lecture 5 Flashcards
number of combinational diversity possible
10^6
VDJ combinations, less than junctional
heavy chain has a lot more V gene segments
light chain has no D gene segments
number of junctional diversity possible
10^11
VDJ a lot more than combinatinoal because of the N and P nucleotides
can really respond to any attack
antibody heavy chain isotype switchin
only happens in B cells
will keep the arms but switch the tail - each tail comes with own unique function
will change messengers produced depending on secretions from B cell -> helper T cell
activation induced cystidine deaminase
AID
converts IgM to IgG, IgE, IgA antibodies
involved in high rate of CDR mutation
improves affinity of BCR:
1. b cells w strongest affinity to an antigen receive greater survival signals
2. those differentiate to become plasma cells and generate memory!
pathway from B cell to messengers/antibodies
B cell -> IgM
- > helper T cell (CD40L, cytokines) -> IFNgamma -> IgG
- > IL4 -> IgE
- > cytokines produced in mucosal tissues (TGFbeta, BAFF) -> IgA
B1 B cells cycle
come from fetal liver as primary lymphoid organ
FLHSC -> pro B -> pre B -> immature B -> B1 B cell w IgM and CD5
B2 B cells cycle
come from bone marrow as primary lymphoid organ
BM HSC -> pro -> pre -> immature -> a. SPLEEN -> transtional B2 (igM) -> a. follicular B2 bcell w IgM and IgD (most common) b. marginal zone B2 Bcell w Igm and CD21/CR2
b. immature B straight to B cell follicles -> follicular B2 (conventional)
B1 Bcell details
- develop from fetal liver HCS
- large # of B1 found as self renewing population in peritoneum and mucosal sites - continue secreting IgMs (antibodies)
- B1 develop earlier during ontogeny than conventional (b2) and express a relatively limited repertoire of V genes and far less junctional diversity than conventional (B2) cells - decreased recognizing ability and are always present
- B1 and marginal zone B cells (B2) spontaneously secrete igm antibodies (natural antibodies) that often react to microbil polysacharides and lipids (PAMPS) - t cell independent responses
- B1 provide source of rapid antibody production against microbes in particular sites (peritoneum)
- at mucosal sites B1 may differentiate into half Iga secreting in lamina propria (IgA microbe biome in gut will stimulate the igM to igA)
T cell independent responses
no generation of memory
B1 cells and marginal zone cells responding to PAMPS
marginal zone B2 cell
- located primarily in vicinity of marginal zone in spleen
- limited diversity, ability to respond to polysaccharide/phospholipid antigens to create natural antibodies (IgM)
- express igM and CD21 surface markers, respond very rapidly to blood borne microbes and differentiate into short lived igM secreting plasma cells (which is good becasue the spleen filters all blood borne pathogens which allows Bcells to make new antibodies)
- dont need t cell help (like B1 does) but do appreciate it
b2 bcells details
- develop in bone marrow HCS
- conventional B cells found in follicle of lymph nodes and spleen
- require dual activation via BCR and T cell interaction
- activation occurs w/in germinal centers of lymph nodes and spleen
- affinity maturation - the more it binds to antigen the more efficient the claws come to bind antigen for antibodies
- generate large number of plasma cells and memory B cells (B2 memory follicular) - long term protection
affinity maturation of B2 follicular B cells
naive B cell from bone marrow -> clonal expansion (army!) -> somatic hypermutation (uber recongnition) -> improved affinity (claw shortens so closer to B cell) -> selection (only B cells that bind remain) -> class switching -> differentiation
into plasma cells, or memory B cells
have help from follicular DC and follicular helper T cells
B10 details
immune regulation
- develop from B1 or B2 after specific stimulation
- T cell independent or dependent
- characterized by presence and secretion of IL10!
- similar to regulatory T cells (Tregs): Bregs modulate immune response to limite inflammation
- lack of b10 b cells lead to increase in inflammation and some diseases - rheumatoid arthritis
B cell activation and signaling
immunogens
requires cross linking of multiple BCRs or recquires protein antigens to attract T cell help
only macromolecules are capable of stimulating B cells to initiate antibody responses
epitope (antigenic determinant): portion of macromolecule that an antibody binds (can see 2D epitope)
immunogens
B10 activators/signalers
molecules that stimulate an immune response
ex: sugars, lipids, complex carbohydrates, phospholipids, nucleic acids, and proteins
Bcell activation and signaling results
transcription factors (through CD79 signal transducing components) proliferation differentiation cytokine secretion antibody secretion
inflammation/immune system help!
CR2 role in B cell activation
aids in binding to C3d (complement proteins that tagged for opsonization) and holds microbe to B cell for more improved activation
drawn in through signals of Ig’s and CR2 complex
TLR role in B cell activation
B1 or marginal zone (B2) cells
TLR is PAMP recognizer of microbe that signals different TLRs that will lead to specific responses to specific microbe
TLR2/1
gram + PAMP
TLR2/6
zymosan PAMP
TLR3
dsRNA PAMP
TLR4
gram - PAMP
TLR5
flagellin PAMP
TLR7
ssRNA PAMP
TLR8
ssRNA PAMP
TLR9
CpG DNA
Tcell dependent B cell activation
follicular MZ Bcells (B2) that need T cell help
helper tcell activation of bcells
needed for costimuating follicular b cells and sometimes MZ Bcells
two BCRs recognize antigen and internalize it then MHC2 presents peptides (epitope) to T cell CD40 is required for B - T interaction cytokines released and attracts RESULT: -enhanced proliferation -differntiation -cytokine secretion -antibody secretio -affinity maturation -isotype switching -memory -plasma cells produced
Tcell independent Bcell activation
bacterial cell walls have multiple identical linear nonprotein epitopes:
- ex: haemophilus influenzae polysaccharide (Gram - LPS)
- bind to BCR (same 2) leading to B cell activation
- immediate activation is short lived response w only IgM produced!
TI -1 antigen
TI -2 antigen
TI - 1 antigen
mitogen/TLR agonist
T1 -2 antigen
repeating motif of encapsulated bacteria
secondary antibody response
each subsequent challenge creates more and more memory cells - exposure after primary antibody response (plasma cells, memory b cell and antibodies secreted)
plasma cells are
antibody factories which express few surface markers
anti RBC antibodies
complement mediated RBC lysis (IMHA)
anti platelet antibodies
thrombocytopenia
anti penicillin antibodies
anemia, shock, allergic reaction
rheumatoid arthritis
rheumatoid factor build up, immune complexes
SLE (lupus)
systemic inflammation affecting one or multiple organs
antinuclear antibodies
lupus or lupus like symptoms
lymphoma
uncontrolled expansion of B cells or T cells
leukemia
uncontrolled expansion of immature B cells or T cells
cancer transformation
bovine leukemia virus (B cell)
multiple B cell subsets…
exist and have unique activation and signaling pathways
T cell independent
T cell dependent
VDJ re arrangement of BCR
generates extensive diversity to recognize pathogens
heavy has VDJ junctional and combinaitonal
light doesnt have D
only follicular B cell responses generate
long lived plasma and memory cells
MZ B cells act as
early sentinels for blood borne pathogens
B1 act as
innate effector cells, producing antibody for protection prior to encounter with antigen
B10 play a
regulatory antiinflammation role via production of IL10
b cell activation occurs through the
BCR BCR, BCR CR2complex, or BCRTLR ligation
t cell independent B cell responses occur via
recognition of some antigens conserved patterns (repetitive motifs)
tolerance protects the body from
self-reactive B cells
clinical responses to antibody mediated diseases
lots of examples and really dangerous bc mess up immune system and inflammation
