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Transcript
Immunology
IMMUNOLOGY
Sherko A Omer
MB ChB, MSc., PhD
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Immunology
THE COMPLEMENT SYSTEM
Complement system includes more than 30 soluble
and cell-bound proteins.
The biological activities of this system affect both
innate and acquired immunity.
They are proteins or glycoproteins synthesized mainly
by hepatocytes, although significant amounts are also
produced by blood monocytes, tissue macrophages,
and epithelial cells of the gastrointestinal and
genitourinary tracts.
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Immunology
THE COMPLEMENT SYSTEM
These components constitute 5% (by weight) of the
serum globulin fraction.
Most circulate in the serum in functionally inactive
forms as proenzymes, or zymogens, which are
inactive until proteolytic cleavage, which removes an
inhibitory fragment and exposes the active site.
The complement-reaction sequence starts with an
enzyme cascade.
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Immunology
THE COMPLEMENT SYSTEM
Nomenclature
Classical pathway components are labelled with a C
and a number (e.g., C1, C3).
Alternative pathway components are lettered (e.g., B, P,
D). Some components are called factors (e.g., factor B,
factor D).
Activated components or complexes have a bar over
them to indicate activation (e.g., C4b2a).
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Immunology
THE COMPLEMENT SYSTEM
Nomenclature
Cleavage fragments are designated with a small letter
after the component (e.g., C3a and C3b are fragments
of C3).
Inactive C3b is designated iC3b.
Polypeptide cell membrane receptors for C3 are
abbreviated CR1, CR2, CR3, and CR4.
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Immunology
THE COMPLEMENT SYSTEM
Complement activation can occur by three different
mechanisms:
• The classical pathway
• The alternative pathway
• The lectin pathway
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THE COMPLEMENT SYSTEM
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THE CLASSICAL PATHWAY
Classical pathway is initiated by
Formation of soluble antigen-antibody complexes
(immune complexes) or with the binding of antibody to
antigen on a suitable target, such as a bacterial cell.
IgM and certain subclasses of IgG (human IgG1, IgG2,
and IgG3) can activate the classical complement
pathway.
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Structure of the C1 macromolecular complex. (a) Diagram of C1qr2s2
complex. A C1q molecule consists of 18 polypeptide chains arranged into
six triplets, each of which contains one A, one B, and one C chain. Each
C1r and C1s monomer contains a catalytic domain with enzymatic activity
and an interaction domain that facilitates binding with C1q or with each
other. (b) Electron micrograph of C1q molecule
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Immunology
CLASSICAL PATHWAY
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CLASSICAL PATHWAY
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CLASSICAL PATHWAY
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CLASSICAL PATHWAY
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THE ALTERNATIVE PATHWAY
The alternative pathway is initiated by pathogens and
particles of microbial origin (lipopolysaccharides from
gram-negative bacteria, teichoic acid from gram-positive
cell walls, fungal and yeast cell walls, some viruses and
parasites)
Non pathogen materials (cobra venom factor, nephritic
factor, heterologous erythrocytes and pure carbohydrates)
and aggregated IgA.
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Immunology
THE ALTERNATIVE PATHWAY
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Immunology
THE ALTERNATIVE PATHWAY
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Immunology
THE LECTIN PATHWAY
The lectin pathway is activated by the binding of
mannose-binding lectin (MBL) to mannose residues on
glycoproteins or carbohydrates on the surface of
microorganisms including certain Salmonella, Listeria, and
Neisseria strains, as well as Cryptococcus neoformans
and Candida albicans.
MBL is an acute phase protein produced in inflammatory
responses. Its function in the complement pathway is
similar to that of C1q.
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Immunology
THE LECTIN PATHWAY
The lectin pathway, like the alternative pathway, does not
depend on antibody for its activation.
However, the mechanism is more like that of the classical
pathway, because after initiation, it proceeds, through the
action of C4 and C2, to produce a C5 convertase, this
mechanism also called the MB Lectin pathway or
mannan-binding lectin pathway.
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MEMBRANE ATTACK COMPLEX
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Immunology
MEMBRANE ATTACK COMPLEX
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Immunology
MEMBRANE ATTACK COMPLEX
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REGULATION OF COMPLEMENT SYSTEM
The classical pathway is regulated by C1 inhibitor (C1
Inh), a serine esterase inhibitor that causes C1r2s2 to
dissociate from C1q preventing further activation of C4 or
C2. C1Ihb absence leads to a condition called
hereditary angioedema.
Factor J is a cationic glycoprotein that also inhibits C1
activity.
C4-binding protein (C4bBP) disassembles the C4b2a
complex, allowing factor I to inactivate C4b.
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Immunology
REGULATION OF COMPLEMENT SYSTEM
Factor H or decay- accelerating factor (DAF) compete
with factor B for binding to C3b (e.g., to produce C3bH),
decreasing the half-life of the C3bBb complex and
causing dissociation of the complex into C3b and Bb.
Factor I acts on C3bH to degrade C3b.
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Immunology
REGULATION OF COMPLEMENT SYSTEM
The MAC is regulated by S protein which binds soluble
C5b67 and prevents its insertion into cell membrane.
Membrane bound factors such as homologous
restriction factor (HRF) and membrane inhibitor of
reactive lysis (MIRL) bind to C5b678 on autologous
cells, blocking binding of C9.
Anaphylatoxin inactivator are soluble factors that
inactivates anaphylatoxin activity of C3a, C4a, and C5a
by carboxypeptidase N removal of C-terminal Arg.
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REGULATION OF COMPLEMENT SYSTEM
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REGULATION OF COMPLEMENT SYSTEM
MCP: membrane cofactor protein
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REGULATION OF COMPLEMENT SYSTEM
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BIOLOGIC CONSEQUENCES OF COMPLEMENT
ACTIVATION
Cell lysis is achieved through MAC, The MAC formed
by complement activation can lyse gram-negative
bacteria, parasites, viruses, erythrocytes, and nucleated
cells.
Cleavage products of complement components mediate
inflammation. C3a, C4a and C5a have anaphylatoxin
activity. Anaphylatoxins, bind to receptors on mast cells
and blood basophils and induce degranulation, with
release of histamine and other pharmacologically active
mediators.
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Immunology
BIOLOGIC CONSEQUENCES OF COMPLEMENT
ACTIVATION
The anaphylatoxins also induce smooth muscle
contraction and increased vascular permeability.
C3a, C5a, and C5b67 each can induce monocytes and
neutrophils to adhere to vascular endothelial cells,
extravasate through the endothelial lining of the
capillary, and migrate toward the site of complement
activation in the tissues.C5a is most potent in mediating
these processes.
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Immunology
BIOLOGIC CONSEQUENCES OF COMPLEMENT
ACTIVATION
C3b is the major opsonin of the complement system,
although C4b and iC3b also have opsonizing activity.
The amplification that occurs with C3 activation result
in a coating of C3b on immune complexes and
particulate antigens.
Phagocytic cells, as well as some other cells, express
complement receptors (CR1, CR3, and CR4) that bind
C3b, C4b, or iC3b.
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Immunology
CLEARING IMMUNE COMPLEXES FROM
CIRCULATION
The coating of soluble immune complexes with C3b is
thought to facilitate their binding to CR1 on erythrocytes.
Erythrocytes play an important role in binding C3bcoated immune complexes and carrying these
complexes to the liver and spleen.
In these organs, immune complexes are stripped from
the red blood cells and are phagocytosed, thereby
preventing their deposition in tissues.
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Immunology
BIOLOGIC CONSEQUENCES OF COMPLEMENT
ACTIVATION
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Immunology
BIOLOGIC CONSEQUENCES OF COMPLEMENT
ACTIVATION
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Immunology
COMPLEMENT-BINDING RECEPTORS
Receptor
Major ligand
Activity
Cellular Distribution
CR1 (CD35)
C3b, C4b
Blocks formation of C3,
convertase; binds immune
complexes to cells
Erythrocytes, neutrophils,
monocytes, macrophages,
eosinophils, follicular dendritic
cells, B cells, some T cells
CR2 (CD21)
C3d, C3dg, iC3b
Part of B-cell co receptor; binds
Epstein-Barr virus
B cells, follicular dendritic cells,
Some T cells
CR3 (CD11b/18)
CR4 (CD11c/18)
iC3b
Bind cell-adhesion molecules
on neutrophils, facilitating their
extravasation; bind immune
complexes, enhancing their
phagocytosis
Monocytes, macrophages,
neutrophils, natural killer cells ,
some T cells
C3a/C4a receptor
C3a, C4a
Induces degranulation of mast
cell and basophils
Mast cells, basophils,
granulocytes
C5a receptor
C5a
Induces degranulation of mast
cells and basophils,
Mast cells, basophils,
granulocytes, monocytes,
macrophages, platelets,
endothelial cells
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Immunology
COMPLEMENT ASSAYS
Complement protein levels assayed by:
Nephelometry
Agar gel diffusion
Radial immunodiffusion
ELISA.
Functional assays include hemolytic assays to measure
functional activity of specific components of either
pathways.
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Immunology
COMPLEMENT ASSAYS
The total hemolytic complement assay (CH50) measures
the ability of the classical pathway and the MAC to lyse
sheep RBC to which antibodies has been attached.
The alternative pathway CH50 measures the ability of the
alternative pathway and the MAC to lyse rabbit RBC.
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Immunology
ANTIGEN-ANTIBODY INTERACTION
A bimolecular association similar to an enzymesubstrate interaction.
It does not lead to an irreversible chemical alteration
in either the antibody or the antigen.
The association between an antibody and an antigen
involves various noncovalent interactions between the
antigenic determinant (epitope), of the antigen and the
paratope region of the antibody, (VH/VL) domain,
particularly the hypervariable regions, or
complementarity-determining regions (CDRs).
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ANTIGEN-ANTIBODY INTERACTION
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ANTIGEN-ANTIBODY INTERACTION
The antigen antibody complex is
not bounded firmly and may
dissociate spontaneously
Binding is affected by
environmental factors like pH in
which binding is weaker in pH <4
or >10, increased salt
concentration leads to weaker
binding.
Temperatures of 50-55 C cause
stronger binding.
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Immunology
ANTIGEN-ANTIBODY INTERACTION
The noncovalent binding is
critically dependent on the
distance (d) between the
interacting groups.
As force is proportional to 1/d2 for
electrostatic force and 1/d7 for
Vander Waals force, so
accordingly there must be a high
degree of fitness between antigen
and antibody (complementary
binding) in order to these forces
come to work.
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Immunology
ANTIGEN-ANTIBODY INTERACTION
Affinity
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Immunology
ANTIGEN-ANTIBODY INTERACTION
The combined strength of the noncovalent interactions
between a single antigen-binding site on an antibody
and a single epitope is the affinity of the antibody for
that epitope.
Low-affinity antibodies bind antigen weakly and tend to
dissociate readily, whereas high-affinity antibodies bind
antigen more tightly and remain bound longer.
In some biological reactions high affinity is superior to
low affinity like in haemagglutination, haemolysis,
complement fixation and enzyme inactivation.
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Immunology
ANTIGEN-ANTIBODY INTERACTION
Experimentally antigen antibody complexes containing
low affinity antibody persist longer in circulation and
localized in glomerular basement membranes, this
may lead to impairment of renal function.
In contrast high affinity antigen-antibody complexes are
readily removed from circulation and tend to localize
in mesangium of kidney and have little effect on
kidney’s function.
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Immunology
ANTIGEN-ANTIBODY INTERACTION
The strength with which a multivalent antibody binds a
multivalent antigen, avidity, is affected by affinity and
valency.
Multivalent means that the molecule has more than
one binding sites. A simple IgG molecules is multivalent
as it has two antigen binding sites while an antigen may
be monovalent (e.g. in hapten) or multivalent.
When an antigen binds an antibody with more than two
binding sites the avidity become grater than the sum of
individual binding sites (individual affinities).
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Immunology
ANTIGEN-ANTIBODY INTERACTION
Although Ag-Ab reactions are highly specific, in some
cases antibody elicited by one antigen can cross-react
with an unrelated antigen.
Cross-reactivity occurs if two different antigens share an
identical or very similar epitope.
In the latter case, the antibody’s affinity for the crossreacting epitope is usually less than that for the original
epitope.
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Immunology
ANTIGEN-ANTIBODY INTERACTION
Cross-reactivity usually characterised by less avidity
than specific reaction which occur between antibody
and the original antigen.
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Immunology
ANTIGEN-ANTIBODY INTERACTION
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Immunology
ANTIGEN-ANTIBODY INTERACTION
A number of viruses and bacteria have antigenic
determinants identical or similar to normal host-cell
components.
In some cases, these microbial antigens have been
shown to elicit antibody that cross-reacts with the host-cell
components, resulting in a tissue-damaging autoimmune
reaction.
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Immunology
ANTIGEN-ANTIBODY INTERACTION
The bacterium Streptococcus pyogenes, expresses cellwall proteins called M antigens. Antibodies produced to
streptococcal M antigens have been shown to crossreact with several myocardial and skeletal muscle
proteins and have been implicated in heart and kidney
damage following streptococcal infections.
Some vaccines also exhibit cross-reactivity, vaccinia virus,
which causes cowpox, expresses cross-reacting epitopes
with variola virus, the causative agent of smallpox.
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