Lymphocyte Differentiation

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Lymphocyte Differentiation
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Genetic Models
B cell development?activation and maturation

• Genetic models
• Germ-Line model
• The genome contributed by the grem cells contains
  a large repertoire of immunoglobulin genes.
• No special genetic mechanisms to account for
  antibody diversity
• Somatic-Variation model
• The genome contains a small number of
  immunoglobulin genes, from which a large number
  of antibody specificities are generated in
  somatic cells by mutation or recombination.
• Two-Gene model, 1965 by W. Dryer and J. Bennett
• Two separate genes encode a single immunoglobulin
  heavy and light chain, one gene for the V region
  and the other for the C region

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B cell development?activation and maturation
Verification of the two-gene model
1967, by S. Tonegawa and N. Hozumi 1987, Tonegawa
got Nobel Prize

• Digested DNA fragemnts from embryonic and myeloma
  cells hybridized with radiolabel-RNA
• (b) V and C gene are brought closer together and
  intervening DNA sequence is eliminated

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Immunoglobulin Gene
B cell development?activation and maturation

• ???7????? (gene segments) ??????????????
• ??
• V?D?J?C?4??????
• ???14?????
• ???VH???DH?6?JH?9?CH(Cµ?Cd?C?3?C?1?Ca1?C?2?C?4?Ce?
  Ca2)?
• ??(???type light chains)
• V?J?C?3??????
• ?type(??V??5?J?????C???)???2?????
• ?type(??V? ???J????C???)???22?????

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B cell development?activation and maturation
Immunoglobulin Germline Gene Segments in Human
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B cell development?activation and maturation
Immunoglobulin Germline Gene Segments in Mouse
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B cell development?activation and maturation
Heavy-Chain Gene Rearrangement in Human V-D-J
joining
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B cell development?activation and maturation
?- Light-Chain Gene Rearrangement in Human V-J
joining
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B cell development?activation and maturation
?- Light-Chain Gene Rearrangement in Human V-J
joining
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B cell development?activation and maturation
Heavy-Chain Gene Rearrangement in the mouse
V-D-J joining
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B cell development?activation and maturation
Kappa Light-Chain Gene Rearrangement in mouse
V-J joining
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B cell development?activation and maturation
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B cell development?activation and maturation
Overview

• Antigen-independent phase
• Immunocompetent B cells expressing membrane IgM
  and IgD are generated in the bone marrow
• Antigen-dependent phase
• B cells are activated and proliferated with
  secondary lymphoid organs
• To differentiate into memory B cell and plasma
  cells

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Differentiation of B cell
B cell development?activation and maturation
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Differentiation of B cell
B cell development?activation and maturation

• pro-B cell??heavy-chain genes(DH/ JH
  joining),??????????
• pre-B cell??heavy-chain genes(VH /DH/ JH
  joining),?VDJ???Cµ??,??µpolypeptidelight-chain
  genes?????
• late pre-B cell?????????heavy chain?Ig-a?Ig-ß?sur
  rogate light chain
• immature B cell?????????surface IgM(s
  IgM),??????????,????????????????,??????????

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Differentiation of B cell
B cell development?activation and maturation

• mature B cell?????surface IgM?IgD(????????????)??
  ?????,?
• 5 nucleotidase(CD73)??????????
• CD23????(oligosaccharide-bing portein)?
• adhesion proteinsLFA-1?ICAM-1?CD22?
• L-selectinsurface homing receptor,???????????????
  ???
• MHC class II?????T?????
• CD40??T?????
• ??B????????????????virgin B cell(naïve B cell)?
• ???B??????????,??????????antigen-independent??matu
  re B cell??secondary lymphoid organs?,????????????
  ?plasma cell????????(IgM)?

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B cell development?activation and maturation
?
?
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B cell development?activation and maturation

• Pro B-cells contact with stromal cells in the
  bone marrow
• c-kit on pro B-cell interacts with stem-cell
  factor on surface of stromal cells
• Pro B-cells begin to divide and differentiate
  into pre B-Cell
• To express the receptor of IL-7 on the surface of
  pre B-Cell

Back
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B-1 B cell
Back
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B cell development?activation and maturation
The Cell Cycle of B lymphocytes
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B cell activation and maturation
B cell development?activation and maturation

• B????????
• Ig-a?Ig-ß
• ??B????????????protein tyrosine
  kinases(PTKs,CD45??????domain?????)?
• ??
• Thymus-dependentB?????(????????)???,???T?????????
  ??B??????CD40??TH??????CD40L(CD40 ligand)??????

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B cell activation and maturation
B cell development?activation and maturation

• Thymus-independenB????????,?????????,????T???????
  ????B????????IgM?IgD????????B?????
• T????
• B???????????TH?????,T??????helper factors??B???
• ????B?????B7 proteins(T cell costimulators)???????
  ?(IL-6?TNFa)??TH???????????
• B????T??????????T???????,???????????,?????????????
  isotype (class)switching?????,???IgG?IgA?IgE?

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B cell development?activation and maturation

• Ig-a?Ig-ß
• Immunoreceptor tyrosine-based activation motif
  (ITAM)
• The cytoplasmic tail of both Ig-a(61 amino acids
  ) and Ig-ßlong (48 amino acids), 18-residue motif
• To transduce the antigen-mIg binding stimulus
  into cell to become an effective intracellular
  signal
• Binding stimulus is mediated by tyrosine kinases
  (PTKs)
• The BCR itself has no PTK activity
• Modification of coreceptors
• B-cell coreceptor
• To provide stimulatory modifying signals
• Complex of CD19, CR2 (CD21) and TAPA-1 (CD18)
• CD22
• Associated with the B-cell receptor in resting B
  cells
• A negative signal to make B-cell more difficult
  to activate

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B cell development?activation and maturation
The initial stage of signal transduction by an
activated BCR
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B cell development?activation and maturation

• CD19 immunoglobulin superfamily protein, long
  cytoplasma tail, and three extracellular Ig-fold
  domain
• CR2 receptor of complement (C3d)
• TATP-1 transmembrane protein

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B cell development?activation and maturation

• Thymus-dependent antigens (TD antigens)
• Require to interact with TH cell
• Thymus-independent antigens (TI antigens)
• Not to require to interact with TH cell
• Typ1, such as lipopolysaccharide of bacterial
  cell wall
• Polyclonal B-cell activators
• Activate immature and mature B cells
• Fully T-cell independence
• Type2, highly repetitious molecules, such as
  polymeric proteins
• Not polyclonal B-cell activators
• Activate mature B cells
• need T-cell cytokines

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B cell development?activation and maturation
Signals from TI and TD Antigens for B-cell
Activation
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B-cell Activation by TD antigens
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The Humoral Responses- Primary and Secondary
Response
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Class Switching

• isotype (class)switching(?????)
• ?B????(?????????)???????
• ??heavy chain gene rearrangment???????????(???????
  ??VDJ joining???????,?????????V????,??????????????
  ????????)?
• T????????????????????????T???????IgA???,IL-4??B??
  ??IgG??

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Plasma cell and Memory B cell

• Plasma cell
• Plasma cells???bone marrow?,??marrow???plasma
  cell?????????????????????
• Plasma cells ??????,????????????
• ????????
• Memory B cell(????)
• ?????????,?????????isotype?????????,??????,???????
  ??????homing(????)????????
• ?????????????,??B???????????????,??????(??????????
  ???)?
• ?????B?????????????,???????,????????B????B?????,??
  ????????

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