B Cell Activation and Antibody Isotypes Flashcards
Describe antibodies
- random arrangement of Ig genes allows response to any protein/glycan
- battle pathogens that evolve very quickly
- create a stronger immune response the second time
- however includes food, gut bacteria, organs, unborn child
Describe Tolerance
Prevents adaptive immune system from incorrect response:
- central tolerance - primary lymphoid organs
- peripheral tolerance - secondary lymphoid organs
Describe B cell development
- primary lymphoid organ is bone marrow
- stromal cells provide appropriate factors (soluble) and cell-cell interactions for B cell development
- multipotent progenitor cell -> common lymphoid progenitor -> early pro-B cell -> late pro-B cell -> pre-B cell -> immature B cell
Describe central tolerance in B cells
- stromal cells aid
- where BCR genomic rearrangement and negative selection for B cell occurs
- negative selection - removal of lymphocytes encoding self-reactive antigen receptors
Describe the 4 outcomes of immature B cells in bone marrow
- no self reaction -> migrates to periphery -> mature B cell
- multivalent self molecules -> clonal deletion or receptor editing -> apoptosis or generation of non-subreactive mature B cell
- soluble self molecule -> migrates to periphery -> anergic B cell
- low affinity non-cross-linking self molecule -> migrates to periphery -> mature B cell (clonally ignorant)
Describe B cell activation from Signal 1
- BCR interaction with specific antigen
- BCR binds epitopes on pathogen antigen
- mediates endocytosis of antigen
- follicular DC assist and maintain intact antigens on surface
- present on lymph nodes
- can also involve interactions with antigen
Describe antigen interactions from Signal 1 B cell activation
- CD35 (CR1) and CD21 (CR2)
- these can bind antigens opsonised with complement
Describe activation of B cells via Signal 2
- interaction with specific antigen T-cell
- B cell processes antigen
- presents on surface MHC II molecule
- interaction with TCR on activated specific T cell
- not necessarily same epitope or antigen the B and T cell are responding to
- linked recognition
- T cell produces cell-bound co-stimulatory signals and cytokines
- activation of B cell
Describe co-stimulation
- CD40 receptor on B cell
- CD154 receptor (CD40L) on T cell
- cytokines such as IL-4
What are the key cells involved in B cell activation
- B cells
- follicular dendritic cells - signal 1 for B cells
- T cells - signal 2 for B cell activation
- dendritic cells - activate T cells
Where do B and T cells reside before activation and what do they express?
- resting B cells express CXCR5 in follicles
- resting T cells express CCR7 in T cell zones
Describe naive B cells expression of CXCR5
- chemokine receptor
- binds CXCL13
- released by FCDs
Describe naive T cell expression of CCR7
- chemokine receptor
- binds CCL21
- released by DCs
What do activated B and T cells induce?
- activated B cells induce CCR7 and EB12
- activated T cells induce CXCR5
both cells migrate to follicular and interfollicular regions
What does interactions with T cells sustain on B cells?
- EB12 expression on b cells
- which move to outer follicular and interfollicular regions
What happens to some T and B cells after Signal 2 is recieved?
- some B cells migrate to form a primary focus and differentiate into plasmablasts
- some T cells induce Bcl-6 and become TFH cells
What are the 3 outcomes of activated B cells?
- rapid proliferation and differentiation into plasmablasts or plasma cells - short lived
- migration to germinal centre before differentiation into plasma cells - long lived
- development into a memory B cell
What are the response characteristics of secondary response?
- faster response
- more antibodies produced
- isotype switching occurs: IgM -> IgG, IgA, IgE
What are the main 5 antibody types and what are their constant regions on heavy chains?
IgM - µ
IgD - δ
IgG - ү
IgA - α
IgE - ϵ
Describe antibody isotypes
- class-switching leads to removal of DNA encoding constant regions 5’ of selected
- can’t go back to IgM/D after switching to IgG/A/E
- heavy chains determine distinct properties of isotopes
- antibodies interact with host cell receptors via Fc region
- range of Fc receptors (FcR) found on immune system cells
- different isotypes activate different effector immune responses
What occurs before any class switching?
- BCRs present on B cell surface are IgD and IgM
- can express both due to alt. splicing mechanism
- both IgM and IgD can be secreted after activation
Describe IgM
- most commonly first Ab detected in a primary immune response
- can form pentamers but not always - sometimes monomers, hexamers
- low affinity before affinity maturation occurs
- efficient in stimulating complement system
- occurs in blood and lymph - pentamers too big to cross easily into tissues
Describe IgD
- fails to activate classical complement pathway
- no link to phagocytosis or helminth responses
- very limited levels in blood
- evolutionarily highly conserved
- can bind FcR to mast cell/basophils
- present in mucosa, especially nasopharyngeal cavities
What does evidence suggest about IgD?
- associated with regulatory responses
- peripheral tolerance against commensals, food antigens etc
Describe IgG
- class-switching to IgG common in most primary responses
- dominant in most memory responses
- multiple subclasses - different constant region
Where is IgG located?
- most common Ab in blood
- present in mucosal surfaces - esp reproductive and lower respiratory tracts
What is the function of IgG?
- effective as neutralizing antibody in blood & extracellular spaces
- opsonizes pathogens
- some subclasses activates complement
Describe IgA
- opsonizes pathogens less well and weakly activates complement
- dimeric IgA occurs in secretions on epithelia
- dimeric IgA secreted by plasma cells in lamina propria of gut
Describe IgE
- acts in conjunction with eosinophils, mast cells and basophils
- very little free IgE in blood
- bound to resting & activated mast cells by high affinity receptors - FcR (FcϵR1)
- key in response to larger organisms - too large to phagocytoze
- attacked by eosinophils which bind to surface antibody via FcRs
What is high IgE / mastocytosis associated with?
resistance to intestinal helminths
