Lecture 7 Continued for Individual Exam 3 Flashcards
What Ig’s are naturally expressed in BCRs?
Monomeric IgD (Cδ) and IgM (Cµ)
- expressed naturally in the constant region of the BCR
- 2 antigen binding sites
- transmembrane anchor
What is Igα/Igβ?
Responsible for intracellular signalling for B cell activation
-similar to the CD3 complex on T Cells
What kinds of antigens can BCRs and TCRs bind?
BCR = Native Antigen
TCR = Processed Antigen
What is TD B Cell activation?
Thymus Dependent
-Requires TH help for B Cell activation
What are the steps of Thymus Dependent B Cell Activation?
1a. Exogenous antigen binds BCR
-entire antigen is endocytosed, processed, loaded on MHC II
1b. Peptides presented with MHC II to TH
-Intracellular signalling with Igα/Igβ in B cell
2. Co-stimulation by CD40/CD40L
-CD40L on TH binds CD40 on B Cell = more intracellular signals
3. Cytokine stimulation by TH
- TH recognizes same antigen as B cell and releases cytokines
- The type of TH it binds results in different cytokines being released by TH
What does presentation to a TH always result in?
Cytokine signalling
What is activated by presentation by the various APCs?
Dendritic Cells and Macrophages
-present to T cell to active that T cell
B Cells
-present to T cell to activate itself
What can a B cell differentiate into with and without presentation to a TH cell?
Thymus Dependent (TD)
- TH1 ⇒ IFγ ⇒ B Cell ⇒ Plasma Cell ⇒ IgG
- TH2⇒ IL-5⇒ B Cell ⇒ Plasma Cell ⇒ IgE or IgA
Thymus Independent-1 (TI-1)/Thymus Independent-2 (TI-2)
- no cytokine signalling
- B Cell ⇒ Plasma Cell ⇒ IgM or IgD
What are the steps of thymus independent-1 B cell activation?
1. Antigen (e.g. LPS) binds BCR
-1st intracellular signal
2. Antigen binds TLR (e.g. TLR4) on same cell
-2nd intracellular signal
What are the steps of thymus independent-2 B cell activation?
1. CD21 and BCR are cross-linked by bacterium opsonized by C3d
- Antigen binds BCR
- Antigen has been opsonized with C3d
- C3d binds to CD21 on B cell
- 2 signals= 1 from BCR binding and one from CD21 binding
OR
1. Antigen with repetitive epitopes (e.g. capsular polysaccharides) cross-links multiple BCRs
- One BIG signal from the repetitive epitopes on antigen
- Repetitive epitopes are additive
After activation and clonal expansion occurs, what happens next to the B cell and where does this occur?
Activation occurs in the T cell zone
The activated B cell moves to the geminal center where Affinity selection and Class switching occurs
What is affinity selection and class switching?
Affinity selection
- somatic hypermutation and affinity selection
- antigen fits in the antigen binding site due to VDJ recombination
- mutations in the VDJ region to make antigen bind better
Class switching
- changes in the constant region of antibody
- changes class of antibody to correct type to fight infection
What is somatic hypermutation?
Random point mutations are created in the V region
- AID: activation-induced cytifine deaminase
- gene involved in somatic hypermutation that causes mutations
- does not affect specificity of Ag binding
- affects affinity of Ag binding
What is affinity selection?
After somatic hypermutation the new BCRs are tested for binding
- follicular dendritic cell (FDC) presents same antigen
- must receive positive signal from FDC to survive
What is class switch recombination?
Determines isotype of immunoglobulin produced by plasma cells
-AID cuts out CX regions we don’t want then splices in remainder to change class
What happens to the B cells after affinity selection and class switching?
Once the infection is over some of these new B cells are kept as memory cells
-improves 2nd response
The process is repeated to continuously refine the B Cells and make them better
What is class switching influenced by? What would happen if we had a TH defect?
Class switching is influenced by cytokines and CD40 ligand co-stimulation
- If there is a mutation in the TH cell, especially CD40/CD40L, it will prevent class switching
- No class switching means only IgM and IgD produced
- Leads to X-Linked HIGM = Immunodeficiency/infection prone
What does the following graph tell you?
During primary response
- innate immunity important and holds the line during latent period
- IgM initially produced and then as IgG starts being produced IgM declines
During secondary response
- much faster almost no latent period
- IgG produced immediately
- IgM produced more slowly
What are the functional differences between Naive and Memory B cells for
- Magnitude of peak antibody resposne
- antibody isotype produced
- antigens
- antibody affinity
- lifespan
Magnitude of peak antibody response
- Naive: varies
- Memory: 10-100x higher than naive
antibody isotype produced
- Naive: IgM during early primary response
- Memory: IgG predominates, except in mucosal tissue=IgA
antigens
- Naive: TD and TI-1, TI-2
- Memory: TD
antibody affinity
- Naive: low
- Memory: high
lifespan
- Naive: short lived
- Memory: long lived
How does IgM and IgG help fight infection?
IgM - complement activation
IgG - opsonization and complement activation
-increased affinity too
What is antibody-mediated (humoral) immunity?
Plasma cells produce antibodies that specifically bind to microbial antigens which leads to clearance
- B Cells activated⇒Plasma Bodies⇒Tag antigen
- extracellular pathogens
What is cell-mediated immunity?
Cytotoxic T cells and NK cells destroy virus-infected cells
- Assisted by non-lymphoid effector cells (macrophages, neutrophils, eosinophils) that directly eliminate a variety of microbes (e.g. phagocytosis)
- intracellular pathogens
What is the difference between a BCR and an Antibody?
BCRs are expressed by B cells
- surface Ig
- have transmembrane region
Antibodies are secreted by plasma cells
- soluble Ig
- no transmembrane region
The Fc region is where the different Ig Isotypes occur
What are the different antibody mechanisms?
- Virus and Toxin Neutralization
- Opsonization
- Complement forms Membrane Attack Complex
- Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
