IMMUNE SYSTEM

Although the immune response normally is protective, it also can produce undesirable effects
such as when the response is excessive, as in allergies, or when it recognizes self-tissue as
foreign, as in autoimmune disease.
Defense against pathogens consists of two types of reactions. Innate immunity (also called
natural, or native, immunity) is mediated by cells and proteins that are always present (hence
the term innate), poised to react against infectious pathogens.The major components of innate
immunity are the skin and mucous membranes, phagocytic leukocytes (mainly neutrophils and
macrophages), specialized lymphocytes (the natural killer cells), and several plasma proteins,
including the proteins of the complement system.
The innate immune system is able to distinguish self from nonself and is able to recognize and
react against microbial agents. The response of the innate immune system is rapid, usually
within minutes to hours, and prevents the establishment of infection and deeper tissue
penetration of microorganisms. The microorganisms not controlled by innate immunity are
usually controlled by the more specific approaches of adaptive immunity.
The adaptive immune system consists of two groups of lymphocytes and their products,
including antibodies. Whereas the cells of the innate immune system recognize structures
shared by classes of microorganisms, the cells of the adaptive immune system are capable of
recognizing numerous microbial and noninfectious substances and developing a unique specific
response for each substance. Substances that elicit adaptive immune responses are called
antigens.There are two types of adaptive immune responses: humoral and cell-mediated
immunity. Humoral immunity is mediated by molecules called antibodies that are produced by
cells called B lymphocytes. Antibodies are secreted into the circulation and mucosal fluid, where
they neutralize or eliminate extracellular microbes and microbial toxins.One of the important
functions of humoral immunity is to stop microbes that are present on mucosal surfaces and in
the blood from gaining access to and colonizing body tissues. Cell-mediated immunity,
which defends against intracellular microbes such as viruses, is provided by cells called T
lymphocytes. SomeT lymphocytes activate phagocytes to destroy microbes that have been
engulfed. Cooperative interactions exist between innate and adaptive immunity. Innate immunity
communicates to lymphocytes involved in adaptive immunity the characteristics of the pathogen
and information about its intracellular or extracellular location.
Both innate and adaptive immunity destroy the invading agent by using the effector responses
of phagocytosis and the complement system.Both innate and adaptive immunity destroy the
invading agent by using the effector responses of phagocytosis and the complement system.
The cells of the immune system are present in large numbers in the central and peripheral
lymphoid organs. These organs and tissues are widely distributed in the body and provide
different, but often overlapping,functions . The lymphoid organs are connected by networks of
lymph channels, blood vessels,and capillaries. The immune cells continuously circulate through
the various tissues and organs to seek out and destroy foreign material.
Central Lymphoid Tissues
The central lymphoid tissues, the bone marrow and thymus gland, provide the environment for
immune cell production and maturation. T-cell progenitors migrate from the bone marrow to
the thymus where the process of maturation occurs. The function of the thymus is central to the
development of the immune system because it generates mature, immunocompetent T
lymphocytes expressing appropriate receptors.
The process of B-cell maturation, which is similar to that of T-cell maturation, occurs in the bone
marrow. Here, the B cells multiply and acquire immunoglobulin (Ig) signaling molecules and cell
markers that distinguish them from nonself.
Peripheral Lymphoid Tissues
The peripheral lymphoid structures, which consist of the lymph nodes, the spleen, and other
secondary lymphoid tissues, function to concentrate antigen, aid in processing of antigen, and
promote the cellular interactions necessary for development of adaptive immune responses.
Although cells of both the innate and adaptive immune systems communicate critical
information by cell-to-cell contact, many interactions and effector responses depend on the
secretion of short-acting soluble molecules called cytokines.Cytokines are low–molecular-weight
regulatory proteins that are produced by cells of the innate and adaptive immune systems and
that mediate many of the actions of these cell. For example, interleukins (ILs) were found to be
made by leukocytes and to act on leukocytes, and interferons (IFNs) were found to interfere with
virus multiplication.
Cytokines That Mediate and Regulate Immunity
Although cytokines have many diverse actions, Most cytokines are released at cell-to-cell
interfaces, where they bind to specific receptors on the membrane surface of their target cells.
Chemokines are cytokines that stimulate the migration and activation of immune and
inflammatory cell.There are two major subclasses, termed CC chemokines and CXC
chemokines,the CC chemokines, attracts mononuclear leukocytes to sites of chronic
inflammation. The CXC chemokines attract neutrophils to sites of acute inflammation.
Colony-stimulating factors (CSFs) are cytokines that stimulate bone marrow pluripotent stem
and progenitor or precursor cells to produce large numbers of platelets, erythrocytes,
lymphocytes, neutrophils, monocytes, eosinophils, basophils, and dendritic cells.
The CSFs were named according to the type of target cell on which they act .

The innate immune system consists of the epithelial barriers; phagocytic neutrophils,
macrophages, dendritic cells, NK cells; and several plasma proteins, including those of the
complement system. These mechanisms are present in the body before an encounter with an
infectious agent and are rapidly activated by microbes before the development of adaptive
immunity. The innate immune system also interacts with and directs adaptive immune
responses.the innate immune system not only protects against microbial agents, but may also
play a role in the pathogenesis of disease. Among the functions of the innate immune system is
induction of a complex cascade of events known as the inflammatory response. Recent
evidence suggests that low-grade inflammation and activation of the innate immune system play
a key role in the pathogenesis of a number of disorders, such as atherosclerosis and coronary
artery disease, bronchial asthma, type 2 diabetes mellitus, rheumatoid arthritis, multiple
sclerosis, and systemic lupus erythematosus.
The intact skin is a formidable physical barrier because of its closely packed cells, multiple
layers, continuous shedding of cells, and presence of the protective protein keratin. the skin
has chemicals that create a salty and acidic environment, and antibacterial proteins, such as
the enzyme lysozyme, that inhibits the colonization of microorganisms and aids in their
destruction.
The mucous membrane linings of the gastrointestinal, respiratory, and urogenital tracts are
protected by sheets of tightly packed epithelial cells that block the entry of microbes and destroy
them by secreting antimicrobial enzymes, proteins, and peptides. Specialized cells in these
linings secrete a viscous material called mucus. Mucus traps and washes away
microorganisms, especially with the help of additional secretions such as saliva. Also in the
lower respiratory tract hairlike structures called cilia protrude through the epithelial cells. The
synchronous action of the cilia moves many microbes trapped in the mucus toward the throat.
The physiologic responses of coughing and sneezing further aid in their removal from the body.
Once microbes are trapped, various chemical defenses come into play. These include
lysozyme, a hydrolytic enzyme capable of cleaving the walls of bacterial cells;complement,
which binds and aggregates bacteria to increase their susceptibility to phagocytosis or disrupt
their lipid membrane; and members of the collectin family of surfactant proteins in the
respiratory tract. The best-defined function of the surfactants is their ability to opsonize
pathogens, including bacteria and viruses, and to facilitate phagocytosis by innate immune cells
such as macrophages. In the stomach and intestines, death of microbes results from the action
of digestive enzymes, acid conditions and secretions of defensins, small cationic peptides that
rapidly kill many types of bacteria.

CELLS OF INNATE IMMUNITY

The key cells of innate immunity include phagocytic leukocytes and NK cells. Several types of
phagocytic leukocytes recognize and kill infectious agents during an innate immune response.
The early-responding phagocytic cell is the neutrophil, followed shortly by the more efficient
multifunctional macrophage. Phagocytes are activated to engulf and digest microbes that attach
to their cell membrane.
Dendritic cells, which are derived from bone marrow cells and related in lineage to the
macrophage, also play important roles in the innate immune response to infections and in
linking innate and adaptive immune responses. One subpopulation of dendritic cells governs the
early response to viral infections. They recognize phagocytosed viruses and produce type 1
interferons that have potent antiviral actions.
NK cells are a class of lymphocytes that recognize infected and stressed cells and respond by
killing these cells. Activation of NK cells triggers the release of cytoplasmic granules toward the
infected cells. These NK granules contain molecules that form pores in the cell membrane and
other molecules that induce apoptosis (programmed cell death). NK cells control their
responses by using both activating and inhibitory receptors. Their activating receptors (i.e.,killer
cell receptors) recognize altered host molecules expressed on stressed tissue cells that may be
infected with intracellular microbes. The inhibitory receptors
on NK cells recognize molecules on normal host cells and function to stop the killing response.
This control ensures that normal body cells are not inappropriately destroyed. In contrast to the
cytotoxic T lymphocytes of the adaptive immune system, which need to undergo amplification
and maturation to become cytotoxic, the NK cell is directly programmed to kill foreign cells.

PATHOGEN RECOGNITION
The ability of leukocytes and epithelial cells to participate in innate immunity depends on their
first recognizing molecules that are a normal component of microbes but not host cells.The
receptors that the innate immune system uses to recognize and react against microbes are
expressed on phagocytic leukocytes, NK cells, and other cells that participate in defense
against various classes of microbes. These receptors are molecules that first tag the microbe
and then bind it to the effector cell of the innate immune system. Microbial binding results in
effector cell activation, phagocytosis, and subsequent killing of the microbe. Several classes of
receptors have been identified that are specific for different types of microbial products including
pattern receptors, Toll-like receptors, and serum proteins (e.g., complement proteins) that
promote phagocytosis.

The Complement System

The complement system is an important effector of both innate and humoral immunity that
enables the body to localize and destroy infectious pathogens. The complement system, like the
blood coagulation system, consists a group of proteins that are present in the circulation
as functionally inactive precursors. These proteins, mainly proteolytic enzymes.
The reactions of the complement system can be divided into three phases: (1) the initial
activation phase, (2) the early-step inflammatory responses, and (3) the late-step membrane
attack responses.
 There are three pathways for recognizing microbes and activating the complement system: (1)
the alternative pathway, which is activated by microbial cell surfaces in the absence of antibody
and is a component of innate immunity; (2) the classical pathway, which is activated by certain
types of antibodies bound to antigen and is part of humoral immunity; and (3) the lectin pathway,
which is activated by a plasma lectin that binds to mannose on microbes and activates the
classical system pathway in the absence of antibody.all converge in the process by acting
on the key complement protein C3, essential for the amplification phase. All generate a series of
enzymatic reactions that prompt enzymatic cleavage of C3 into two fragments. The larger C3b
fragment is a key opsonin that coats microbes and allows them to be phagocytized after binding
to the type 1 complement receptor on leukocytes. The smaller C3a fragment triggers an influx
of neutrophils to enhance the inflammatory response. Production of C3a and C5a also leads to
the activation of basophils and mast cells and the release of inflammatory mediators that
produce smooth muscle contraction, increased vascular permeability, and changes in
endothelial cells to enhance migration of phagocytes. The late phase of the complement
cascade triggers the assembly of a membrane attack complex (MAC) made up of complement
proteins C5 to C9. The membrane attack complex leads to the lytic destruction of many kinds of
cells, including bacteria and altered blood cells.

The multiple functions of the complement system, including enhanced inflammatory

responses, increased phagocytosis, and destruction and clearance of the pathogen from the
body.
The innate immune response generates molecules that function as “second signals” together
with antigens to activate the adaptive immune response. Full activation of antigen-specific B and
T lymphocytes requires two signals. Antigen provides the first signal. Microbes, the response of
the innate immune system to microbes, and host cells damaged by microbes all may provide the
second signal. This requirement for a second microbe-initiated signal ensures that lymphocytes
respond to microbes (the natural inducers of innate immunity) and not to harm-

less noninfectious substances. For the purpose of inducing immunity through vaccination,
adaptive immune responses may be induced by antigens without microbes. The second signals
that are necessary for activation of the adaptive immune system can be generated by
antigen-presenting dendritic cells and macrophages or by activation of the complement system.
Microbes that breach the epithelial barriers of the innate immune system stimulate dendritic cells
and macrophages to produce two types of second signals that activate T lymphocytes. First, the
dendritic cells and macrophages express surface molecules called co-stimulators, which bind to
receptors on naive T cells and function together with antigen recognition to activate T cells.
Second, the dendritic cells and macrophages secrete cytokines that stimulate the differentiation
of naive T cells into effector cells of cell-mediated adaptive immunity.

■ Innate immunity consists of the physical, cellular,chemical, and molecular defenses that are
ready for activation and mediate rapid initial protection against infectious agents. Epithelial cells
of the skin and mucous membranes, which are the first line of defense, block the entry of
infectious agents and secrete antimicrobial molecules that can effectively kill a wide variety of
microbes.
■ The effector responses of innate immunity involve viral destruction by natural killer (NK) cells,
phagocytosis of microbes by neutrophils and monocytes, initiation of the inflammatory
response, and recruitment of the complement system.
■ Development of innate immunity and regulation of effector cells depends on the secretion of
soluble mediators, such as opsonins, cytokines, and acute-phase proteins. Opsonins bind to
and tag microorganisms for more efficient recognition by phagocytes. Cytokines released from
activated leukocytes regulate the activity of other cells, amplify inflammation, stimulate the
production of acute-phase proteins, and aid in the initiation of an adaptive immune response.
■ The complement system, which is a primary effector system for both the innate and adaptive
immune systems, consists of a group of proteins that are activated by microbes and promote
inflammation and destruction of the microbes.
DEFECTS IN INNATE IMMUNITY

Inherited defects in the early innate immune response typically affect leukocyte functions or the
complement system and lead to increased vulnerability to infections .

Defects in Leukocyte functions.

• Chronic granulomatous disease results from inherited defects in the genes encoding
components of phagocyte oxidase, the phagolysosomal enzyme that generates ROS such as
superoxide (O2 • ), resulting in defective bacterial killing and susceptibility to recurrent bacterial
infection. The name of this disease comes from the macrophage-rich chronic inflammatory
reaction that appears at sites of infection if the initial neutrophil defense is inadequate. These
collections of activated macrophages form granulomas in an effort to wall off the microbes.
 • Chédiak-Higashi syndrome is characterized by defective fusion of phagosomes and
lysosomes, resulting in defective phagocyte function and susceptibility to infections. The main
leukocyte abnormalities are neutropenia, defective degranulation, and delayed microbial killing.
• TLR defects are rare but informative. Mutations in TLR3, a receptor for viral RNA, result in
recurrent herpes simplex encephalitis, and
Leukocyte adhesion deficiency (LAD ) disorders
Leukocyte adhesion deficiencies (LADs) stem from inherited defects in adhesion molecules that
impair leukocyte recruitment to sites of infection, resulting in recurrent bacterial infections
• Autosomal recessive inheritance pattern.
(2) LAD type 1 (LAD -1) is a deficiency of 2-integrin( D 11a:CD 18) on neutrophils.
• CD stands for cluster of designation.
• LAD type 2 (LAD -2) is a deficiency of an EC selectin that normally binds neutrophils.

Neutrophil killing of bacteria/fungi by the oxygen (O2)-dependent myeloperoxidase

(MPO ) system;
- The O 2-dependent MPO system in neutrophils and monocytes uses the
(N A D P H ) oxidase enzyme complex to convert molecular O2 to superoxide free radicals to
kill bacteria and fungi.
- O2-dependent MPO system is only present in neutrophils and monocytes (not
macrophages).
- MPO is a neutrophil/monocyte lysosomal enzyme.
--Production of superoxide FRs. N A D P H oxidase enzyme complex converts molecular
O2 to superoxide FRs, which releases energy called the respiratory, or oxidative, burst.
Chronic granulomatous disease and MPO deficiency are examples of diseases that
have a defect in the O2 -dependent MPO system.
Chronic granulomatous disease (CGD) is an X-linked recessive disorder (XR; 65% of cases) or
autosomal recessive disorder (30% of cases). The X-linked type is characterized by a mutation
in the CYBB gene that encodes for a
component of the NADPH oxidase enzyme complex (PHOX system) rendering the complex
dysfunctional. Results in an absent respiratory (oxidative) burst. Catalase-positive organisms
that produce H2O2 (e.g., Staphylococcus aureus, Aspergillus species, and Candida species)
are ingested but not killed, because the catalase degrades the H2O2 produced by these
pathogens. Myeloperoxidase is present, but HOCl is not synthesized because of the absence of
H2O2. However, catalase-negative organisms (e.g., Streptococcus species) that produce H2O2
are ingested and can be killed when MPO combines H2O2 (derived from the bacteria) with Cl-
to form HOCl-. Granulomatous
inflammation occurs in tissue, because the neutrophils, which can phagocytose bacteria but not
kill.
MPO deficiency is an autosomal recessive disorder that differs from CGD in that both O2" and
H2O2 are produced (normal respiratory burst). However, the absence of MPO prevents the
synthesis of HOCl-.
 Complement system disorders
Complement deficiencies are uncommon. Complement deficiencies predispose to infections
via the following mechanisms:
- Ineffective opsonization, due to a lack of C3b
- Defects in cell lysis, due to a lack of MAC components
- Opsonization defects are usually present with recurrent pyogenic infections due to
encapsulated bacteria (e.g., Streptococcus pneumoniae). Infections are more likely to
occur at an early age (few months to a few years of age).
- Patients with deficiencies in early classical pathway components (i.e., C1, C 4, C2) do not
have recurrent infections but are more often predisposed to developing autoimmune
disease, particularly SLE.
- Adults with deficiencies in the formation of MAC have a high risk for developing
recurrent infection with Neisseria gonorrhoeae and/or Neisseria meningitidis. Children and
neonates with deficiency of M A C are more likely to have severe pyogenic infection and
sepsis.
-C2 deficiency • Most common complement deficiency • Associated with septicemia (usually
Streptococcus pneumoniae) and SLE
-C6-C9 deficiency • Increased susceptibility for disseminated Neisseria gonorrhoeae or
Neisseria meningitidis infections.
Paroxysmal nocturnal hemoglobinuria (PNH)

• Acquired stem cell disease with a mutation in the PIG (phosphatidylinositol glycan)
complementation
group A gene in a myeloid stem cell clone. This results in a defect in the anchoring of inhibitors
of complement (CD55 [decay accelerating factor] and CD59) on the surface of RBCs,
neutrophils, and platelets. In normal people, these inhibitors degrade C3 and C5 convertase on
hematopoietic cell membranes so that RBCs, neutrophils, and platelets are not destroyed.
• This is an example of complement-mediated intravascular lysis of RBCs (hemoglobinuria),
platelets, and neutrophils that leads to pancytopenia (all hematopoietic cell lines destroyed).
• Hereditary angioedema - Autosomal dominant disorder with deficiency of C1 esterase
inhibitor, which normally inactivates the protease activity of C1. Activated C1 normally cleaves
C2 and C4 to produce C4b2a complex (C3 convertase). Hereditary angioedema is associated
with episodic attacks of edema formation that can sometimes be life-threatening if it involves the
larynx. Nonpitting edema involving the face, extremities, upper airways, and gastrointestinal
tract (abdominal pain, diarrhea, vomiting) develops suddenly. The edema is thought to be due to
increased levels of C2-derived kinins produced by excessive amounts of activated C1. These
kinins increase vessel permeability and are primarily responsible for the swelling of
tissue in hereditary angioedema. Hereditary angioedema is not associated with allergic
diseases and is not associated with urticaria (a characteristic finding in allergic skin diseases).
 ADAPTIVE IMMUNITY

The components of the adaptive immune system are lymphocytes and their products. Foreign
substances that elicit specific responses are called antigens.There are two types of adaptive
immune responses: humoral and cell-mediated immunity. Humoral immunity is mediated by
secreted molecules and is the principal defense against extracellular microbes and toxins.
Cell-mediated immunity, or cellular immunity, is mediated by specific T lymphocytes and
defends against intracellular microbes such as viruses.
Antigens, also called immunogens, are substances foreign to the host that can stimulate an
immune response. These foreign molecules are recognized by receptors on immune cells and
by secreted proteins, called antibodies or immunoglobulins, made in response to the antigen.
B and T lymphocytes possess all of the key properties associated with the adaptive immune
response—specificity, diversity, memory, and self–nonself recognition.
Adaptive immune responses are initiated when the antigen receptors of lymphocytes recognize
antigens. The key trigger for the activation of B and T cells is the recognition of the antigen by
unique surface receptors. B-cell antigen receptors and antibodies that B cells secrete are able
to recognize a broad range of structurally different molecules.On recognition of antigen and after
additional stimulation by cytokines, the B and T lymphocytes divide several times to form clonal
cell populations that continue to differentiate into effector and memory cells. After antigen binds
to a B-cell receptor, the cell proliferates and differentiates into plasma cells that secrete
antibodies that are a form of the B-cell receptor and have identical antigen
Immunoglobulins, or antibodies, function as antigen receptors for B cells or as effector
molecules of the humoral immune response. The immunoglobulins have been divided into five
classes—IgG, IgA, IgM, IgD, and IgE—each with a different role in the immune defense
strategy.
- Immunoglobulin A, a secretory immunoglobulin, is found in saliva, tears, breast milk, and
bronchial, gastrointestinal, prostatic, and vaginal secretions. This dimeric secretory
immunoglobulin is considered a primary defense against local infections in mucosal
tissues.Immunoglobulin A prevents the attachment of viruses and bacteria to epithelial
cells
- Immunoglobulin M is a macromolecule It cannot cross the placenta and thus does not
transfer maternal immunity. It is the first circulating immunoglobulin to appear in
response to an antigen and is the first antibody type made by a newborn. This is
 diagnostically useful because the presence of IgM suggests a current infection in the
infant by a specific pathogen.
- Immunoglobulin D is found primarily on the cell membranes of B lymphocytes. It serves
as an antigen receptor for initiating the differentiation of B cells.
- Immunoglobulin E is involved in inflammation, allergic responses, and combating
parasitic infections. It binds to mast cells and basophils. The binding of antigen to mast
cell– or basophil-bound IgE triggers these cells to release histamine and other mediators
important in inflammation and allergies.
- Immunoglobulin G (gamma globulin) is the most abundant of the circulating
immunoglobulins. It is present in body fluids and readily enters the tissues.
Immunoglobulin G is the only immunoglobulin that crosses the placenta and can transfer
immunity from the mother to the fetus This antibody can also bind to target cells and Fc
receptors on NK cells and macrophages, leading to lysis of the target cell.

Activation of the lymphocytes depends on appropriate processing and presentation of antigen to

T lymphocytes by antigen-presenting cells such as macrophages and dendritic cells. On
recognition of antigen and after additional stimulation by cytokines, the B and T lymphocytes
divide several times to form clonal cell populations that continue to differentiate into effector and
memory cells. After antigen binds to a B-cell receptor, the cell proliferates and differentiates into
plasma cells that secrete antibodies that are a form of the B-cell receptor and have identical
antigen specificity. T cell is activated by its first encounter with an antigen, it proliferates and
differentiates into helper or cytotoxic T cells. Helper T cells provide signals that activate
antigen-stimulated B cells to differentiate and produce antibody. Some helper T cells also
activate macrophages to become more efficient at killing engulfed pathogens.
Cytotoxic T cells kill cells that are infected with viruses and other intracellular pathogens.
Major histocompatibility complex molecules are membrane-bound proteins encoded by a MHC
gene locus that display peptides for recognition by T lymphocytes.In humans, the genes
encoding MHC molecules are clustered on a small segment of chromosome 6.
MHC proteins are also known as human leukocyte antigens (HLA s), which are expressed on
the surface of all nucleated cells with the exception of nucleated red blood cell.
- HLA genes and their subtypes are transmitted from parents to their children
- Class I molecules interact with CD8 T cells and NK cells.
0.
- Class II proteins interact with CD4 Th cells.
- Antigen-presenting cells (APC s) include B cells, macrophages, and DCs.
(2) Example: extracellular microbes that are phagocytosed by macrophages (APC s) are
digested in lysosomes and the peptides released from the lysosomes associate with class II
molecules that eventually are transported in vesicles to the surface of the macrophage, where
they interact with CD4 T h cells.
Class I MHC molecules are found on the surface of most somatic cells except mature red blood
cells and platelets. Class II MHC molecules are found on the surface of antigen-presenting cells
only macrophages.

T lymphocytes arise from bone marrow stem cells, but unlike B cells, pre-T cells migrate to the
thymus for their maturation. Maturation of subpopulations of T cells (i.e. CD4+ CD8+) also
occurs in the thymus. Mature T cells migrate to the peripheral lymphoid tissues and, upon
encountering antigen, multiply and differentiate into memory T cells and various mature T-cell
populations. The two main populations of mature T cells are CD4+(helper) and CD8+ (cytotoxic)
T cells.
Activation of CD4+ helper T cells depends on the recognition of antigen in association
with class II MHC molecules, the helper T cells secrete cytokines that influence the function of
nearly all other cells of the immune system. These cytokines activate and regulate B cells,
cytotoxic T cells, NK cells, macrophages, and other immune cells.The activated CD4+helper T
cell can differentiate into distinct subpopulations of helper T cells (e.g.TH1, TH2, and TH17)
based on the cytokines secreted by the antigen-presenting cell at the site of activation.The
distinct pattern of cytokines secreted by mature TH1 and TH2 cells defines these
subpopulations of T cells and determines their functions. Activated TH1 cells stimulate
phagocyte- ingestion and killing of microbes. TH1 cells produce the cytokine IFN-γ,which
activates macrophages and stimulates B cells to produce IgG antibodies that activate
complement and coat pathogens for phagocytosis. TH2 cells produce IL-4, which stimulates B
cells to differentiate into IgE-secreting plasma cells; IL-5, which activates eosinophils; and IL-13,
which activates mucosal epithelial cells to secrete mucus and expel microbes.
Activated CD8+ lymphocytes become cytotoxic T cells after recognition of class I MHC–antigen
complexes on target cell surfaces, such as body cells infected by viruses or transformed by
cancer.The recognition the CD8+ cytotoxic T cells are especially important in controlling
replicating viruses and intracellular bacteria because antibodies cannot readily penetrate the
membrane of living cells.

IMMUNODEFICIENCY DISORDERS

These disorders can be classified into two groups: primary and secondary. The primary or
congenital immunodeficiencies are genetic defects that result in increased susceptibility to
infection that is frequently manifested early in life. Secondary or acquired immunodeficiency is
not inherited but develops as a consequence of malnutrition, selective loss of immunoglobulins
through the gastrointestinal or genitourinary tracts, treatment with immunosuppressant drugs, or
human immunodeficiency virus (HIV), the etiologic agent of acquired immunodeficiency
syndrome (AIDS).
Primary immunodeficiency diseases are inherited genetic disorders that impair mechanisms
of innate immunity (phagocytes, NK cells, or complement) or the humoral and/or cellular arms of
adaptive immunity (mediated by B lymphocytes and T lymphocytes, respectively).
 X-linked agammaglobulinemia of Bruton is an immunodeficiency characterized by a
developmental failure to produce mature B cells and plasma cells resulting in
agammaglobulinemia. The condition occurs because of loss of function mutations of B-cell
Bruton tyrosine kinase (BTK). Clinically, the disease affects male infants who have recurrent
infections beginning at 6 months of life due to the loss of passive maternal immunity. Common
infections include pharyngitis, otitis media, bronchitis, and pneumonia; common infecting
organisms include H. influenza, S. pneumococcus, and S. aureus.
Common variable immunodeficiency is a group of disorders characterized by
defects in B-cell maturation that can lead to defective IgA or IgG production.
Clinically, both sexes are affected with onset in childhood of recurrent bacterial
infections and with increased susceptibility to Giardia lamblia. Complications
include increased frequency of developing autoimmune disease, non-Hodgkin
lymphoma, and gastric cancer
DiGeorge syndrome is an embryologic failure to develop the 3rd and 4th pharyngeal pouches,
resulting in the absence of the parathyroid glands and thymus. Clinical findings can include
neonatal hypocalcemia and tetany, T-cell deficiency, and recurrent infections with viral and
fungal organisms. DiGeorge Syndrome (Thymic Hypoplasia) is caused by a congenital defect in
thymic development resulting in deficient T-cell maturation. T cells are absent in the lymph
nodes, spleen, and peripheral blood, and infants with this defect are extremely vulnerable to
viral, fungal, and protozoal infections. Patients also are susceptible to infection with intracellular
bacteria, because of defective T cell mediated immunity.
Severe combined immunodeficiency (SCID) is a combined deficiency of cell-
mediated and humoral immunity that is often caused by a progenitor-cell defect. The modes of
inheritance are variable and can include X-linked (mutation of the common [gamma] chain of the
interleukin receptors IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) and autosomal recessive (deficiency
of adenosine deaminase). Clinical features include recurrent infections with bacteria, fungi,
viruses, and protozoa; susceptibility to Candida, cytomegalovirus (CMV) and Pneumocystis
jiroveci infections, and adverse reactions to live virus immunizations. SCID is treated with
hematopoietic stem cell transplantation since the prognosis without treatment is death of most
infants within a year.
Hyper IgM syndrome is characterized by normal B and T lymphocyte numbers
and normal to elevated IgM levels but significantly decreased IgA, IgG and IgE
levels. Mutations in the gene for CD40 ligand result in the most common form
of X-linked hyper IgM syndrome.
Selective IgA deficiency has unknown genetic etiology. Many affected individuals appear
healthy while others have significant illness.Isolated IgA Deficiency- IgA is the major
immunoglobulin in mucosal secretions and is thus involved in defending the airways and the
gastrointestinal tract. Weakened mucosal defenses due to IgA deficiency predispose patients to
recurrent sinopulmonary infections and diarrhea.

Immunodeficiencies Associated With Systemic Diseases

In some inherited systemic disorders, immune deficiency is a prominent clinical problem. Two
representative examples of such diseases are :
 • Wiskott-Aldrich syndrome is an X-linked disease characterized by thrombocytopenia, eczema,
and a marked vulnerability to recurrent infection that results in early death. The thymus is
normal, at least early in the disease course, but there is progressive loss of T lymphocytes from
the blood and the T cell zones (paracortical areas) of lymph nodes, with variable defects in
cellular immunity.
• Ataxia telangiectasia is an autosomal-recessive disorder characterized by abnormal gait
(ataxia), vascular malformations (telangiectasia), neurologic deficits, increased incidence of
tumors, and immunodeficiency. The immunologic defects are of variable severity and may affect
both B cells and T cells.
Of all the primary immunodeficiency diseases, those affecting antibody production and
humoral immunity are the most common. Antibody production depends on the differentiation of
hematopoietic stem cells into mature B lymphocytes and the antigen-dependent generation of
immunoglobulin-producing plasma cells.

Acquired Immunodeficiency Syndrome

Acquired immunodeficiency syndrome is a disease caused by infection with human
immunodeficiency virus (HIV) and is characterized by profound immunosuppression with
associated opportunistic infections, malignancies, wasting, and central nervous system
degeneration. HIV is a retrovirus that selectively attacks the CD4+T lymphocytes . As a
consequence, persons with HIV infection have a deteriorating immune system, and thus are
more susceptible to severe infections from ordinarily harmless organisms.

Human immunodeficiency virus is transmitted through conditions that facilitate the exchange of
blood or body fluids that contain the virus or virus-infected cells, the major routes being sexual
contact;
HIV infects a limited number of cell types in the body,including CD4+T lymphocytes,
macrophages, and dendritic cells. The CD4+T cells are necessary for recognition of foreign
antigens, activating antibody-producing B lymphocytes, and orchestrating cell-mediated
immunity, in which cytotoxic CD8+T cells and NK cells directly destroy virus-infected cells,
tubercle bacilli, and foreign antigens. The phagocytic function of monocytes and macrophages
is also influenced by CD+T cells.
The human immunodeficiency virus (HIV) is an enveloped RNA retrovirus that contains reverse
transcriptase. HIV infects CD4-positive cells, including CD4+ T lymphocytes, all macrophages,
lymph node follicular dendritic cells, and Langerhans cells. The mechanism of infection is by
binding of CD4 by the viral gp120, followed by entry into cell by fusion, which requires gp41 and
coreceptors CCR5 (β-chemokine receptor 5) and CXCR4 (α-chemokine receptor).

Clinical Principles
Transmission of HIV can occur by many mechanisms, including sexual contact (most common
mode, including both homosexual transmission and an increasing rate of heterosexual
transmission, with important cofactors including herpes and syphilis infection); parenteral
transmission; IV drug use; blood transfusions (including those done in hemophiliacs); accidental
needle
The clinical manifestations of HIV infection vary over time.
• The acute phase is characterized by viremia with a reduction in CD4 count,mononucleosis-like
viral symptoms and lymphadenopathy, and seroconversion.
• The latent phase is characterized by asymptomatic or persistent generalized lymphadenopathy
with continued viral replication in the lymph nodes and spleen, low level of virus in the blood,
and minor opportunistic infections including oral thrush (candidiasis) and herpes zoster. The
average
Duration of the latent phase is 10 years.
• Progression to AIDS (third phase) occurs with reduction of CD4 count to <200 cells/mL, which
is accompanied by reemergence of viremia and development of AIDS-defining diseases,
possibly to eventual death.

AIDS-Defining Diseases

These neoplastic and nonneoplastic conditions can establish a diagnosis of AIDS

in HIV+ individuals, regardless of CD4 counts.
Hairy leukoplakia is an Epstein-Barr virus (EBV)–associated condition due to
infection of squamous cells. White plaques are present on the tongue.
Kaposi sarcoma is the most common neoplasm in AIDS patients.