Introduction Abbas Chapter 10: B Cell Activation and Antibody Production January 25, 2010 Children s Mercy Hospitals and Clinics Humoral immunity is mediated by secreted antibodies (Ab) Ab function to neutralize and eliminate antigens (Ag) Different types of Ag requires different effector mechanisms, mediated by different classes of Ab General Features B cell activation consists of sequential phases Recognition Activation Proliferation Differentiation General Features Ab responses to proteins require Th Ab responses to multivalent Ag do not require Th Polysaccharides Lipids Activated B cells differentiate into Absecreting plasma cells & memory cells General Features Heavy chain isotype switching and affinity maturation are typically seen in Th-dependent humoral response to protein Ag 1 and 2 Ab responses to protein antigens differ qualitatively and quantitatively 1
General Features Distinct subsets of B cells respond preferentially to different types of Ag Follicular B cells => proteins Marginal zone B cells => multivalent Ag B-1 B cells => multivalent Ag Antigen Recognition and Activation B cell activation requires Ag recognition in lymphoid tissues Entry into follicles CXCR5 (CXCL13) BAFF (B cell activating factor of the TNF family; aka BLyS B lymphocyte stimulator) APRIL TACI (Selective IgA def and CVID!) BCMA http://www.nature.com/nrd/journal/v3/n2/images/nrd1305- f4.jpg&imgrefurl=http://www.nature.com/nrd/journal/v3/n2/fig_tab/nrd1305_f4.ht ml&usg= kf98jtx5v6fcnjwh-vyjubd4us=&h=380&w=600&sz=39&hl=en&start=1&um=1&tbnid=bouim1h2uynlym :&tbnh=86&tbnw=135&prev=/images%3fq%3dbaff%2bapril%26um%3d1%26 hl%3den%26rlz%3d1t4ggll_en%26sa%3dn Antigen Recognition and Activation Activation is initiated by binding of Ag to membrane Ig molecule Associated with invariant Igα and Igβ 2
Antigen Recognition and Activation B cell signals when 2 or more receptor molecules are cross-linked by multivalent Ag CR2/CD21 Coreceptor B cell activation is enhanced by signals provided by complement proteins Review: C3 is cleaved => C3b => C3b- Ag => C3d-Ag C3d binds to CR2 or CD21 CD21 is the EBV receptor CR2/CD19/CD81 complex is coreceptor Response of B Cell to Ag Recognition Cross-linking initiate proliferation and differentiation Prepare B cells for interaction with Th 3
Th-Dependent Ab Responses Ab response to protein Ag requires recognition by Th AND B cells and cooperation between the two Th stimulate Clonal expansion Isotype switching Affinity maturation Differentiation Ag is taken up by DC and presents to Th Th are activated and express CD40L Th move toward follicle B cells are activated by soluble Ag Alter chemokine profile and migrate toward T cell zone T and B cells interact (CD40L) B cells migrate back into follicle and form germinal centers Plasma cells are generated and migrate to the bone marrow 4
Hapten-Carrier Effect Haptens are small chmicals that can be bound by Ab but are not immunogenic by themselves If haptens are coupled to proteins, the conjugates induce Ab response Hapten-Carrier Effect Require: Hapten specific B cells Carrier specific Th To stimulate a response hapten-carrier must by physically linked MHC class II restricted Basis for conjugate vaccines Germinal Center Reaction 5
CD40L:CD40 Interactions CD40L:CD40 Interactions (Activated) Th express CD40L that engages CD40 on (ALL) B cells Stimulates B cell proliferation, differentiation, and germinal center formation Induces AID (somatic mutation and isotype switching) Induces association of TRAFs (TNF receptor-associated factors) CD40L:CD40 Interactions Cytoplasmic tail of EBV protein, LMP1, associates with TRAF triggering B cell proliferation Activated Th secrete cytokines that act with CD40L to stimulate B cell production of different isotypes Isotype Switching 6
Switch Recombination VDJ recombines with a downstream C region gene and the DNA in between is deleted Switch Recombination Activation-induced deaminase (AID) is a DNA deaminase that deaminates cytosines converting C to uracil (U) Uracil N-glycosylase (UNG) removes the U Ape1 endonuclease cleaves abasic sites 7
Affinity Maturation Process that leads to increased affinity of Ab for a particular Ag Occurs only in response to Thdependent protein Ag Occurs in dark zone of germinal center Mechanisms poorly understood (AID) FDCs display Ag and select high affinity B cells to survive Differentiation into Plasma Cells Involves major morphologic alterations Change in Ig heavy chain gene expression from membrane to secreted form Change is in MRNA 8
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