Lymphoma : Malignancy of Lymphocytes Lymphocytes B-cells T-cells NK-cells (Natural Killer Cells)
Chapter 14 B Lymphocytes
description
Transcript of Chapter 14 B Lymphocytes
-
Chapter 14
B Lymphocytes
-
Contents B cell receptor and B cell complexB cell accessory molecules B cell subpopulationsFunctions of B cellsB cell maturationBCR diversity and TCR diversity
-
I. B cell antigen receptor and B cell receptor complexBCRBCR complexFunction: Recognize antigen
-
1. B cell receptor----BCRMembrane immunoglobulin (mIg) on B cells: mIgM, mIgDRecognize and bind antigen specifically
-
2. BCR complexBCR and Ig - Ig (heterodimer) Ig (CD79a) , Ig (CD79b) Participate in BCR formationITAM------bind to tyrosine kinaseTransmit activating signal
-
II. Accessory membrane molecules on B cellsCD19, CD21(CR2), CD81(TAPA-1) ----B cell co-receptor complexCD21(CR2): receptor of C3dg,C3d and iC3b ----Enhance the binding of BCR and antigen ----Pass activating signal to CD19 ----EB virus receptor
CD19: Transmit activating signal into B cell
-
CD40 on B cell binds to CD40L on activated T cellTransmit an important co-stimulatory signal to B cells Upregulate expression of B7 on B cells Participate in class switching of antibody2. CD40----co-stimulatory receptor
-
3. Co-stimulatory molecule: B7B7-1 (CD80) and B7-2 (CD86) Expressed on B cells or other APCB7-CD28: activation signalB7-CTLA-4: inhibitory signal
4. MHC moleculesClass , MHC molecules
-
5. Mitogen receptorSPA, LPSPWM
6. Cytokine receptorIL-4R, IL-5R, IL-6R
7.Fc receptor (CD32---FcRII-b) ------Related to immunological regulation
-
III. B cell subpopulationsAccording to expression of CD5 or notB1 cell (CD5+) B2 cell (CD5-)
-
Comparison of B1 and B2 cells
B1 B2
Development early late BCR mIgM mIgM and mIgD CD5 + - Reproduction self-renewing from pre-B cell in BM Recognized Ag TI-Ag and auto-Ag TD-Ag Ab type IgM >IgG IgG >IgM Ab avidity low high Second IR - + Function innate immunity adaptive immunity
-
IV. Functions of B cellsProduce the antibody----HIPresent antigen----APC Participate in immunological regulation: secrete various cytokines, FcRII-b
-
The comparison of main membrane molecules between T and B cells
T lymphocyteB lymphocytefunctionsAntigen receptorTCRBCRBind to Ag,First signalAg receptor complexCD3 and Igand IgTransmit first signalCo-receptorCD4,CD8CD19-CD21 complexHelp to bind AgTransmit first signalCo-stimulatory receptorCD28CD40Second signal,Transmit second signalCo-stimulatory moleculesCD40LB7(CD80/CD86)Offer second signalMHC I expressionexpressionAntigen processingMHC II Activated expressionexpressionAntigen processing
-
Section Development and differentiation of B cellsDifferentiation of B cells in Bone marrow
Differentiation of B cells in peripheral lymphoid tissue (B cell mediate immune response, HI)
-
Differentiation of B cells in Bone marrow----Ag independentHematopoietic stem cells Lymphoid progenitor Pro-B cells( chain rearrangement) Pre-B cell( chain + surrogate light chain ) Immature B(mIgM, chain +chain orchain) Mature B(mIgM, mIgD) Functional B repertoire
-
Negative selection of B cells inbone marrow
-
2. Differentiation of B cells in peripheral lymphoid tissue----Ag dependantVirgin B/nave B cell most diePlasma cell AbMemory B cell secondary immune response
-
3. Events in the differentiation of B cells:
Gene rearrangement of Ig Negative selection
Immature B cells : mIgM--self antigen mIgM -- self antigen
apoptosis or anergy surviving to develop
mature B cells
-
Questions?Why can TCR or BCR recognize so many Ag in nature? Why does IgM produce earlier than others?How does Ig produce BCR and Ab?How can B produce different type of Igs?---------------?
-
Part BCR diversity and TCR diversityBCR diversity
TCR diversity
-
Gene structure of Ig Gene rearrangement of Ig Characteristics of Ig gene expression Mechanism of Ig diversity Section BCR diversity
-
1. Germ line gene structure of Ig (human)H chain:14 chromosome V region encoding genes: VH (variable gene segments) 65 DH (diversity gene segments) 27 JH (joining gene segments) 6 Leader sequencesignal peptide C region encoding genes: CH (constant gene segments): C, C, C et al. (11)
-
L chain(--2 chromosome, --22 chromosome)
V region encoding genes: --V, J 40, 5 -- V, J 30, 4 Leader sequencesignal peptide
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 whilethe C segment encodes the constant domain.
-
VJC JC JC JC(a) Chain (22 chromosome))(2 chromosome)
-
2. Gene rearrangement of Ig
V-D-J rearrangement of H chain pro-B cells: D-J V-DJ VDJ DNA
pre-B cells: VDJC VDJ- C RNA mRNA
V-J rearrangement of L chain pre-B cells: V -J V J DNA immature B cells: V J C V J -C RNA mRNAtranscriptionsplicing
-
C C C3 C 1 C1 C2 C4 C C2C C C3 C1 C1 C2 C4 C C2C C C3 C1 C1 C2 C4 C C2CCCC
-
The expression of BCR Intranuclear:DNA rearrangement: ------- V region encoding gene (VDJ or VJ) Transcription and splicing -------leader sequence + V region encoding gene + C region encoding gene (L gene-V gene C gene)Extranuclear:Translation -------- nascent peptide L-V-CEndoplasmic reticulum:assembly--------H chain and L chain (IgM or IgD)
transportation------BCR (membrane Ig, mIg)
-
3. Characteristics of Ig gene expression recombination enzyme: RAG (recombination activating gene) TdT (terminal deoxynucleotidyl transferase) other DNA enzymes
-
Allelic exclusion and isotype exclusion Allelic exclusion: only one of the two alleles in homologous chromosomes can be expressed. Isotype exclusion: only one of the two types of light chain genes can be expressed(:=65:35).
-
Kuby Figure 5-10Read Kuby pages 115-117: Allelic Exclusion Ensures a Single Antigenic Specificity
-
Isotype switching ( class switching )
Ag
activated B cells proliferate
VDJ is switched to recombine with another C region encoding gene
IgM IgD, IgG, IgA, IgE
Switching region
-
Membrane type (BCR) and Secretory type Ig (Ab)
-
4. Mechanism of Ig diversity Combinatorial diversity human Ig: 65VH27DH 6JH=10530V 40V 5J =200V 30V 4J =120V
-
C C C3 C 1 C1 C2 C4 C C2C C C3 C1 C1 C2 C4 C C2C C C3 C1 C1 C2 C4 C C2CCCC
-
Junctional diversity
CDR3 lies in V-DJ or D-J junctionsLose or insert of several nucleotides will increase the diversity of CDR3.N-nucleotides insert by TdT without templateThere is no N-nucleotides insert in L chain
-
Somatic hypermutation Ag
activated B cells proliferate
gene mutation in V region encoding genes
affinity maturation
mature B cells which finished V gene rearrangement
-
Section Gene structure and rearrangement of TCRGene structure of TCR chain (14 chromosome): V, J, C chain (7 chromosome): V, D, J, C
-
(14 chromosome)(7 chromosome)
-
2. Gene rearrangement of TCR TCR chain rearrange first Inactivate gene within gene
-
3. Gene structure of TCR chain (7 chromosome): V, J, C chain (14 chromosome): V, D, J, C
-
(14 chromosome)(7 chromosome)4. Gene rearrangement of TCR No junctional diversity in TCR
-
5. Characteristics of TCR gene expressionWithout somatic hypermutationMore N- nucleotides insert than BCRMore valid rearrangement in V region of TCR BCR: 1014 TCR: 1016
-
Comparison of BCR and TCR functional genes
NO. of chain Chromosome V D J C----------------------------------------------------------------------- BCR H 14 65 27 6 11 2 40 5 1 22 30 4 4 TCR 14 70-80 61 1 7 52 2 13 2 7 12 5 2 14 4 3 3 1-------------------------------------------------------------------------
-
What you should know of this lectureDefinition of BCR/BCR complexMajor surface membrane molecules on B cells (comparison) Comparison of B1 cell and B2 cellFunctions of B cellsB cell maturation
*Clonal deletion: Functionally immature cells of a clone encountering antigen undergo a programmed cell death. For example, auto-reactive T-cell are eliminated in the thymus following interaction with self antigen during their differentiation (negative selection). Clonal deletion has been shown to occur also in the periphery. B cells expressing only IgM (no IgD) on their surface when exposed to antigen are eliminated.