Disorders in Immunity pdf - D. Talib

Talaro−Talaro: Foundations

in Microbiology, Fourth

Edition

17. Disorders in Immunity

Text

Companies, 2002

497

umans possess a powerful and intricate system of defense,
which by its very nature also carries the potential to cause
injury and disease. In most instances, a defect in immune

function is expressed in commonplace, but miserable, symptoms such
as those of hay fever and dermatitis. But abnormal or undesirable
immune functions are also actively involved in debilitating or life-
threatening diseases such as asthma, anaphylaxis, rheumatoid arthri-
tis, graft rejection, and cancer.

Chapter Overview

• The immune system is subject to several types of dysfunctions termed

immunopathologies.

• Some dysfunctions are due to abnormally heightened responses to

antigens as manifested in allergies, hypersensitivities, and

autoimmunities.

• Some dysfunctions are due to the reduction or loss in protective immune

reactions due to genetic or environmental causes, as exemplified by

immunodeficiencies and cancer.

• Some immune damage is caused by normal actions that are directed at

foreign tissues placed in the body for therapy, such as transfusions and

transplants.

• Hypersensitivities are divided into immediate, antibody-mediated,

immune complex, and delayed allergies.

• Allergens are the foreign molecules from the environment, other

organisms, or even from the body that cause a hypersensitive or allergic

response.

• Most hypersensitivities require an initial sensitizing event, followed by a

later contact that causes symptoms.

• The immediate type of allergy is mediated by special types of B cells

that produce an antibody called IgE. IgE can cause mast cells to

release allergic chemicals such as histamine that stimulate symptoms.

• Examples of immediate allergies are atopy, asthma, food allergies, and

anaphylaxis.

• Another type of hypersensitivity arises from the action of other

antibodies (IgG and IgM) that can fix complement and lyse foreign

cells. An example is the reaction due to incompatible blood transfusions

or placental transfer.

• Immune complex reactions are caused by large amounts of circulating

antibodies against foreign molecules accumulating in tissues and

organs.

• Autoimmune diseases are due to the production of B and T cells that

are abnormally sensitized to react with the body’s natural molecules and

thus can damage cells and tissues. Some examples of these diseases

include rheumatoid arthritis, systemic lupus erythematosus, myasthenia

gravis, and multiple sclerosis.

• T cells are involved in delayed-type hypersensitivities wherein allergens

cause damage to cells and graft rejection.

• Immunodeficiencies are pathologies in which B and T cells and other

immune cells are missing or destroyed. They may be inborn and

genetic or acquired.

• The primary outcome of immunodeficiencies is manifest in recurrent

infections and lack of immune competence.

• Cancer is an abnormal overgrowth of cells due to a genetic defect and

the lack of effective immune surveillance.

This delicate poison ivy plant, along with its close relatives poison oak and
sumac, is one of the most common causes of allergy in the United States.
Its leaves contain an oil that many people are sensitive to. The nature of its
effects are covered in this chapter.

CHAPTER

Disorders in Immunity

Talaro−Talaro: Foundations

in Microbiology, Fourth

Edition

17. Disorders in Immunity

Text

Companies, 2002

498

CHAPTER 17 Disorders in Immunity

The Immune Response:
A Two-Sided Coin

With few exceptions, our previous discussions of the immune re-
sponse have centered around its numerous beneficial effects. The
precisely coordinated system that seeks out, recognizes, and de-
stroys an unending array of foreign materials is clearly protective,
but it also presents another side—a side that promotes rather than
prevents disease. In this chapter, we will survey

immunopathol-

ogy, the study of disease states associated with overreactivity or un-
derreactivity of the immune response (figure 17.1). In the cases of
allergies and autoimmunity, the tissues are innocent bystanders
attacked by excessive immunologic functions. In

grafts and trans-

fusions, a recipient reacts to the foreign tissues and cells of another
individual. In

immunodeficiency diseases, immune function is in-

completely developed, suppressed, or destroyed.

Cancer falls into

a special category, because it is both a cause and an effect of im-
mune dysfunction. As we shall see, one fascinating by-product of
studies of immune disorders has been our increased understanding
of the basic workings of the immune system.

Overreactions to Antigens:
Allergy/Hypersensitivity

The term

allergy* means a condition of altered reactivity or

exaggerated immune response that is manifested by inflammation.
Although it is sometimes used interchangeably with

hypersensitiv-

ity, some experts refer to immediate reactions such as hay fever as
allergies and to delayed reactions as hypersensitivities. Allergic
individuals are acutely sensitive to repeated contact with antigens,
called

allergens, that do not noticeably affect nonallergic individu-

als. Although the general effects of hyperactivity are detrimental,
we must be aware that it involves the very same types of immune
reactions as those at work in protective immunities. These include
humoral and cell-mediated actions, the inflammatory response,
phagocytosis, and complement. Such an association means that all
humans have the potential to develop hypersensitivity under
particular circumstances.

Immunodeficiency

rre

actio

Over

rea

Cancer

tig

enic

Stimu

tio

unity

Hyper

sen

sit

iti

Type I.
Immediate
(hay fever,
anaphylaxis)

Type II.
Antibody-mediated (blood type
incompatibilities)

Type III.
Immune complex
(rheumatoid arthritis, serum
sickness)

Type IV.
Cell-mediated, cytotoxic
(contact dermatitis, graft rejection)

allergy

(al

-er-jee) Gr. allos, other, and ergon, work.

FIGURE 17.1

Overview of diseases of the immune system.

Just as the system of T cells and B cells provides necessary protection against infection and

disease, the same system can cause serious and debilitating conditions by overreacting or underreacting to immune stimuli.

Talaro−Talaro: Foundations

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499

Originally, allergies were defined as either immediate or

delayed, depending upon the time lapse between contact with the
allergen and onset of symptoms. Subsequently, they were differ-
entiated  as  humoral  versus  cell-mediated.  But  as  information  on
the  nature  of  the  allergic  immune  response  accumulated,  it  be-
came  evident  that,  although  useful,  these  schemes  oversimplified
what  is  really  a  very  complex  spectrum  of  reactions.  The  most
widely accepted classification, first introduced by immunologists
P. Gell  and  R. Coombs,  includes  four  major  categories:  type  I
(atopy  and  anaphylaxis),  type  II  (IgG-  and  IgM-mediated  cell
damage), type III (immune complex), and type IV (delayed hyper-
sensitivity) (table 17.1). In general, types I, II, and III involve a
B-cell–immunoglobulin response, and type IV involves a T-cell re-
sponse (figure 17.1). The antigens that elicit these reactions can be
exogenous,  originating  from  outside  the  body  (microbes,  pollen
grains, and foreign cells and proteins), or endogenous, arising from
self tissue (autoimmunities).

One of the reasons allergies are easily mistaken for infections

is  that  both  involve  damage  to  the  tissues  and  thus  trigger  the
inflammatory  response  (see  figure  14.18).  Many  symptoms  and
signs  of  inflammation  (redness,  heat,  skin  eruptions,  edema,  and
granuloma) are prominent features of allergies.

Type I Allergic Reactions:
Atopy and Anaphylaxis

All  type  I  allergies  share  a  similar  physiological  mechanism,  are
immediate  in  onset,  and  are  associated  with  exposure  to  specific
antigens.  However,  it  is  convenient  to  recognize  two  subtypes:
Atopy* is any chronic local allergy such as hay fever or asthma;
anaphylaxis* is a systemic, often explosive reaction that involves
airway obstruction and circulatory collapse. In the following sec-
tions, we will consider the epidemiology of type I allergies, aller-
gens and routes of inoculation, mechanisms of disease, and specific
syndromes.

EPIDEMIOLOGY AND MODES OF
CONTACT WITH ALLERGENS

Allergies exert profound medical and economic impact. Allergists
(physicians who specialize in treating allergies) estimate that about
10% to 30% of the population is prone to atopic allergy. It is gener-
ally acknowledged that self-treatment with over-the-counter medi-
cines accounts for significant underreporting of cases. The 35 million
people  afflicted  by  hay  fever  (15–20%  of  the  population)  spend
about  half  a  billion  dollars  annually  for  medical  treatment.  The
monetary loss due to employee debilitation and absenteeism is im-
measurable. The majority of type I allergies are relatively mild, but
certain forms such as asthma and anaphylaxis may require hospi-
talization  and  cause  death. About  2  million  people  in  the  United
States suffer from asthma.

The predisposition for type I allergies is inherited. Be aware

that what is hereditary is a generalized susceptibility, not the allergy
to a specific substance. For example, a parent who is allergic to rag-
weed pollen can have a child who is allergic to cat hair. The
prospect of a child’s developing atopic allergy is at least 25% if one
parent is atopic, increasing up to 50% if grandparents or siblings
are also afflicted. The actual basis for atopy appears to be a genetic

TABLE 17.1

Hypersensitivity States

Type

Systems and Mechanisms Involved

Examples

Immediate hypersensitivity

IgE-mediated; involves mast cells,

Anaphylaxis, atopic allergies such as hay

basophils, and allergic mediators

fever, asthma

II.

Antibody-mediated

IgG, IgM antibodies act upon cells with

Blood group incompatibility, pernicious

complement and cause cell lysis; includes

anemia; myasthenia gravis

some autoimmune diseases

III.

Immune complex–mediated

Antibody-mediated inflammation; circulating

Systemic lupus erythematosus; rheumatoid

IgG complexes deposited in basement

arthritis; serum sickness; rheumatic fever

membranes of target organs; includes
some autoimmune diseases

IV.

T cell–mediated

Delayed hypersensitivity and cytotoxic

Infection reactions; contact dermatitis; graft

reactions in tissues

rejection; some types of autoimmunity
such as diabetes

Immunopathology is the study of diseases associated with excesses and

deficiencies of the immune response. Such diseases include allergies,
autoimmunity, grafts, transfusions, immunodeficiency disease, and
cancer.

An allergy or hypersensitivity is an exaggerated immune response that

injures or inflames tissues.

There are four categories of hypersensitivity reactions: type I (atopy and

anaphylaxis), type II (transfusion reactions), type III (immune complex
reactions), and type IV (delayed hypersensitivity reactions).

Antigens that trigger hypersensitivity reactions are allergens. They can be

either exogenous (originate outside the host) or endogenous (involve the
host’s own tissue).

CHAPTER CHECKPOINTS

atopy

(at

-oh-pee) Gr. atop, out of place.

anaphylaxis

(an

-uh-fih-lax-us) Gr. ana, excessive, and phylaxis, protection.

Talaro−Talaro: Foundations

in Microbiology, Fourth

Edition

17. Disorders in Immunity

Text

Companies, 2002

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CHAPTER 17 Disorders in Immunity

program that favors allergic antibody (IgE) production, increased
reactivity of mast cells, and increased susceptibility of target tissue
to allergic mediators. Allergic persons often exhibit a combination
of syndromes, such as hay fever, eczema, and asthma.

Other factors that affect the presence of allergy are age,

infection, and geographic locale. New allergies tend to crop up
throughout an allergic person’s life, especially as new exposures
occur after moving or changing life-style. In some persons, atopic
allergies last for a lifetime; others “outgrow” them, and still others
suddenly develop them later in life. Some features of allergy are not
yet completely explained.

THE NATURE OF ALLERGENS AND
THEIR PORTALS OF ENTRY

As with other antigens, allergens have certain immunogenic char-
acteristics. Not unexpectedly, proteins are more allergenic than
carbohydrates, fats, or nucleic acids. Some allergens are haptens,
non-proteinaceous substances with a molecular weight of less than
1,000 that can form complexes with carrier molecules in the body
(see figure 15.11). Organic and inorganic chemicals found in indus-
trial and household products, cosmetics, food, and drugs are com-
monly of this type. Table 17.2 lists a number of common allergenic
substances.

Allergens typically enter through epithelial portals in the res-

piratory tract, gastrointestinal tract, and skin. The mucosal surfaces
of the gut and respiratory system present a thin, moist surface that
is normally quite penetrable. The dry, tough keratin coating of skin
is less permeable, but access still occurs through tiny breaks,
glands, and hair follicles. It is worth noting that the organ of aller-
gic expression may or may not be the same as the portal of entry.

Airborne environmental allergens such as pollen, house dust,

dander  (shed  skin  scales),  or  fungal  spores  are  termed  inhalants.
Each  geographic  region  harbors  a  particular  combination  of  air-
borne substances that varies with the season and humidity (figure
17.2a). Pollen, the most common offender, is given off seasonally
by the reproductive structures of pines and flowering plants (weeds,
trees,  and  grasses).  Unlike  pollen,  mold  spores  are  released
throughout the year and are especially profuse in moist areas of the
home and garden. Airborne animal hair and dander, feathers, and
the saliva of dogs and cats are common sources of allergens. The
component of house dust that appears to account for most dust al-

lergies is not soil or other debris, but the decomposed bodies of tiny
mites that commonly live in this dust (figure 17.2b). Some people
are allergic to their work, in the sense that they are exposed to al-
lergens on the job. Examples include florists, beauty operators,
woodworkers, farmers, drug processors, welders, and plastics man-
ufacturers whose work can aggravate inhalant allergies.

Allergens that enter by mouth, called ingestants, often cause

food  allergies:  Injectant allergies  are  an  important  adverse  side
effect of drugs or other substances used in diagnosing, treating, or
preventing  disease. A natural  source  of  injectants  is  venom  from
stings by hymenopterans, a family of insects that includes honey-
bees  and  wasps.  Contactants are  allergens  that  enter  through  the
skin.  Many  contact  allergies  are  of  the  type  IV,  delayed  variety
discussed later in this chapter.

MECHANISMS OF TYPE I ALLERGY:
SENSITIZATION AND PROVOCATION

What causes some people to sneeze and wheeze every time they
step out into the spring air, while others suffer no ill effects? In
order to answer this question, we must examine what occurs in the
tissues of the allergic individual that does not occur in the normal
person. In general, type I allergies develop in stages (figure 17.3).
The initial encounter with an allergen provides a

sensitizing dose

that primes the immune system for a subsequent encounter with
that allergen but generally elicits no signs or symptoms. The mem-
ory cells and immunoglobulin are then ready to react with a subse-
quent

provocative dose of the same allergen. It is this dose that

precipitates the signs and symptoms of allergy. Despite numerous
anecdotal reports of people showing an allergy upon first contact
with an allergen, it is generally believed that these individuals un-
knowingly had contact at some previous time. Fetal exposure to
allergens from the mother’s bloodstream is one possibility, and
foods can be a prime source of “hidden” allergens such as penicillin.

The Physiology of IgE-Mediated Allergies

During primary contact and sensitization, the allergen penetrates the
portal of entry (figure 17.3a). When large particles such as pollen
grains, hair, and spores encounter a moist membrane, they release
molecules of allergen that pass into the tissue fluids and lymphatics.
The lymphatics then carry the allergen to the lymph nodes, where
specific clones of B cells recognize it, are activated, and proliferate
into plasma cells. These plasma cells produce

immunoglobulin E

(IgE), the antibody of allergy. IgE is different from other im-
munoglobulins in having an Fc receptor region with great affinity
for mast cells and basophils. The binding of IgE to these cells in the
tissues sets the scene for the reactions that occur upon repeated ex-
posure to the same allergen (see figures 17.3b and 17.6).

The Role of Mast Cells and Basophils

The most important characteristics of mast cells and basophils
relating to their roles in allergy are:

1. Their ubiquitous location in tissues. Mast cells are

located in the connective tissue of virtually all organs, but
particularly high concentrations exist in the lungs, skin,
gastrointestinal tract, and genitourinary tract. Basophils
circulate in the blood but migrate readily into tissues.

TABLE 17.2

Common Allergens, Classified by Portal of Entry

Inhalants

Ingestants

Injectants

Contactants

Pollen

Food

Hymenopteran

Drugs

Dust

(chocolate,

venom (bee,

Cosmetics

Mold spores

wheat, eggs,

wasp)

Heavy metals

Dander

milk, nuts,

Drugs

Detergents

Animal hair

strawberries;

Vaccines

Formalin

Insect parts

fish)

Serum

Rubber

Formalin

Food additives

Enzymes

Glue

Drugs

Drugs (aspirin,

Hormones

Solvents

Enzymes

penicillin)

Dyes

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2. Their capacity to bind IgE during sensitization (figure

17.3). Each cell carries 30,000 to 100,000 cell receptors
that attract 10,000 to 40,000 IgE antibodies.

3. Their cytoplasmic granules (secretory vesicles), which

contain physiologically active cytokines (histamine,
serotonin—introduced in chapter 14).

4. Their tendency to degranulate (figures 17.3b and 17.4),

or release the contents of the granules into the tissues
when properly stimulated by allergen.

Let us now see what occurs when sensitized cells are challenged
with allergen a second time.

The Second Contact with Allergen

After sensitization, the IgE-primed mast cells can remain in the tis-
sues  for  years.  Even  after  long  periods  without  contact,  a  person
can retain the capacity to react immediately upon reexposure. The
next  time  allergen  molecules  contact  these  sensitized  cells,  they
bind  across  adjacent  receptors  and  stimulate  degranulation.  As
chemical mediators are released, they diffuse into the tissues and
bloodstream. Cytokines give rise to numerous local and systemic
reactions, many of which appear quite rapidly (figure 17.3b). The
symptoms of allergy are not caused by the direct action of allergen
on tissues but by the physiological effects of mast cell mediators on
target organs.

Pollen in Los Angeles

Outlook for January

Trees

: Alder and walnut are blooming extremely early this year.

Black walnut is the worst allergy offender of the walnut family.

Weeds

: Weed season has finally ended.

Grasses

: Grasses will be mostly dormant until late February,

early March.

Molds

: Molds will continue to be sporadic and with major increases

following periods of precipitation.

Weekly Levels for December

Major

Moderate

Minor

Trees

Weeds

Grasses

Mold spores

Week 1

Week 2

Week 3

Week 4

(a)

(b)

(c)

FIGURE 17.2

Monitoring airborne allergens.

(a) The air in heavily vegetated places with a mild climate is especially laden with allergens such as pollen and

mold spores. In just one month in southern California, weed pollen subsided to near zero and mold spore levels doubled. (b) Because the dust mite

Dermatophagoides feeds primarily on human skin cells in house dust, these mites are found in abundance in bedding and carpets. Airborne mite feces
and particles from their bodies are an important source of allergies. (c) Scanning electron micrograph of a single pollen grain from a rose (6,000!).
Millions of these are released from a single flower.

(a) Source: Data from the Asthma and Allergy Foundation of America, Los Angeles, CA.

Talaro−Talaro: Foundations

in Microbiology, Fourth

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17. Disorders in Immunity

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CHAPTER 17 Disorders in Immunity

CYTOKINES, TARGET ORGANS,
AND ALLERGIC SYMPTOMS

Numerous  substances  involved  in  mediating  allergy  (and  inflam-
mation)  have  been  identified.  The  principal  chemical  mediators
produced by mast cells and basophils are histamine, serotonin, leu-
kotriene, platelet-activating factor, prostaglandins, and bradykinin
(figure 17.4). These chemicals, acting alone or in combination, ac-
count  for  the  tremendous  scope  of  allergic  symptoms.  For  some
theories  pertaining  to  this  function  of  the  allergic  response,  see
Medical Microfile 17.1. Targets of these mediators include the skin,
upper respiratory tract, gastrointestinal tract, and conjunctiva. The
general responses of these organs include rashes, itching, redness,
rhinitis, sneezing, diarrhea, and shedding of tears. Systemic targets

include smooth muscle, mucous glands, and nervous tissue. Be-
cause smooth muscle is responsible for regulating the size of blood
vessels and respiratory passageways, changes in its activity can
profoundly alter blood flow, blood pressure, and respiration. Pain,
anxiety, agitation, and lethargy are also attributable to the effects of
mediators on the nervous system.

Histamine* is the most profuse and fastest-acting allergic

mediator. It is a potent stimulator of smooth muscle, glands, and
eosinophils. Histamine’s actions on smooth muscle vary with lo-
cation. It constricts the smooth muscle layers of the small bronchi
and intestine, thereby causing labored breathing and increased

Allergen particles enter

Lymphatic vessel

carries them to

Lymph node

B cell recognizes
allergen

Fc fragments

Mast cell in tissue

IgE binds to
mast cell surface

Granules
with
inflammatory
mediators

Time

Sensitization/IgE Production

Degranulation

Mast cells

trigg

ers

Allergen particle is encountered again

End result: Symptoms in various organs

Red, itchy eyes

Hives

Runny
nose

Subsequent Exposure to Allergen

Systemic distribution of
mediators in bloodstream

proliferates
into

Plasma cells

Synthesize

IgE

B cell

(b)

(a)

FIGURE 17.3

A schematic view of cellular reactions during the type I allergic response.

(a) Sensitization (initial contact with sensitizing dose).

(b) Provocation (later contacts with provocative dose).

histamine

(his´-tah-meen) Gr. histio, tissue, and amine.