What are the general features of humoral immunity?
- Major arm of “adaptive immune response”
- Defend against extracellular microbes
- Neutralize & eliminate extracellular microbes & microbial toxins
- Mediated by Abs that are produced by activated B cells
Where is humoral immunity initiated?
Initiated in peripheral (2) lymphoid organs
1. Spleen - for blood borne Ag
2. Lymph nodes - for Ag entering via skin & other epithelial lining
3. Mucosal lymphoid tissues - for some inhaled & ingested Ag
What are the two types of antigens? State their differences.
- Protein Ag
- Require both B & T cells
- Generate Abs of different isotypes (distinct effector function) & high affinity
- Affinity maturation - repeated exposure to protein Ag results in the production of Abs with increasing affinity for the Ag - Non protein Ag (polysaccharides, lipids)
- Require little or no Ag specific T helper cells
- Abs produced show little heavy chain isotype switching & affinity maturation
What are the Ab responses in humoral immunity? Compare and contrast the responses.
- Primary response (1st exposure to Ag)
- 5-10 days
- Amount Abs produced are smaller* - Secondary response (subsequent exposure)
- 1-3 days
- Amount Abs produced are larger*
- With protein Ag, the responses also show increased heavy chain isotype switching (IgG & possibly IgA or IgE) & affinity maturation
*What are the different phases of B cell activation?
- Recognition of foreign Ag
- Activation of B-lymphocytes (Th stimulate B cells to produce Abs)
- Proliferation - giving rise to clonal expansion
- Differentiation
- some activated B cells undergo heavy chain isotype switching ex. IgM/IgD into IgG
- affinity maturation: some become long-lived memory B cells
What signals are required for B cell activation?*
- Signal 1 - B cell receptors recognize the Ag
- Signal 2
- Produced during innate immune reactions to microbes (ex. complement proteins C3d binds to complement receptor on B cells CR2)
- Derived from cell-cell interaction with T helper cells: CD40 (on B cells) interacts with CD40L (on Th cells)
Describe the B cell receptor complex.
BCR attached to Ig-alpha & Ig-beta
Describe the Ag receptor-mediated signal transduction in B cells.
- When 2 or more Ag receptors clustered, tyrosine in ITAMs get phosphorylated
- Net result of receptor-induced signalling in B cells = activation of transcription factors that turn on genes whose protein products are involved in B cell proliferation & differentiation
What are the components of B cell co-receptors?
Co-receptor complex = CR2, CD19 & CD81 on mature B cell surface
What is the significance of B cell co-receptors in B cell activation?
- Microbial Ag + bound C3d can simultaneously engage both membrane IgM and CR2
- Initiate signalling cascade from both BCR complex and CR2 complex
- Response is greatly enhanced when compared with the response to Ag alone
- Complement proteins provide 2nd signal for B cell activation, functioning in concert with Ag (signal 1) to initiate B cell proliferation & differentiation
Can T cells of different Ag specialties bind to the same B cell?
Yes
Describe the Ag presentation by B cells to T helper cells
- Ag bound to receptors, endocytosed & processed in the endosomal vesicles & displayed by MHC class II for recognition by CD4+ T helper cells
- B and Th cells are specific for the same Ag, however, B cells recognize a conformational epitope of a protein Ag and Th cells recognize peptide fragments of the same Ag
- *** Recognize different epitopes of the same protein Ag - Activated B cells express costimulators B7-1/B7-2 that interact with CD28 on Th cells
How do Th cells and B cells interact in lymphoid tissues?
- CD4+ Th cells recognize processed protein Ag & become activated (proliferate and differentiate)
- Effector T cells migrate toward lymphoid follicles
- T-B cell interactions at the edge of follicle
- Naive B cells recognize Ag and are activated, migrate out of follicle
Describe the mechanisms of Th cell activation of B lymphocytes.
- Th cells recognize Ag presented by B-cells and co-stimulators (ex. B7) on B cells
- Th cells are activated to express CD40L and secrete cytokines, both of which bind to their receptors on the same B cell and activate the B cell
- CD40L-CD40 interaction is very important - isotype switching, affinity maturation and memory B cell generation in response to protein Ag
Th function cannot be replaced by cytokines, need direct Tcell-Bcell contact
What are the outcomes of B cell activation?
- T cell - independent: production of IgM Abs
- T cell - dependent
- Production of IgG or IgA Abs
- Provide cytokines needed for both class switching and somatic hypermutation
- Both processes require ligation of CD40 on B cells by CD40L on T cells
Outline the terminating process of the humoral immune response.
- Ab binds to Ag that is still available in the blood and tissues to form immune complexes (IC)
- B cells specific for the Ag bind to the Ag part of the IG with their Ig receptors while the Fc tail of the attached Ab is recognized by a special type of Fc receptor on B cells
- This delivers inhibitory signals which terminates B cell responses
This process (Ab bound to Ag inhibits further Ab production) is called ANTIBODY FEEDBACK ***
What are the factors the affect the immune response?
- Chemical nature - proteins, lipids, etc.
- Chemical complexity - more complex, better
- Molecular size - Good > 10000d
- Conformation - folding vs denatured
- Foreignness - more foreign, better
- Mode of administration - route (IV, IM), dose
- Genetic constitution of the recipient - MHC
- Condition of recipient - age, health status
- Adjuvant - important in enhancing the immune response
