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B CELLS
Public Health MSc
6th week, 2015
Arpad Lanyi, PhD
The two „arms” of the immune system
Innate immunity: always present (ready to attack); many pathogenic
microbes have evolved to resist innate immunity
Adaptive immunity: stimulated by exposure to microbe; more potent !
Some key questions:
1) How cab the immune system respond to so any different pathogens….
2) Specific antibodies can be made to almost any antigens. How is this possible?
3) How many genes do we (humans) have?
4) How many species of pathogens and antigens are out there?
5) Does a single B cell recognize all antigens or only one?
ADAPTIVE IMMUNE SYSTEM
Diversity of receptor strucure
How can the antigen receptors of lymphocytes recognize
extremly diverse antigens
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
The early stages of B-cell development are
dependent on bone marrow stromal cells
60 billion B cells/day
The immune system practically regenerates the immune repertoare an a dayly basis
Several antibodies are expressed on B cells (around
100.000) but each of them has the same specificity
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 cell
Secreted
antibodies
Some key questions:
1) How can the immune system respond to so any different pathogens….
2) Specific antibodies can be made to almost any antigens. How is this possible?
3) How many genes do we (humans) have?
4) How many species of pathogens and antigens are out there?
5) Does a single B cell recognize all antigens or only one?
Random selection of gene segments ensures millions of
different receptors (variable domains)
A BCR is assembled from several small gene segments in a random
fashion. It happens during the development of B cells in the red bone
marrow
Estimates of combinatorial diversity
Taking account of functional V D and J genes:
65 VH x 27 DH x 6JH = 10,530 combinations
40 Vk x 5 Jk = 200combinations
30 Vl 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 unstable
Certain 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
VARIABILITY OF B-CELL ANTIGEN RECEPTORS AND ANTIBODIES
B cells of one individual
2
3
1
4
V-Domains
C-Domains
VH
D
JH
VL
VH-D-JH
JL
VL-JL
B – CELL ACTIVATION
Occurs in peripheral lymphoid
organs
SECONDARY LYMPHOID ORGANS/TISSUES
Sites of lymphocyte activation and terminal differentiation
•
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)
B-cell recycling in the absence of antigen
(lymph node)
T cell area
B cells
in blood
B cell
area
Efferent
lymph
Recirculating B cells are trapped by foreign
antigens in lymphoid organs
Antigen enters
node in afferent
lymphatic
YY
Y
B cells
proliferate
rapidly
B cells leave blood &
enter lymph node via
high endothelial venules
Y
YY
Y
Y
Y
GERMINAL CENTRE
Transient structure of
Intense proliferation
YY
Y
Germinal centre
releases B cells
that differentiate
into plasma cells
Antigen presentation by B cells
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
Activation of B-cells by T lymphocytes in the lymph nodes
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 border of the T
cell zone to help the activation of B cells
T-DEPENDENT ACTIVATION OF B CELLS
MHC-II
+
MHCII
peptide
+
peptid
1 B-sejt
B CELL
T
CELL
T-sejt
CD4
TCR
2
citokinek
cytokines
only works in the presence
of pathogenic proteins!
T-INDEPENDENT ACTIVATION OF B CELLS
aggregation of multiple BCRs  cross-phosphorylation  signaling
The Germinal Center (GC) reaction
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!
AFFINITY MATURATION
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
Antigen recognition by specific BCR induces clonal
expansion and differentiation of the sepcific B cells.
Specific B cells
Non-specific B cells
Activation
Clonal expansion
Differencaition
Memory B cells
Circulation
Restricted lifespan
Apoptosis
Plasma cells
Antibody production
Antigen recognition by specific BCR induces clonal
expansion and differentiation of the sepcific B cells.
Plasma
cells,
antibody
production
A n ti g e n
2.Differen
tiation
Activation of
specific B cells
1. Clonal
expansion
A n ti g e n
MEMORY B CELLS
A n ti g e n
A n ti g e n
A n ti g e n
Antigen recognition by specific BCR induces clonal
expansion of the sepcific B cells.
B cell
Antigen
receptor, BCR
A n ti g e n
Ag
Activation
Clonal expansion
A n ti g e n
A n ti g e n
A n ti g e n
Clonal antigen receptors are expressed exclusively on Tand B lymphfocyties.
Immune response to pathogens
are POLYCLONAL responses
B cell repertoire
Ag
Specific,
activated B cells
Plasma cells
Antigen specific
antibodies
Several individual B-cells gets activated and proliferate
in a regular immune response
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
ANTIGENIC DETERMINANT
(=EPITOPE)
part of the antigen that
directly interacts with
the antigen-specific
receptors of
lymphocytes (TCR or
BCR/antibody)
B cell epitope
T cell epitope
(recognized by B cells)
(recognized by T cells)
proteins
polysaccharides
lipids
DNA
steroids
etc. (even artificial
molecules)
cell or matrix associated
or soluble
proteins mainly
(8-23 amino acids)
requires processing and
presentation by APCs
Several epitops of one microbes can be recognized by different B cells