INNATE IMMUNE RESPONSES

• (antigens). Host defense has been classically subdivided into the two categories
• innate immunity and adaptive immunity. The innate immune system, which

• functions as a “first-line” of defense to invading pathogens (antigens), is com-

• posed of cells and molecules that provide rapid host protection without memory

• or specificity for the responses in which they engage. The principal cell types in
• innate immunity are phagocytes (macrophages and neutrophils) and natural

• killer (NK) cells. A system of serum proteins, the complement system, is also inti-
• mately involved in innate immunity.
• In marked contrast to the rapidity with which the innate immune system is
• activated, naive cells engaged in adaptive immune responses require several days

• to develop their effector function. Moreover, the cells (lymphocytes), characteris-

• tic of adaptive immune responses, are restricted in their recognition repertoire in

• that each cell recognizes only one antigen. As a result, following initial encounter
• with antigen, adaptive immune responses are dependent upon mechanism(s) that
• ensure clonal expansion of the activated cells. Adaptivity and specificity, which
• are hallmarks of lymphocyte-mediated immune responses, refer to the pre-exist-
• An Introduction to the Immune System 3
• 1 ing “infinite” array of cells each with a unique receptor, such that this pool of cells
• provides immunity to all conceivable antigens. Another feature of the adaptive
• immune response is that, following initial antigen encounter, the immune system
• retains a supply of memory cells, which can respond more quickly to rechallenge
• with the same antigen than the naive (uneducated) immune system. Soluble
• molecules produced by activated lymphocytes include antibodies, cytokines, and
• chemokines.
• The immune system is further subdivided according to the tissues involved in
• differentiation/maturation of immune responses. Development of lymphocytes

• takes place in primary immune tissues (bone marrow/spleen/thymus), while ac-

• tivation of lymphocytes takes place in secondary immune tissues(lymph nodes,

• tonsils and adenoids, spleen, and mucosa-associated lymphoid tissues (MALT)).

• The two classes of lymphocytes, B and T cells are found in discrete areas of these

• secondary tissues. In addition, other cells implicated in the development of ac-

• quired immune reactions, such as dendritic cells and macrophages, are also found

• in distinct areas of the lymphoid organs.

• Finally, we need to consider classification of adaptive immune reactions in

• terms of the stimulus that induces immunity. Molecules that activate a single (an-
• tigen-specific) clone of responding cells are called monoclonal activators, while

• those stimulating multiple clones (mitogens) are called polyclonal activators. Small
• molecules are often nonimmunogenic until coupled to larger molecules. In this
• scenario, the small molecule is called a hapten, and the larger one a carrier. When
• B cells are activated to produce antibodies, they may need “help” from T cells
• (T-dependent antigen responses), or activation may occur independently of this

• help (T-independent antigens). Immune responses to antigens (especially T-de-

• pendent ones) are often enhanced by adjuvants.
• Our ability to coexist with the vast array of microbes present in our environ-
• ment is a measure of the efficacy of various defense systems to monitor insults to

• the internal cellular environment from the extracellular world. Arguably the most
• important of these defense systems is the immune system. In essence the immune
• system is the instrument by which the body discriminates self from nonself, and
• destroys nonself. Important functional elements of the immune system include
• several cell types, tissues, serum proteins, and small peptides such as chemokines

• and cytokines. While components of the immune system interact with one an-
• other, detailed discussion is simplified by classification into two categories, innate

• immunity and adaptive immunity.

Innate immune responses
• Our first lines of defense against infectious agents are the natural physical and
• chemical barriers that prevent microbes from invading our bodies. Intact skin
• and mucosal linings are effective physical barriers unless they are compromised.
• Chemical barriers also serve as deterrents to infectious agents. As example,

• lysozyme present in secretions splits the cell walls of gram positive bacteria; sper-
• mine (in semen) prevents the growth of gram positive bacteria; the acid pH of the
stomach prevent colonization bacteri
Adaptive imune
• Adaptive immune responses (also known as acquired immune
responses) are
• mediated by lymphocytes (Fig. 1.2). The system is “adaptive” in that,
even before
• exposure to the pathogen, lymphocytes have been developed that
recognize an
• infinite array of antigens. While there are millions of each lymphocyte
type (T
• and B) present, each antigen is recognized by only a few (in the limit
one) cells.
• In

• fact, each lymphocyte responds to only one unique portion (epitope) of an anti-
• gen. Effective immunity following exposure to a pathogen requires multiple cop-
• ies of the lymphocytes recognizing the pathogen. As a result, specific lymphocytes

• undergo binary division (proliferation) that leads to the generation of numerous

• progeny specific for an epitope on the pathogen. Because the progeny respond to

• the same antigenic epitope as that of the parent, the parent and the progeny con-
• stitute what is termed a clone (Fig. 1.3). Clonal
• Clonal expansion is crucial to generate

• effective immunity against pathogens during first exposure (primary response),

• thus ensuring that a sufficient number of lymphocytes specific for that pathogen
• are available. After the pathogen is cleared not all of the cells that encountered
• antigen die. Rather the immune system retains a supply of memory cells, which
• can respond much more quickly to rechallenge (secondary response) with the
• same antigen that induced the clonal expansion. This constitutes the process of
• antigen-specific immunological memory.
• Phagocytes are cells whose function is primarily phagocytosis. Phagocytosis
• is a defense mechanism by which microorganisms, especially bacteria and other
• extracellular microbes are engulfed and destroyed by phagocytes. Predominant
• phagocytes include neutrophils and monocytes/macrophages (Figs. 1.1, 1.4). The
• neutrophil is the dominant type of circulating polymorphonuclear granulocyte.
• The term monocyte refers to immature macrophages. Monocytes are typically
• found in circulation and have a limited capacity for phagocytosis. When monocytes
• migrate to different tissues, they mature into macrophages.
• Antigen presenting cells
• Antigen presenting cells (APC) are cells that endocytose antigen, process it
• into fragments (peptides), and then display various fragments on the cell surface.

• For effective presentation antigen fragments must be expressed on the APC sur-
• face, cradled within the groove of special molecules termed, class II major histo-
• compatibility proteins (class II MHC). These cell surface complexes of peptide/

• class II MHC represent the form of antigen that is recognized by a subset of lym-
• phocytes, T lymphocytes. Antigen presenting cells include dendritic cells, mac-
• rophages, and B cells (Figs. 1.1, 1.4). B cells are lymphocytes that function as anti-
• gen presenting cells in addition to their role in adaptive immunity.
• Natural killer cells
• The main role of natural killer (NK) cells is destruction of virally infected
• autologous (self) cells. There is evidence that natural killer cells also destroy some
• tumor cells (Figs. 1.1, 1.4). Exposure to certain small molecules termed cytokines
• (e.g., interleukin-2 and interleukin-12), enhances the ability of NK cells to kill
• their targets. In the presence of high concentrations of interleukin-2, NK cells

• differentiate to lymphokine activated killer cells (LAK cells). LAK cells are cyto-
• toxic and are more potent killers than the NK cells.
• Inflammatory cells include mast cells, basophils, and eosinophils (Figs.
1.1,
• 1.4). Basophils are the circulating counterpart of the tissue mast cells.
Eosinophils
• are found primarily in tissues, and in smaller numbers, in the circulation.
These

• inflammatory cells play a role in the development and/or maintenance of

the in-
• flammatory response, which is an integral part of immunity.
CELLS THAT FUNCTION IN ADAPTIVE
IMMUNE RESPONSES
• Cells that function in adaptive immunity are lymphocytes(Figs. 1.2, 1.4). There
• are two broad classes of lymphocytes, B lymphocytes and T lymphocytes. Each
• cell type has a distinct function and mode of activation. In addition, subsets of
• cells within each class of lymphocytes have distinct roles. Lymphocytes possess

• unique antigen recognizing receptors, which endows them with the ability to
in-
• teract with one antigen, but not another.
• teract with one antigen, but not another.

• B lymphocytes
• B lymphocytes express cell surface antigen receptors termed antibodies or
• immunoglobulins. These cell surface antibodies are the instruments by which
• B cells recognize and interact with antigen. In the presence of specific antigen,

• and appropriate costimulatory molecules, B cells will clonally expand and differ-
• entiate into antibody secreting plasma cells. For protein antigens, B-cell differen-
• tiation requires stimulation with cytokines secreted by T cells, as well as cognate

• interaction with a subset of T lymphocytes.

lymphocite
• T lymphocytes are cells that express antigen recognizing receptors termed T cell
• receptors. T cells express one of two types of T-cell receptor, alpha/beta receptors
• or gamma/delta receptors. This designation refers to the polypeptides that make

• up the receptor. Most of the T cells in the body express alpha/beta receptors. Un-
• less otherwise specified, the term T cell in this book refers to T cells expressing

• alpha/beta T-cell receptors. Alpha/beta T-cell receptors recognize, and interact with,
• antigen fragments that are displayed in the groove of proteins expressed on the
• surface of cells. The proteins
• There are two major subsets of T lymphocytes, defined by the presence of pro-
• tein markers, CD4 and CD8, on the cell surface. The CD4+ subset of T cells rec-
• ognize antigen fragments presented in association with class II MHC expressed

• on the surface of antigen presenting cells. T cells expressing the CD4 marker
are
• also referred to as T helper (Th) cells, because they secrete cytokines required
for
• both innate and adaptive immunity.
• TISSUES OF THE IMMUNE SYSTEM: GENERAL FEATURES

• Immune tissues are broadly classed according to their role in the immune sys-
• tem. Tissues that serve as developmental sites for lymphocytes are termed pri-
• mary immune tissues, while those tissues that serve as activation sites are termed

• secondary immune tissues. Primary immune tissues include the bone marrow

• and thymus. Although there is evidence for the development of lymphocytes out-
• side these primary tissues, the sites have not been identified. Secondary immune

• tissues include the lymph nodes, tonsils and adenoids, spleen, and mucosa-associ-
• ated lymphoid tissue.
• TISSUES OF THE IMMUNE SYSTEM: PRIMARY LYMPHOID ORGANS
• Bone marrow
• In the early stage of embryogenesis, blood cells arise from the yolk sac, and
• later from the liver and spleen. During the later stages of embryogenesis,
and after
• birth, the bone marrow is the hematopoietic tissue that gives rise to most
mature

• nonlymphoid blood cells including

• Thymus
• The thymus is the site of T-cell maturation. At puberty the thymus weighs 30-

• 40 grams. Thereafter, it undergoes progressive involution and extensive fatty

infil-
• tration. Whether the remaining thymic rudiment is responsible for adult T-cell

• maturation and selection, or whether an extra thymic source exists for these
adult
• functions, is not known.
• TISSUES OF THE IMMUNE SYSTEM: SECONDARY LYMPHOID TISSUES
• Secondary lymphoid tissues include the lymph nodes, tonsils and adenoids,
• spleen, and mucosa-associated lymphoid tissues (MALT). These tissues are the
• major sites of adaptive immune responses, though the actual site where the initial
• immune response occurs is determined by the mode of antigen entry (Fig. 1.6). If

• antigen is carried via the lymphatics, the initial site of the adaptive immune re-
• sponse is the lymph node; if antigens are blood-borne, the initial site of the adap-
• tive immune response is the spleen; and if antigens enter via mucosal tissue, MALT

• serves as the initial site of the adaptive immune response.

• Spleen

• The spleen is an encapsulated secondary lymphoid organ containing two ma-

• jor types of tissues, red pulp and white pulp (Fig. 1.8). The white pulp is the

• region of the spleen that functions as a secondary lymphoid tissue because it con-
• tains the majority of lymphoid cells. The predominant T-cell region, the area sur-
• rounding the central arteries and arterioles, is termed the periarteriolarlymphatic

• sheath (PALS). The predominant B-cell regions are the primary and secondary
• follicles that exist as outgrowths of the PALS.
• Mucosa-associated lymphoid tissue
• The human body is in constant contact with microorganisms, most of which
• never penetrate the internal milieu due to the presence of intact skin, or
mucosal
• surfaces. Mucus forms a protective surface in the respiratory, genitourinary, and
• gastrointestinal tracts, as well as in the buccal cavity and on adenoids and
tonsils
• (Fig. 1.9). Although intact skin is essentially impenetrable, the mucus covering is
• neither as impervious nor as continuous.
• Antibodies
• Antibodies, also known as immunoglobulins(Igs), are bifunctional molecules
• whose polypeptide chains define an antigen binding site and a site that carries out
• the biological activity of the molecule. The polypeptide chain of the antibody that
• determines biological activity also defines its isotype. The antibody isotypes IgM,

• IgD, IgG, IgE, and IgA correspond to the μ, δ, γ, ε, and α, polypeptides, respec-
• tively. Hence, biological activity and antibody isotype are closely related. Antibodies

• are expressed on the cell surface of B cells. When these cells are stimulated (e.g., by
• antigen) they differentiate into antibody secreting plasma cells. These secreted
• antibodies serve as effector molecules for cells functioning in the innate and/or

• adaptive immune systems. As example, particular antibodies trigger the activa-

• tion of the classic complement pathway (see below).
• Complement

• Complementis a term used to describe a family of proteins that facilitate elimi-

• nation of microorganisms, particularly extracellular bacteria. The complement

• system is composed of numerous (~30) activation and regulatory proteins syn-

• thesized mainly by the liver. Many of these proteins circulate as dormant enzymes

• serving as substrates for other complement proteins that have, themselves, been

• sequentially activated. This mode of sequential activation gives rise to the expres-
• sion, complement pathway. There are two pathways of complement activation, the

• alternative pathway of activation

• pathway. There are two pathways of complement activation, the

• alternative pathway of activation and the classical pathway, each

converging into

• a common/terminal pathway.
chemokyn
• Chemokines are molecules that were first identified by nature of their ability

• to induce leukocyte accumulation in tissue sites of inflammation. Interest has fo-

• cused on the role of chemokine production in clinical diseases. Chemokines have

• been subdivided into four classes based on the position of invariant cysteine resi-
• dues in their amino acid sequence. Most prominent amongst these classes are the

• so-called CC and CXC chemokines, members of which include monocyte

• chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1α
• (MIP-1α), and RANTES (regulated on activation, normal T cell expressed and

• secreted cytokine); and IL-8, IFN inducible protein 10 (IP-10), and cytokine in-
• duced neutrophil chemoattractants (CINC, GRO) respectively (Fig. 1.11).
antigen

• An antigen is a substance that is recognized by lymphocytes. Historically, an-

• tigens were defined as molecules that induce an immune response. More recently,
• the term immunogen has been designated to refer to molecules that induce the
• activation of T cells or B cells in the presence of appropriate costimulatory mol-
• ecules. Although not technically correct, the term antigen is still commonly used
• to refer to substances that induce an immune response. In this book, we use the
• historical definition of the term antigen, in place of the term immunogen. Al-
• though antigens induce immune responses, the B cells and T-cell antigen recep-
• torsrecognize a unique region of the antigen (epitope). Other terms, interchange-
• able for epitope, are determinant group, or antigenic determinant. Complex
• antigens contain several different epitopes. For some antigens, particularly pro-
• tein antigens, B-cell activation occurs only in the presence of T-cell cytokines, and
• cognate interaction with activated T cells. Consequently, these antigens are termed
• T-dependent antigens.
• effect.
• T-independent antigens
• Polysaccharide molecules can activate B cells in the absence of T cell help. (T cells
• do not recognize polysaccharides). These antigens are termed T-independent
• antigens. T-independent antigens are divided into two categories, Type I and

• Type II. The prototypic Type I T-independent antigen is pneumococcal polysac-

• charide, a component of the capsule surrounding Streptococcus pneumoniae. Pneu-
• mococcal polysaccharide does not possess mitogenic activity.
• Enhancing immunogenicity of monoclonal activators

• The immune response to an antigen can be enhanced in the presence of

adju-
• vants. This is important for immunization when administering vaccines.
Alum

• precipitate, a suspension of aluminum hydroxide mixed with antigen, is used

in
• human vaccines to enhance immunogenicity.
Mitogens are naturally occurring molecules with the capacity to
bind to, and
trigger proliferation of, many clones of lymphocytes. B-cell
mitogens include

An Introduction to the Immune System 25

1 pokeweed mitogen (PWM) and high concentrations of
lipopolysaccharide. T cell
mitogens include concanavalin A (Con A), phytohemagglutinin
(PHA), and
pokeweed mitogen. Con A and PHA are plant glycoproteins,
more commonly
called lectins.