Download Origins and means of the immune response

Lecture 3
ORIGINS AND MEANS OF
THE IMMUNE RESPONSE
Jan Żeromski
2013/2014
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Points to be discussed
• Rationale and phases of the immune response
• The role of inflammation and tissue injury
• Cytokines and chemokines
• Cell adhesion molecules
• Leucocyte-endothelial cell interactions
• Origin and subsets of T and B cells
• CD (Cluster Determinants) classification
• Intracellular biochemical events following Ag
recognition
• Patterns and mechanisms of cell migration
• Immunoglobulins and generation of diversity
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Rationale of immune response
• Recognition of foreign structure or organism
• Detection of its pathogenicity
• Prevention of its unwanted effects
• Destruction of invader
• Elimination it from the body
Phases of the immune response
• Induction phase – recognition of antigen
• Central (activation) phase – cell
proliferation and differentiation into various
subsets,
• Effector phase – engagement of various
mechanisms and cells
Factors participating in particular phases of
the immune response
• Induction phase: PRRs, MHC antigens, T and B
cell receptors,
• Central ph: adhesion molecules, cytokines,
antigen-presenting cells (APCs), macrophages
• Effector ph: cytotoxic T lymphocytes (CTLs),
immunoglobulins, activ. macrophages, NK cells
The role of inflammation
• Inflammatory agent leads to activation of PRRs and results
in tissue injury
• Injury induces chemotaxis of various cells to the site of
damage, such neutrophils, macrophages, APCs
• APCs ingest foreign antigens, process them to peptides
suitable for the presentation to T cells
• Cytokines released by neutrophils, macrophages and other
cells activate APCs and enhance them to migration to
lymph nodes. Cytokines secreted by APC activate T cells
responding to given antigen
Main properties of some interleukins
•IL-1 – proinflammatory, pleotropic
•IL-2 – growth factor for T, B and NK cells
•IL-4 –maturation and differentiation of B cells
•IL-5 – as above but of eosinophils
•IL-6 – proinflammatory, differentiating agent for B cells,
•IL-7 – lymphocyte development in primary lymph organs ,
•IL-10 – immunosuppressive
•IL-12 – strong activator of cellular immune response
•IL-15 – maturation of NK cells in bone marrow
•IL-17 – proinflammatory, pleotropic
•IL-18 – production of interferon gamma przez T and NK cells
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CELL ADHESION MOLECULES (CAM)
Integrins:
adhesion to endothelium and extracellular matrix
(VLA-1 to 6, LFA-1)
CAM of the immunoglobulin supergene family:
various (ICAM-1-3, VCAM-1, PECAM-1, NCAM, CEA)
Selectins:
molecules on leucocytes and endothelium which bind
to carbohydrate (E, P, L-selectins, )
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CELL ADHESION MOLECULES (CAM)-2
Cadherins:
bind to catenins, cytoskeleton elements in
calcium dependent manner (E, N,Tcadherins)
CD44 and it variants:
cell hyaluronate receptor involved in cell-tocell and cell-to-matrix interactions
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LEUCOCYTE-ENDOTHELIAL CELL
INTERACTIONS
• Leucocytes interact with the vessel wall in
multistep fashion, using several leucocyte
surface molecules that recognize their
counter-receptors on endothelial cells
• The rolling and tethering of leucocytes on
vessel wall is mediated by selectins (a
subtype of cell adhesion molecules)
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LEUCOCYTE-ENDOTHELIAL CELL
INTERACTIONS -2
• Chemokines and their receptors are needed
to activate leucocyte integrins
• Only activated integrins are able to mediate
firm adhesion between leucocytes and
endothelium
• The transmigration of leucocytes into the
tissues requires proteinases and repair
mechanisms
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Subdivision of T lymphocytes
• T helper (CD4+)
• Th1
• Th2
• T cytotoxic(CD8+)
• Tc1
• Tc2
• Treg (CD25, Foxp3)
• Th17
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CD (CLUSTER DETERMINANTS)
CLASSIFICATION
• Based on the identification of single epitopes by
monoclonal antibodies
• Involves mainly differentiation antigens of cells and
cell receptors, but also various proteins, enzymes
• Most, but not all, CD markers are at cell surface
• Actual number of CD markers is above 360.
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EXAMPLES OF CD MARKERS
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•
•
•
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CD3
CD4
CD8
CD10
CD19
CD45
CD62L
TCR signalling complex:
MHC class II receptor:
MHC class I receptor:
neutral endopeptidase:
co-receptor subunit:
LCA (tyrosine phosphatase):
L-selectin:
• CD247 zeta chain of TCR :
T cells
T cells
T cells
ALL cells
B cells
leukocytes
T cells, mono-,
granulocytes
T cells, NK cells
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CD4 Th1 and Th2 T cells:
profile of produced cytokines
Th1
IL-2
IFN-gamma
TNF-beta
Th2
IL-4
IL-5
IL-6
IL-10
IL-13
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T CELL ACTIVATION-EARLY STEPS
• Formation of immunological synapse –
lymphocyte polarization, adhesion to APC,
maturation of synapse
• Microdomains (lipid rafts) – regions of cell
membranes rich in lipids: contain several
proteins able for fast signal transduction,
kinases from Src family, and other
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T CELL ACTIVATION-EARLY STEPS-2
• Lymphocyte activation leads to
microdomain grouping- so called
supramolecular activation clusters-SMAC
• First (Ag-TCR) and second signal (CD28CD80, CD86, CD58-CD2) concept; naive
lymphocytes need 2 signals, activated cells
– only the first one
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INTRACELLULAR SIGNALING
IN T CELL ACTIVATION
• Involves transduction of signals
from both T cell receptor and CD28
• CD4 bound lck kinases become activated by
CD45 phosphatase
• ITAM (Immunoreceptor Tyrosine-based Activation
Motif) domains of CD3 (zeta chains) become
phosphorylated by lck
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INTRACELLULAR SIGNALING
IN T CELL ACTIVATION
• ITAMs associate with other kinases such as
ZAP-70 and fyn
• Fyn activates phopholipase C (PLC) which
cause release of intracellular calcium
(calcium flux)
• Calcium binds to calcineurin and activates
transcription factors (NF-AT, NF-kappa B,
AP-1)
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LAT signaling pathology (LSP)
• LAT - Linker for activation of T cells
• Functional defect of Lat gene results in –
• Lymphoproliferative syndrome – LSP
• It is manifested by polyclonal proliferation of
CD4+ T cells, secreting chronically in excess
cytokines typical for Th2 response
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SIGNALING IN B CELL ACTIVATION
• Tyrosine kinases lck, lyn ,fyn become
activated via Ig and Ig of B cell receptor
• They phosphorylate BCR ITAM domains
• These can then bind Syk, another kinase,
which activates phospholipase C (PLC-)
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WHAT ARE TRANSCRIPTION FACTORS?
• Answer: transcription factors are complex
protein molecules residing in cytoplasm,
which after stimulation and assembly are
able to enter cell nucleus and induce
several genes transcription.
• The most common: NF-κB, NF-AT, AP-1
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LYMPHOCYTE RECIRCULATION
• Lymphocytes recirculate continuously
between blood and lymphoid organs
• 80% of lymphocytes enter the lymph nodes
via specialized vessels called high endothelial
venules (HEV)
• The remaining lymphocytes enter the lymph
nodes together with dendritic cells and
antigens via afferent lymphatics
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LYMPHOCYTE RECIRCULATION - 2
• Lymphocytes leave the lymph nodes via
efferent lymphatics
• Lymphocyte recirculation allows the
lymphocytes to meet their cognate
antigens and other leukocyte subsets to
evoke an efficient immune response
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IMMUNOGLOBULINS
KEY CONCEPTS
• Isotype:
antigenic differences between classes,
subclasses and types
• Allotype:
antigenic differences between Ig
constant domains of various individuals
• Idiotype:
antigenic differences within variable
domains reflecting antigen binding site
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IMMUNOGLOBULINS
KEY CONCEPTS - 2
• Isotype (class) switching: the change of
produced Ig (from IgM to other Ig),
usually in secondary immune response
• Polyclonal Ig: a mixture of Igs having either
kappa or lambda chains (3:1 ratio in humans)
• Monoclonal Ig: either kappa or lambda light
chain – incidence in tumors such as myeloma,
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or produced in vitro (monoclonal Abs)
Main Immunoglobulin Classes
• IgG – the most abundant Ig. Exists in 4 subclasses
(IgG1, IgG2, IgG3, IgG4)
• IgA – exists as serum and secretory Ig present on
mucosal surfaces, 2 subclasses (IgA1 and IgA2).
• IgM – present in bloodstream is composed of 5
molecules forming pentamer. Protects from sepsis.
Produced mainly in spleen.
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Immunoglobulin classes - 2
• IgD –with IgM forms antigen receptor on B
cells. In serum in trace amounts.
• IgE – anti-parasitic. Participates in allergic
reactions. Very short lifetime when free, but
stable when bound to cell surface such as
mast cells.
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FEATURES OF IMMUNOGLOBULIN
SUPERFAMILY
• Large family of ancestrally related
genes-probably >100 (MHC molecules,
TCRs, some cytokine receptors etc.)
• Most products involved in immune
system function or other cell – cell
interactions
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THANK YOU!
Sorry for a huge
amount of difficult new
data and terms!
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