Schaum’s Outline of Theory & Problems of Immunology

318 Pages·2001·7.278 MB·English

by  George Pinchuk

Pinchuk: Schaum’s Outline Front Matter Preface © The McGraw−Hill
of Theory & Problems of Companies, 2004
Immunology
This book is an attempt to provide students who study immunology in colleges
anduniversities,aswellaseveryonewhowantstorefresh,deepen,andsystematize
their knowledge of immunology, with an outline of an up-to-date immunology
course. Its focus is on cellular and molecular mechanisms of immune responses.
The author considers this book to be an attempt to supplement such excellent
comprehensive immunology textbooks as Cellular and Molecular Immunology (by
A.K. Abbas, A.H. Lichtman, and J.S. Pober, W.B. Saunders Co., Philadelphia et
al., Fourth edition, 2000), Kuby Immunology (by R.A. Goldsby, T.J. Kindt, and
B.A. Osborne, W.H. Freeman and Co., New York, Fourth edition, 2000), and
others. Throughout the book, the author used a question-and-answer format
(which is so characteristic for Schaum’s Outlines), based on real questions that
realstudents–bothundergraduateandgraduate–ask,andrealanswersthatreal
immunology professors, including the author himself, try to give.
Iamgratefultoalargenumberofpeoplewhohelpedmeduringtheconception
andthewritingofthisbook.Iwillmentionbutafew.JohnWelborn,mycolleague
and friend in the Department of Biological Sciences of the College of Arts and
SciencesatMississippiStateUniversity,MississippiState,MS,wasfirsttosuggest
that I might write the book, and graciously served as a go-between the publishers
andmeatthestageofitsconception.GlennMott,theEditoroftheMcGraw-Hill
ProfessionalBookGroup,NewYork,NY;JenniferChongandMaureenWalker,
ofthesamecompanyprovidedmewithinvaluableguidanceandadviceduringthe
course of the writing. Tracy Sanchez Ambrose of TypeMaster Inc., Choudrant,
LA, proofread and edited a number of chapters and gave me a tremendous
encouragement during the writing, making me believe that I can write and sup-
porting me with her steadfast friendship and humor. Jeff Rudis helped me with a
competent and sound advice in word processing and file management. Maureen
Allen and her associates of Keyword Publishing Services, Barking, UK, were
extremely collegial and efficient during the final preparation of the manuscript
for printing. My colleagues at the Department of Biological Sciences and, of
course, my students deserve my warmest acknowledgment for being patient and
forgiving at the times when I was somewhat overwhelmed with the work on this
bookattheexpenseofmyresponsibilitiesatschool.Lastbutinnowayleast,Iam
very much indebted and thankful to my family members – to my wife Lesya,
daughter Maryana, and to my mother, Ludmila Pinchuk, for bearing with me
and being there for me always.
Feci quod potui, faciunt meliora potentes.
GEORGE V. PINCHUK
v
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
Overview of Immunity
and the Immune
System
Introduction
Immunology is a science that studies immunity. Historically, immunity has been
understood as a defense against, or resistance to, contagious (infectious) diseases.
It has become apparent, however, that the mechanisms that confer protection
against the above diseases also operate when a body mounts a reaction against
some innocuous substances. Such a reaction is triggered when certain substances
that are not made in the body (‘‘foreign’’ substances) invade the body from out-
side. The mechanisms of immunity can protect against diseases that might be
caused by the foreign agents but, on the other hand, these same mechanisms
can themselves injure the body and cause disease. Therefore, immunity was re-
defined as a reaction against foreign substances, including – but not limited to –
infectious microorganisms. This reaction may or may not be protective. In some
instances, it is aimed at altered (e.g., malignantly transformed) self substances, or
even to unaltered self substances. This reaction is quite complex, involves many
differentcells,molecules,andgenes(collectivelytermedtheimmunesystem),andis
aimedessentiallyatmaintainingthegeneticintegrityofanindividual,protectingit
fromtheinvasionofsubstancesthatcanbeartheimprintofaforeigngeneticcode.
The response of the immune system to the introduction of foreign substances is
called the immune response.
Immunity is a part of a complex system of defense reactions of the body.
These defense reactions can be innate or acquired. Innate (or natural) immunity
refers to the work of mechanisms that pre-exist the invasion of foreign sub-
stances. These include physical barriers like the skin and mucosal surfaces;
1
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
2 CHAPTER 1 Immunity and the Immune System
chemical substances (mostly proteins) that neutralize microorganisms and other
foreign particles; and specialized cells that engulf and digest foreign particles.
The mechanisms of innate immunity are non-specific, i.e., they do not discrimi-
nate between different kinds of foreign substances. Also, the innate immunity is
non-adaptive, i.e., the nature or quality of the reaction to a foreign substance
does not change when the organism encounters this substance repeatedly.
Acquired immunity refers to a reaction that is caused by the invasion of a certain
foreign substance. The elements of this reaction pre-exist the invasion of the
foreign substance, but the reaction itself is generated strictly in response to a
certain foreign agent (which is called an antigen) and changes its magnitude as
well as quality with each successive encounter of the same antigen. The acquired
immunity is highly specific, i.e., the system discriminates between various anti-
gens, responding with a unique reaction to every particular antigen. The
acquired (or specific) immunity is highly adaptive, i.e., the nature or quality of
the reaction to an antigen changes after the encounter with this antigen, and
especially when the organism encounters the same antigen repeatedly. The ability
of the immune system to ‘‘remember’’ an encounter with an antigen and to
develop a qualitatively better response to it is called the immune memory. This
feature is a paramount property of specific immunity.
In the subsequent sections, we will dissect the particular mechanisms of immu-
nity and characterize the elements of the immune system and the properties of
immune responses.
Discussion
GENERAL FEATURES OF IMMUNE RESPONSES
1.1 What is the purpose of the immune reaction?
Essentially,itistoridtheorganismofforeignantigens.Frombirthuntildeath,an
organism is surrounded by a host of microorganisms, many of which are danger-
ous.Usingantigenreceptors,theimmunesystemcontinuouslyscreensmyriadsof
substances in the body, discerning among them and mounting an attack against
thosethatareforeign.Theendresultofasuccessfulimmuneattackisthedestruc-
tion of foreign substancesand particles, including microbial cells, viruses, various
toxinsandalsotumors.Oncedestroyedbytheimmunesystem,foreignsubstances
or particles or their remains are cleared from the body.
1.2 What is an antigen?
Immunologists use the term ‘‘antigen’’ in two senses. Originally, antigens were
understood as substances that can trigger, or generate, immune responses. The
other definition of antigen is a substance that the immune system can specifically
recognizewiththehelpofantigenreceptorsexpressedonlymphocytesorsecreted
by them (see below).
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
CHAPTER 1 Immunity and the Immune System 3
1.3 Can all substances be antigens?
No. In order to be an antigen, a substance must be of enough complexity to bear
an imprint of potential ‘‘foreignness.’’ For example, a protein can be an antigen,
because it has acomplex structuredeterminedby the sequenceof its amino acids.
The latter, in turn, is determined by an individual’s genetic code. A different
individual may have (and usually does have) a different genetic code for the
same protein. On the other hand, simple inorganic chemicals like water or salt,
or simple organic molecules like glucose, cannot be antigens because it does not
matter in which biological individual they have been synthesized: their structure
will be the same anyway.
1.4 Can substances other than proteins be antigens?
Yes. Most antigens are proteins, but polysaccharides, certain lipids, and nucleic
acids also can trigger immune reactions. Besides, some relatively simple organic
chemicals and chemical groups can be specifically recognized by the immune
system,althoughtheycannottriggerimmunereactions.Suchsubstancesarecalled
haptens.Theimmuneresponsespecifictoahaptencanbetriggeredifthehaptenis
chemically coupled with a protein. The latter in this case will be called a carrier.
1.5 How does the immune system react against antigens?
For this purpose, the immune system uses molecules called antibodies, and cells
called lymphocytes. Antibodies are protein molecules synthesized by a class of
lymphocytescalledBlymphocytes(orBcells).Antibodymoleculesrecognizeanti-
gens through physical contact. They can be either expressed on the surface of B
cells, or secreted. The other class of lymphocytes, T lymphocytes (or T cells)
expresses molecules that also can recognize antigens through physical contact.
These molecules are somewhat similar to antibodies, yet of a different structure
and, unlike antibodies, they are never secreted. The molecules that are made by
both classes of lymphocytes (T and B) and that are able to recognize antigens are
calledantigenreceptors.AntibodiesareB-cellantigenreceptors,andantibody-like
molecules expressed on T lymphocytes are T-cell antigen receptors (TCRs). The
antigen receptor is what determines the specificity of any given lymphocyte. Only
lymphocytes can make antigen receptors and, therefore, recognize antigens.
However, some other cell types can be, and often are, involved in the immune
response, although they cannot specifically discern between antigens. These anti-
gen-nonspecific cells aid lymphocytes during specific immune responses and are
called accessory cells. (See a more detailed discussion of lymphocytes and acces-
sory cells in Chapter 2.)
1.6 Do all organisms have lymphocytes and antibodies?
The specific immune system, or the system that mediates adaptive immunity, is a
feature of higher vertebrates. Lymphocytes and their specific antigen receptors
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
4 CHAPTER 1 Immunity and the Immune System
appear in jawed fishes and are more diverse and efficient in amphibians, reptiles,
birds, and mammals. More primitive organisms have nonspecific immunity, how-
ever.Moleculesandcells,resemblingthosethatarepartsofthenonspecificimmune
system in higher organisms, are operative in insects, worms, and even sponges.
1.7 How did immunologists learn about T and B
lymphocytes?
From observations and experiments with components of immune reactions.
Immunitycanbeactiveorpassive.Activeimmunityreferstotheimmunereaction
that develops in an organism after the introduction of an antigen (immunization).
An organism that is not immunized but receives blood cells or serum from an
actively immunized individual acquires passive immunity. From observations on
animalsacquiringpassiveimmunitywithatransferofeitherserumorcells,immu-
nologists learned that immunity could be humoral or cellular (or cell-mediated).
The former is conferred by substances dissolved in serum and other body fluids
(Latin humori). Today we know that these soluble substances are antibodies and
that they are produced by B lymphocytes. Cells, more precisely, lymphocytes and
accessory cells with the necessary participation of T lymphocytes, confer cellular
immunity.Tlymphocytesplayamajorroleintherecognitionofantigensandtheir
elimination, but they do not produce antibodies (Fig. 1-1).
1.8 Why does the immune system need both T and B
lymphocytes?
Thesetwoclassesoflymphocytesaredesignedtotakecareoftwodifferentclasses
of antigens. T cells are designed primarily to fight foreign substances that are
hidden within the organism’s cells (intracellular). Among these substances are
viruses and intracellular bacteria. Proteins made by these intracellular parasites
are displayed on the membranes of the infected cells. The TCR (see Chapter 7) is
built so that itcan recognizepartsof theseproteins (peptides)in conjunctionwith
certain structures expressed on host’s cell membranes and called major histocom-
patibility complex(MHC)molecules. (We willdiscuss themindetail in Chapters5
and 6.) T cells can, therefore, exclusively recognize entities attached to the mem-
branes of the host’s own cells. This pattern of recognition helps them to ‘‘concen-
trate their attention’’ exclusively on the organism’s own cells, screening them for
signs of infection by viruses or other intracellular parasites, as well as of malignant
transformation.Ontheotherhand,Bcellsandantibodiesthattheymake(Chapter
3) are designed primarily to fight foreign antigens that are located in the extra-
cellular space. Among these substances are extracellular microorganisms, toxins,
and extraneous chemicals. Unlike TCRs, antibodies recognize antigens in their
native form, which does not require the antigen’s attachment to cellular mem-
branes and conjunction with MHC. Thus, B cells are very efficient weapons
against ‘‘loose’’ extracellular microbes. They can reach them with the help of
secreted antibodies that can float almost everywhere in the body. The T cells,
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
CHAPTER 1 Immunity and the Immune System 5
Fig. 1-1. Humoral and cellular immunity as two ‘‘arms’’ of the specific immunity. Antigens that
invadehighervertebratestriggerhumoralandcellular(orcell-mediated)specificimmune
responses.TheformerinvolveBcellsthatmaydifferentiateintoantibody(Ab)-secreting
plasma cells; the latter involve T cells that may differentiate into T or T. While anti-
h c
bodiesrecognizeantigensintheirnativeform,Tcellsrecognizeantigenicpeptidesthatare
incorporatedintoselfMHCmolecules(‘‘alteredself’’).
however, not only recognize intracellular antigens, but also control and regulate
the function of B cells in most immune responses.
1.9 How exactly does the immune system deal with antigens?
A complex series of processes, collectively called the immune response, followsthe
contact of antibody or TCR with antigen. All specific immune responses undergo
phases.Initially,theantigenrecognitionmustoccur,whichmeansthatanantibody,
expressedonthesurfaceofaBlymphocyte,oraTCR,expressedonthesurfaceofa
Tlymphocyte,mustbinditwithacertainaffinity.OnlythoseantibodiesorTCRs
that are specific, i.e., complementary, to an antigen can bind it. Processes of lym-
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
6 CHAPTER 1 Immunity and the Immune System
phocyteactivationanddifferentiationfollowtheseprocessesofantigenrecognition.
Lymphocyte activation means, essentially, that lymphocytes activate many com-
plicated enzymatic processes, begin to transcribe previously silent genes, produce
new proteins, change their shape and size, and begin to divide mitotically.
Lymphocyte differentiation means that the activated and dividing cells acquire
new functional properties. For example, B lymphocytes may become able to
secrete large amounts of antibodies; thus making a major contribution in the
humoralimmunity.Tlymphocytesmaybecomeabletoproducespecialsubstances
called cytokines and activate other cells, thus making a major contribution in the
cellular (or cell-mediated) immunity. These functionally active cells are called
effector lymphocytes.
Processes of lymphocyte activation and differentiation are accompanied by
death of many cells by apoptosis. The surviving cells may be either effector lym-
phocytes or the so-called memory cells. The memory cells are functionally quies-
cent but able to live for a very long time and become rapidly activated when they
encounter the same antigen again. Because of the existence of memory cells a
second, third, fourth, etc. encounter with the same antigen will lead to faster,
stronger,andqualitativelybetterimmuneresponses.Antibodiesandeffectorlym-
phocytes generated during the primary immune response as well as during sec-
ondaryimmuneresponsesacttogetherwithmacrophages,granulocytes,andother
cellsand,eventuallydestroytheantigen.Thislatterphaseoftheimmuneresponse
is called the effector phase of immunity. In subsequent chapters of this book, we
will examine the recognition, activation, and effector phases of the specific immu-
nityindetail.Wewillalsoanalyzetheinteractionofthespecific(adaptive)andthe
nonspecific (innate) immunity during these phases.
1.10. What is common to all specific immune responses?
There are several features that pertain to all specific immune responses.
(cid:1)
Specificity. Each response is uniquely specific to a particular antigen. In fact,
antigen receptors of lymphocytes are able to recognize parts of complex anti-
genic molecules. The part of an antigen that an antigen receptor uniquely
recognizes is called antigenic determinant or epitope.
(cid:1)
Diversity.Allimmuneresponsesinvolvelymphocyteswhoseantigenspecificity
is already determined. The array of antigenic specificities of lymphocytes that
existatanygivenmomentoftimeistremendous(approximatelyonebillionor
more).Ithasbeenproven(seebelow)thatthisenormousdiversityofspecificities
existsindependentlyofexposuretoantigens,andisbeingcreatedbymolecular
mechanisms intrinsic to T and B lymphocytes. The total number of antigenic
specificitiescreatedbythesemechanismsiscalledthelymphocyterepertoire.As
wewilldiscussinlaterchaptersofthisbook,thesizeofnormalimmunereper-
toireishuge;itincludesbillionsofdifferentantibodyandTCRspecificities.
(cid:1)
Memory. Immunological memory is the ability to ‘‘remember’’ a previous
encounterwiththeantigen,andtodevelopafaster,stronger,andqualitatively
betterresponsetotheantigenwhenitisencounteredagain.Suchresponsesare
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
CHAPTER 1 Immunity and the Immune System 7
called secondary (or second-set) or recall immune responses. As we stated in
the previous section, these responses are faster, stronger, and qualitatively
betterthanprimaryresponsesduetothefactthatmemorycellsmediatethem.
(cid:1)
Specialization. Immune responses to different antigens may involve different
molecularandcellularmechanismsforthesakeofmaximizingtheefficiencyof
these responses. For example, antiviral responses are most efficient when T
lymphocytesareinvolved;responsestoextracellularbacteriaworkbestwhenB
cells produce antibodies of certain classes; responses to parasites must involve
B cells, T cells, and nonlymphoid cells called eosinophils; etc.
(cid:1)
Self-limitation. Normally, all immune responses wane with time after antigen
stimulation. One reason for that is the successful elimination of the antigen
thatcausedtheresponse.Theotherreasonistheexistenceofnegativefeedback
mechanisms, which will be discussed later.
(cid:1)
The ability to discriminate between self and nonself. The immune system is said
to ‘‘tolerate’’ self-antigens. The latter are substances that are produced by the
organism that is the host of the immune system; these same substances can
behaveasforeignantigenswhenexposedtoanimmunesystemofagenetically
different individual. Because of tolerance of the self, the host normally is not
harmedbyitsownimmunesystem.Cellularandmolecularmechanismsofself-
tolerance are being intensively studied and will be discussed later.
CLONAL SELECTION HYPOTHESIS
1.11 Are antigen receptors made before the immune
response commences?
Yes. The molecular mechanisms that create antigen receptors operate indepen-
dently of antigen exposure. If a laboratory rodent is raised under germ-free con-
ditions, its lymphocytes will still have antigen receptors specific to various
microbial and viral antigens. The hypothesis that antibodies are made before
the antigen invasion and independently of this invasion was first advanced by
Paul Ehrlich in the early 1900s. Later, when immunologists discovered a tremen-
dous variety of antigens, Ehrlich’s hypothesis became unpopular and was chal-
lenged by an ‘‘instructionist’’ theory, proposed by K. Landsteiner; it stated that
immune cells make nonspecific molecules that become specific antigen receptors
only after antigens ‘‘shape’’ or ‘‘mold’’ them. This theory implied that antigens
served as ‘‘templates’’ for antigen receptors. The instructionist theory was proven
wrong by N.-K. Jerne, who showed (in the late 1950s to early 1960s) that labora-
tory mice produced antibodies to antigens they had never encountered.
1.12 Can lymphocytes change the specificity of their
antigen receptors during their lifetime?
As a general rule, this does not happen. The specificity of one unique antigen
receptor, expressed by one given lymphocyte, is not changed throughout the lym-
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
8 CHAPTER 1 Immunity and the Immune System
phocyte’s life. (An exception from this rule is the so-called receptor editing, a
phenomenonthatwewilldiscusslater.)Moreover,daughterlymphocytesresulting
fromaparentallymphocyte’smitoticdivisionalsodonotchangethespecificityof
theantigenreceptorsthattheyinherit.In1957,Burnetpostulatedthatcellsofthe
specific immune system develop as clones. A cell that makes a receptor specific to
certain antigen originates from a separate precursor, and can make genetically
identical progeny (clone). While all cells of any given clone have identical recep-
tors, each clone differs from any other clone by the specificity of its antigen
receptor.AccordingtoBurnet,theentirediversityoflymphocyteclonespre-exists
antigen encounter. Further, Burnet hypothesized that in the absence of antigen,
lymphocyte clones do not live long. The encounter of a lymphocyte clone with its
specific antigen, however, selectively rescues this particular clone from death,
sending a signal that stimulates the viability and expansion of this particular
clone (Fig. 1-2). This clonal selection hypothesis later received tremendous experi-
mental support, and it is currently considered that this hypothesis more or less
adequately explains the work of immune system in vivo.
Fig. 1-2. The clonal selection hypothesis. Each antigen (A or B) selects a pre-existing clone of
specific lymphocytes and stimulates the proliferation of that clone. The diagram shows
onlyBcells,butthesameprincipleappliestoTcells.
Pinchuk: Schaum’s Outline 1. Overview of Immunity Text © The McGraw−Hill
of Theory & Problems of and the Immune System Companies, 2004
Immunology
CHAPTER 1 Immunity and the Immune System 9
1.13 How do we know that the clonal selection hypothesis
is largely correct?
In the late 1960s to early 1970s, immunologists learned how to culture lympho-
cytes at limiting dilution, i.e., in such a way that one lymphocyte is placed in a
miniaturewellofatissueculturetray.Undertheseconditions,singlelymphocytes
may divide and produce antibodies. If the cultured lymphocytes were taken from
an animal that had been immunized with several different antigens, antibodies to
these different antigens were detected in different cultures, and never in one. In
other words, individual lymphocytes and their clonal progeny always produce
antibody of one specificity. Later, the same was shown to be true for T lympho-
cytes and their antigen receptors. Further, the binding of an antigen to an indivi-
duallymphocytecanbevisualizedbylabeling.Usingthisapproach,experimenters
showed that one lymphocyte could be bound by one antigen, but never by many.
Also, antigens can be radioactively labeled, and when such antigens bind their
specific lymphocytes, the latter are killed by the radiation. Still, the animal that
receivedtheinjectionoftheradioactiveantigenwillbeperfectlyabletorespondto
a very wide array of other antigens, indicating that only the clone specific to the
radioactively labeled antigen was killed.
Finally, proteins that make up antigen receptors have been examined in detail.
The amino acid sequence of these proteins, as well as the sequence of nucleotides
inthegenesthatcodefortheseproteins,hasbeensolved.Thesestudiesshowthat
individual antigen receptors have unique combining sites (the parts of their mol-
ecules that combine directly with the antigen). Any two different lymphocyte
clones will always have two distinct antigen receptors, each with its own amino
acid sequenceat the combining site. Taken together, this entire evidence supports
Burnet’s hypothesis very strongly.
1.14 If antigen encounter stimulates proliferation of
lymphocyte clones, will an immunization or infection
lead to a massive increase in the number of blood
cells?
No. We have to realize that at any given moment of time a vertebrate organism
has at its disposal at least 109 different lymphocyte clones, each with its own
specificity. The invasion of any individual antigen will cause proliferation of the
clone that is specific to it, exclusively. (Some antigens, for example, large protein
and polysaccharide antigens, have more than one epitope, i.e., more than one site
thatcanbeboundbyantibodiesorTCR;inthiscase,severaldifferentclonesmay
react to the antigen, each of them to a separate epitope.) The nonspecific clones
will not be affected, however. Therefore, no matter how strong the proliferative
reaction is, the overall increase in the number of cells in the blood will be negli-
gible. Suppose two clones react to two distinct epitopes of an antigen and each
clone expands 10,000-fold. The overall increase in the number of cells will be
20,000, which is still a negligible increase (0.002%) over the number of all lym-
phocyte clones ((cid:2)1 billion).