B CELL Public Health MSc 6th week, 2014. DEFINITIONS Antigen (Ag) - any substance, which is...
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Transcript of B CELL Public Health MSc 6th week, 2014. DEFINITIONS Antigen (Ag) - any substance, which is...
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B CELL
Public Health MSc
6th week, 2014
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DEFINITIONS
• Antigen (Ag) - any substance, which is recognized by the mature immune system of a given organism
– antigenicity - specific reactivity with cells or molecules of the immune system (weak antigen vs. strong antigen)
– immunogenicity - capability to elicit an immune response
– tolerogenicity - capability to induce immunological tolerance
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part of the antigen that directly interacts with the antigen-specific receptors of lymphocytes (TCR or BCR/antibody)
ANTIGENIC DETERMINANT (=EPITOPE)
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B cell epitope(recognized by B cells)
T cell epitope(recognized by T cells)
proteinspolysaccharideslipidsDNAsteroidsetc. (even artificial molecules)
cell or matrix associated or soluble
proteins mainly (8-23 amino acids)
requires processing and presentation by APCs
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Several epitops of one microbes can be recognized by different B cells
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approx. 10 – 1000 million (107 - 9) different antigen receptors, unique specificity of B cells
approx. 10 – 1000 million (107 - 9) different antigen receptors, unique specificity of T cells
ADAPTIVE IMMUNE SYSTEM
Diversity of receptor strucure
How can the antigen receptors of lymphocytes recognize extremly diverse antigens
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Random hands, millions of variations
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Random selection of gene segments ensures millions of different receptors (variable domains)
Happens during the maturation of B cells in the red bone marrow
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VH D JH
VL JL
V-Domains
C-Domains
VH-D-JH VL-JL
VARIABILITY OF B-CELL ANTIGEN RECEPTORS AND ANTIBODIES
B cells of one individual 1 2 3 4
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Estimates of combinatorial diversity
Taking account of functional V D and J genes:
65 VH x 27 DH x 6JH = 10,530 combinations
40 V k x 5 Jk = 200combinations30 V l x 4 Jl = 120 combinations
= 320 different light chains
If H and L chains pair randomly as H2L2 i.e. 10,530x 320 = 3,369,600 possibilities Due only to COMBINATORIAL diversity
In practice, some H + L combinations do not occur as they are unstableCertain V and J genes are also used more frequently than others.
There are other mechanisms that add diversity at the junctions between genes - JUNCTIONAL diversity
GENERATES A POTENTIAL B-CELL REPERTOIRE
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Several antibodies are expressed on B cells (arround 100.000) but all of them has the same specificity
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Forms of immunoglobulins:• membrane-bound (expressed as BCR on the surface of B cells)• soluble (secreted by plasma cells [antibody])
Membrane bound and soluble Igs recognize the same antigen when originated from the same B cell
Differentiation
Plazma cellSecreted
antibodies
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B – CELL ACTIVATION
Where and how do all these things take place?
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SECONDARY LYMPHOID ORGANS/TISSUES
• LYMPH NODES
• SPLEEN
• TONSILS (Waldeyer’s ring)
• Diffuse lymphoid layers under the
epithelial barriers:
– SALT (skin-associated lymphoid
tissue)
– MALT (mucosa-associated lymphoid
tissue)
• BALT (bronchus-associated lymphoid tissue)
• GALT (gut-associated lymphoid tissue)
Sites of lymphocyte activation and terminal differentiation
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B-cell recycling in the absence of antigen (lymph node)
B cells in blood
Efferentlymph
T cell area
B cell area
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Antigen entersnode in afferent
lymphatic
Y
Y
Y
Y
Y
YY
Y
Y
Y
Y
Y
Y
Y
YY
Y
YB cells leave blood & enter lymph node via
high endothelial venulesB cellsproliferate
rapidly
GERMINAL CENTRETransient structure ofIntense proliferation
Germinal centrereleases B cellsthat differentiateinto plasma cells
Recirculating B cells are trapped by foreign antigens in lymphoid organs
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when B cells recognize their antigens originated from the afferent lymphatics, they start to migrate to the boarder of the B cell zone for the help of helper T cells
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After helper T cells become activated by APCs (mostly DCs) in the T cell zone, and they differentiate into effector cells, they start to migrate to the boarder of the T cell zone to help the activation of B cells
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B-se jt
c itokinek
C D4TC R
MHC II+ pep tid
T-se jt
2
1
only works in the presence of pathogenic proteins!
T-DEPENDENT ACTIVATION OF B CELLS
B CELLT CELL
cytokines
MHC-II +
peptide
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T-INDEPENDENT ACTIVATION OF B CELLS
aggregation of multiple BCRs cross-phosphorylation signaling
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GC reaction:
• proliferation (clonal expansion) of activated B cells
• affinity maturation (stronger binding to epitopes)
• isotype switch (different effector functions)
• memory B cell formation (from improved clones)
Only by the help of Th cells!
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AFFINITY MATURATION
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B cells compete for the antigen
High affinity B cells can grab the antigen and get survival signals while low affinity cells will lack those and undergo
apoptosis selection of high affinity clones
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ActivationClonal expansionDifferencaition
Plasma cells Antibody production
Memory B cells
CirculationRestricted lifespan
(few days)Apoptosis
Specific B cells Non-specific B cells
Antigen recognition by specific BCR induces clonal expansion and differentiation of the sepcific B cells.
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Antigen
Activation of specific B cells
1. Clonal expansion
Antigen Antigen
2.Differentiation
Plasma cells, antibody production
MEMORY B CELLS
Antigen
Antigen
Antigen recognition by specific BCR induces clonal expansion and differentiation of the sepcific B cells.
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Antigen
ActivationClonal expansion
B cell
Antigen receptor, BCR
Ag
Clonal antigen receptors are expressed exclusively on T- and B lymphfocyties.
Antigen
Antigen
Antigen
Antigen recognition by specific BCR induces clonal expansion of the sepcific B cells.
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Ag
Ag
B cell repertoire
Specific, activated B cells
Plasma cells
Antigen specific antibodies
POLYCLONAL RESPONSE
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EFFECTOR FUNCTIONS OF ANTIBODIES
Antibody-mediated immune responses
• NEUTRALIZATION
• OPSONIZATION
• opsonized phagocytosis (IgG)
• ADCC (NK cell-mediated killing) (IgG)
• mast cell degranulation (IgE)
• COMPLEMENT ACTIVATION
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Antigen
Activation1. Clonal expansion
Antigen Antigen
2.Differentiation
Plasma cells
MEMORY B cells
Antigen recognition by specific BCR induces clonal expansion and differentiation of the sepcific B cells.
Antigen
Antigen