B-cell Development and ActivationChapter 5

Self-Test Questions:Sections A, B & C: all(section D covered previously)

A LPSa TI-type1 B-cell activator

What are the 2 phases of B-cell development?

Antigen-Independent (Maturation) -- mostly in bone marrow

vs Antigen-dependent (Activation)-- mainly in periphery

Antigen-Independent (Maturation)

1) Pro-B stages-- B-cell markers

2) Pre B-stages-- H- an L- chain loci rearrangements

3) Immature B-cell-- functional BCR

-- but… “Is it safe”?

How are self-tolerant B-cell selected?

Screening on bone marrow stromal cells

“2nd chance” -- Receptor editing-- mainly LC-- alternative V segments

Survival signals (<10%) or apoptosis

What happens during T-cell dependent B-cell activation?“Td antigens”

1) Antigen crosslinking of antibodies-- antigen engagement-- Igα/Igβ signalling-- up-regulation of CD40 & MHC

2) TH cell engagement-- cell/cell interactions-- MHC presentation -- TCR recognition-- CD40/CD40L coupling

3) Cytokine stimulation-- IL4, IL2, etc.-- class switching to IgG-- memory cell formation

Why so complicated?

B-cell activation can occur without T-cell help“T-independent” B-cell activation

Two types:

Ti type-1 – e.g., LPS

-- many are mitogens; -- bind to TLRs

--can activate polyclonally without BCR engagement

-- some activate through binding to BCR & TLR

Yield only…Predominantly IgM, maybe some IgGNo memory cells

See Table 5-1

T-independent activation cont.

Ti type-2 – AGs have repetitive, polymeric structure -- crosslink Abs-- e.g. capsule polysaccharides

bacterial flagellin

Yield only…IgM, maybe some IgG

-- high avidity

No memory cells- ??

See Table 5-1

Some are important bacterial AGs, but pose problems for vaccine development-- infants do not respond well

Revisiting the lymph node

Development of 1O to 2O folliclesWith germinal centers

What happens in GC?-- affinity maturation via

“somatic hypermutation”-- memory cells produced-- class switching

How does affinity maturation occur?

Key role of AID-- Activation-Induced

Cytidine Deaminase-- induced DNA repair

Several rounds of selection-- long-lived B-cells

1000 X Increased AG affinity

Bind or Die!

How does class switching occur?

Alternative RNA processing and . . .IgM and IgDSecreted IgM

Gene splicing and switch to:IgG, IgE, and IgA

Cytokines influence class switching

The humoral 1O vs 2O responses

What are the key differences?. . . in lag. . . in magnitude. . . in isotypes

How do properties of memory cells account for this?

In peripheral tissuesOther isotypes in BCRHigher affinity AbGreater # of cells against AGMore rapid TH cell stimulationMore rapid class switch

Receptor antibody ligand Cell distribution Effect following binding to antibody

FcγRI (CD64)

IgG1 and IgG3

MacrophagesNeutrophilsEosinophilsDendritic cells

PhagocytosisCell activationActivation of respiratory burstInduction of microbe killing

FcγRIIIA (CD16a)

IgGNK cellsMacrophages (certain tissues)

Induction of antibody-dependent cell-mediated cytotoxicity (ADCC)Induction of cytokine release by macrophages

FcεRI IgE

Mast cellsEosinophilsBasophilsLangerhans cells

Degranulation

FcεRII (CD23)

IgEB cellsEosinophilsLangerhans cells

Possible adhesion molecule

FcαRI (CD89)

IgA

MonocytesMacrophagesNeutrophilsEosinophils

PhagocytosisInduction of microbe killing

Fc Receptors and antibody effector functionsWhat does “FcγRII” mean?

Some example FcR mediated functions

B-cell malignancies can involve different stages of B-cells

Types of lymphocyte malignancies Myeloma

Leukemia

lymphoma

Chronic vs acute

Clinical Diagnosis1) Microscopy2) gel electrophoresis of

serum proteins