introduction to medical immunology

Page i
Introduction to Medical Immunology
Fourth Edition
Edited by
Gabriel Virella
Medical University of South Carolina
Charleston, South Carolina
MARCEL DEKKER, INC.
N
EW
Y
ORK
• B
ASEL
• H
ONG
K
ONG


Page ii
Library of Congress Cataloging-in-Publication Data
Introduction to medical immunology / edited by Gabriel Virella. — 4th ed.
p. cm.

Includes bibliographical references and index.
ISBN 0-8247-9897-X (hardcover : alk. paper)

1. Clinical immunology. 2. Immunology. I. Virella, Gabriel.
[DNLM: 1. Immunity. 2. Immunologic Diseases. QW 504 I6286 1997]
RC582.I59 1997
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DNLM/DLC
for Library of Congress
97-22373
CIP
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Page iii
PREFACE
Ten years after the publication of the first edition of
Introduction to Medical Immunology
, the ideal immunology
textbook continues to be a very elusive target. The discipline continues to grow at a brisk pace, and the concepts tend to

become obsolete as quickly as we put them in writing. It is very true of immunology that the more we know, the greater
our ignorance. This represents the challenge that makes teaching immunology so exceptional and writing immunology
textbooks such a daunting task.
The fourth edition of
Introduction to Medical Immunology
retains the features that make this textbook unique—
particularly, its emphasis on the clinical application of immunology
—but represents a significant departure from the
earlier editions. Most changes have resulted from our strong conviction that this textbook is not written to impress our
peers with extraordinary insights or revolutionary knowledge, but rather to be helpful to medical students and young
professionals who need an introduction to the field. The requirements that we tried to fulfill were sometimes difficult to
conciliate. The text needs to be updated and relatively complete, but not overwhelming. The scientific basis of
immunology needs to be clearly conveyed without allowing the detail to obscure the concept. The application to
medicine needs to be transparently obvious, but without unnecessary exaggeration. The text must present a reasonably
general and succinct overview, while covering areas that appear likely to have a strong impact in the foreseeable future.
The book needs to stimulate students to seek more information and to develop their own “thinking” without being
merely a model of theoretical dreams (and nightmares).
In what is probably not an entirely successful attempt to fulfill some of these goals, we have extensively revised the
book, added significant new concepts, and deleted areas that were clearly obsolete. The clinical sections are peppered
with cases in order to provide a solid link between the discussion of concrete problems presented by patients with
diseases of immunological basis and the relevant immunological principles. More significantly, the book has been
rewritten in an outline format. This format allows us to keep the conceptual approach while facilitating the
understanding of a reader facing the complexities of immunology with very little background. Of necessity, the book
emphasizes that which is well understood, as clearly as we can present it, and we try to promote a general understanding
of the discipline at the end of the twentieth century. It is not, and never will be, a finished work. We are certain that we
will always wish we could add here and revise there. But we hope that this new edition will be even more successful in
focusing the


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attention of our readers toward an intrinsically fascinating discipline that seeks understanding of fundamental biological
knowledge that has direct impact on the diagnosis and treatment of a variety of conditions in which the immune system
plays a key role.
GABRIEL VIRELLA, M.D., PH.D.



Page v
CONTENTS
Preface
iii
Contributors
ix
Part I. Basic Immunology
Gabriel Virella
1. Introduction
1
Gabriel Virella and Jean-Michel Goust
2. Cells and Tissues Involved in the Immune Response
11
Jean-Michel Goust
3. Major Histocompatibility Complex
31
Gabriel Virella and Barbara E. Bierer
4. The Induction of an Immune Response: Antigens, Lymphocytes, and Accessory
Cells
49
Gabriel Virella and An-Chuan Wang
5. Immunoglobulin Structure
75

Gabriel Virella and An-Chuan Wang
6. Biosynthesis, Metabolism, and Biological Properties of Immunoglobulins
91
Janardan P. Pandey
7. Genetics of Immunoglobulins
105
Gabriel Virella
8. Antigen-Antibody Reactions
121
Robert J. Boackle
9. The Complement System
137
Jean-Michel Goust and Anne L. Jackson
10. Lymphocyte Ontogeny and Membrane Markers
163
Jean-Michel Goust and Barbara E. Bierer
11. Cell-Mediated Immunity
187

Page vi
Gabriel Virella
12. The Humoral Immune Response and Its Induction by Active Immunization
217
Gabriel Virella
13. Infections and Immunity
239
Part II. Diagnostic Immunology
Gabriel Virella
14. Immunoserology
259

Gabriel Virella
15. Diagnostic Evaluation of Humoral Immunity
283
Gabriel Virella and Jean-Michel Goust
16. Diagnostic Evaluation of Lymphocyte Functions and Cell-Mediated Immunity
297
Gabriel Virella
17. Diagnostic Evaluation of Phagocytic Function
317
Part III. Clinical Immunology
Jean-Michel Goust, George C. Tsokos, and Gabriel Virella
18. Tolerance and Autoimmunity
335
Christian C. Patrick, Jean-Michel Goust, and Gabriel Virella
19. Organ-Specific Autoimmune Diseases
363
Jean-Michel Goust and George C. Tsokos
20. Systemic Lupus Erythematosus
383
Jean-Michel Goust
21. Rheumatoid Arthritis
399
Gabriel Virella
22. Hypersensitivity Reactions
417
Jean-Michel Goust and Albert F. Finn, Jr.
23. IgE-Mediated (Immediate) Hypersensitivity
433
Gabriel Virella and Mary Ann Spivey
24. Immunohematology

453
Gabriel Virella and George C. Tsokos
25. Immune Complex Diseases
475
Jean-Michel Goust, Henry C. Stevenson-Perez, and Gabriel Virella
26. Immune System Modulators
495
Gabriel Virella and Jonathan S. Bromberg
27. Transplantation Immunology
517



Page vii
Henry C. Stevenson-Perez and Kwong-Y. Tsang
28. Tumor Immunology
535
Gabriel Virella and Jean-Michel Goust
29. Malignancies of the Immune System
553
Gabriel Virella
30. Immunodeficiency Diseases
579
Index
621


Page ix
CONTRIBUTORS
Barbara E. Bierer, M.D.

Associate Professor of Medicine, Department of Pediatric Oncology, Dana Farber Cancer
Institute, Boston, Massachusetts
Robert J. Boackle, Ph.D.
Professor and Director of Oral Biology and Professor of Immunology, Division of
Stomatology, Medical University of South Carolina, Charleston, South Carolina
Jonathan S. Bromberg, M.D., Ph.D.
Associate Professor of Surgery, Microbiology, and Immunology, Department of
General Surgery, Transplant Division, University of Michigan Hospitals, Ann Arbor, Michigan
Albert F. Finn, Jr., M.D.
Clinical Assistant Professor, Departments of Medicine, Microbiology and Immunology,
Medical University of South Carolina, Charleston, South Carolina
Jean-Michel Goust, M.D.
Professor of Immunology, Department of Microbiology and Immunology, Medical
University of South Carolina, Charleston, South Carolina
Anne L. Jackson, Ph.D.
Consultant, Ridgefield, Washington
Janardan P. Pandey, Ph.D.
Professor, Department of Microbiology and Immunology, Medical University of South
Carolina, Charleston, South Carolina
Christian C. Patrick, M.D., Ph.D.
Director of Academic Programs and Associate Member, Department of Infectious
Diseases and Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee
Mary Ann Spivey, M.H.S., M.T. (A.S.C.P.), S.B.B.
Department of Pathology-Laboratory Medicine, Transfusion
Medicine Section, Medical University of South Carolina, Charleston, South Carolina
Henry C. Stevenson-Perez, M.D.
Senior Investigator, Biologics Evaluation Section, Investigational Drug Branch,
National Cancer Institute, National Institutes of Health, Rockville, Maryland

Page x
Kwong-Y. Tsang, Ph.D.
Senior Scientist, Laboratory of Tumor Immunology and Biology, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland
George C. Tsokos, M.D.
Professor, Department of Medicine, Uniformed Services University of Health Sciences,
Bethesda, Maryland, and Department of Clinical Investigations, Walter Reed Army Medical Center, Washington, D.C.
Gabriel Virella, M.D., Ph.D.
Professor and Vice Chairman of Education, Department of Microbiology and
Immunology, Medical University of South Carolina, Charleston, South Carolina.
An-Chuan Wang, Ph.D.
Professor, Department of Microbiology and Immunology, Medical University of South
Carolina, Charleston, South Carolina


Page 1
1
Introduction
Gabriel Virella
I. Introduction
A.
The fundamental observation that led to the development of immunology as a scientific discipline was that an
individual can become resistant for life to a certain disease after having contracted it only once. The term immunity,
derived from the Latin “immunis” (
exempt), was adopted to designate this naturally acquired protection against diseases
such as measles or smallpox.
B.
The emergence of immunology as a discipline was closely tied to the development of microbiology. The work of
Pasteur, Koch, Metchnikoff, and many other pioneers of the golden age of microbiology resulted in the rapid
identification of new infectious agents, closely followed by the discovery that infectious diseases could be prevented by

exposure to killed or attenuated organisms, or to compounds extracted from the infectious agents. The impact of
immunization against infectious diseases such as tetanus, pertussis, diphtheria, and smallpox, to name just a few
examples, can be grasped when we reflect on the fact that these diseases, which were significant causes of mortality and
morbidity, are now either extinct or very rarely seen. Indeed, it is fair to state that the impact of vaccination and
sanitation on the welfare and life expectancy of humans has had no parallel in any other developments of medical
science.
C.
In the second part of this century, immunology started to transcend its early boundaries and become a more general
biomedical discipline. Today, the study of immunological defense mechanisms is still an important area of research, but
immunologists are involved in a much wider array of problems, such as self-nonself discrimination, control of cell and
tissue differentiation, transplantation, cancer immunotherapy, etc. The focus of interest has shifted toward the basic
understanding of how the immune system works in the hope that this insight will allow novel approaches to its
manipulation.
II. General Concepts
A. Specific and Nonspecific Defenses.
The protection of the organism against infectious agents involves many different
mechanisms, some nonspecific (i.e.,


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generically applicable to many different pathogenic organisms), and others specific (i.e., their protective effect is
directed to one single organism).
1.
Nonspecific defenses,
which as a rule are innate (i.e., all normal individuals are born with it), include:
a. Mechanical barriers, such as the integrity of the epidermis and mucosal membranes.
b. Physicochemical barriers, such as the acidity of the stomach fluid.
c. Antibacterial substances (e.g., lysozyme) present in external secretions.
d. Normal intestinal transit and normal flow of bronchial secretions and urine, which eliminate infectious
agents from the respective systems.

e. Ingestion and elimination of bacteria and particulate matter by
granulocytes,
which is independent of the
immune response.
2.
Specific defenses,
as a rule, are induced during the life of the individual as part of the complex sequence of
events designated as the
immune response.
B. Unique Characteristics of the Immune Response.
The immune response has two unique characteristics:
1.
Specificity
for the eliciting antigen. For example, immunization with poliovirus only protects against
poliomyelitis, not against the flu. The specificity of the immune response is due to the existence of exquisitely
discriminative antigen receptors on lymphocytes. Only a single or a very limited number of similar structures can
be accommodated by the receptors of any given lymphocyte. When those receptors are occupied, an activating
signal is delivered to the lymphocytes. Therefore, only those lymphocytes with specific receptors for the antigen in
question will be activated.
2.
Memory,
meaning that repeated exposures to a given antigen elicit progressively more intense specific
responses. Most immunizations involve repeated administration of the immunizing compound, with the goal of
establishing a long-lasting, protective response. The increase in the magnitude and duration of the immune
response with repeated exposure to the same antigen is due to the proliferation of antigen-specific lymphocytes
after each exposure. The numbers of responding cells will remain increased even after the immune response
subsides. Therefore, whenever the organism is exposed again to that particular antigen, there is an expanded
population of specific lymphocytes available for activation and, as a consequence, the time needed to mount a
response is shorter and the magnitude of the response is higher.
C. Stages of the Immune Response.

To better understand how the immune response is generated, it is useful to
consider it as divided into separate sequential stages (Table 1.1). The first stage (induction) involves a small lymphocyte
population with specific receptors able to recognize an antigen or a fragment generated by specialized cells known as
antigen-presenting cells (APC). The proliferation and differentiation of antigen-responding lymphocytes is usually
enhanced by amplification systems involving APC and specialized T-
cell subpopulations (T helper cells, defined below)
and is followed by the production of effector molecules (antibodies) or by the differentiation of effector cells (cells
which directly or indirectly mediate the elimination of undesirable elements). The final outcome, therefore, is the
elimination of the microbe or compound that triggered the



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Table 1.1
A Simplified Overview of the Three Main Stages of the Immune Response
Stage of the immune
response
Induction
Amplification
Effector
Cells/molecules
involved
Antigen-presenting cells;
lymphocytes
Antigen presenting cells; helper
T lymphocytes
Antibodies (+ complement or
cytotoxic cells); cytotoxic T
lymphocytes; macrophages
Mechanisms

Processing and/or presentation
of antigen; recognition by
specific receptors on
lymphocytes
Release of cytokines; signals
mediated by interaction between
cell membrane molecules
Complement-mediated lysis;
opsonization and phagocytosis;
cytotoxicity
Consequences
Activation of T and B
lymphocytes
Proliferation and differentiation
of T and B lymphocytes
Elimination of non-self;
neutralization of toxins and viruses
reaction by means of activated immune cells or by reactions triggered by mediators released by the immune system.
III. The Cells of the Immune System
A. Lymphocytes and Lymphocyte Subpopulations.
The peripheral blood contains two large populations of cells: the red
cells, whose main physiological role is to carry oxygen to tissues, and the white blood cells, which have as their main
physiological role the elimination of potentially harmful organisms or compounds. Among the white blood cells,
lymphocytes are particularly important because of their primordial role in the immune response. Several subpopulations of
lymphocytes have been defined:
1.
B lymphocytes,
which are the precursors of antibody-producing cells, known as plasma cells.
2.
T lymphocytes,

or T-cells, which are further divided into several subpopulations:
a.
Helper T lymphocytes (TH),
which play a very significant amplification role in the immune responses. Two
functionally distinct subpopulations of T helper lymphocytes have been well defined in mice.
i. TH1 lymphocytes, which assist the differentiation of cytotoxic cells and also activate macrophages, which
after activation play a role as effectors of the immune response.
ii. TH2 lymphocytes, which are mainly involved in the amplification of B lymphocyte responses.
These amplifying effects of helper T lymphocytes are mediated in part by soluble mediators
—
interleukins—
and in part by signals delivered as a consequence of cell-cell contact.


Page 4
b.
Cytotoxic T lymphocytes,
which are the main immunological effector mechanisms involved in the
elimination of non-self or infected cells.
3.
Antigen-presenting cells,
such as the macrophages and macrophage-related cells, play a very significant role in
the induction stages of the immune response by trapping and presenting both native antigens and antigen fragments
in a most favorable way for the recognition by lymphocytes. In addition, these cells also deliver activating signals
to lymphocytes engaged in antigen recognition, both in the form of soluble mediators (interleukins such as IL-12
and IL-1) and in the form of signals delivered by cell-cell contact.
4.
Phagocytic and cytotoxic cells,
such as monocytes, macrophages, and granulocytes, also play significant roles
as effectors of the immune response. Once antibody has been secreted by plasma cells and is bound by the

microbes, cells, or compounds that triggered the immune response, it is able to induce their ingestion by
phagocytic cells. If bound to live cells, antibody may induce the attachment of cytotoxic cells that cause the death
of the antibody-coated cell
(antibody-dependent cellular cytotoxicity; ADCC).
The ingestion of microorganisms
or particles coated with antibody is enhanced when an amplification effector system known as
complement
is
activated.
5.
Natural killer (NK) cells
play a dual role in the elimination of infected and malignant cells. These cells are
unique in that they have two different mechanisms of recognition: they can identify directly virus-infected and
malignant cells and cause their destruction, and they can participate in the elimination of antibody-coated cells by
ADCC.
IV. Antigens and Antibodies
A. Antigens
are non-self substances (cells, proteins, polysaccharides) that are recognized by receptors on lymphocytes,
thereby eliciting the immune response. The receptor molecules located on the membrane of lymphocytes interact with
small portions of those foreign cells or proteins, designated as
antigenic determinants
or
epitopes.
An adult human
being has the capability of recognizing millions of different antigens, some of microbial origin, others present in the
environment, and even some artificially synthesized.
B. Antibodies
are proteins that appear in circulation after immunization and that have the ability to react specifically
with the antigen used to immunize. Because antibodies are soluble and are present in virtually all body fluids
(“humors”), the term

humoral immunity
was introduced to designate the immune responses in which antibodies play
the principal role as effector mechanisms. Antibodies are also generically designated as
immunoglobulins.
This term
derives from the fact that antibody molecules structurally belong to the family of proteins known as globulins (globular
proteins) and from their involvement in immunity.
C. Antigen-Antibody Reactions, Complement, and Phagocytosis.
The knowledge that the serum of an immunized
animal contained protein molecules able to bind specifically to the antigen led to exhaustive investigations of the
characteristics and consequences of the
antigen-antibody reactions.


Page 5
1. If the antigen is soluble, the reaction with specific antibody under appropriate conditions results in
precipitation

of large antigen-antibody aggregates.
2. If the antigen is expressed on a cell membrane, the cell will be cross-
linked by antibody and form visible clumps
(agglutination).
3. Viruses and soluble toxins released by bacteria lose their infectivity or pathogenic properties after reaction with
the corresponding antibodies
(neutralization).
4. Antibodies complexed with antigens can activate the
complement system.
This system is composed of nine
major proteins or components which are sequentially activated. Some of the complement components are able to
promote ingestion of microorganisms by phagocytic cells

(phagocytosis),
while others are inserted into
cytoplasmic membranes and cause their disruption, leading to cell death.
5. Antibodies can cause the destruction of microorganisms by promoting their ingestion by
phagocytic cells
or
their destruction by
cytotoxic cells.
Phagocytosis is particularly important for the elimination of bacteria and
involves the binding of antibodies and complement components to the outer surface of the infectious agent
(opsonization)
and recognition of the bound antibody and/or complement components as a signal for ingestion by
the phagocytic cell.
6. Antigen-antibody reactions are the basis of certain pathological conditions, such as allergic reactions. Antibody-
mediated allergic reactions have a very rapid onset, in a matter of minutes, and are known as
immediate
hypersensitivity reactions.
V. Lymphocytes and Cell-Mediated Immunity
A. Lymphocytes as Effector Cells.
Lymphocytes play a significant role as effector cells in two types of situations:
1.
Immune destruction of infected cells,
which are not amenable to destruction by phagocytosis or complement-
mediated lysis. The study of how the immune system recognizes and eliminates infected cells resulted in the
definition of the
biological role of the histocompatibility antigens
that had been described as responsible for
graft rejection (see below).
a. Intracellular organisms, such as viruses, need to replicate. During the replication cycle of a virus, for
example, the infected cells will synthesize viral proteins and viral nucleic acids.

b. Some of the synthesized viral proteins are cleaved by proteolytic enzymes, and the small peptides resulting
from this process become associated with histocompatibility antigens, at which point the complex is
transported to the membrane and presented to the immune system.
c. The immune system does not respond (i.e., is tolerant) to self antigens, including antigens of the
major
histocompatibility complex (MHC),
an extremely polymorphic system with hundreds of alleles, which is
responsible for the rejection of tissues and organ grafts (see below). However, the complex formed by an
autologous MHC antigen and a


Page 6
non-self viral peptide is recognized by the immune system and an immune response is mounted against cells
expressing these complexes.
d. The same general process is involved in the elimination of cells infected by bacteria, parasites, or fungi.
2. The fight against intracellular infections involves several effector mechanisms.
a. Specific
cytotoxic T lymphocytes
are able to destroy infected cells expressing complexes of MHC
molecules and microbial-derived peptides on their membrane.
b.
TH1 lymphocytes
can also recognize microbial peptides expressed on the membrane of infected cells,
particularly of macrophages and related APC. The responding TH1 cells, in turn, release cytokines, such as
interferon-
γ
,
which activate macrophages and increase their ability to destroy the intracellular infecting
agents.
3. Because of the primary involvement of lymphocytes in these reactions, they fall under the category of

cell-
mediated immunity.
The elimination of intracellular infectious agents can be considered as the main
physiological role of cell
-mediated immunity. Other immune reactions mediated by cells are responsible for
pathological conditions, as described below.
4. Some inflammatory processes, particularly skin reactions known as
cutaneous hypersensitivity,
which are
induced by direct skin contact or by intradermal injection of antigenic substances, are also mediated by T
lymphocytes. These reactions express themselves 24 to 48 hours after exposure to an antigen to which the patient
had been previously sensitized. For this reason, these reactions are designated as
delayed hypersensitivity
and are
a pathological manifestation of
cell-mediated immunity.
5. Transplantation of tissues among genetically different individuals of the same species or across species is
followed by rejection of the grafted organs or tissues
(graft rejection).
Cell-mediated immunity triggered by
differences in
transplantation
or
histocompatibility antigens,
which are generically grouped as the
MHC,
is
responsible for graft rejection.
VI. Self Versus Non-Self Discrimination
The immune response is triggered by the interaction of an antigenic determinant with specific receptors on lymphocytes.

It is calculated that there are several million different receptors in lymphocytes necessary to respond to the wide
diversity of epitopes presented by microbial agents and exogenous particles that stimulate immune responses. The basis
for such discrimination between self and non-self is the array of structural differences between self and non-self:
A.
Infectious agents have marked differences in their chemical structure, easily recognizable by the immune system.
B.
Cells, proteins, and polysaccharides from animals of different species have differences in chemical constitution
which, as a rule, are directly related to the degree of phylogenetic divergence between species. Those also elicit potent
immune responses.


Page 7
C.
Many polysaccharides and proteins from individuals of the same species show antigenic heterogeneity, reflecting the
genetic diversity of individuals within a species. Those differences are usually minor (relative to differences between
species), but can still be recognized by the immune system. Transfusion reactions, graft rejection, and hypersensitivity
reactions to exogenous human proteins are clinical expressions of the recognition of this type of difference between
individuals.
D.
An important corollary of the exquisite ability of the immune system to recognize differences in chemical structure
between self tissues and foreign cells or substances is the need for the immune system not to respond to self, in spite of
having the potential to generate lymphocytes with receptors able to interact with epitopes expressed by self-antigens.
During embryonic differentiation the immune system eliminates or turns off auto-reactive lymphocytes. The state of
tolerance is maintained during the lifetime of healthy individuals by mechanisms not fully understood.
VII. General Overview
One of the most difficult intellectual exercises in immunology is to try to understand the organization and control of the
immune system. Its extreme complexity and the wide array of regulatory circuits involved in fine-tuning the immune
response pose a formidable obstacle to our understanding. A concept map depicting a simplified view of the immune
system is reproduced in Figure 1.1.
A.

If we use as an example the activation of the immune system by an infectious agent that has managed to overcome
the innate anti-infectious defenses, the first step must be the uptake of the infectious agent by an
antigen-presenting
cell,
such as a tissue
macrophage.
Such uptake will most likely be productive in terms of the activation of an immune
response when it takes place in a lymphoid organ (lymph node, spleen), where there is ample opportunity for
interactions with the other cellular elements of the immune system.
B.
The antigen-presenting cells will adsorb the infectious agent to their surface, ingest some of the absorbed
microorganism, and process it into small antigenic subunits. These subunits become intracellularly associated with
histocompatibility antigens, and the resulting complex is transported to the cytoplasmic membrane, allowing stimulation
of
helper T lymphocytes.
C.
The interaction between surface proteins expressed by antigen-presenting cells and T lymphocytes as well as
interleukins released by the antigen-presenting cells act as co-stimulants of the helper T cells.
D.
Once stimulated to proliferate and differentiate, helper T cells become able to assist the differentiation of
effector
cells.
1. Activated
TH1 helper lymphocytes
secrete interleukins that will act on a variety of cells, including
macrophages
(further increasing their level of activation and enhancing their ability to eliminate infectious agents
that may be surviving intracellularly), and
cytotoxic T cells,
which are very efficient in the elimination of virus-

infected cells.
2. Activated
TH2 helper lymphocytes
secrete a different set of cytokines


Page 8
Figure 1.1
A concept map representing the main components of the immune system
and their interactions.
that will assist the proliferation and differentiation of antigen-stimulated B lymphocytes, which then differentiate
into
plasma cells.
The plasma cells are engaged in the synthesis of large amounts of antibody.
E.
Specific antibody will bind to the microorganism and promote its elimination, by one or several of three major
mechanisms:
1. Complement-mediated lysis
2. Phagocytosis
3. ADCC
F.
Once the microorganism is removed, negative feedback mechanisms become predominant, turning off the immune
response. The down-regulation of the immune response appears to result from the combination of several factors, such
as the elimination of the positive stimulus that the microorganism represented, and the activation of lymphocytes with
suppressor activity, known as
suppressor T cells.
G.
At the end of the immune response, a residual population of long-lived lymphocytes specific for the offending
antigen will remain. This is the population of

Page 9
memory cells
that is responsible for protection after natural exposure or immunization. It is also the same generic cell
subpopulation that may cause accelerated graft rejections in recipients of multiple grafts. As discussed in greater detail
below, the same immune system that protects us can be responsible for a variety of pathological conditions.
VIII. Immunology and Medicine
Immunological concepts have found ample application in medicine, in areas related to diagnosis, treatment, prevention,
and pathogenesis.
A.
The exquisite specificity of the antigen-antibody reaction has been extensively applied to the development of
diagnostic assays
for a variety of substances.
B.
Also, experiments with malignant plasma cell lines obtained from mice with plasma cell tumors culminated
serendipitously in the discovery of the technique of hybridoma production, the basis for the production of
monoclonal
antibodies,
which have had an enormous impact in the fields of diagnosis and immunotherapy.
C. Immunotherapy,
once derided as little more than wishful thinking, is coming of age. The therapeutic use of
interleukins, activated cytotoxic cells, monoclonal antibodies, anti-idiotypic antibodies, and immunotoxins are being
extensively investigated, particularly in oncology and transplantation.
D.
The study of children with deficient development of their immune systems
(immunodeficiency diseases)
has
provided the best tools for the study of the immune system in humans, while at the same time giving us ample
opportunity to devise corrective therapies. The emergence of the acquired immunodeficiency syndrome (AIDS)
underscores the delicate balance that is maintained between the immune system and infectious agents in the healthy

individual.
E.
The importance of maintaining self tolerance in adult life is obvious when we consider the consequences of the loss
of tolerance. Several diseases, some affecting single organs, others of a systemic nature, have been classified as
autoimmune diseases.
In those diseases, the immune system reacts against cells and tissues and this reactivity can
either be the primary insult leading to the disease, or may represent a factor contributing to the evolution and increasing
severity of the disease. New knowledge of how to induce a state of unresponsiveness in adult life through oral ingestion
of antigens has raised hopes for the rational treatment of autoimmune conditions.
F.
Not all reactions against non-self are beneficial. If and when the delicate balance that keeps the immune system from
overreacting is broken,
hypersensitivity diseases
may become manifest. The common allergies, such as asthma and hay
fever, are prominent examples of diseases caused by hypersensitivity reactions. The manipulation of the immune
response to induce a protective rather than a harmful immunity was first attempted with success in this type of disease.
G.
Research into the mechanisms underlying the normal state of tolerance against non-self attained during normal
pregnancy
continues to be intensive, since this knowledge could be the basis for more effective manipulations of the


Page 10
immune response in patients needing organ transplants and for the treatment or prevention of infertility.
H.
The concept that malignant mutant cells are constantly being eliminated by the immune system
(immune
surveillance)
and that malignancies develop when the mutant cells escape the protective effects of the immune system
has been extensively debated, but not quite proven. However, anticancer therapies directed at the enhancement of

antitumoral responses
continue to be evaluated.
In the following chapters of this book, we will illustrate abundantly the productive interaction that has always existed in
immunology between basic concepts and clinical applications. In fact, no other biological discipline illustrates better the
importance of the interplay between basic and clinical scientists; in this probably lies the main reason for the
prominence of immunology as a biomedical discipline.


Page 11
2
Cells and Tissues Involved in the Immune Response
Gabriel Virella and Jean-Michel Goust
I. Introduction
The fully developed immune system of humans and most mammals is constituted by a variety of cells and tissues whose
different functions are remarkably well integrated. Among the cells, the lymphocytes play the key roles in the control
and regulation of immune responses as well as in the recognition of infected or heterologous cells, which the
lymphocytes can recognize as undesirable and promptly eliminate. Among the tissues, the thymus is the site of
differentiation for T lymphocytes during embryonic differentiation and, as such, is directly involved in critical steps in
the differentiation of the immune system.
II. Cells of the Immune System
A. Lymphocytes.
The lymphocytes (Fig. 2.1A) occupy a very special place among the leukocytes that participate in one
way or another in immune reactions due to their ability to interact specifically with antigenic substances and to react to
non-self antigenic determinants. Lymphocytes differentiate from stem cells in the fetal liver, bone marrow, and thymus
into two main functional classes. They are found in the peripheral blood and in all lymphoid tissues.
1.
B lymphocytes
or
B cells
are so designated because the

Bursa of Fabricius,
a lymphoid organ located close to
the caudal end of the gut in birds, plays a key role in their differentiation. Removal of this organ, at or shortly
before hatching, is associated with lack of differentiation, maturation of B lymphocytes, and the inability to
produce antibodies. A mammalian counterpart to the avian bursa has not yet been found. Some investigators
believe that the bone marrow is the most likely organ for B lymphocyte differentiation, while others propose that
the peri-intestinal lymphoid tissues play this role.
a. B lymphocytes carry
immunoglobulins
on their cell membranes, which function as antigen receptors.
After proper stimulation, B cells differentiate into antibody-producing cells (plasma cells).


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Figure 2.1
Morphology of the main types of human leukocytes. (A) lymphocyte;
(B) plasma cell; (C) monocyte; (D) granulocyte. (Reproduced with
permission from Reich, P.R., Manual of Hematology. Upjohn,
Kalamazoo, MI, 1976.)
b. B lymphocytes can also play the role of
antigen-presenting cells (APC),
which is usually attributed to
cells of monocyte/macrophage lineage.
2.
T lymphocytes
or
T cells
are so designated because the
thymus
plays a key role in their differentiation.

a. The functions of the T lymphocytes include the
regulation of immune responses,
and various effector
functions (cytotoxicity and lymphokine production being the main ones) that are the basis of
cell-mediated
immunity (CMI).


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b. T lymphocytes also carry an antigen-recognition unit on their membranes, known as
T-cell receptor.
T-
cell receptors and immunoglobulin molecules are structurally unrelated.
c. Several subpopulations of T lymphocytes with separate functions have been recognized:
i.
Helper T lymphocytes
are involved in the induction and regulation of immune responses
ii.
Cytotoxic T lymphocytes
are involved in the destruction of infected cells.
iii. It is also known that at specific stages of the immune response T lymphocytes can have
suppressor

functions.
d. To date, there are no known markers that perfectly differentiate T lymphocytes with different functions,
although it is possible to differentiate cells with predominant helper function from those with predominant
cytotoxic function.
e.
T-cell mediated cytotoxicity is an apoptotic process
that appears to be mediated by two separate

pathways. One involves the release of proteins known as
perforins,
which insert themselves in the target cell
membranes forming channels. These channels allow the diffusion of enzymes
(granzymes,
which are serine
esterases) into the cytoplasm. The exact way in which granzymes induce apoptosis has not been established,
but granzyme-induced apoptosis is Ca
2+
-dependent. The other pathway, which can be easily demonstrated in
knock-out laboratory animals in whom the perforin gene is inactivated or by carrying out killing experiments
in buffers without Ca
2+
, depends on signals delivered by the cytotoxic cell to the target cell which require
cell-cell contact
(see Chapter 11).
f. T lymphocytes have a longer life span than B lymphocytes. Long-lasting lymphocytes are particularly
important because of their involvement in immunological
memory.
3. Upon recognizing an antigen and receiving additional signals from auxiliary cells, a small, resting T lymphocyte
rapidly undergoes
blastogenic transformation
into a large lymphocyte (13–15
µ
m). This large lymphocyte
(lymphoblast) then subdivides to produce an expanded population of medium (9–12
µ
m) and small (5–8
µ
m)

lymphocytes with the same antigenic specificity.
a. Activated and differentiated T lymphocytes are morphologically indistinguishable from small, resting
lymphocytes.
b. Activated B lymphocytes differentiate into plasma cells, easy to distinguish morphologically from resting
B lymphocytes.
B. Plasma Cells
are morphologically characterized by their eccentric nuclei with clumped chromatin, and a large
cytoplasm with abundant rough endoplasmic reticulum (Fig. 2.1B). Plasma cells produce and secrete large amounts of
immunoglobulins, but do not express membrane immunoglobulins. Plasma cells divide very poorly, if at all. Plasma
cells are usually found in the bone marrow and in the perimucosal lymphoid tissues.
C. Natural Killer (NK) Cells
are morphologically described as
large granular lymphocytes.
These cells do not carry
antigen receptors of any kind, but can recognize antibody molecules bound to target cells and destroy those cells using


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the same general mechanisms involved on T-lymphocyte cytotoxicity
(antibody-dependent cellular cytotoxicity).

They also have a recognition mechanism that allows them to destroy tumor cells and virus-infected cells.
D. Monocytes and Macrophages
1. The
monocyte
(Fig. 2.1C) is considered a leukocyte in transit through the blood which will become a
macrophage
when fixed in a tissue.
2. Monocytes and macrophages, as well as granulocytes (see below), are able to ingest particulate matter
(microorganisms, cells, inert particles) and for this reason are said to have phagocytic functions. The phagocytic

activity is greater in macrophages (particularly after activation by soluble mediators released during immune
responses) than in monocytes.
3. Macrophages, monocytes, and related cells play an important role in the inductive stages of the immune
response by processing complex antigens and concentrating antigen fragments on the cell membrane. In this form,
the antigen is recognized by helper T lymphocytes, as discussed in detail in Chapters 3 and 11. For this reason,
these cells are known as antigen-presenting cells.
4. APC include other cells sharing certain functional properties with monocytes and macrophages are present in
skin
(Langerhans cells),
kidney, brain (microglia), capillary walls, and lymphoid tissues. The Langerhans cells
can migrate to the lymph nodes, where they interact with T lymphocytes and assume the morphological
characteristics of
interdigitating cells
(see below).
5. One type of monocyte-derived cell, the
dendritic cell
(Fig. 2.2), is present in the spleen and lymph nodes,
particularly in follicles and germinal centers. This cell, apparently of monocytic lineage, is not phagocytic, but
appears particularly suited to carry out the antigen-presenting function by concentrating antigen on its membrane
and keeping it there for relatively long periods of time, a factor that may be crucial for a sustained immune
response. The dendritic cells form a network in the germinal centers, known as the
antigen-retaining reticulum.
6. All antigen-presenting cells express one special class of histocompatibility antigens, designated as
class-II
MHC
or
Ia
(I region-associated) antigens (see Chapter 3). The expression of MHC-
II molecules is essential for the
interaction with helper T lymphocytes.

7. Antigen-presenting cells also release cytokines, which assist the proliferation of antigen-stimulated
lymphocytes, including interleukins 1, 6, and 12.
E. Granulocytes
are a collection of white blood cells with segmented or lobulated nuclei and granules in their
cytoplasm which are visible with special stains.
1. Because of their segmented nuclei, which assume variable sizes and shapes, these cells are generically
designated as
polymorphonuclear (PMN)
leukocytes (Fig. 2.1D).
2. Different subpopulations of granulocytes
(neutrophils, eosinophils,
and
basophils)
can be distinguished by
differential staining of the cytoplasmic granules, which reflect their different chemical constitution.
3.
Neutrophils
are the largest subpopulation of white blood cells and have two types of cytoplasmic granules
containing compounds with bactericidal activity.


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Figure 2.2
Electron microphotograph of a dendritic cell isolated from a
rat lymph node (×5000). The inset illustrates the in vitro
interaction between a dendritic cell and a lymphocyte as seen
in phase contrast microscopy (×300). (Reproduced with
permission from Klinkert, W.E.F., Labadie, J.H., O'Brien,
J.P., Beyer, L.F., and Bowers, W.E., Proc. Natl. Acad. Sci.
USA, 77:5414, 1980.)

i. Neutrophils are phagocytic cells. As with most other phagocytic cells, they ingest with greatest
efficiency microorganisms and particulate matter coated by antibody and complement (see Chapter 9).
However, nonimmunological mechanisms have also been shown to lead to phagocytosis by neutrophils,
perhaps reflecting phylogenetically more primitive mechanisms of recognition.
ii. Neutrophils are attracted by chemotactic factors to areas of inflammation. Those factors may be
released by microbes (particularly bacteria) or may be generated during complement activation as a
consequence of an antigen-antibody reaction.
iii. The attraction of neutrophils is specially intense in bacterial infections. Great numbers of neutrophils
may die trying to eliminate the invading bacteria. Dead PMN and their debris become the primary
component of
pus,
characteristic of many bacterial infections. Bacterial infections associated with the
formation of pus are designated as purulent.
4.
Eosinophils
are PMN leukocytes with granules that stain orange-red with cytological stains containing eosin.
These cells are found in high concentra-