Transcript Immunology

Immunology
IMMUNOLOGY
Sherko A Omer
MB ChB, MSc., PhD
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Immunology
LYMPHOID ORGANS AND TISSUES
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LYMPHOID ORGANS AND TISSUES
In the primary organs (thymus and mammalian
bursa equivalent) lymphopoiesis occurs, lymphoid
stem cells differentiates to lymphocytes which
acquire several surface markers and become able to
discriminate between self and non self.
In secondary lymphoid organs (lymph nodes,
spleen, MALT), there are the environments in which
the lymphocytes can interact with immunogens to
induce an immune response.
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THYMUS
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THYMUS
Thymus is composed from cortical and
medullary epithelial cells, stromal cells,
interdigitating cells and macrophages.
These ‘accessory’ cells are important in the
differentiation of the immigrating T cell
precursors and their ‘education’ (positive and
negative selection) prior to their migration into
the secondary lymphoid tissues.
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THYMUS
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THYMUS
The thymus has an interactive role with the
endocrine.
Thymic epithelial cells produce the hormones
thymosin and thymopoietin and in concert with
cytokines (such as IL-7) are probably important for
the development and maturation of thymocytes into
mature T cells.
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THYMIC SLECTION
Positive selection of cells
whose receptor binds MHC
molecules.
Negative selection and death
of cells with high-affinity
receptors for self-MHC or selfMHC+ self-antigen.
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THYMIC DISORDERS
Impairment of thymus development
leads to immune deficiency such as in
DiGeorge Syndrome (cellular immune
deficiency, congenital cardiac
anomalies, abnormal fascies and
hypoparathyroidism).
Patient with systemic lupus
erythematosus (SLE) or myasthenia
gravis may show lymphoid hyperplasia
or thymoma.
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MAMMALIAN EQUIVALENT BURSA
Not identical organ such as bursa
Gut associated lymphoid tissue (appendix, Peyer’s
patches) histologically resembles the birds bursa.
In human foetal liver and bone marrow are
equivalent to bursa where B cell differentiation and
maturation take place.
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MAMMALIAN EQUIVALENT BURSA
The bone marrow gives rise to all of the lymphoid
cells that migrate to the thymus and mature into T
cells, as well as to the major population of
conventional B cells.
B cells mature in the bone marrow and undergo
selection for non-self before making their way to the
peripheral lymphoid tissues.
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LYMPH NODES
Encapsulated round or beanshaped structures that are present
in high numbers at junctions of
major lymphatic tracts.
In the resting state lymph nodes
are about 1-25 mm in length but
they enlarges during infection and
when they are invaded by
malignancy.
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Structure of a lymph node
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LYMPH NODES
Within the cortex there are few
aggregations of predominately B
cells with mIgD (primary
follicles).
Activation of B cells in the
germinal centre of primary
follicles results in division of B
cells to generate secondary
follicles that contain mostly
IgG-bearing B cells.
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LYMPH NODES
In secondary follicles stimulated B cells matures to plasma
cells in cords in the medulla where they secrete
Immunoglobulin.
In the deep cortex or paracortical area, T lymphocytes are
the predominant cell population. DCs are also present in
this area, where they present antigen to T lymphocytes.
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LYMPH NODES
The medulla, less densely populated, is organized into
medullary cords draining into the hilar efferent
lymphatic vessels.
Plasmablasts can be easily identified in the medullary
cords.
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SPLEEN
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SPLEEN
The spleen is the major site of
immune responses to bloodborne antigens.
The spleen is also an important
filter for the blood. Its red pulp
macrophages clear the blood of
microbes and other particles.
The spleen is the major site for the
phagocytosis of antibody-coated
(opsonised) microbes.
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MUCOSAL-ASSOCIATED LYMPHOID TISSUES
MALT encompass the lymphoid tissues of the
intestinal tract, genitourinary tract, tracheobronchial
tree, and mammary glands.
MALT are unencapsulated and contain both T and B
lymphocytes, the latter predominating.
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MUCOSAL-ASSOCIATED LYMPHOID TISSUES
GALT (Gut-associated lymphoid tissues) is the
designation proposed for all lymphatic tissues found
along the digestive tract.
Three major areas of GALT that can be identified
 Tonsils
 Peyer’s patches, located on the submucosa of the
small intestine and the appendix
 Scanty lymphoid tissue is present in the lamina
propria of the gastrointestinal tract
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MUCOSAL-ASSOCIATED LYMPHOID TISSUES
Lymphoid complexes along the gastrointestinal tract; volume of the rings
indicates the relative amount of lymphoid tissue.
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MUCOSAL-ASSOCIATED LYMPHOID TISSUES
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MUCOSAL-ASSOCIATED LYMPHOID TISSUES
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MUCOSAL-ASSOCIATED LYMPHOID TISSUES
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MUCOSAL-ASSOCIATED LYMPHOID TISSUES
M cells, present largely in the dome epithelia of
Peyer’s patches, particularly at the ileum.
These cells take up small particles, virus, bacteria,
and deliver them to sub-mucosal macrophages,
where the engulfed material will be processed and
presented to T and B lymphocytes.
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LYMPHOCYTE RECIRCULATION
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LYMPHOCYTE RECIRCULATION
The cells of the lymphatic system circulate continuously
and reach all parts of the body with a few exceptions
(vitreous body, brain, testicles).
They reach the lymph nodes, skin, and intestine via a
specialized endothelium of post-capillary venules, the
so-called high endothelial venules (HEV).
The cells of this endothelium are much higher than
normal endothelial cells.
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LYMPHOCYTE RECIRCULATION
In response to certain chemotactic factors, lymphocytes
migrate to the underlying tissue (diapedesis).
The lymphatic cells re-enter the circulation through
efferent lymph vessels that merge into the thoracic
duct.
The lymphocytes enter the spleen via arterioles and
sinusoids and exit the organ via the splenic vein
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LYMPHOCYTE RECIRCULATION
Mucosal B cells circulate between different segments of
the MALT, including the GALT, the mammary glandassociated lymphoid tissue, and the lymphoid tissues
associated with the respiratory tree and urinary tract.
T cells migrate to lymph nodes.
The selectivity in migration is due to presence of homing
receptors on lymphocytes surface that can bind with the
endothelial cells in HEV. CD44, on lymphocytes and
endothelium are important in these routings.
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LYMPHOCYTE RECIRCULATION
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ADHESIOIN MOLECULES
Surface molecules called cell adhesion molecules
(CAMs) that interact with ligands, including other CAMs,
expressed on the membrane of T and B lymphocytes.
Three main families of CAMs have been defined:
Selectins
Immunoglobulin superfamily of CAMs
Integrins
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MAJOR HISTOCOMPALABILITY COMPLEX
Mammalian species possess a tightly linked cluster
of genes, the major histocompatibility complex
(MHC).
The MHC is referred to as the Human Leukocyte
Antigen (HLA) complex in humans and as the H-2
complex in mice.
MHC are important in graft rejection.
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MAJOR HISTOCOMPALABILITY COMPLEX
Class I MHC genes encode glycoproteins expressed on
the surface of nearly all nucleated cells; the major function
of the class I gene products is presentation of peptide
antigens to TC cells.
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MAJOR HISTOCOMPALABILITY COMPLEX
Class II MHC genes encode glycoproteins expressed
primarily on antigen-presenting cells (macrophages,
dendritic cells, and B cells), where they present
processed antigenic peptides to TH cells.
Class III MHC genes encode, in addition to other
products, various secreted proteins that have immune
functions, including components of the complement
system and molecules involved in inflammation
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MAJOR HISTOCOMPALABILITY COMPLEX
Class II MHC genes encode glycoproteins expressed
primarily on antigen-presenting cells (macrophages,
dendritic cells, and B cells), where they present
processed antigenic peptides to TH cells.
Class III MHC genes encode, in addition to other
products, various secreted proteins that have immune
functions, including components of the complement
system and molecules involved in inflammation.
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INHERITANCE OF MHC
An individual inherits one haplotype from the mother and
one haplotype from the father.
The alleles are codominantly expressed; that is, both
maternal and paternal gene products are expressed in
the same cells.
The chance of two siblings to have both haplotypes
identical is 25%, one haplotype identical is 50% and zero
haplotype identical is 25%, provided the chance of
recombination is neglected.
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INHERITANCE OF MHC
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INHERITANCE OF MHC
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MHC CLASS I MOLECULE
45-kiloDalton (kDa),  chain associated noncovalently with
a 12-kDa 2-microglobulin molecule.
The  chain is a transmembrane glycoprotein encoded by
polymorphic genes within the A, B, and C regions of the
human HLA complex.
2-Microglobulin is a protein encoded by a highly
conserved gene located on chromosome 15.
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MHC CLASS I MOLECULE
Class I molecules are present on
the surface of all nucleated cells
and on platelets.
CD8+ cells can recognize
antigen only when this antigen is
associated with self class I
molecule on the surface of cells
(virally infected, tumour cell) this
is called MHC restriction.
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MHC CLASS I MOLECULE
CD8+ cells cannot recognize
antigen alone or when these
antigens are associated with
different MHC class I molecules.
Class I molecules are called
major transplantation antigens
because they are recognized by
host during graft rejection.
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MHC CLASS II MOLECULE
Consist of two different polypeptide chains, a 33-kDa 
chain and a 28-kDa  chain.
1 and 2 domains in one chain and 1 and 2 domains
in the other.
The membrane-proximal 2 and 2 domains, like the
membrane-proximal 3/-2-microglobulin domains of class
I MHC molecules, bear sequence similarity to the
immunoglobulin-fold structure.
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MHC CLASS II MOLECULE
The membrane-distal portion
of a class II molecule is
composed of the 1 and 1
domains and forms the antigen
binding cleft for processed
antigen.
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MHC CLASS II MOLECULE
Class II molecules are present on
surface of B cells, APCs, activated
T cells, and in some conditions on
resting T cells, thyroid cells.
CD4+ cells can recognize antigens
only when the antigen is associated
with self MHC class II molecule and
these molecules are responsible for
Graft Versus Host reaction (GVH).
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DETECTION OF HLA MOLECULES
HLA molecules can be identified on
lymphocytes by:
 Lymphocytotoxicity test (antibody against HLA
molecules with added complement) for
detection of both class I and II molecules.
 Molecular methods.
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HLA AND DISEASE ASSOCIATION
Most of the diseases associated with HLA are autoimmune
in nature; some are infectious (e.g., malaria).
Diseases are of unknown aetiology and pathophysiology
and with a hereditary pattern of distribution.
The diseases are related to immunological abnormalities.
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HLA AND DISEASE ASSOCIATION
The explanation of HLA disease relation:
 HLA molecules may act as receptors for etiological
agents
 HLA may act as selective sites for antigen and then the
cell present this antigen to induces an immune response
 The causative agent may mimic HLA molecule
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HLA AND DISEASE ASSOCIATION
Disease
Ankylosing spondylitis
Rheumatoid arthritis
SLE
Multiple sclerosis
ID diabetes mellitus
Myasthenia gravis
Associated HLA Allele
B27
DR4
DR3
DR2
DR4/DR3
DR3
Relative Risk
90
10
5
5
20
10
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ANTIGEN AND IMMUNOGEN
Immunogenicity and antigenicity are related but distinct
Immunogenicity is the ability to induce a humoral and/or
cell-mediated immune response.
Antigenicity is the ability to combine specifically with
antibodies and/or TCR.
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ANTIGEN AND IMMUNOGEN
Small molecules called haptens, are antigenic but
incapable, by themselves, of inducing a specific immune
response. Haptens lack immunogenicity.
Although a substance that induces a specific immune
response is usually called an antigen, it is more
appropriately to be called an immunogen
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IMMUNOGENICITY DETERMINANTS
Foreignness, immune system can distinguish
self from nonself (foreign) and only reacts against
nonself molecules to induce an immune response.
Molecular size, potent immunogens have
molecular weight more than 100 000 Da while
molecules with less than 10 000 Da are none or
weak immunogens.
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IMMUNOGENICITY DETERMINANTS
Chemical complexity, proteins and
polysaccharides are among the most potent
immunogens, small polypeptide chains, nucleic
acids, and even lipids can be immunogenic provided
given in an appropriate circumstances.
Susceptibility to antigen processing and
presentation, Macromolecules that cannot be
degraded and presented with MHC molecules are
poor immunogens.
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IMMUNOGENICITY DETERMINANTS
Genetic background of the host, different animal
species and different strains of one given species
may show different degrees of responsiveness to a
given immunogen.
Dosage and method of antigen administration,
an insufficient dose will not stimulate an immune
response either because it fails to activate enough
lymphocytes or it may induce tolerance, conversely,
an excessively high dose can also induce tolerance
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IMMUNOGENICITY DETERMINANTS
The method of immunogen administration, a
given dose of antigen may elicit no detectable
response when injected intravenously, but a strong
immune response is observed if injected
intradermally. The presence of DCs in the dermis
may be a critical factor determining the enhanced
immune responses when antigens are injected
intradermally.
Use of Adjuvants, adjuvants when administered
along with immunogens enhance the specific
response.
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ADJUVANTS
Substances that, when mixed with an immunogen and
injected with it, enhance the immunogenicity of that
immunogen.
Adjuvants are often used to boost the immune response
when immunogenicity to a material is low or when only
small amounts of an immunogen/antigen are available.
Examples of adjuvant are Freund’s complete adjuvant
(mineral oil, lanolin and killed Mycobacteria) used in
animal experiments and Aluminum hydroxide used in
vaccines
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ADJUVANTS
Adjuvants augment the immune response appear to be
through one or more of the following effects:
 Antigen persistence is prolonged
 Co-stimulatory signals are enhanced
 Local inflammation is increased
 The nonspecific proliferation of lymphocytes is stimulated
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HAPTEN
Chemical coupling of a hapten to a large protein, called a
carrier, yields an immunogenic hapten-carrier conjugate
Animals immunized with such a conjugate produce
antibodies specific for:
 Hapten determinant
 Unaltered epitopes on the carrier protein
 New epitopes formed by combined parts of both the
hapten and carrier
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EPITOPE (Antigenic Determinate)
Sites on or within the antigens with which the antibody or
TCR reacts.
Structurally an epitope may be in the form of 4-5 amino
acids or sugar resides in a linear or conformational form.
The numbers of epitopes of an antigen are vary and
related to the size of the antigen, the sum of the epitopes
determines the specificity of that antigen.
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EPITOPE
T cells can be trigged by
immunogen with one epitope
while B cells need at least two
epitopes to be triggered.
Diagram of sperm whale myoglobin showing
locations of five sequential (linear) epitopes
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EPITOPE
Linear sequence of peptides
recognized by T cells
Antigenic determinants (epitopes) required by antibodies
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T-DEPENDENT AND T-INDEPENDENT
ANTIGEN
B cells respond to antigen either in a T- dependent (needs
TH) or a T- independent fashion.
T- independent antigens have high molecular weight
with linearly arranged repeating antigenic determinants
and are highly resistant to degradation by body enzymes
Examples of T-independent antigens are Pneumococcal
polysaccharides, Escherichia coli lipo-polysaccharides,
and polyvinyl pyrolidine.
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T-DEPENDENT AND T-INDEPENDENT
ANTIGEN
Most natural antigens are TD and requires antigen
processing by antigen presenting cells (APCs).
Feature
Immune response
Secondary response
Isotype switching
Memory cell induction
T- independent antigen
T- dependent antigen
Weak
Strong
IgM
IgM or IgG
Negative
Positive
Poor
Good
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EXOGENOUS & ENDOENOUS ANTIGEN
Exogenous (foreign)… from outside
Exogenous antigen include microbial, environmental
(pollens and pollutants) and medications.
Immune system try to eliminate foreign antigens, but in
some instances, the immune response itself may have a
deleterious effect, resulting in hypersensitivity or in
autoimmune disease.
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EXOGENOUS & ENDOENOUS ANTIGEN
Endogenous antigens are part of self, the immune system
is usually tolerant to them.
The response to self-antigens may have an important role
in normal catabolic processes (i.e., antibodies to denatured
IgG may help in eliminating antigen-antibody complexes
from circulation; antibodies to oxidized low density
lipoprotein (LDL) may help in eliminating a potentially
toxic lipid .
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EXOGENOUS & ENDOENOUS ANTIGEN
However, the loss of tolerance to self-antigens can also
result in autoimmune diseases.
Endogenous antigens that distinguish one individual from
another within the same species and are termed
“alloantigens”, these elicit immune responses when cells
or tissues of one individual are introduced into another.
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EXOGENOUS & ENDOENOUS ANTIGEN
Separate antigen-presenting pathways are utilized
for endogenous and exogenous antigens.
The mode of antigen entry into cells and the site of
antigen processing determine whether antigenic
peptides associate with class I MHC molecules in the
rough endoplasmic reticulum or with class II molecules
in endocytic compartments
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MITOGEN
A substance which causes DNA synthesis and blast
transformation, mitogen has also immunostimulatory
effects by increasing expansion of B and/or T cells.
Concanavalin A (Con A)
Phytohaemagglutinin (PHA)
Pokeweed mitogen (PWM)
Lipopolysaccharide (LPS)
T cells
T cells
T and B cells
B cells
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