B Cells - Denzin 4/5/16 Flashcards
B cell mediated immune responses
in general…
APC (major: DCs)
- phagocytose pathogens, process, present on MHC receptors
helper T cells (CD4)
- produce cytokines → activate B cells
- interact with BCRs to trigger antigen-specific B cell response
B cells (with antigen-specific BCR)
- clones of plasma cells → secreted antibodies
- clones of memory B cells → secondary immune response
BCR
BCR = antibody bound on B cell surface
each B cell expresses only one specificity (lots of antibodies of the same specificity)
humoral immune response
humoral immune response involves destruction of extracellular pathogen, prevention of spread of intracellular infection through antibodies
4 main mechs:
- neutralization
- opsonization
- ADCC: antibody-dep cellular cytolysis
- complement activation
antibody fx:
neutralization
antibodies bind to microbes extracellularly
- blocks binding to healthy cells → prevents infection
- prevents spread of infection from one cell to adjacent cells (binds microbes released from infected cells)
-
prevents pathologic/toxic activity of microbe (by binding it before it can bind to cell)
* point of tetanus boosters
antibody fx:
opsonization
opsonization is the process by which antibodies coat/tag a microbe or infected cell
process:
- IgG binds to microbe (opsonization)
- opsonized microbe binds to phagocyte Fc receptors (constant region) : Fc-gamma-RI
- Fc receptors can positively and negatively regulate immune fx
- approp Fc receptor signals activate phagocytes → phagocytosis → killing of ingested microbe
antibody fx:
ADCC
antibody-dependent cellular cytotoxicity
occurs via NK cells!
- unique bc dont have TCRs
- recognize Fc regions via their Fc-gamma-RIII receptor → leading to killing of infected cell
antibody fx:
complement activation
functions of complement
1. opsonization
- C3 cut → C3b binds to pathogens → C3b is recognized by C3b receptors on phagocytes → phagocytosis!
2. stimulation of inflammatory rxn
- binding of C3b, release of C3a → proteolysis of C5, release of C5a → recruitment of leukocytes by C3a and C5a → destruction of microbes by leukocytes
3. complement-mediated cytolysis
- binding of C3b to bacteria, activation of later components of complement → formation of MAC (membrane attack complex) → pokes holes, promotes osmotic lysis of bacteria
ordered stages of B cell devpt
goal: generate a B cell with a BCR on the surface
multipotent progenitor cell (hematopoeitic stem cell) in bone marrow (stromal signals critical for devpt)
→ common lymphoid progenitor
→ early pro-B cell
→ late pro-B cell
→ pre-B cell [has BCRs]
from here onwards, devpt in secondary lymphoid organs
→ immature B cell
checkpoints during B cell devpt
- Ig devpt involves V(D)J recombination, which involves cutting and splicing together DNA (with a dose of random nt addition) → DANGEROUS!!!
- often leads to unsuccessful arrangements, so need to have checkpoints to ensure fxal heavy and light chain production
- after heavy chain is made, BCR (with surrogate light chain) put out on cell surface to make sure it can bind tonic signal
* if tonic signal not bound → cell killed. if tonic signal bound → cell lives. - after light chain is made, BCR put out on cell surface to make sure it can bind tonic signal
* signal indicates productive arrangement → live
* however…just bc there’s a tonic signal, doesn’t mean you have a good, desirable B cell.*
enter: tolerance
- BCR generation via gene rearragement → potential for self-reactive autoimmunity
- curtailing self-reactivity occurs via central tolerance in central lymphoid regions (bone marrow) and peripheral tolerance for cells that escape central tol
mechanisms mediating B cell central tolerance
only 5% of B cells make it through central tolerance
high avidity self antigen recognition indicates potential autoimmunity, resulting in either:
- apoptosis
- receptor editing of V region : continued light chain rearrangement → altered cell specificity
- if still self-reactive → apoptosis
- if no longer self-reactive → migration of immature B cell to periphery, where it can mature
low avidity self antigen recognition occurs when soluble self antigen binds to BCRs → signals B cells to reduce receptor expression → functional anergy (still there, but not doing much)
mechanisms mediating B cell peripheral tolerance
high avidity self antigen recognition (in resp to antigen not seen in bone marrow, but encountered later on in periph) indicates potential autoimmunity, resulting in either:
- apoptosis
- anergy
self antigen recognition (low or high avidity) is also regulated by inhibitory receptors (ex. CD22)
*in autoimmunity, certain helper T cells have TCRs specific for self antigen, which allows B cells and their BCRs to escape these tolerance mechs
T-dependent B cell responses
vs.
T-indep B cell responses
humoral response is initiated by B cell binding of antigen via repetitive patterns that crosslink BCRs
there are 2 types of antigens:
-
protein antigens (require T cell help)
* T-dependent/thymus-dependent: unable to induce antibody responses in humans or mice that lack T cells - microbial antigens (DO NOT require T cell help) (ex. bacterial polysacchs)
*
B cell activation
requires two signals (similar to T cells) so as to mediate specificity of immune response!
- don’t want to activate an immune response when you dont need it
signal 1 : crosslinking of BCRs
- polyvalent antigen (> 1 of the same epitope available for binding) can cause crosslinking directly
- monovalent antigen → antigen is presented in “clusters” to B cell via APC (DC or macrophage)
- complement can also assist in crosslinking! can crosslink BCR and complement receptor
leads to…
- increased survival, proliferation
- increased expression of B7-1, B7-2
- increased expression of cytokine receptors (IL4 receptors, BAFF-R)
- increased expression of CCR7 and migration from follicle to T cell areas
promote T cell interaction
signal 2 : interaction with helper T cell
T-dep : mediated mainly through CD40 (on B cell) + CD40L (CD40 ligand on T cell) + cytokines
-
class II MHC presentation is key for signal 2
- crosslinking of BCR → endocytosis of microbe, processing, presentation on MHC II → allows specific TCR recognition!
- get a specific immune response as needed
T-indep : occurs via innate immune system → activation of TLR by LPS
B cell maturation
immature B cells mature in periphery (read: spleen) → mature B cells
- diff subpops can mediate diff fx
B-1 B cells : fetal liver (present v early on)
- make IgM that circulates in blood early (“natural antibodies”)
- highly reactive, bind with low affinity to microbial antigens
B-2 B cells : bone marrow → transitional B-2 B cells
- follicular B cells : usually T-dependent responses [most adaptive immune responses!)
- marginal zone B-2 B cells : usually T-indep responses [might have role against bacteria in blood stream; hang in spleen white pulp sinuses]
overview of B cell fates
[recognition phase] : B cell + antigen → crosslinking (signal1)
helper T cells or innate immune system come through with signal2 → activated B cell!
[activation phase] : clonal expansion and differentiation to…
- plasma cells → antibody secretion
- IgG-expressing B cell → class switching
- high affinity Ig-expressing B cell → affinity maturation [plays role in secondary immune response being BETTER/LOWER DOSE REQ]
- memory cells → primed for secondary response
B cell subtype involvement in T-dep and T-indep responses
in spleen and other lymphoid organs…
follicular B cells : protein antigen + helper T → germinal center rxn → T-dep, isotype-switched, high-affinity antibodies + long-lived plasma cells
marginal zone B cells : recog polysacchs/lipids → T-indep, mostly IgM; short-lived plasma cells
in mucosal tissues, peritoneal cavity…
B-1 B cells : recog polysacchs/lipids → T-indep, mostly IgM; short-lived plasma cells
germinal center rxn
second phase of immune response in T-dep responses only
process: activated B cells move into lymphoid centers and form germinal centers in follicles → undergo heavy prolif (bc not many will make it out…), followed by:
affinity maturation
- run into follicular dendritic cells, which serve as antigen depots in follicles
- B cells begin to undergo serious mutation (mediated by AID, activation induced cytidine deaminase, which is turned on by CD40 ligation) → affinity maturation aka somatic hypermutation
- AID activity specifically targeted to CDR binding regions
- B cells with best affinity to antigens are the ones that bind, get survival signals, survive: selection of high-affinity antibodies
isotype switching aka class switch recombination
- production of antibodies with diff heavy chain classes (via switching of constant regions)
- depends on cytokine signal received
- IFN gamma : IgM → IgG
- IL4 : IgM → IgE
- mucosal tissues, cytokines (BAFF, TGFbeta, APRIL, etc) : IgM → IgA
principal effector fx of each Ig class
IgM : sits on surface of naive B cells (along with IgD)
- secreted as pentamer (low affinity, but 10 binding sites → overall high avidity)
- complement pathway activation
IgG : switching induced by IFN-gamma
- Fc receptor mediated fx : phagocytosis, opsonization, complement activation, placental transfer
IgE : switching induced by IL4
- immunity against helmiths
- mast cell degranulation : allergic responses
IgA : switching induced by TGFbeta, APRIL, BAFF
- dimeric
- specialized for fx in gut (with commensal organisms)
primary response vs secondary response
- peak response
- antibody isotypes
- antibody affinity
- induced by…
primary // secondary
peak response: lower // higher
isotypes: usually IgM > IgG // relative increase in IgG (sometimes in IgA, IgE)
affinity: lower, more variable // higher (affinity maturation)
induction: all immunogens // only protein antigens
