b cell public health msc 6th week, 2014. definitions antigen (ag) - any substance, which is...
TRANSCRIPT
B CELL
Public Health MSc
6th week, 2014
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
part of the antigen that directly interacts with the antigen-specific receptors of lymphocytes (TCR or BCR/antibody)
ANTIGENIC DETERMINANT (=EPITOPE)
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
Several epitops of one microbes can be recognized by different B cells
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
Random hands, millions of variations
Random selection of gene segments ensures millions of different receptors (variable domains)
Happens during the maturation of B cells in the red bone marrow
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
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
Several antibodies are expressed on B cells (arround 100.000) but all 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 cellSecreted
antibodies
B – CELL ACTIVATION
Where and how do all these things take place?
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
B-cell recycling in the absence of antigen (lymph node)
B cells in blood
Efferentlymph
T cell area
B cell area
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
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
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
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
T-INDEPENDENT ACTIVATION OF B CELLS
aggregation of multiple BCRs cross-phosphorylation signaling
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
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.
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.
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.
Ag
Ag
B cell repertoire
Specific, activated B cells
Plasma cells
Antigen specific antibodies
POLYCLONAL 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
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