Disorders in Immunity pdf - D. Talib

Talaro−Talaro: Foundations
in Microbiology, Fourth

Edition

17. Disorders in Immunity

Text

508

CHAPTER 17 Disorders in Immunity

Type II Hypersensitivities: Reactions
That Lyse Foreign Cells

The diseases termed type II hypersensitivities are a complex group
of syndromes that involve complement-assisted destruction (lysis)
of cells by antibodies (IgG and IgM) directed against those cells’
surface antigens. This category includes transfusion reactions and
some types of autoimmunities (discussed in a later section). The
cells targeted for destruction are often red blood cells, but other
cells can be involved.

HUMAN BLOOD TYPES

Chapters 14 and 15 described the functions of unique surface re-
ceptors or markers on cell membranes. Ordinarily, these receptors
play essential roles in transport, recognition, and development, but
they become medically important when the tissues of one person
are placed into the body of another person. Blood transfusions and
organ donations introduce alloantigens (molecules that differ in the

same species) on donor cells that are recognized by the lympho-
cytes of the recipient. These reactions are not really immune dys-
functions as allergy and autoimmunity are. The immune system is
in fact working normally, but it is not equipped to distinguish
between the desirable foreign cells of a transplanted tissue and the
undesirable ones of a microbe.

THE BASIS OF HUMAN ABO
ANTIGENS AND BLOOD TYPES

The existence of human blood types was first demonstrated by an
Austrian pathologist, Karl Landsteiner, in 1904. While studying in-
compatibilities in blood transfusions, he found that the serum of one
person could clump the red blood cells of another. Landsteiner iden-
tified four distinct types, subsequently called the ABO blood groups.

Like the MHC antigens on white blood cells, the ABO anti-

gen markers on red blood cells are genetically determined and com-
posed of glycoproteins. These ABO antigens are inherited as two
(one from each parent) of three alternative

alleles:* A, B, or O. A

and B alleles are dominant over O and codominant with one an-
other. As table 17.3 indicates, this mode of inheritance gives rise to
four blood types (phenotypes), depending on the particular combi-
nation of genes. Thus, a person with an

AA or AO genotype has

type A blood; genotype BB or BO gives type B; genotype AB

Type I hypersensitivity reactions result from excessive IgE production in

response to an exogenous antigen.

The two kinds of type I hypersensitivities are atopy, a chronic, local

allergy, and anaphylaxis, a systemic, potentially fatal allergic response.

The predisposition to type I hypersensitivities is inherited, but age,

geographic locale, and infection also influence allergic response.

Type I allergens include inhalants, ingestants, injectants, and contactants.

The portals of entry for type I antigens are the skin, respiratory tract,

gastrointestinal tract, and genitourinary tract.

Type I hypersensitivities are set up by a sensitizing dose of allergen and

expressed when a second provocative dose triggers the allergic
response. The time interval between the two can be many years.

The primary participants in type I hypersensitivities are IgE, basophils,

mast cells, and agents of the inflammatory response.

Allergies are diagnosed by a variety of in vitro and in vivo tests that

assay specific cells, IgE, and local reactions.

Allergies are treated by medications that interrupt the allergic response at

certain points. Allergic reactions can often be prevented by
desensitization therapy.

CHAPTER CHECKPOINTS

Allergen

IgG
"blocking
antibodies"

B Cell / Plasma Cell

Mast Cell

IgE

No IgE

FIGURE 17.8

The blocking antibody theory for allergic
desensitization.

An injection of allergen

causes IgG antibodies to be formed instead of
IgE; these blocking antibodies cross-link and
effectively remove the allergen before it can react
with the IgE in the mast cell.

TABLE 17.3

Characteristics of ABO Blood Groups

Phenotype A
or B* RBC

Prevalence in

Serum Content

Genotype

Antigen

Population**

of Antibodies

Neither

Most common

Both anti-a

and anti-b

AA, AO

Second most

Anti-b

common

BB, BO

Third most

Anti-a

common

Least common

Neither

antibody

*Capital letters generally denote antigen; lowercase denotes antibody.
**True of most large populations of mixed racial and ethnic groups.

allele

(ah-leel

) Gr. allelon, of one another. An alternate form of a gene for a given trait.

Talaro−Talaro: Foundations
in Microbiology, Fourth

Edition

17. Disorders in Immunity

Text

Type II Hypersensitivities: Reactions That Lyse Foreign Cells

509

produces

type AB; and genotype OO produces type O. Some im-

portant points about the blood types are: (1) They are named for the
dominant antigen(s); (2) the RBCs of type O persons have antigens,
but not A and B antigens; and (3) tissues other than RBCs carry A
and B antigens.

The actual origin of the AB antigens and blood types are

shown in figure 17.9. The A and B genes each code for an enzyme
that adds a terminal carbohydrate to RBC receptors during matura-
tion. RBCs of type A contain an enzyme that adds N-acetylgalac-
tosamine to the receptor; RBCs of type B have an enzyme that adds
D-galactose; RBCs of type AB contain both enzymes that add both
carbohydrates; and RBCs of type O lack the genes and enzymes to
add a terminal molecule.

ANTIBODIES AGAINST A AND B ANTIGENS

Although an individual does not normally produce antibodies in
response to his or her own RBC antigens, the serum can contain
antibodies that react with blood of another antigenic type, even
though contact with this other blood type has

never occurred.

These  performed  antibodies  account  for  the  immediate  and  in-
tense  quality  of  transfusion  reactions.  As  a  rule,  type  A blood
contains  antibodies  (anti-b)  that  react  against  the  B  antigens  on
type B and AB red blood cells. Type B blood contains antibodies
(anti-a)  that  react  with  A antigen  on  type  A and  AB  red  blood

cells. Type O blood contains antibodies against both A and B anti-
gens. Type AB blood does not contain antibodies against either
A or B antigens

(table 17.3). What is the source of these anti-a

and anti-b antibodies? It appears that they develop in early in-
fancy because of exposure to certain heterophile antigens that are
widely distributed in nature. These antigens are surface molecules
on bacteria and plant cells that mimic the structure of A and B
antigens. Exposure to these sources stimulates the production of
corresponding antibodies.

Clinical Concerns in Transfusions

The presence of ABO antigens and a, b antibodies underlie several
clinical concerns in giving blood transfusions. First, the individual
blood types of donor and recipient must be determined. By use of a
standard technique, drops of blood are mixed with antisera that
contain antibodies against the A and B antigens and are then ob-
served for the evidence of agglutination (figure 17.10).

Knowing the blood types involved makes it possible to deter-

mine which transfusions are safe to do. The general rule of compat-
ibility is that the RBC antigens of the donor must not be aggluti-
nated by antibodies in the recipient’s blood (figure 17.11). The ideal
practice is to transfuse blood that is a perfect match (A to A, B to
B). But even in this event, blood samples must be cross-matched
before the transfusion because other blood group incompatibilities
can exist. This test involves mixing the blood of the donor with the
serum of the recipient to check for agglutination.

Under certain circumstances (emergencies, the battlefield),

the concept of universal transfusions can be used. To appreciate
how this works, we must apply the rule stated in the previous para-
graph. Type O blood lacks A and B antigens and will not be agglu-
tinated by other blood types, so it could theoretically be used in any
transfusion. Hence, a person with this blood type is called a

univer-

sal donor. Because type AB blood lacks agglutinating antibodies,
an individual with this blood could conceivably receive any type of
blood. Type AB persons are consequently called

universal recipi-

ents. Although both types of transfusions involve antigen-antibody
incompatibilities, these are of less concern because of the dilution
of the donor’s blood in the body of the recipient. Additional RBC
markers that can be significant in transfusions are the Rh, MN, and
Kell antigens (see next sections).

Transfusion of the wrong blood type causes various degrees

of  adverse  reaction.  The  severest  reaction  is  massive  hemolysis
when  the  donated  red  blood  cells  react  with  recipient  antibody
and trigger the complement cascade (figure 17.11). The resultant
destruction of red cells leads to systemic shock and kidney failure
brought on by the blockage of glomeruli (blood-filtering appara-
tus) by cell debris. Death is a common outcome. Other reactions
caused  by  RBC  destruction  are  fever,  anemia,  and  jaundice.  A
transfusion reaction is managed by immediately halting the trans-
fusion,  administering  drugs  to  remove  hemoglobin  from  the
blood, and beginning another transfusion with red blood cells of
the correct type.

RBC

Terminal sugar

Common receptor

Type A

Type B

Type AB

Type O

FIGURE 17.9

The genetic/molecular basis for the A and B antigens (receptors) on
red blood cells.

In general, persons with blood types A, B, and AB

inherit  a  gene  for  the  enzyme  that  adds  a  certain  terminal  sugar  to  the
basic  RBC  receptor.  Type  O  persons  do  not  have  such  an  enzyme  and
lack  the  terminal  sugar.

1. Why would this be true? The answer lies in the first sentence of the paragraph.

2. Evidence comes from germ-free chickens, which do not have antibodies against the

antigens of blood types, whereas normal chickens possess these antibodies.

Talaro−Talaro: Foundations
in Microbiology, Fourth

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CHAPTER 17 Disorders in Immunity

THE RH FACTOR AND ITS
CLINICAL IMPORTANCE

Another RBC antigen of major clinical concern is the

Rh factor (or

D antigen). This factor was first discovered in experiments explor-
ing  the  genetic  relationships  among  animals.  Rabbits  inoculated
with the RBCs of rhesus monkeys produced an antibody that also
reacted with human RBCs. Further tests showed that this monkey
antigen (termed Rh for rhesus) was present in about 85% of humans
and absent in the other 15%. The details of Rh inheritance are more
complicated than those of ABO, but in simplest terms, a person’s
Rh  type  results  from  a  combination  of  two  possible  alleles—a
dominant one that codes for the factor and a recessive one that does
not. A person  inheriting  at  least  one  Rh  gene  will  be  Rh

; only

those persons inheriting two recessive genes are Rh

. This factor is

denoted by a symbol above the blood type, as in O

or AB

(see

figure 17.10

c). However, unlike the ABO antigens, exposure to nor-

mal flora does not sensitize Rh

persons to the Rh factor. The only

ways one can develop antibodies against this factor are through pla-
cental sensitization or transfusion.

(a)

(b)

Type A Donor

Type B Recipient

Complement

Hemoglobin
being released

FIGURE 17.10

Interpretation of blood typing.

In this test, a drop of blood is mixed with a specially

prepared  antiserum  known  to  contain  antibodies  against  the  A,  B,  or  Rh  antigens.  (a) If
that  particular  antigen  is  not  present,  the  red  blood  cells  in  that  droplet  do  not  agglutinate
and  form  an  even  suspension.  (b) If  that  antigen  is  present,  agglutination  occurs  and  the
RBCs  form  visible  clumps.  (c) Several  patterns  and  their  interpretations.  Anti-a,  anti-b,
and  anti-Rh  are  shorthand  for  the  antiserum  applied  to  the  drops.  (In  general,  O

is the

most common blood type, and AB

is the rarest.)

FIGURE 17.11

Microscopic view of a transfusion reaction.

(a) Incompatible

blood. The red blood cells of the type A donor contain antigen A,

while the serum of the type B recipient contains anti-a antibodies that can
agglutinate donor cells. (b) Agglutination particles can block the
circulation in vital organs. (c) Activation of the complement by antibody on
the RBCs can cause hemolysis and anemia. This sort of incorrect
transfusion is very rare because of the great care taken by blood banks to
ensure a correct match.

(a)

(b)

(c)

Blood
type

O+

Anti-Rh

Anti-b

Anti-a

B+

(c)

Talaro−Talaro: Foundations
in Microbiology, Fourth

Edition

17. Disorders in Immunity

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Type II Hypersensitivities: Reactions That Lyse Foreign Cells

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Hemolytic Disease of the Newborn
and Rh Incompatibility

The potential for placental sensitization occurs when a mother is
Rh

and her unborn child is Rh

. The obvious intimacy between

mother and fetus makes it possible for fetal RBCs to leak into the
mother’s circulation during childbirth, when the detachment of the
placenta creates avenues for fetal blood to enter the maternal circu-
lation. The mother’s immune system detects the foreign Rh factors
on the fetal RBCs and is sensitized to them by producing antibod-
ies and memory B cells. The first Rh

child is usually not affected

because  the  process  begins  so  late  in  pregnancy  that  the  child  is
born  before  maternal  sensitization  is  completed.  However,  the
mother’s  immune  system  has  been  strongly  primed  for  a  second
contact with this factor in a subsequent pregnancy (figure 17.12

a).

In the next pregnancy with an Rh

fetus, fetal blood cells es-

cape into the maternal circulation late in pregnancy and elicit a
memory response. The fetus is at risk when the maternal anti-Rh
antibodies cross the placenta into the fetal circulation, where they
affix to fetal RBCs and cause complement-mediated lysis. The out-
come is a potentially fatal

hemolytic disease of the newborn

(HDN) called erythroblastosis fetalis (eh-rith

-roh-blas-toh-sis

fee-tal

-is). This term is derived from the presence of immature nu-

cleated RBCs called erythroblasts in the blood. They are released
into the infant’s circulation to compensate for the massive destruc-
tion of RBCs by maternal antibodies. Additional symptoms are se-
vere anemia, jaundice, and enlarged spleen and liver.

Maternal-fetal incompatibilities are also possible in the ABO

blood group, but adverse reactions occur less frequently than with

First Rh

fetus

Anti-Rh antibody

fetus

Rh factor
on RBCs

Placenta breaks
away

–

mother

Erythroblasts

in blood

Second Rh

fetus

Late in second pregnancy

of Rh

child

First Rh

fetus

Anti-Rh
antibodies
(RhoGAM)

RBCs

–

mother

(a) The development and aftermath of Rh sensitization.

(b) Prevention of erythroblastosis fetalis with anti-Rh immune globulin (RhoGAM)

FIGURE 17.12

Development and control of Rh incompatibility.

(a) Initial

sensitization  of  the  maternal  immune  system  to  fetal  Rh  factor  occurs
when  fetal  cells  leak  into  the  mother’s  circulation  late  in  pregnancy,  or
during  delivery,  when  the  placenta  tears  away.  The  child  will  escape
hemolytic  disease  in  most  instances,  but  the  mother,  now  sensitized,
will  be  capable  of  an  immediate  reaction  to  a  second  Rh

fetus and its

Rh-factor  antigen.  At  that  time,  the  mother’s  anti-Rh  antibodies  pass
into  the  fetal  circulation  and  elicit  severe  hemolysis  in  the  fetus  and
neonate.  (b) Prevention  of  erythroblastosis  fetalis  with  anti-Rh  immune
globulin  (RhoGAM).  Injecting  a  mother  who  is  at  risk  with  RhoGAM
during  her  first  Rh

pregnancy helps to inactivate and remove the fetal

Rh-positive cells before her immune system can react and develop
sensitivity.

Talaro−Talaro: Foundations
in Microbiology, Fourth

Edition

17. Disorders in Immunity

Text

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CHAPTER 17 Disorders in Immunity

Rh sensitization because the antibodies to these blood group anti-
gens are IgM rather than IgG and are unable to cross the placenta in
large numbers. In fact, the maternal-fetal relationship is a fascinat-
ing instance of foreign tissue not being rejected, despite the exten-
sive potential for contact (Medical Microfile 17.2).

Preventing Hemolytic Disease of the Newborn

Once sensitization of the mother to Rh factor has occurred, all other
Rh

fetuses will be at risk for hemolytic disease of the newborn.

Prevention requires a careful family history of an Rh

pregnant

woman. It can predict the likelihood that she is already sensitized or
is carrying an Rh

fetus. It must take into account other children

she has had, their Rh types, and the Rh status of the father. If the fa-
ther is also Rh

, the child will be Rh

and free of risk, but if the fa-

ther is Rh

, the probability that the child will be Rh

is 50% or

100%, depending on the exact genetic makeup of the father. If there
is any possibility that the fetus is Rh

, the mother must be pas-

sively immunized with antiserum containing antibodies against the
Rh factor (

[

D] immune globulin, or RhoGAM*). This anti-

serum, injected at 28 to 32 weeks and again immediately after de-
livery, reacts with any fetal RBCs that have escaped into the mater-
nal circulation, thereby preventing the sensitization of the mother’s
immune system to Rh factor (figure 17.12

b). Anti-Rh antibody

must be given with each pregnancy that involves an Rh

fetus. It is

ineffective if the mother has already been sensitized by a prior Rh

fetus or an incorrect blood transfusion, which can be determined by
a serological test. As in ABO blood types, the Rh factor should be
matched for a transfusion, although it is acceptable to transfuse
Rh

blood if the Rh type is not known.

OTHER RBC ANTIGENS

Although the ABO and Rh systems are of greatest medical signifi-
cance, about 20 other red blood cell antigen groups have been
discovered. Examples are the

MN, Ss, Kell, and P blood groups.

Because of incompatibilities that these blood groups present, trans-
fused blood is screened to prevent possible cross-reactions. The
study of these blood antigens (as well as ABO and Rh) has given
rise to other useful applications. For example, they can be useful in

forensic medicine (crime detection), studying ethnic ancestry, and
tracing prehistoric migrations in anthropology. Many blood cell
antigens are remarkably hardy and can be detected in dried blood
stains, semen, and saliva. Even the 2,000-year-old mummy of King
Tutankhamen has been typed A

MN!

MEDICAL MICROFILE

17.2

Why Doesn’t a Mother Reject Her Fetus?

what ways do fetuses avoid the surveillance of the mother’s immune sys-
tem? The answer appears to lie in the placenta and embryonic tissues.
The fetal components that contribute to these tissues are not strongly
antigenic, and they form a barrier that keeps the fetus isolated in its own
antigen-free environment. The placenta is surrounded by a dense, many-
layered envelope that prevents the passage of maternal cells, and it ac-
tively absorbs, removes, and inactivates circulating antigens.

Think of it: Even though mother and child are genetically related, the fa-
ther’s genetic contribution guarantees that the fetus will contain mole-
cules that are antigenic to the mother. In fact, with the recent practice of
implanting one woman with the fertilized egg of another woman, the sur-
rogate mother is carrying a fetus that has no genetic relationship to her.
Yet, even with this essentially foreign body inside the mother, dangerous
immunologic reactions such as Rh incompatibility are rather rare. In

RhoGAM

Immunoglobulin fraction of human anti-Rh serum, prepared from pooled

human sera.

Type II hypersensitivity reactions occur when preformed antibodies

react  with  foreign  cell-bound antigens. The most common type II
reactions  occur  when  transfused  blood  is  mismatched  to  the  recipient’s
ABO  type. IgG  or  IgM  antibodies  attach  to  the  foreign  cells,  resulting
in  complement  fixation. The  resultant  formation  of  membrane  attack
complexes  lyses  the  donor  cells.

Type II hypersensitivities are stimulated by antibodies formed against red

blood cell (RBC) antigens or against other cell-bound antigens
following prior exposure.

Complement, IgG, and IgM antibodies are the primary mediators of

type II hypersensitivities.

The concepts of universal donor (type O) and universal recipient

(type  AB)  apply  only  under  emergency  circumstances. Cross-matching
donor  and  recipient  blood  is  necessary  to  determine  which
transfusions  are  safe  to  perform.

Type II hypersensitivities can also occur when Rh

mothers are sensitized

to Rh

RBCs of their unborn babies and the mother’s anti-Rh antibodies

cross the placenta, causing hemolysis of the newborn’s RBCs. This is
called hemolytic disease of the newborn, or erythroblastosis fetalis.

CHAPTER CHECKPOINTS

Type III Hypersensitivities: Immune
Complex Reactions

Type  III  hypersensitivity  involves  the  reaction  of  soluble  antigen
with antibody and the deposition of the resulting complexes in base-
ment membranes of epithelial tissue. It is similar to type II, because
it involves the production of IgG and IgM antibodies after repeated
exposure  to  antigens  and  the  activation  of  complement.  Type  III
differs from type II because its antigens are not attached to the sur-
face  of  a  cell.  The  interaction  of  these  antigens  with  antibodies