Download Lecture Notes: Immune System (Part I)

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Immune System Adaptive Immune System
I.
Adaptive or Specific Immune System
General Characteristics
1.
Specific so that it can eliminate with equal precision almost any type of
pathogen
2.
Functional System
a.
can eliminate specific foreign substances as well as abnormal body
cells
b.
can magnify the inflammatory response
i.
responsible for most complement activation
3.
Must be primed by an initial exposure to a specific foreign substance called
an antigen
a.
takes time
important findings about the adaptive immune response
a.
antigen-specific
b.
systemic
c.
has “memory”
Two branches of adaptive immunity
1.
Humoral immunity or antibody-mediated immunity consists of antibodies
circulating in the fluids of the body
a.
produced by lymphocytes or their offspring
2.
Cellular or cell-mediated immunity – lymphocytes themselves
a.
Targets – virus or parasite-infected tissue cells, cancer cells, foreign
graft cells
b.
can act directly by lysing foreign cells or indirectly by releasing
chemicals that enhance the inflammatory response or activate other
lymphocytes or macrophages.
II.
Antigens
Antigens vs. Haptens:1. Antigens – substances that can mobilize the immune system and
provoke an immune response
a.
most large, complex molecules that are NOT normally present in the
body
b.
help distinguish “self” from “nonself”
2. Complete antigens
a.
they have immunogenicity – the ability to stimulate formation
of specific lymphocytes and antibody production
b.
have reactivity – the ability to react with the lymphocytes and
antibodies
c.
antigens include nearly all foreign proteins, nucleic acids, lipids, and
many large polysaccharides.
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3.
proteins are the strongest antigens
d.
other antigens can be pollen grains or microorganisms
e.
generally small molecules like peptides, nucleotides, and many
hormones are NOT immunogenic
f.
these small particles can link with other substances though and
become immunogenic
allergies
Haptens – small molecules that are reactive but not immunogenic unless
attached to a protein carrier
Cytokines
Cytokines are hormone-like molecules that actto regulate immune responses. They are secreted
not only by lymphocytes and macrophages but by endothelial cells, neurons, glial cells, and
other types of cells. Most of the cytokines are initially named for their actions, eg, B celldifferentiating factor, B cell-stimulating factor 2. However, there is a convention that once the
amino acid sequence of a factor in humans is known, its name is changed to interleukin. Thus,
for example, the name of B cell- differentiating factor was changed to interleukin-4(IL4).
The effects of the principal cytokines Some of them have systemic as well as local effects. For
example, IL-1, IL-6, and tumor necrosis factor α cause fever, and IL-1 increases slow-wave
sleep and reduces appetite.
Another superfamily of cytokines is the chemokine family. Chemokines are substances that
attract neutrophils and other white blood cells to areas of inflammation or immune response.
The Complement System
The cell-killing effects of innate and acquired immunity are mediated in part by a system of
plasma enzymes originally named the complement system because they "complemented" the
effects of antibodies. Nomenclature for the over 30 proteins in the system is confusing because
it is a mixture of letters and numbers: examples include C1q, C3, and C3b. Three different
pathways or enzyme cascades activate the system: the classic pathway, triggered by immune
complexes; the mannose-binding lectin pathway, triggered when this lectin binds mannose
groups in bacteria; and the alternative or properdin pathway, triggered by contact with various
viruses, bacteria, fungi, and tumor cells. The proteins that are produced have three functions:
They help kill invading organisms by opsonization, chemotaxis, and eventual lysis of the cells;
they serve in part as a bridge from innate to acquired immunity by activating B cells and aiding
immune memory; and they help dispose of waste products after apoptosis. Cell lysis, one of the
principal ways the complement system kills cells, is brought about by inserting proteins called
perforins into their cell membranes. The holes produced in this fashion permit free flow of ions,
with disruption of membrane polarity.
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Innate Immunity
The cells that mediate innate immunity include neutrophils, macrophages, and natural killer
(NK) cells, large lymphocytes that are not T cells but are cytotoxic. All these cells respond to
lipid and carbohydrate sequences unique to bacterial cell walls and to other substances
characteristic of tumor and transplant cells. They exert their effects by way of the complement
and other systems, with the cells they attack frequently dying by osmotic lysis or apoptosis.
Their cytokines also activate cells of the acquired immune system.
Acquired Immunity
the key to acquired immunity is the ability of lymphocytes to produce antibodies that are
specific for one of the many millions of foreign agents that may invade the body. The antigens
stimulating antibody production are usually proteins and polypeptides, but antibodies can also
be formed against nucleic acids and lipids if these are presented as nucleoproteins and
lipoproteins, and antibodies to smaller molecules can be produced experimentally when the
molecules are bound to protein. Acquired immunity has two components: humoral immunity
and cellular immunity.
Humoral immunity is mediated by circulating immunoglobulin antibodies in the γ-globulin
fraction of the plasma proteins. Immunoglobulins are produced by B lymphocytes, and they
activate the complement system and attack and neutralize antigens. Humoral immunity is a
major defense against bacterial infections.
Cellular immunity is mediated by T lymphocytes. It is responsible for delayed allergic reactions
and rejection of transplants of foreign tissue. Cytotoxic T cells attack and destroy cells that have
the antigen which activated them. They kill by inserting perforins (see above) and by initiating
apoptosis. Cellular immunity constitutes a major defense against infections due to viruses,
fungi, and a few bacteria such as the tubercle bacillus. It also helps defend against tumors.
Development of the Immune System
During fetal development, lymphocyte precursors come from the bone marrow. Those that
populate the thymus become transformed by the environment in this organ into the lymphocytes
responsible for cellular immunity (T lymphocytes).
humoral immunity (B lymphocytes the transformation to B lymphocytes occurs in bursal
equivalents, ie, the fetal liver and, after birth, the bone marrow. After residence in the thymus or
liver, many of the T and B lymphocytes migrate to the lymph nodes and bone marrow. Most of
the processing occurs during fetal and neonatal life. However, there is also a slow, continuous
production of new lymphocytes from stem cells in adults.
T and B lymphocytes are morphologically indistinguishable but can be identified by markers on
their cell membranes. B cells differentiate into plasma cells and memory B cells. There are three
major types of T cells: cytotoxic T cells, helper T cells, and memory T cells.
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There are two subtypes of helper T cells: T helper 1 (TH1) cells secrete IL-2 and γ-interferon
and are concerned primarily with cellular immunity; T helper 2 (TH2) cells secrete IL-4 and
IL-5 and interact primarily with B cells in relation to humoral immunity. Cytotoxic T cells
destroy transplanted and other foreign cells, with their development aided and directed by
helper T cells. Markers on the surface of lymphocytes are assigned CD (clusters of
differentiation) numbers on the basis of their reactions to a panel of monoclonal antibodies.
Most cytotoxic T cells display the glycoprotein CD8, and helper T cells display the
glycoprotein CD4. These proteins are closely associated with the T cell receptors and may
function as coreceptors.
Natural killer cells are also cytotoxic lymphocytes, though they are not T cells.
Memory B Cells & T Cells
After exposure to a given antigen, a small number of activated B and T cells persist as memory
B and T cells. These cells are readily converted to effector cells by a later encounter with the
same antigen. This ability to produce an accelerated response to a second exposure to an antigen
is a key characteristic of acquired immunity. The ability persists for long periods of time, and in
some instances (eg, immunity to measles) it can be lifelong.
After activation in lymph nodes, lymphocytes disperse widely throughout the body and are
especially plentiful in areas where invading organisms enter the body, eg, the mucosa of the
respiratory and gastrointestinal tracts. This puts memory cells close to sites of reinfection and
may account in part for the rapidity and strength of their response. Chemokines are involved in
guiding activated lymphocytes to these locations.
It had been argued that the long life of memory cells involves their repeated exposure to small
amounts of antigen. However, memory cells persist when infused into mice in which the ability
to process the antigen to which they are sensitive has been abolished by gene knockout. It may
be that they avoid apoptosis by taking up nerve growth factor in the peripheral tissues.
Antigen Recognition
The number of different antigens recognized by lymphocytes in the body is extremely large.
The recognition ability is innate and develops without exposure to the antigen. Stem cells
differentiate into many million different T and B lymphocytes, each with the ability to respond
to a particular antigen. When the antigen first enters the body, it can bind directly to the
appropriate receptors on B cells. However, a full antibody response requires that the B cells
contact helper T cells. In the case of T cells, the antigen is taken up by an antigen-presenting
cell and partially digested. A peptide fragment of it is presented to the appropriate receptors on
T cells. In either case, the cells are stimulated to divide, forming clones of cells that respond to
this antigen (clonal selection).
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Antigen Presentation
Antigen-presenting cells (APCs) include specialized cells called dendritic cells in the lymph
nodes and spleen and the Langerhans dendritic cells in the skin. Macrophages and B cells
themselves can also function as APCs. In APCs, polypeptide products of antigen digestion are
coupled to protein products of the major histocompatibility complex (MHC) genes and
presented on the surface of the cell. The products of the MHC genes are called human leukocyte
antigens (HLA).
The class I MHC proteins (MHC-I proteins) are coupled primarily to peptide fragments
generated from proteins synthesized within cells. The peptides to which the host is not tolerant,
eg, those from mutant or viral proteins, are recognized by T cells.
The class II MHC proteins (MHC-II proteins) are concerned primarily with peptide products of
extracellular antigens, such as bacteria, that enter the cell by endocytosis and are digested in the
late endosomes.
n the upper pathway; foreign protein or antigen (1) is taken up by an antigen-presenting cell (2). The antigen is
processed and displayed on an MHC II molecule (3), which interacts with a T helper cell (4). In the lower
pathway; whole foreign proteins are bound by membrane antibodies (5) and presented to B lymphocytes (6),
which process (7) and present antigen on MHC II (8) to a previously activated T helper cell (10), spurring the
production of antigen-specific antibodies (9).
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Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.
T Cell Receptors
The MHC protein-peptide complexes on the surface of the antigen-presenting cells bind to
appropriate T cells. Therefore, receptors on the T cells must recognize a very wide variety of
complexes.
CD8 occurs on the surface of cytotoxic T cells that bind MHC-I proteins.
CD4 occurs on the surface of helper T cells that bind MHC-II proteins
The CD8 and CD4 proteins facilitate the binding of the MHC proteins to the T cell receptors.
The activated CD8 cytotoxic T cells kill their targets directly, whereas the activated CD4 helper
T cells secrete cytokines that activate other lymphocytes.
B Cells
B cells can bind antigens directly, but they must contact helper T cells to produce full activation
and antibody formation. It is the TH2 subtype that is mainly involved. Helper T cells are pushed
along the TH2 line by the cytokine IL-4 .
On the other hand, IL-12 pushes helper T cells along the TH1 line. IL-2 acts in an autocrine
fashion to cause activated T cells to proliferate.
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The activated B cells proliferate and transform into memory B cells (see above) and plasma
cells. The plasma cells secrete large quantities of antibodies into the general circulation. The
antibodies circulate in the globulin fraction of the plasma (see below) and, like antibodies
elsewhere, are called immunoglobulins. The immunoglobulins are actually the secreted form of
antigen-binding receptors on the B cell membrane.
Immunoglobulins
Circulating antibodies protect their host by binding to and neutralizing some protein toxins, by
blocking the attachment of some viruses and bacteria to cells, by opsonizing bacteria and by
activating complement.
Five general types of immunoglobulin antibodies are produced by the lymphocyte-plasma cell
system. The basic component of each is a symmetric unit containing four polypeptide chains
The two long chains are called heavy chains, whereas the two short chains are called light
chains. There are two types of light chains, κ and λ, and eight types of heavy chains. The chains
are joined by disulfide bridges that permit mobility, and there are intrachain disulfide bridges as
well. In addition, the heavy chains are flexible in a region called the hinge. Each heavy chain
has a variable (V) segment in which the amino acid sequence is highly variable, a diversity (D)
segment in which the amino acid segment is also highly variable, a joining (J) segment in which
it is moderately variable, and a constant (C) segment in which the sequence is constant. Each
light chain has a V, a J, and a C segment. The V segments form part of the antigen-binding sites
(Fab portion of the molecule). The Fc portion of the molecule is the effector portion, which
mediates the reactions initiated by antibodies.
Two of the classes of immunoglobulins contain additional polypeptide components :
IgMs, five of the basic immunoglobulin units join around a polypeptide called the J chain to
form a pentamer.
IgAs, the secretory immunoglobulins, the immunoglobulin units form dimers and trimers
around a J chain and a polypeptide that comes from epithelial cells, the secretory component
(SC).
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1. IgG - Gamma heavy chains
2. IgM - Mu heavy chains
3. IgA - Alpha heavy chains
4. IgD - Delta heavy chains
5. IgE - Epsilon heavy chains
Recognition of Self
A key question is why T and B cells do not form antibodies against and destroy the cells and
organs of the individual in which they develop. Current evidence indicates that self antigens are
presented along with nonself antigens but are then eliminated during development (tolerance).
Central tolerance occurs in the thymus for T cells and the bone marrow for B cells. This is
supplemented by peripheral tolerance occurring in the lymph nodes and elsewhere in the body.
Autoimmunity
Sometimes the processes that eliminate antibodies against self antigens fail, and a variety of
different autoimmune diseases are produced. These can be B cell- or T cell-mediated and can be
organ-specific or systemic. They include type 1 diabetes mellitus (antibodies against pancreatic
islet B cells), myasthenia gravis (antibodies against nicotinic cholinergic receptors), and
multiple sclerosis (antibodies against myelin basic protein and several other components of
myelin). In some instances, the antibodies are against receptors and are capable of activating
receptors; for example, antibodies against TSH receptors increase thyroid activity and cause
Graves' disease . Other conditions are due to the production of antibodies against invading
organisms that cross-react with normal body constituents . An example is rheumatic fever
following a streptococcal infection; a portion of cardiac myosin resembles a portion of the
streptococcal M protein, and antibodies induced by the latter attack the former and damage the
heart. Some conditions may be due to bystander effects, in which inflammation sensitizes T
cells in the neighborhood, causing them to become activated when otherwise they would not
respond. However, much is still uncertain about the pathogenesis of autoimmune disease.
Tissue Transplantation
The T lymphocyte system is responsible for the rejection of transplanted tissue. When tissues
such as skin and kidneys are transplanted from a donor to a recipient of the same species, the
transplants "take" and function for a while but then become necrotic and are "rejected" because
the recipient develops an immune response to the transplanted tissue. This is generally true even
if the donor and recipient are close relatives, and the only transplants that are never rejected are
those from an identical twin.
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A number of treatments have been developed to overcome the rejection of transplanted organs
in humans. The goal of treatment is to stop rejection without leaving the patient vulnerable to
massive infections. One approach is to kill T lymphocytes by killing all rapidly dividing cells
with drugs such as azathioprine, a purine antimetabolite, but this makes patients susceptible to
infections and cancer. Another is to administer glucocorticoids, which inhibit cytotoxic T cell
proliferation by inhibiting production of IL-2, but these cause osteoporosis, mental changes, and
the other stigmas of Cushing's syndrome . A third is treatment with cyclosporine .
Other Clinical Correlates
As knowledge about the immune system has increased, over 50 immunodeficiency syndromes
due to abnormalities in the function of immune cells have been described. These produce
abnormalities ranging from a moderate increase in the incidence of infections to severe, usually
fatal conditions.
Malignant transformation can occur at various stages of lymphocyte development. Most if not
all cases of chronic lymphocytic leukemia are due to uncontrolled proliferation of B
lymphocytes, whereas multiple myeloma is due to malignant proliferation of clones of mature
plasma cells. Some cases of acute lymphocytic leukemia are T lymphocyte cancers.
Acquired immune deficiency syndrome (AIDS), a disease that is currently a major worldwide
problem, is unique in that HIV (human immunodeficiency virus), the retrovirus that causes
many cases of it, binds to CD4 and produces a decrease in the number of CD4 helper T cells.
The loss of helper lymphocytes leads in turn to failure of proliferation of CD8 and B cells, with
eventual loss of immune function and death from infections due to normally nonpathogenic
bacteria or cancer.