HIS09 Lymphocyte Development Flashcards
***B cell development process in Bone marrow
2 aspects:
- Intracellular change —> **Ig gene rearrangement + **Expression of poIypeptide Ig H+L chains (Status of Ig genes)
- Extracellular change —> ***Expression of molecules on cell surface
Process:
HSC / Lymphoid progenitor in bone marrow (mature in bone marrow as well)
—> Progenitor-B (Pro-B, Early / Late) cells: Intranuclear
- undergo Ig μ ***heavy chain gene rearrangement
—> Precursor-B (Pre-B) cells: Intracellular
- express μ ***heavy chain in cytoplasm
- ***light chain genes rearranged (κ first, if unsuccessful then λ later) —> expressed in cytoplasm (packed together, move to surface)
- **Pre-B cell receptor: small amounts of μ Heavy chain + Surrogate Light chain (not involved in antigen recognition, only interaction with **growth factor, cytokines (e.g. from stromal cells) in bone marrow micro-environment for delivering signal for ***survival, proliferation, differentiation of Pre-B cell)
—> Immature B cells: Cell surface expression
- Monomeric ***IgM (2 μ heavy + 2 light) molecules on cell surface (as antigen receptor)
—> ready to leave bone marrow (central lymphoid organs) to secondary lymphoid organs (spleen, LN)
—> Mature B cells (Naive B cell): Monomeric **IgM + **IgD on cell membrane
—> Plasma cells (Effector cells): Ab production —> ***Humoral immunity
5-15% circulating lymphoid pool are B cells, defined by ***presence of surface Ig
Phenotypic changes on cell surface during B cell differentiation
Main markers (surface molecules):
—> Cluster designation / Clusters of Differentiation (CD molecules: leukocyte cell-surface molecules recognised by clusters of mAbs, each cluster of mAb bind specifically to a particular CD molecule —> ∴ some mAB can attack human leukocyte)
—> Identification of immune cells in lymphoid organs
Examples:
- CD34 (early progenitor B cell)
- ***CD19 (throughout the development in bone marrow, also in peripheral B cell)
- CD20 (B cell, T cell)
- CD22
- CD40 (throughout the development in bone marrow)
Microenvironmental factors
Stromal cell-derived cytokines:
- ***SCF (stem cell derived factors)
- ***IL-7 (enhance B cell survival) —> clinical manifestation: leukaemia / lymphoma changes
Pro-B cells bind to stromal cells via
- **CD44 + **c-kit (on B cell surface)
- **Hyaluronic acid + **SCF (on stromal cells)
—> activate Tyrosine kinase and stimulate proliferation
Late Pro-B cell, Pre-B cell:
- ***IL-7 receptors (bind to IL-7 to promote further maturation)
B cell deletion during development in bone marrow
- 5-10% survive (successfully rearrange Ig gene), 80% lost
—> Reason: Ig gene rearrangement is an error-prone process (only 3-5% successfully complete gene rearrangement) - By Apoptosis
—> condensed
—> apoptotic bodies without releasing intracellular contents
—> no inflammation
(Necrosis: release intracellular contents, trigger inflammation
Necroptosis (programmed necrosis) for infected cells)
**Allelic exclusion:
- productive Ig gene rearrangement can only occurs on **one chromosome (H chain locus for H chain; κ, λ light chain locus for L chain)
- one chromosome fail —> other one activated
- one chromosome succeed —> proceed
- suppression of non-expressed H chain loci and non-expressed L chain loci
—> **ensure each cell only expresses Ig of a **single H chain isotype and V region specificity, and a ***single L chain isotype and V region specificity
***B cell selection during development
***ONLY Negative selection
When **immature B cell express functional surface **IgM but not IgD
—> ready for selection by self-antigens (self MHC molecules: cell bound / soluble)
—> occurs in ***Bone marrow
—> successful in selection
—> proceed to express IgD
—> peripheral secondary lymphoid organs
- Autoreactive B cells to multivalent self molecule (**Cell-bound self MHC)
—> Deletion by Apoptosis (Negative selection)
—> Immune **tolerance induction - Autoreactive B cells to **soluble self MHC molecule
—> migrates to periphery
—> **Anergy (suppression; cell life prolonged)
—> Deletion by Apoptosis (Negative selection) - No self reaction
—> migrates to periphery
—> Proliferation and Maturation -
**Receptor editing in autoreactive B cell
—> strong ligation of IgM by self antigen
—> trigger arrest of B-cell development and continue **light-chain rearrangement (再黎過)
—> a new receptor specificity expressed
—> if still reactive —> Apoptosis
—> if no longer self-reactive —> migrates to periphery —> Proliferation and Maturation (rescue some autoreactive B cells)
Clinical significance of B cell development
- Defective B cell development —> Immunodeficiency
- Autoreactive B cells escape selection —> Autoimmune disease
- B cells with aberrant Ig gene rearrangement —> B cell tumours
***T cell development process in Thymus
HSC in bone marrow
—> progenitors migrate to Thymus for differentiation
- Undergo gene rearrangement
—> produce unique antigen receptor of ***different isotypes (T cell receptor)
—> stage and nature of gene rearrangement an indication of maturation level - Unlike B cells:
1. Gene rearrangement: **2 different sets of receptor genes (TCR is a Heterodimer)
2. Gene rearrangement give rise to **2 T cell lineages (α:β and γ:δ)
3. Rate of T cell production greatest ***before puberty
—> after puberty, Thymus shrink and production of new T cell is very low
—> T cells very long-lived (unlike B cell) - Thymus ***fully developed before birth
—> young individuals: numerous developing T cell embedded in Thymic stroma (epithelial network)
—> unique microenvironment for T cell development
**3 stages (migrate from capsule —> cortex of thymic lobules —> medulla of Thymus: 8-10 days):
**Double negative thymocytes (CD4-, CD8-) + no surface marker CD3 (associated with TCR)
—> **Double positive thymocytes (CD4+, CD8+, CD3+) (Cortico-medullary junction)
—> **Positive selection + **Negative selection
—> **Single positive (CD4+ or CD8+) + CD3+ (during migration through medulla)
—> leave thymus and migrate to peripheral lymphoid organs
—> **Cell-mediated immunity + **Induction of Humoral immune responses
CD4: co-receptor for MHC class II molecule, occurs on helper T cells CD8: co-receptor for MHC class I molecule, occurs on cytotoxic T cells
***T-cell subset
2 types of T cells:
- α:β T cells (expressing α:β TCRs) (95%)
- γ:δ T cells (expressing γ:δ TCRs) (5%)
α:β T cells:
—> CD4+ cells (Th): Help / induce immune responses —> Th1 (IL-2, IFN) + Th2 (IL-4, IL-5, IL-6, IL-10)
—> CD8+ cells (Tc): Cytotoxic
***T cell selection in Thymus
***Positive selection —> Negative selection —> Only T cells that do not recognise self antigens will leave Thymus
Positive selection (要bind到self-MHC + foreign peptide):
- double-positive T cell are screened for their ability to recognise **foreign peptides when presented to TCR by **self-MHC
—> T cell has opportunity to test several **consecutive α chain rearrangements
—> recognise peptide bound to self-MHC class I molecules
—> programmed to express CD8 co-receptors (vice versa)
- Mediated by **Thymic cortical epithelial cells
- **Ensures mature T cells can recognise antigens **in context of self-MHC molecules
- T cells with TCRs having moderate affinity for self-MHC are allowed to further develop
Negative selection (唔可以bind self peptide):
- T cells with receptors that recognise **self peptides:self MHC complex too well will be destroyed
—> eliminating potentially **self-reactive cells
- Mediated by ***Dendritic cells, Macrophages
Clinical significance of T cell development
Primary T-cell deficiency
- **DiGeorge syndrome (1 in 5 per 100,000)
—> arises from defect in Thymus **embryogenesis
—> ***non-functional Thymus
—> impaired cell immunity + cannot support B cell responsiveness
—> critically susceptible to infectious diseases
—> die at young age
Clinical significance of lymphocyte development and selection
- Self from Non-self
- Autoreactive lymphocytes —> Autoimmune disease - Immune surveillance
- Abnormal lymphocyte —> Lymphocyte malignancy
B cell-targeted therapy for RA, Lymphoma, SLE
Rituximab
- monoclonal Ab against CD20 (expressed mainly in B cell)
—> deplete most B cell in immune system
—> treatment of RA, Lymphoma, SLE
B cell heterogeneity
B2 cells (conventional B cells)
B1 cells (10% of B cells) (IgM+, IgD-)
- produce natural Ab
- located in body cavity
- generated by HSC in fetus
- may have role in autoimmunity
