Part I T lymphocyte - Shandong University

B cells I. Differentiation of B cells in Bo ne marrow II. BCR and B cell accessory mol ecules III. The subsets of B cells

I. Differentiation of B cells in Bone marrow 1. process of B cell maturation 2. events in the differentiation of B cells 3. mechanisms of Ig diversity I. Differentiation of B cells in Bone marrow

1.Process pro-B cell chain pre-B cell surrogate light chain + chain immature B cell

chain or chain + chain (membrane IgM,mIgM) mature B cell mIgM, mIgD 2. Events in the differentiation of B cells 1) Negative selection

immature B cells : mIgM--self antigen apoptosis or anergy mIgM

self antigen surviving to develop mature B cells 2) gene rearrangement

It is estimated that in the mouse the bone marrow produces about 5x107 B cells/day but only 5x106 (or about 10%) are actually recruited into the recirc ulating B-cell pool. This means that 90% of the B c ells produced each day die without ever leaving th

e bone marrow. negative selection Immature B cells that express auto-antibodies agai nst self-antigens are eliminated in the bone marro w.

2) gene rearrangement (1) germline gene structure of Ig (2) rearrangement of Ig genes (3) characteristics of Ig gene rearrangement (1) Germ-line gene structure of BCR H chain: chromosome 14

V region encoding genes: VH (variable gene segments), DH (diversity gene segments), JH (joining gene segments) C region encoding genes: CH (constant gene segments): C , C, C et

al. (9) L chain(-- chromosome 2, -- chromosome 22) V region encoding genes: --V, J

-- V, J C region encoding genes: C (1); C(4) In heavy chains, the V, D and J segments encode the variable

domain while the C segment encodes the constant domain. In light chains, the V and J segments encode the variable domain while the C segment encodes the constant domain.

(2) Gene rearrangement of BCR VDJ rearrangement of H chain pro-B cells: D-J V-DJ VDJ

DNA transcripti on pre-B cells: VDJC

VDJ- C mRNA splicing V-J rearrangement of L chain pre-B cells:

V-J VJ immature B cells: VJC RNA DNA

VJ-C RNA BCR(membrane type) and secretory type Ig

(3) Characteristics of BCR gene r earrangement

Allelic exclusion: only one of the two alleles in homologous chromosomes can be expressed. isotypic exclusion: only one of the two types of light chain gen es can be expressed.

Allelic exclusion Kuby Figure 5-10 Read Kuby pages 115-117: Allelic Exclusion Ensures a Single Antigenic Specificity

3. mechanisms of diversity of Ig (BCR or Ab) 1). Mutiple germline gene segments 2). Combinatorial V(D)J joining 3). Junctional flexibility

4). combinatorial assocination of heavy and light chain 5). somatic hypermutation 1). Mutiple germline gene segments There Are Numerous Germ-Line V, D, and J

Gene Segments. 2). combinatorial V(D)J joining The multiple germ-line gene segments are c ombined randomly during the rearrangement of BCR genes.

human Ig: 51VH27DH 6JH= 8262 possible combinations 3). Junctional flexibility imprecise joining In the junction of V-J, V-DJ or D-J, several nucleoti des are lost to increase the diversity of the V regio

n encoding gene of L chain or H chain. N-nucleotides addition During the D-J and V to D-J joining process, seve ral nucleotides are inserted to increase the diversi ty of V region encoding gene of H chain. N-nucleotides insert by TdT(terminal deoxynucle

otidyl transferase) without template There is no N-nucleotides insert in L chain. 4). Combinatorial association of heavy and ligh t chains 5).Somatic hypermutation

Somatic hypermutation occurs at a frequency a pproaching 10-3 per base pair per generation. T his rate is at least a hundred thousand-fold hig her (hence the name hypermutation) than the s pontaneous mutation rate, about 10-8 /bp/generation, in other genes.

Somatic hypermutation adds diversity in already-rearranged gene segments Somatic hypermutation Ag activated B cell proliferate

gene mutation in V region encoding genes affinity maturation II. BCR and accessory molecul es of B lymphocytes B cell receptor complex

B cell accessory molecules 1.BCR complex a group of membrane molecules on B cells that can specifically bind to the antigen and pass an activation signal into B cells, consi

sting of BCR and Ig-Ig heterodimer BCR membrane immunoglobulin on B cell, mIg: IgM, IgD Ig-Ig , (CD79))

ITAM transduce an activation signal ITAM An immunoreceptor tyrosine-based activation motif (ITA M) is a conserved sequence of amino acids (YXX(L/V)X7-1 1YXX(L/V)) in the cytoplasmic tails of certain cell surface p

roteins of the immune system. The tyrosine residues withi n these motifs become phosphorylated following interacti on of the receptor molecules with their ligands and transd uce an activation signal. ITIM An immunoreceptor tyrosine-based inhibition motif (ITIM),

is a conserved sequence of amino acids (S/I/V/LxYxxI/V/L) in the cytoplasmic tails of many inhibitory receptors of the immune system. After ITIM-possessing inhibitory receptor s interact with their ligand, their ITIM motif becomes phos phorylated and tranduce an inhibitory signal.

2. Co-receptors complex 1) CD19, CD21, CD81, CD19: CD21(CR2): receptor of iC3b

and C3d 3.CD40 ---co-stimulatory receptor CD40 on B cell binds to CD40L on activated T cel l---pass a costimulatory signal into B cells

4. B7 5. CD45 6. MHC molecules 7. Mitogen receptors 8. Cytokine receptors

B7(CD80,CD86) ------co-stimulator to T cells ligand of CD28 3.CD40 ---co-stimulatory receptor

CD40 on B cell binds to CD40L on activated T cell---pass a costimulatory signal into B cells 4. B7 5. CD45 The cytoplasmic domain of CD45 has an intrin sic phosphatase activity that removes an inhi

bitory phosphate group on a tyrosine kinase called Lck (in T cells) or Lyn/Fyn/Lck (in B cel ls) and activates it. 6. MHC molecules 7. Mitogen receptors 8. Cytokine receptors

6. MHC molecules MHC-I and MHC- 7. Mitogen receptors Receptors of mitogen: SPA,PWM (pokeweed), LPS 8. Cytokine receptors

III. Subset of B cell --------------------------------------------------------------------Comparison of B1 and B2 cells -----------------------------------------------------------------------------------B1 B2

CD5 location + thorax, abdominal cavity lymph organs

lamina propria of intestine Recognized Ag TI Ag and auto-Ag TD Ag --------------------------------------------------------------------------------

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