to
**common environmental allergens**, such as pollen, animal dander, house dust, foods, and the
like.
Specific diseases include\_\_\_\_\_\_\_\_\_\_\_\_ these are discussed elsewhere in the book.
urticaria, angioedema, allergic rhinitis (hay fever), and bronchial
asthma;
91
What is Antibody-Mediated (Type II) Hypersensitivity
**This type of hypersensitivity is caused by _antibodies that react with antigens present on cell_
surfaces or in the extracellular matrix.**
The antigenic determinants may be intrinsic to the cell
membrane or matrix, or they may take the form of an exogenous antigen, such as a drug
metabolite, that is adsorbed on a cell surface or matrix. In either case the hypersensitivity
reaction results from the binding of antibodies to normal or altered cell surface antigens. The
antibody-dependent mechanisms that cause tissue injury and disease are illustrated in Figure
6-16 and described next.
Hypersensitivity & Autoimmune Disorders
380
92
FIGURE 6-16 Mechanisms of antibody-mediated injury.
* A, **Opsonization and Phagocytosis**
* **Opsonization of cells** by antibodies and complement components and ingestion by phagocytes.
* B Inflammation,
* **Inflammation** **induced by antibody** binding to Fc receptors of leukocytes and by complement breakdown products.
* C, **Cellular Dysfunction**
* **Anti-receptor antibodies** disturb the normal function of receptors. In these examples, antibodies to the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis, and antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease.
93
Phagocytosis is largely responsible for depletion of cells coated with antibodies.
So how does phagocytosis takes place?
Cells opsonized by **IgG antibodies** are **recognized by phagocyte Fc receptors**, which are specific for
the Fc portions of some IgG subclasses.
In addition, when **IgM or IgG antibodies are deposited**
**on the surfaces of cells,** they may **activate the complement system by the classical pathway.**
Complement activation generates by-products, mainly **C3b and C4b**, which are **deposited on**
**the surfaces of the cells and recognized by phagocytes** that express receptors for these
proteins.
The net result is **phagocytosis of the opsonized cell**s **and their destruction** ( Fig. 6-16A
).
Complement activation on cells also leads to the formation of the **membrane attack complex,**
which **disrupts membrane integrity by “drilling holes”** through the **lipid bilayer,** thereby causing
osmotic lysis of the cells.
This mechanism of depletion is probably effective only **with cells that** **have thin cell walls, such as Neisseria bacteria.**
94
Antibody-mediated destruction of cells may occur by another process called
**dependent cellular cytotoxicity (ADCC**
95
What is ADCC?
Cells that are coated with low concentrations of IgG
antibody are killed by a variety of effector cells, which bind to the target by their receptors for
the Fc fragment of IgG, and cell lysis proceeds without phagocytosis.
ADCC may be mediated
by monocytes, neutrophils, eosinophils, and NK cells. The role of ADCC in particular
hypersensitivity diseases is uncertain.
96
Clinically, antibody-mediated cell destruction and phagocytosis occur in the following situations:
(1) transfusion reactions, in which cells from an incompatible donor react with and are opsonized by preformed antibody in the host;
(2) hemolytic disease of the newborn
(erythroblastosis fetalis), in which there is an antigenic difference between the mother and the fetus, and antibodies (of the IgG class) from the mother cross the placenta and cause destruction of fetal red cells;
(3) autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia, in which individuals produce antibodies to their own blood cells, which are
then destroyed; and
(4) certain drug reactions, in which a drug acts as a “hapten” by attaching to surface molecules of red cells and antibodies are produced against the drug–membrane protein complex.
97
Explain how INFLAMMATION can cause type II hypersensitivity?
When **antibodies deposit in fixed tissue**s, such as **basement membranes and extracellular**
matrix, the **resultant injury is due to inflammation.**
The **deposited antibodies activate**
**complement,** generating by-products, including chemotactic agents (mainly C5a), which direct
the migration of polymorphonuclear leukocytes and monocytes, and anaphylatoxins (C3a and
C5a), which increase vascular permeability ( Fig. 6-16B ).
The leukocytes are activated by
engagement of their C3b and Fc receptors.
This results in the release or generation of a
variety of pro-inflammatory substances, including prostaglandins, vasodilator peptides, and
chemotactic substances.
Leukocyte activation leads to the production of other substances that damage tissues, such as lysosomal enzymes, including proteases capable of digesting
basement membrane, collagen, elastin, and cartilage, and reactive oxygen species. It was once
thought that complement was the major mediator of antibody-induced inflammation, but
knockout mice lacking Fc receptors also show striking reduction in these reactions. It is now
believed that inflammation in antibody-mediated (and immune complex–mediated) diseases is
due to both complement- and Fc receptor–dependent reactions. [
98
TABLE 6-4 -- Examples of Antibody-Mediated Diseases (Type II Hypersensitivity
Disease
* Autoimmune hemolytic anemia
* Autoimmune thrombocytopenic purpura
* Pemphigus vulgaris
* Vasculitis caused by ANCA
* Goodpasture syndrome
* Acute rheumatic fever
* Myasthenia gravis
* Graves disease (hyperthyroidism)
* Insulin-resistant diabetes
* Pernicious anemia
99
Autoimmune
hemolytic anemia
Target Antigen
Red cell membrane proteins
(Rh blood group antigens, I
antigen)
100
Autoimmune
hemolytic anemia
Mechanisms of Disease
Opsonization and
phagocytosis of red cells
101
Autoimmune
hemolytic anemia
Clinicopathologic
Manifestations
Hemolysis, anemia
102
Autoimmune
thrombocytopenic
purpura
Target Antigen
Platelet membrane proteins
| (Gpllb: Illa integrin)
103
Autoimmune
thrombocytopenic
purpura
Target Antigen
104
Autoimmune
thrombocytopenic
purpura
Clinicopathologic
Manifestations
Bleeding
105
Pemphigus
vulgaris
Target Antigen
Proteins in intercellular
junctions of epidermal cells
(epidermal cadherin)
106
Pemphigus
vulgaris
Mechanisms of Disease
Antibody-mediated
activation of proteases,
disruption of intercellular
adhesions
107
Pemphigus
vulgaris
Clinicopathologic
Manifestations
Skin vesicles
| (bullae)
108
Vasculitis caused
by ANCA
Target Antigen
Neutrophil granule proteins,
presumably released from
activated neutrophils
109
Vasculitis caused
by ANCA
Mechanisms of Disease
Neutrophil degranulation
and inflammation
110
Vasculitis caused
by ANCA
Clinicopathologic
Manifestations
Vasculitis
111
Goodpasture
syndrome
Target Antigen
Noncollagenous protein in
basement membranes of kidney glomeruli and lung
alveoli
112
Goodpasture
syndrome
Mechanisms of Disease
Complement- and Fc
receptor–mediated inflammation
113
Goodpasture
syndrome
Clinicopathologic
Manifestations
114
Acute rheumatic
fever
Target Antigen
Streptococcal cell wall
antigen; antibody cross-reacts
with myocardial antigen
115
Acute rheumatic
fever
Mechanisms of Disease
Inflammation, macrophage
activation
116
Acute rheumatic
fever
Clinicopathologic
Manifestations
Myocarditis,
arthritis
117
Myasthenia
gravis
Target Antigen
Acetylcholine receptor
118
Myasthenia
gravis
Mechanisms of Disease
Antibody inhibits
acetylcholine binding, downmodulates
receptors
119
Myasthenia
gravis
Clinicopathologic
Manifestations
Muscle weakness,
paralysis
120
Graves disease
Target Antigen
| (hyperthyroidism)
TSH receptor
121
Graves disease
Mechanisms of Disease
| (hyperthyroidism)
Antibody-mediated
stimulation of TSH receptors
122
Graves disease
Clinicopathologic
Manifestations
| (hyperthyroidism)
123
Insulin-resistant
diabetes
Target Antigen
124
Insulin-resistant
diabetes
Mechanisms of Disease
Antibody inhibits binding of
insulin
125
Insulin-resistant
diabetes
Clinicopathologic
Manifestations
Hyperglycemia,
ketoacidosis
126
Pernicious
anemia
Target Antigen
Intrinsic factor of gastric
parietal cells
127
Pernicious
anemia
Mechanisms of Disease
Neutralization of intrinsic
factor, decreased
absorption of vitamin B12
128
Pernicious
anemia
Clinicopathologic
Manifestations
Abnormal
erythropoiesis,
anemia
129
In some cases, antibodies directed against cell surface receptors impair or dysregulate function
without causing cell injury or inflammation ( Fig. 6-16C ). For example, in myasthenia gravis,
antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscles
block neuromuscular transmission and therefore cause muscle weakness.
The converse (i.e.,
antibody-mediated stimulation of cell function) is the basis of Graves disease. In this disorder,
antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate
the cells, resulting in hyperthyroidism.
130
What is Immune Complex–Mediated (Type III) Hypersensitivity ?
*Antigen-antibody complexes produce tissue damage mainly by **eliciting inflammation at the sites
of deposition.***
131
How is type III hypersensitivy initiated?
The pathologic reaction is **initiated when antigen combines with antibody** within
the **circulation (circulating immune complexes)**, and **these are deposited typically in vessel**
**walls**. [34]
Sometimes the complexes are formed at extravascular sites where antigen may have
been “planted” previously (**called in situ immune complexes).**
132
The antigens that form immune
complexes may be **exogenous**, such as a foreign protein that is injected or produced by an
infectious microbe, or **endogenous**, if the individual produces antibody against self-components
(autoimmunity).
T or F
T
133
When is immune complex-mediated disease said to be systemic?
Immune complex–mediated diseases can be **systemic**, if immune complexes are
**formed in the circulation** and are deposited in many organs,.
134
When can you say the type III hypersensitivity is localized?
or localized to particular organs,
such as the kidney (glomerulonephritis), joints (arthritis), or the small blood vessels of the skin if
the **complexes are deposited or formed in these tissues.**
135
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Disease
* Systemic lupus erythematosus
* Poststreptococcal glomerulonephritis
* Polyarteritis nodosa
* Reactive arthritis
* Serum sickness
* Arthus reaction (experimental)
136
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Systemic lupus
erythematosus
Antigen Involved
Nuclear antigens
137
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Systemic lupus
erythematosus
Clinicopathologic
Manifestations
Nephritis, skin lesions,
arthritis, others
138
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Poststreptococcal
glomerulonephritis
Antigen Involved
Streptococcal cell wall antigen(s); may be “planted”
in glomerular basement membrane
139
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Poststreptococcal
glomerulonephritis
Clinicopathologic
Manifestations
Nephritis
140
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Polyarteritis nodosa
Antigen Involved
Hepatitis B virus antigens in some cases
141
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Polyarteritis nodosa
Clinicopathologic
Manifestations
Systemic vasculitis
142
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Reactive arthritis
Antigen Involved
Bacterial antigens (e.g., Yersinia)
143
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Reactive arthritis
Clinicopathologic
Manifestations
Acute arthritis
144
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Serum sickness
Antigen Involved
Various proteins, e.g., foreign serum protein (horse
anti-thymocyte globulin)
145
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Serum sickness
Clinicopathologic
Manifestations
Arthritis, vasculitis,
nephritis
146
TABLE 6-5 -- Examples of Immune Complex–Mediated Diseases
Arthus reaction
(experimental)
Antigen Involved
Various foreign proteins
147
What is the **prototype of a systemic immune complex** disease; it was once a
frequent sequela to the administration of large amounts of foreign serum (e.g., serum from
immunized horses used for protection against diphtheria). In modern times the disease is
infrequent, but it is an informative model that has taught us a great deal about systemic immune
complex disorders.
Acute serum sickness
148
The pathogenesis of systemic immune complex disease can be divided into three phases:
(1) formation of **antigen-antibody complexe**s in the **circulation;**
(2) **deposition** of the immune complexes in various tissues, thus initiating
(3) an **inflammatory reaction** at the sites of immune
complex deposition
149
Explain the Formation of Immune Complexes.
The introduction of a protein antigen triggers an immune response that **results in the formation
of antibodies**, typically about a week after the injection of the protein. These antibodies are
secreted into the blood, where they react with the antigen still present in the circulation and
form antigen-antibody complexes.
150
Explain how does the deposition of Immune Complexes happen
In the next phase the circulating antigen-antibody complexes are deposited in various tissues.
The f**actors that determine whether immune complex formation will lead to tissue deposition** and
**disease are not fully understood**, but the **major influences seem to be the characteristics of the complexes and local vascular alterations.**
In general, complexes that are of medium size, formed in slight antigen excess, are the most
pathogenic. Organs where blood is filtered at high pressure to form other fluids, like urine and
synovial fluid, are favored; hence, immune complexes frequently deposit in glomeruli and
joints.
151
tExplain issue Injury Caused by Immune Complexes.
Once complexes are deposited in the tissues, they **initiate an acute inflammatory reaction** (the
third phase).
During this phase **(approximately 10 days** after antigen administration), **clinical
features such as fever, urticaria, joint pains (arthralgias), lymph node enlargement, and
proteinuria appear.**
Wherever complexes deposit the tissue damage is similar.
The mechanisms
of inflammation and injury were discussed above, in the discussion of antibody-mediated injury.
The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels,
glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.
152
It is clear that **\_\_\_\_\_\_\_\_\_\_\_\_**induce the pathologic lesions of immune
complex disorders.
**complement-fixing antibodie**s (i.e., IgG and IgM) and **antibodies that bind to
leukocyte Fc receptors** (some subclasses of IgG)
The important role of complement in the pathogenesis of the tissue injury is
supported by the observations that during the active phase of the disease, consumption of
complement leads to a decrease in serum levels of C3. In fact, serum C3 levels can, in some
cases, be used to monitor disease activity.
153
What is the principal morphologic manifestation of immune complex injury?
The principal morphologic manifestation of immune complex injury is:
* **acute necrotizing vasculitis,**
* **with necrosis of the vessel wall**
* **and intense neutrophilic infiltration.**
154
What is fibrinoid necrosis?
The
necrotic tissue and deposits of immune complexes, complement, and plasma protein produce
a **smudgy eosinophilic deposit** that **obscures the underlying cellular detail,** an appearance
termed **fibrinoid necrosis**
155
When these immune complexes are deposited in the kidney, how does it appear?
When deposited in the kidney, the complexes can
**be seen on immunofluorescence microscopy** as **granular lumpy deposits of**
**immunoglobulin** and **complement and on electron microscopy as electron-dense deposits**
along the **glomerular basement membrane**
156
If the disease results from a single large exposure to antigen (**e.g., acute serum sickness and
perhaps acute poststreptococcal glomerulonephritis**), the lesions tend to resolve, as a result of
**\_\_\_\_\_\_\_\_\_\_\_\_\_\_**
**catabolism of the immune complexes.**
A chronic form of serum sickness results from repeated or prolonged exposure to an antigen. This occurs in several human diseases, such as **systemic**
**lupus erythematosus (SLE)**, which is associated with **persistent antibody responses** to
autoantigens.
In many diseases, however, the morphologic changes and other findings suggest
immune complex deposition but the inciting antigens are unknown.
Included in this category are
**membranous glomerulonephritis,** many cases of polyarteritis nodosa, and several other
vasculitides.
157
What is an Arthus reaction?
The Arthus reaction is a **localized area of tissue** **necrosis resulting from acute immune complex**
vasculitis, **usually elicited in the skin.**
The reaction can be produced experimentally by
intracutaneous injection of antigen in a previously immunized animal that contains circulating
antibodies against the antigen.
As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally.
These complexes
precipitate in the vessel walls and cause fibrinoid necrosis, and superimposed thrombosis worsens the ischemic injury.
158
What is T Cell–Mediated (Type IV) Hypersensitivity?
The cell-mediated type of hypersensitivity is initiated by **antigen-activated (sensitized) T** lymphocytes, including **CD4+ and CD8+ T cells** ( Fig. 6-19 ).
CD4+ T cell–mediated
hypersensitivity induced by environmental and self-antigens **can be a cause of chronic
inflammatory disease**.
Many autoimmune diseases are now known to be caused by inflammatory reactions driven by CD4+ T cells ( Table 6-6 ).
In some of these T cell–mediated
autoimmune diseases, CD8+ cells may also be involved. In fact, in certain forms of T cell
–mediated reactions, especially those that follow viral infections, CD8+ cells may be the
dominant effector cells.
159
Mechanisms of T cell–mediated (type IV) hypersensitivity reactions.
A, In delayed-type hypersensitivity reactions, **CD4+ TH1 cells (and sometimes CD8+ T cells, not**
* *shown) respond to tissue antigen**s by **secreting cytokine**s that **stimulate inflammation** and
* *activate phagocytes, leading to tissue injury. CD4+**
* *TH17 cells** contribute to inflammation by
* *recruiting neutrophils** (and, to a lesser extent, monocytes).
B, In some diseases, CD8+
cytotoxic T lymphocytes (CTLs) directly kill tissue cells. APC, antigen-presenting cell. See
text for other abbreviations.
160
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
* Type 1 diabetes mellitus
* Multiple sclerosis
* Rheumatoid arthritis
* Crohn disease
* Peripheral neuropathy; Guillain- Barré syndrome
* Contact sensitivity (dermatitis)
161
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Type 1 diabetes
mellitus
Specificity of Pathogenic T Cells
Antigens of pancreatic islet β cells
| (insulin, glutamic acid decarboxylase others)
162
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Type 1 diabetes
mellitus
Clinicopathologic Manifestations
Insulitis (chronic inflammation in
islets), destruction of β cells; diabetes
163
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Multiple sclerosis
Specificity of Pathogenic T Cells
Protein antigens in CNS myelin
(myelin basic protein, proteolipid
protein)
164
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Multiple sclerosis
Clinicopathologic Manifestations
Demyelination in CNS with
perivascular inflammation; paralysis,
ocular lesions
165
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Rheumatoid arthritis
Specificity of Pathogenic T Cells
Unknown antigen in joint synovium
(type II collagen?); role of
antibodies?
166
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Rheumatoid arthritis
Clinicopathologic Manifestations
167
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Crohn disease
Specificity of Pathogenic T Cells
Unknown antigen; role for commensal
bacteria
168
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Crohn disease
Clinicopathologic Manifestations
Chronic intestinal inflammation,
obstruction
169
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Peripheral
neuropathy; Guillain- Barré syndrome?
Specificity of Pathogenic T Cells
Protein antigens of peripheral nerve
myelin
170
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Peripheral
neuropathy; Guillain- Barré syndrome?
Clinicopathologic Manifestations
Neuritis, paralysis
171
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Contact sensitivity
(dermatitis)
Specificity of Pathogenic T Cells
Various environmental antigens (e.g.,
poison ivy)
172
TABLE 6-6 -- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Contact sensitivity
(dermatitis)
Clinicopathologic Manifestations
Skin inflammation with blisters
173
Reactions of CD4+ T Cells: Delayed-Type Hypersensitivity and Immune Inflammation
Inflammatory reactions caused by **CD4+ T cells** were **initially characterized** on the basis of
**delayed-type hypersensitivity (DTH)** to exogenously administered antigens.
The **same
immunological events**are**responsible for chronic inflammatory reactions against self-tissues.**
Because of the central role of the adaptive immune system in such inflammation, it is sometimes
**referred to as immune inflammation.**
**Both TH1 and TH17** cells **contribute to organ-specific**
diseases in which inflammation is a prominent aspect of the pathology. [36]
The inflammatory
reaction associated with **TH1 cells is dominated by activated macrophages**, and that triggered
**by TH17 cells has a greater neutrophil component.**
174
The cellular events in T cell–mediated hypersensitivity consist of a series of reactions in which
cytokines play important roles. The reactions can be divided into the following stages
* Proliferation and Differentiation of CD4+ T Cells.
* Responses of Differentiated Effector T Cells
175
Discuss the Proliferation and Differentiation of CD4+ T Cells.
**Naive CD4+ T** cells **recognize peptides** **displayed by dendritic cells and secrete IL-2**, which
functions as an **autocrine growth facto**r to stimulate proliferation of the antigen-responsive T
cells.
The subsequent differentiation of antigen-stimulated T cells to TH1 or TH17 cells is driven
by the c**ytokines produced by APCs** at the time of T-cell activation (see Fig. 6-13 ). [36]
In some
situations the **APCs (dendritic cells and macrophages) produce IL-12,** which induces
**differentiation of CD4+ T cells** to the **TH1 subset.** IFN-γ produced by these effector cells
promotes further TH1 development, thus amplifying the reaction.
If the APCs produce
inflammatory cytokines such as **IL-1, IL-6,** and a close **relative of IL-12 called IL-23,** these work
in collaboration with **transforming growth factor-β** (TGF-β) (made by many cell types) to
**stimulate differentiation of T cells to the TH17 subset.** Some of the differentiated effector cells
enter the circulation and may remain in the memory pool of T cells for long periods, sometimes
years.
176
Naive CD4+ T cells recognize peptides displayed by dendritic cells and **secrete IL-2, what is the function of this?**
Naive CD4+ T cells recognize peptides displayed by dendritic cells and secrete **IL-2, which
functions as an autocrine growth factor to stimulate proliferation of the antigen-responsive T
cells.**
177
The subsequent differentiation of antigen-stimulated T cells to **TH1 or TH17** cells is driven
by the**\_\_\_\_\_\_**
**cytokines produced by APCs** at the time of **T-cell activation** (see Fig. 6-13 ). [36]
178
In some
situations the **APCs (dendritic cells and macrophages)** produce IL-12, which function to?
* *which induces**
* *differentiation of CD4+ T** cells to the **TH1 subset.**
**IFN-γ** produced by these effector cells
promotes further TH1 development, thus amplifying the reaction
179
WHat stimulates in the differentiation of **T cells to TH17?**
If the APCs produce
inflammatory cytokines such as **IL-1, IL-6,** and a close relative of **IL-12 called IL-23**, these work
in collaboration with **transforming growth factor-β** **(TGF-β) (**made by many cell types) to
s**timulate differentiation of T cells to the TH17 subset.** Some of the differentiated effector cells
enter the circulation and may remain in the memory pool of T cells for long periods, sometimes
years
180
Discuss Responses of Differentiated Effector T Cells.
Upon r**epeat exposure to an antigen,** previously activated T cells recognize the antigen
displayed by APCs and respond.
**TH1 cells secrete cytokines,** mainly **IFN-γ**, which are
r**esponsible for many of the manifestations of delayed**-**type hypersensitivity**.
IFN-γ–activated
macrophages are altered in several ways: their ability to phagocytose and kill microorganisms is markedly augmented; **they express more class II MHC molecules** on the surface, thus facilitating
**further antigen presentation; they secrete TNF, IL-1,** and chemokines, which promote
inflammation ( Chapter 2 ); and they **produce more IL-12, thereby amplifying the TH1 response.**
Thus, activated macrophages serve to eliminate the offending antigen; if the activation is
sustained, continued inflammation and tissue injury result.
181
TH17 cells are activated by some microbial antigens and by self-antigens in autoimmune
diseases. Activated TH17 cells secrete IL-17, IL-22, chemokines, and several other cytokines.
Collectively, these cytokines recruit neutrophils and monocytes to the reaction, thus promoting
inflammation. TH17 cells also produce IL-21, which amplifies the TH17 response.
182
What is the classic example of DTH?
The classic example of DTH is the **tuberculin reaction,** which is **produced by the intracutaneous**
**injection of purified protein derivative** (PPD, also **called tuberculin)**, a protein-containing antigen
of the tubercle bacillus.
In a **previously sensitized individual,** reddening and induration of the site appear in **8 to 12 hours,** reach a **peak in 24 to 72 hours,** and thereafter slowly subside.
183
Morphologically, delayed-type hypersensitivity is characterized by the:
accumulation of
* *mononuclear cells, mainly CD4+ T cells** and **macrophages, around venules**, producing
* *perivascular “cuffing”** ( Fig. 6-20 ).
In fully developed lesions, the venules show **marked**
**endothelial hypertrophy, reflecting cytokine-mediated endothelial activation.**
184
Delayed hypersensitivity reaction in the skin.
morphologically appears as:
A, Perivascular infiltration by T
cells and mononuclear phagocytes.
B, Immunoperoxidase staining reveals a predominantly
perivascular cellular infiltrate that marks positively with antibodies specific to CD4.
185
With certain persistent or nondegradable antigens, such as t**ubercle bacilli** colonizing the lungs
or other tissues, the **perivascular infiltrate** is dominated by \_\_\_\_\_\_\_\_\_
macrophages over a period of 2 or 3
weeks.
186
In certain **persistent or nondegradable antigens**, such as **tubercle bacilli** colonizing the lungs
or other tissues, the **perivascular infiltrate is dominated by macrophages over a period of 2 or 3
weeks.**What is the morphological appearance?
The activated macrophages often undergo a **morphologic transformation** into
**epithelium-like cells** and are then referred to as **epithelioid cells.**
A **microscopic aggregation of
epithelioid cells,**usuall**y surrounded by a collar of lymphocytes**, is referred to as a**granuloma (**
Fig. 6-21 ).
This pattern of inflammation, **called granulomatous inflammation** ( Chapter 2 ), is
typically **associated with strong T-cell activation with cytokine production** ( Fig. 6-22 ).
It can also be caused by foreign bodies that activate macrophages without eliciting an adaptive immune
response.
187
What are epitheloid cells?.
The activated macrophages often undergo a morphologic transformation into
**epithelium-like cells** and are then referred to as epithelioid cells
188
What is a granuloma?
A **microscopic aggregation** of
**epithelioid cells,** usually **surrounded by a collar of lymphocytes,** is referred to as **a granuloma** (
Fig. 6-21 ).
This pattern of inflammation, called **granulomatous inflammation** ( Chapter 2 ), is
typically associated with strong T-cell activation with cytokine production ( Fig. 6-22 ). It can also
be caused by foreign bodies that activate macrophages without eliciting an adaptive immune
response.
189
Give a common example of tissue injury resulting from DTH reactions?
Contact dermatitis is a common example of tissue injury resulting from DTH reactions. It may be
**evoked by contact with urushiol**, the antigenic component of **poison ivy or poison oak,** and
presents as a **vesicular dermatitis**
190
Discuss Reactions of CD8+ T Cells: Cell-Mediated Cytotoxicity
In this type of T cell–mediated reaction**, CD8+ CTLs kill antigen-bearing target cells**
. Tissue
**destruction by CTLs may be an important component** of many **T cell–mediated diseases**, such
as **type 1 diabetes**.
CTLs directed against cell surface histocompatibility antigens play an
important role in graft rejection, to be discussed later. They also play a role in reactions against
viruses.
```
In a virus-infected cell, viral peptides are displayed by class I MHC molecules and the
complex is recognized by the TCR of CD8+ T lymphocytes.
```
The killing of infected cells leads to
the elimination of the infection, and is responsible for cell damage that accompanies the
infection (e.g., in viral hepatitis).
Tumor-associated antigens are also presented on the cell
surface, and CTLs are involved in tumor rejection
191
The **principal mechanism of T cell–mediated killing** of targets involves \_\_\_\_\_\_\_\_\_
perforins and granzymes,
preformed mediators contained in the lysosome-like granules of CTLs. [37]
192
What are serglycin?
CTLs that recognize
the target cells secrete a complex consisting of perforin, granzymes, and a protein called
serglycin, which enters target cells by endocytosis.
In the target cell cytoplasm, perforin
facilitates the release of the granzymes from the complex.
Granzymes are proteases that cleave
and activate caspases, which induce apoptosis of the target cells ( Chapter 1 ).
Activated CTLs
also express Fas ligand, a molecule with homology to TNF, which can bind to Fas expressed on
target cells and trigger apoptosis.
193
CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in inflammatory reactions
resembling DTH, especially following virus infections and exposure to some contact sensitizing
agents.
194
