Introduction to immunology

 Immunity refers to protection against infections.
 The immune system is the system responsible for
defending the body against pathogenic microbes in
the environment.
 Deficiencies in immune defenses result in an
increased susceptibility to infections.
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 The immune system is collection of organs, tissues,
cells, and soluble factors that allow individuals to
defend against harmful agents such as viruses,
bacteria, fungi, parasitic organisms, and tumor
cells.
 The ultimate goal of this system is to prevent or
limit infections or damage by these agents.
 The immune response involves recognizing any
foreign material and mounting a reaction to
eliminate it.
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INNATE AND ADAPTIVE IMMUNITY
The immune response is divided into two categories: the
innate and the adaptive branches.
 Innate immunity (also called natural, or native,
immunity) is mediated by cells and proteins that are
always present to fight against microbes and are called
into action immediately in response to infection.
 The major components of innate immunity are:
1- epithelial barriers of the skin, gastrointestinal tract, and
respiratory tract, which prevent microbe entry;
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2- phagocytic leukocytes (neutrophils and macrophages);
3- the natural killer (NK) cell;
4- several circulating plasma proteins, the most important
of which are the proteins of the complement system.
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MECHANICAL AND SECRETORY BARRIERS
TO INFECTION
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ADAPTIVE IMMUNITY
 The innate immune response is able to prevent and
control many infections. However, many pathogenic
microbes are able to overcome innate immune
defenses.
 Protection against these infections requires the more
powerful mechanisms of adaptive immunity (also
called acquired, or specific, immunity).
 Adaptive immunity is normally silent and responds
(or "adapts") to the presence of infectious microbes by
becoming active, expanding, and generating potent
mechanisms for neutralizing and eliminating the
microbes.
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 The components of the adaptive immune system are
lymphocytes and their products.
 There are two types of adaptive immune responses:
humoral immunity, mediated by soluble antibody
proteins that are produced by B lymphocytes (also
called B cells), and cell mediated immunity, mediated
by T lymphocytes (also called T cells) .
 Antibodies provide protection against extracellular
microbes in the blood, mucosal secretions, and tissues.
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 T lymphocytes are important in defense against
intracellular microbes.
 They work by either directly killing infected
cells (accomplished by cytotoxic T-lymphocytes)
or by activating phagocytes to kill ingested
microbes, via the production of soluble protein
mediators called cytokines (made by helper T
cells).
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 When the immune system is inappropriately
triggered or not properly controlled, the same
mechanisms that are involved in host defense
cause tissue injury and disease.
 The reaction of the cells of innate and adaptive
immunity may be manifested as inflammation.
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COMPARISON BETWEEN ADAPTIVE AND INNATE
IMMUNITY
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STRUCTURAL ORGANISATION OF THE
IMMUNE SYSTEM
 The lymphoid system is composed of:
 The primary lymphoid organs, in which lymphopoiesis
(Lymphopoiesis refers to the generation
of lymphocytes) occur
 The secondary lymphoid organs, in which immune
responses occur.
 The primary, or central, lymphoid organs are the
anatomical locations in which lymphocytes develop the
ability to specifically recognize foreign antigen and to
distinguish self from nonself.
 These lymphoid organs are the bone marrow and thymus.
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SECONDARY LYMPHOID ORGANS
 The secondary lymphoid organs are the sites for
presentation of foreign antigens to cells of the immune
system.
 The major secondary, or peripheral, lymphoid organs and
tissues include:
 The lymph nodes ( (‫الليمفاويه‬ ‫العقد‬
 The spleen
 The mucosa-associated lymphoid tissue (MALT) of the
gut the respiretory and genitourinary tracts.
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THE LYMPHOID ORGANS
AND LYMPHATIC VESSELS
ARE WIDELY
DISTRIBUTED IN THE
BODY.
THE LYMPHATIC VESSELS
COLLECT LYMPH FROM
MOST PARTS OF THE
BODY AND DELIVER IT
TO THE BLOOD
CIRCULATION PRIMARILY
THROUGH THE
THORACIC DUCT.
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CELLS OF THE IMMUNE SYSTEM
 T LYMPHOCYTES,
 B LYMPHOCYTES,
 PLASMA CELLS (MODIFIED B CELLS)
 MACROPHAGES, “HISTIOCYTES”
 “DENDRITIC” CELLS ( Antigen Presenting Cells)
 NK (NATURAL KILLER) CELLS
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 All lymphoid cells originate in the bone marrow
 Lymphoid precursors destined to become T-
lymphocytes mature in the thymus.
 Development of B-lymphocytes occurs entirely
in the bone marrow.
 Lymph nodes, spleen and mucosa-associated
lymphoid tissue are secondary lymphoid organs.
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 Plasma cells are B-lymphocytes that are
specialized to produce antibodies or
immunoglobulins.
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MACROPHAGES are
MONOCYTES that have come
out of circulation and have
gone into tissue.
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 A major function of macrophages is the
phagocytosis of invading organisms and other
antigens.
 Macrophages have prominent lysosomal
granules containing acid hydrolases and other
degradative enzymes with which it destroy
phagocytosed material.
 They are also important for the presentation of
antigen to other cells of the immune system
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DENDRIDIC CELL
 A Dendridic cell is a type of macrophage with many
spiny cytoplasmic processes, found in many places
especially skin (Langhans cells) and brain
(microglia), and
many other places
like liver. They are
APC’s.
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NATURAL KILLER CELLS
 NK cells are types of lymphocytes which
specialize in direct killing of cells that come in
contact with.
 Natural killer cells
(or NK cells) are a type
of cytotoxic lymphocyte
that play a major role in
the rejection of tumors
and cells infected by
viruses.
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NEUTROPHILS OR POLYMORPH NUCLEAR
LEUCOCYTES
 Neutrophils play a major role in the body's
defence against acute infection. They can
migrate out of, blood vessels into tissues
 They do this in response to chemotactic agents
produced at the site of inflammation.
 Neutrophils are phagocytic cells able to kill
ingested microbes.
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 Eosinophils have bilobed nucleus, with large
pink granules.
 Eosinophiliais a hallmark of:
.Allergic reactions
.Worm infections
 It can also be seen in collagen vascular diseases
and any skin disorder.
 Basophils are secretory cells with bilobed
nucleus and large blue granules.
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CYTOKINES/CHEMOKINES
 Cytokines are protiens produced by many cells, but usually
LYMPHOCYTES and MACROPHAGES.
 They have numerous roles in acute and chronic
inflammation, and immunity.
 They are soluble mediators which act as stimulatory or
inhibitory signals between cells. Cytokines which act
between cells of the immune system are called
interleukins.
 CHEMOKINES are small proteins which are attractants
for neutrophils.
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MAJOR HISTOCOMPATIBILITY COMPLEX
 A genetic “LOCUS” on Chromosome 6, which codes for cell
surface compatibility.
 MHC antigens also called HLA (Human Leukocyte
Antigens) are cell surface glycoproteins of two basic types:
class I and class II.
 It’s major job is to make sure all self cell antigens are
recognized and “tolerated”, because the general rule of the
immune system is that all UN-recognized antigens will NOT
be tolerated.
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 Class I are present in all nucleated cells and platelets.
They are designated A, B and C.
 Class II are present in APC and lymphocytes.
 Their subclasses are DP, DQ and DR.
 They play a fundamental role in the normal immune
response by presenting antigenic peptides to T-cells.
 Helper T-cells(CD4+) recognise antigen in association
with MHC class II molecules, while cytotoxic T-
cells(CD8+) recognise antigen associated with MHC
class I.
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HUMAN MHC SUMMARY
MHC Class I MHC Class II
Names HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ, HLA-
DR
Tissue distribution All nucleated cells;
platelets .
B lymphocytes,
monocytes,
macrophages,
dendritic cells,
Langerhans cells,
activated T.
Recognized by Cytotoxic T cells
(CD8+)
Helper T cells (CD4+)
Function Elimination of
abnormal (infected)
host cells by cytotoxic
T cells.
Presentation of foreign
antigen to helper T
cells
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ANTIGEN ANTIBODY REACTION
Dr. Sulafa Eltayeb Ahmed

ANTIGEN
 Antigens are substances able to provoke an
immune response and react with the products of
that response.
 They react both with the T-cell receptor and with
antibody.
 An antigenic molecule may have several antigenic
determinants (epitopes); each epitope can bind with
an individual antibody.
 a single antigenic molecule can therefore provoke
many antibody molecules with different binding
sites.
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 The tertiary structure, as well as the amino acid
sequence, is important in determining antigenicity.
 Some low molecular weight molecules, called
haptens, are unable to provoke an immune
response themselves, but they can react with
existing antibodies.
 Such substances need to be coupled to a carrier
molecule in order to have sufficient epitopes to be
antigenic.
 For some chemicals, such as drugs, the carrier may
be a plasma protein.
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 Complete antigen: A substance that induces an
immune response and that can specifically react
with the product of that response (the antibody).
 Incomplete antigen (hapten): A low-molecular-
weight substance (a short peptide or drug) that only
acts as an antigen once it binds to macro-
molecules like plasma proteins.
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STRUCTURE OF THE IMMUNOGLOBULIN
 1. Basic structure: Immunoglobulins act as
antigen-specific receptors on B cells and,
when secreted by plasma cells, mediate
humoral responses.
 The basic structural unit of an
immunoglobulin molecule is a glycoprotein
monomer, consisting of four polypeptide
chains linked covalently by disulfide bonds.
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 The molecule contains two identical light
chains and two identical heavy chains.
 The structure has two identical antigen
binding sites consisting of both light and
heavy chains.
 Heavy and light chains have variable
regions on their most N terminal ends.
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HEAVY AND LIGHT CHAINS:
 These chains are subdivided into variable and
constant regions.
 The light chains have two domains, one variable
and one constant. The heavy chains have four to
five domains, one variable and three or four
constant depending on the type of immunoglobulin.
 The light chains may be of two different classes,
kappa (к) or lambda (λ),on the basis of structural
differences in the constant domain.
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MAJOR IMMUNOGLOBULIN CLASSES
 There are five classes or isotypes of human
immunoglobulins. These are designated by the type
of heavy chain they have.
1. IgG: gamma( )H(heavy) chain
2. 1gA:alpha(α) H chain
3. IgM: mu (μ) H chain
4. 1gE:epsilon ( ) H chain
5. IgD: delta ( ) H chain
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 Subclasses
1. IgG is further divided into four subclasses: IgGI,
IgG2, IgG3, and IgG4.
2. IgA: There are also two subclasses of IgA, called
IgAl and IgA2.
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CHARACTERISTICS OF THE FIVE CLASSES
IgG
 It is the Ig present at the highest concentration in
plasma;
 It is actively transported across the placenta;
 It activates complement;
 It opsonizes organisms to facilitate phagocytosis;
 It is the Ig characteristically produced during the
secondary immune response.
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IgM
 present in serum it is a pentameric molecule held
together with a J-chain as well as disulfide bonds;
 It is the Ig characteristically produced during the
primary immune response;
 It is the most efficient Ig at activating complement;
 The monomeric form serves as the antigen
receptor on the B-cell surface.
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IgA
 It is the main Ig in external secretions such as milk,
saliva, tears, and respiratory and intestinal mucusa
so it protects mucosal surfaces
 It is the major protective factor in colostrum
 It is present in secretions as a dimer with a J
(joining) chain and secretory piece
 There are two subclasses: IgA1 and IgA2
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1gE
 It is present in plasma as a monomer in very low
levels
 It binds to mast cells and basophils that have FC
receptors for epsilon heavy chains.
 The bridging of two 1gE molecules on cell
membranes causes release of granule contents
 It is important in providing immunity against
parasitic infestation
 It mediates Type I hypersensitivity (allergic)
reactions
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IgD
 It is present in plasma at very low concentrations
 It is present in the membrane of mature B cells at
very high levels
 It functions as an antigen receptor (with IgM
monomers) on B cells.
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 The functions of the constant region of
immunoglobulins are:
1- activation of the complement system,
2- binding to cell surface receptors on granulocytes
or macrophages to initiate phagocytosis
(opsinization).
 The function of the variable region primarily
involves antibody-antigen interactions, including
precipitation, agglutination, and neutralization of
antigen.
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T-CELL RECEPTORS
 The TCR has certain similarities to immunoglobulin
in that it is made up of two non identical polypeptide
chains that have constant and variable regions.
 TCR has only one antigen binding site per
molecule but immunoglobulin has two.
 The majority of TCR have α β chains but < 10%
are γ δ chains.
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ANTIBODY-ANTIGEN INTERACTIONS
 The strength of binding of the Fab portion to the
epitope is known as affinity.
 As antibodies are made in immune responses to
an infectious agent or its toxins, the quality of the
antibody tends to improve, with increasing affinity.
 The total strength of antigen-antibody binding, not
just one interaction, is called avidity.
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The antigen antibody reaction leads to formation of
an antigen antibody complex or immune complex.
Its fate depends on its size and solubility.
The solubility of an immune complex is determined by
the nature of components involved and by their
relative quantities.
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 Where the quantities of antigens and antibodies are
nearly in equilibrium, alarge immune complex will
form.
 This will not remain in solution, but will precipitate
out.
 Across-linked immune complex oragglutination will
form even in reactions with cell bound antibodies,
such as blood group antibodies.
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FATE OF AN IMMUNE COMPLEX AGGREGATION
 Large, precipitating immune complexes are rapidly
attacked by macrophages.
 Large, soluble immune complexes penetrate
vessel walls, successively leading to deposits on
the basement membrane and to tissue damage
from ongoing formation of immune complex.
 Small soluble immune complexes are excreted by
the kidney.
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HUMORAL AND CELL MEDIATED
IMMUNITY

ROLE OF CELL-MEDIATED IMMUNITY IN HOST
DEFENSE
 Host defenses against extracellular infectious
agents, such as extracellular bacteria, protozoa,
worms and fungi, are mediated by antibody,
complement, and phagocytes.
 However, once an infectious agent invades a host
cell, these defenses are virtually useless.
 Recovery from intracellular infection requires an
entirely different defense system ie: the cell-
mediated immunity (CMI)
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 In CMI, the first goal of the immune system is to
destroy the intracellular infectious agent by killing
the host cell that harbors it.
 In many cases, this will also kill the pathogen,
which may require the host cell for its own
reproduction.
 Virus infection always requires the induction of cell-
mediated cytotoxicity, mediated by cytotoxic T cells,
natural killer (NK) cells, or activated macrophages.
 The same cytotoxic mechanisms may be effective
against most tumor cells.
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 In the special case where intracellular organism
infect a macrophage, activation of macrophage by
helper T cell (Thl ) may be sufficient for destruction
of the pathogen.
 This results in the process called delayed-type
hypersensitivity (DTH).
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INDUCTION OF CELL-MEDIATED IMMUNITY
 Like antibody production in humoral immunity, CMI
requires T-cell help.
 Thl cells must first recognize antigen presented by
an MHC class II molecule on an antigen-presenting
cell.
 The activated Thl cell secretes IL-2 and IFN- ,
which activate the cytotoxic effector cells.
 Cytotoxic T-Iymphocyte recognition requires
recognition of both the antigenic peptide in the
infected cell and the MHC class I molecule.
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 How do cytotoxic T cells kill their targets? They use:
a. Perforin: Fully activated CTLs contain granules
that are released when the CTL contacts a target
cell.
The granules contain perforin, a pore-forming
molecule that polymerizes in the membrane of the
target cell.
These pores damage the cell membrane, causing
lysis.
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b. Granzymes: The granules also contain enzymes
that damage the target cell, by passing through the
perforin pores into the target cell.
c. Fas and Fas ligand: Fas ligand interacts with the
Fas molecule on the target cell surface, inducing
apoptosis.
NK cells kill by releasing perforin, granzymes, and
cytokines (IFN- and TNF- ), in a manner similar
to T cells can kill target cells.
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ANTIBODY-DEPENDENT CELLULAR
CYTOTOXICITY ADCC
 NK cells are the major cell type that carries
out antibody-dependent cellular cytotoxicity
(ADCC).
 NK cells have Fc receptors that recognize
the Fc domains of IgG.
 When IgG is bound to foreign antigen on the
surface of an infected cell, NK cells can
recognize it, bind, and deliver a lethal hit.
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HUMORAL IMMUNITY
 When a helper T lymphocyte comes in contact with
the APC, the T cells will be activated to secrete
cytokines.
 The cytokines include interleukin (IL)-4, which
activates B cells, and interferon- , which activates
macrophages.
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REGULATION OF THE IMMUNE RESPONSE
 The naïve helper Tcell, is capable of producing all
T-cell cytokines.
 It may differentiate into either aTh1or a Th2 cell.
 The T h1 cell assists cell mediated immunity by
producing interferon-y and by activating
macrophages and cytotoxic CD8 cells.
 The T h2 cell produces IL-4, IL-5, and IL-6,
provoking plasma cell differentiation from B cells.
 There is also cross-regulation and inhibition
between T hl and T h2 cells mediated by IL-l0 and
IFN-y.
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HUMORAL IMMUNITY
 Mature B cells bind and internalize antigen by using
their antigen receptors, the surface immunoglobulins
(lgM and IgD).
 This binding is antigen specific, and B cells can
recognize, bind, and internalize unprocessed antigen.
 The B cells process the antigenic peptides, and
present them on the B-cell surface bound to MHC class
II molecules.
 When an activated helper T cell bind to the B cell this
will signals the helper T cell to release cytokines (include
IL-2, IL-4, and IL-5) that are essential for B-cell division
and differentiation to antibody-producing plasma cells.
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CLONAL SELECTION
 One B cell, one antibody specificity; one T cell, one
T-cell antigen-receptor specificity.
 All specificities that will ever be needed are made
all the time by random selection of variable region
structures.
 Antigen selects the cells that have complementary
receptors by binding to them, and only those cells
undergo clonal expansion (cell division) and
differentiation.
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 Secondary Immune Response:
 A secondary immune response occurs on
subsequent exposure to an antigen that has
previously been encountered.
 There are many differences between primary and
secondary immune responses.
 In a secondary response:
1. More antibody is produced.
2. The lag phase is always shorter.
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3. Less antigen is required to trigger a response.
4. Antibody affinity changes in the immune response.
5. The antibody isotype (class) differs as follows:
In the primary response, IgM always appears first. In
the secondary response to an injected antigen, IgG
is the predominant antibody;
for an antigen administered via a mucosal route
(oral, inhaled), IgA is usually the predominant
antibody isotype.
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 How humoral immune response combats
microbes:
 Antibodies bind to microbes and prevent them from
infecting cells, thus "neutralizing" the microbes.
 IgG antibodies coat ("opsonize") microbes and
target them for phagocytosis.
 IgG and IgM activate the complement system by
the classical pathway, and complement products
promote phagocytosis and destruction of microbes.
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 Decline of Immune Responses :
The majority of effector lymphocytes induced by an
infectious pathogen die by apoptosis after the
microbe is eliminated, thus returning the immune
system to its basal resting state.
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 The initial activation of lymphocytes also generates
long-lived memory cells, which may survive for
years after the infection.
 Memory cells respond faster and more effectively
against the antigen than do naive cells.
 This is why the generation of memory cells is an
important goal of vaccination.
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Introduction to immunology

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