B cells and associated disease Flashcards
B cell Lymphocytes
8 microns diameter, pivotal role in Humoral Immune response:
- producing antibodies
- providing long term immune protection against infection
B cell development in bone marrow
1) Pluripotent Stem Cell (PPSC)
2) Multipotent Stem Cell (MPSC)
3) Common Lymphoid Progenitor (CLP)
4) B cell
The B Cell Receptor (BCR)
An antigen receptor requiring coreceptors to mediate B cell activity:
- antibody constant domain determines isotype (IgG/IgA…)
- Variability due to VDJ recombination and Antigen Receptor Diversity Generation (3 x 10^11 VDJ combinations)
Early –> Mature B cell differentiation
Common Lymphoid Progenitor (CLP) differentiates into a pro-B cell via immunoglobulin heavy chain rearrangement:
1) V–>J; joining V and D segments
2) Surrogate light chain rearranged and followed by lambda5 and VpreB
3) Cell proliferation and light chains become IgL chains (can undergo receptor editing, with VDJ recombination) to avoid autoimmune disease
4) After positive selection, BCRs can enter mature secondary organs as mature B cells
B cell activation
1) Follicular Dendritic Cells (FDCs) in primary follicle capture antigen complexes and express antigen in MHCII complex
2) MHCII bind to and activate T cells
3) If TCR activated, T cells migrate towards B cells in Primary Follicle
4) If BCR is activated, B cells migrate towards T regions (T cells produce CD40 ligand to further help T-B binding)
5) Some T cells migrate into primary follicle and differentiate into Follicular Helper T cells (Tfh)
B cell activation continued
Follicular Helper T cells (Tfh)
Tfh helps develop Pre-GCB (Germline Centre B cells) whilst other B cells differentiate into Plasmablasts (plasma cell precursor that produces low affinity antibodies like IgM)
The BCL6 transcription factor (repressor) is expressed in GCBs and Tfh, modulating expression of genes required for migrating inside primary follicle and avoiding premature exit from germinal centre
Somatic Hypermutation (SMH)
The introduction of mutations in the variable regions (Vh and Vl) of the Ig genes
Class Switch Recombination (CSR)
The change in constant region
Cell migration in Germinal Centre
Cells migrate from the Dark Zone to the Light zone following SMH and CSR for selection
Mechanism of Ig mutation
- Mediated by Activation Induced Cytidine Deaminase (AICDA): catalysing the deamination of cytosine regions and replacement with uracil
- can undergo normal DNA replication in dark zone (induce mutation)
- Can be processed by UNG (Uracil-DNA Glycosylase) which removes uracil and randomly incorporates new nucleotides (A/T/C/G)
- Can encounter MMR (DNA MisMatch Repair) machinery which catalyse the removal of the DNA region by exonuclease activity & inserts several random nucleotides
Antibody Secreting Cells (ASCs) differentiation from Germinal stage
Activated B cell –> Plasmablast –> Plasma cell
Expression of certain transcription factors promote this:
- Blimp-1 (repressor)
- IRF4
- XBP-1
Antibody Class Switching
Upon maturation, B cells can switch class in response to different cytokines: - IL-4 to switch to IgE
Different immunoglobulins (Ig’s) respond to different Fc receptors, target different cells and cause different effects
Antibody-mediated Autoimmune Disease:
Systemic Lupus Erythematosus (SLE)
Mechanism:
- Autoimmune response by autoantibodies against self-antigens (anti-nuclear antigens)
Systemic: skin, muscles, blood, heart, lungs, kidneys…
Symptoms: Painful and swollen joints, fever, chest pains, swollen lymph nodes (red rash on face)
Treating SLE
No cure
Steroids for immune suppression
NSAIDs for reducing inflammation
Antibody-mediated Autoimmune Disease:
Rheumatoid Arthritis (RA)
Mechanism:
- autoimmune by autoantibodies against Fc portion of IgG (Rheumatoid Factor) and Citrulline-modified proteins (ACPA) inc immune complexes
- Predominantly IgM but can be any isotype
Symptoms:
- Affects joins (swelling and pain) due to erosion of joint surface
Therapy = steroids and NSAIDs
