B cell response Flashcards
BCR signalling
BCR = antibody (IgM and IgD in naive)
Ig-alpha and Ig-beta transduce signals
Co-receptors - increase signal (promote activation if weak signal)
- CD21 (complement receptor 2)
- CD19
- CD81
B cell activation
Antigen:BCR (IgM or IgD + Igalpha + Igbeta) ->
Receptor-mediated endocytosis ->
MHC II presentation to T cells -> stimulatory signals ->
Return to follicle and create germinal center
BCR activation effects
- initial proliferation
- B7/CD80 expression
- cytokine receptors, downregulate chemokine receptors -> migration from follicle to T-cell area
- MHC II production and presentation
T cell -> B cell help
CD40 stimulation is required for survival
Some Th2 cells migrate to germinal center to deliver signals
Also:
- affinity maturation via somatic mutation
- Ig class switching (via chromatin remodeling?)
Other cytokines help - ex IL-4
Primary humoral response
Within a week -> proliferation -> plasma cells ->
IgM, IgG -> form complexes -> phagocytosis
Serum concentrations and timeline vary with Ab production, route, catabolism
Secondary humoral response
Memory T and B cells recognize -> Faster and stronger proliferation -> - high Ab concentration - only IgG (high avidity) - clonal selection - highest affinity survive
Serum memory
Long-lived (years) plasma cells (vs short-lived, high production)
In bone marrow
Replaced by higher affinity plasma cells -> refined response
Class switching
Naive express IgM, IgD
Switch requires CD40, differential cytokine signals (IL-4, IL-F, IFN-g, TNF-a)
- ex mucosal surfaces -> TNF-a -> induces IgA production
DNA recombination - places VDJ next to new constant region
- intervening constant regions (mu, delta) are removed
RNA transcript further refined by splicing
Hyper IgM syndrome
Lack of CD40/CD154 signalling to B cells
Can’t class switch ->
Continue to produce IgM, can’t produce other antibodies
Affinity maturation
Somatic mutations in variable regions -> higher affinity of Fab:antigen (better amino acid residues)
- both H and L chains
Occurs in both plasma and memory cells
Competition for antigen binding between and within germinal center -> more proliferation signals
- antigen binding facilitated by follicular dendritic cells
- signals from follicular Th
T-cell independent activation
Antigens that can’t activate T cells (LPS, capsule, dextrans -> can’t be turned into peptide for MHC)
- > repeating epitopes -> bind to multiple BCR’s -> crosslinking -> signal
- > primary IgM response
- no class switching
- no memory (secondary response is the same)
Infant immune function
Normal/high levels of B and T lymphocytes but
Lower immune response overall
- genetic expression of receptors (TCR, Ig’s)
- immature T, B, or APCs
We still try to vaccinate early - HepB, DPT
Newborn antibodies
IgM - produced at birth
IgG -
- passive through placenta (binds to neonatal FcR)
- produced during first year - exposure to GI flora, env’t, pathogens, vaccines
IgA -
- passive through colostrum/breastmilk
- produced at 1-2 months
Immune-exclusion
sIgA binds to pathogens and prevents any interaction with other cells
Ex: Maternal sIgA coats GI tract of newborn
Protective but also decreases vaccine effectiveness (ex RSV)
Antibody function (alone)
Can neutralize viruses and toxins by direct binding
- bind to functional sites
- must have high affinity to outcompete binding by cell receptors, etc
Bacteria - similar binding -> blocks adherence and colonization
Special cases:
Immuno-exclusion = sIgA binding to protect mucosal surface
Tumor therapy - design antibodies for apoptosis receptors
Fc receptors
Bind to constant region of antibody -> effector function by cell
- allows effector cells to specifically attack without needing specific receptor (ie TCR or BCR)
- Phagocytosis of opsonized bacteria (via PMN’s, macrophages, eosinophils)
- “antibody dependent cellular cytotoxicity” (ADCC) - NK effects lysis via release of perforins or TNF-a
- IgE -> mast cells, basophils -> degranulate -> parasites and inflammation
Phagocytosis
Constitutive/innate - via scavenger and other pattern receptors
Much more efficient when opsonized with antibody or complement (C3b) - “immune adherence”
Internal cell processes necessary to kill pathogen (see separate slide)
Phagocytes can also release chemotaxins to recruit other phagocytes (C3a, C5a)
Neutrophils can also release granules (proteases, lipases) onto pathogen -> inflammation and self-tissue damage
Post-phagocytosis mechanisms
Killing of pathogen
- via enzymes - proteases, lipases -> phagolysosome
- via respiratory burst -> reactive O2 and N2 species
- sometimes neutrophil also dies (can’t produce more granules, runs out) -> pus
Pathogen responses
- Strep and Staph -> leukocidins -> kill phagocyte
- Mycobacteria (TB) and Salmonella (typhoid) can survive inside phagocytes -> transport and new infection
Classical complement pathway
IgM or 2xIgG bound to membrane -> C1q binds to Fc ->
C1 cleaves C2 and C4 -> C2b and C4b attach = C3 convertase (C4bC2b)
C2bC4b cleave C3 -> C3b binds -> C5 convertase (C4bC2bC3b)
C4bC2bC3b cleave C5 ->
C5bC6C7 inserts into lipid membrane -> recruits C8, C9 (membrane attack complex)
SUMMARY:
IgM or IgG -> C1 -> C4, C2 -> C3 -> C5 -> recruits C6-9 (MAC)
General features of complement pathway
Series of activation via cleavage, binding
“b” = larger product -> stays at pathogen
“a” = smaller product - recruits more phagocytes (C3a, C5a)
Amplification at C3 and C5
Covalent binding -> ensures cascade continues
Activate pathway via antibodies, leptin or alternative (pathogen)
- pathways converge at C3 and C5
Effector functions
- lysis via membrane attack complex
- opsonization -> phagocytosis
- inflammation/recruitment
Membrane attack complex
Late stage of complement activation
C5b recruits C6, C7, C8 to membrane
Recruits C9 -> multiple units -> poly-C9 membrane pore
-> membrane disruption -> lysis
Niesseria most susceptible
Leptin complement pathway
Mannose-binding lectin -> binds mannose on pathogen membranes
Similar function to C1 -> activates C4 and C2 -> C3 convertase -> C5 -> etc
Alternative complement pathway
Activates without antibodies (part of innate system)
C3 spontaneously broken down -> C3b
C3b binds membrane -> binds Factor B -> cleaved by Factor D
C3bBb -> cleaves C3 and C5 -> C3b for pathway
C5b -> MAC
Activator - C3b binds to Factor B -> active pathway
Non-activator - C3b binds to Factor H
-> C3bH inactivated by Factor I
Anaphylatoxins
C5a -> recruits and adheres PMNs, respiratory burst, degranulation
-> recruits mast cells -> degranulation
C3a - less active but still causes release of mediators
Immune-adherence
C3b and C4b remain covalently bound to microbe
“Marks” microbe for other cells (ex PMNs)
Even if pathogen escapes direct complement cascade, it is marked for phagocytosis
Complement regulation
Cleavage to activate -> lower binding capacity -> self-limiting
Serum and membrane proteins accelerate degeneration
Most act early (ex C3,C4,C2)
Ex: plasma Factors H and I, C1 inhibitor, membrane “decay accelerating factor”
- hereditary angioedema -> no C1 inhibitor fx -> continuous C3, C4, C2 -> inflammation and anaphylaxis
Complement receptors
Tied to effector functions
CR2 = CD21 - activates B cells with IgM, CD19, CD81
CR3, CR4 = integrins -> slow down PMNs to recruit
CR3a, CR5a - mast and endothelial cells -> inflammation
