Immunity mediated by B cells and antibodies Flashcards
Events that occur in the 1st week of the primary immune response
- B cell activation: Signal 1 and 2
- Short lived plasma cells secreting IgM
- Primary focus for expansion of antigen activated B cells is in the medullary cords
Events that occur in the 2nd week of the primary immune response
Formation of germinal centers
- isotype switching
- somatic hypermutation
- development of memory B cells and long lived plasma cells (expansion of antigen-activated B cells in the primary follicle creates the germinal center)
Different types of B cells
- Mature naive B cells
- Marginal zone B cells
- B-1 B cells
Effector functions of antibodies
- IgM: protects bloodstream
- IgG: protects bloodstream, extracellular spaces, lymphatics
- IgA: 1st line of defense, present in mucous secretions and protects epithelial surfaces
- IgE: 2nd line of defense, stimulates an inflammatory response
- IgD: participates as a BCR on naive B cells
Events that occur in week 1
- recognition of antigen
- activation by helper T cells and formation of a primary focus
- differentiation to short lived plasma cells that produce IgM to clear the infection
Primary focus
A pool of B cells resulting from the proliferation of antigen activated B cells over the course of 3-4 days
Events that occur in week 2
Steps to pathogen-specific memory formation occur
- development of antibodies with a new heavy chain isotope (IgA,G, or E) and with a higher affinity for epitopes derived from original pathogen
- development of long-lived plasma cells
Signal 1
Recognition of antigen
- prepares B cells for collaboration with effector helper T cells
Signal 2
Activation by effector helper T cells
- formation of a primary focus
- must happen within the first 24 hours or cell will undergo apoptosis
What happens to B cells in the first week?
- Some activated B cells differentiate to short-lived plasma cells secreting IgM
- Other activated B cells in the primary focus will participate in the events that take place in the 2nd week of the primary immune response
Germinal center
Site of B cell proliferation in the B cell area of secondary lymphoid tissues
Changes in _______ expression is responsible for the interaction of antigen-activated B cells with effector helper T cells
Chemokine receptor
____ and ____ induce B cell to migrate into T cell area
CXCR5 and CCR7
B cell and T cell migration
Antigen activated B cells migrate to T cell area, and antigen activated helper T cells migrate to B cells
- form a conjugate and synapse so signal 2 is secreted directly on the B cell surface (eliminates bystander effects)
Function of germinal centers
- isotype switching
- somatic hypermutation
- development of memory B cells and long lived plasma cells
Isotype switching
Efficient elimination of the pathogen
- germinal center B cells undergo isotype switching from IgM to an isotype that is most effective in removing the pathogen
Somatic hypermutation
Efficient recognition of the pathogen
- point mutations are generated in the variable region of the heavy chain and light chain genes
- B cells in the germinal center are then selected for high affinity recognition of the original antigen epitope
Protection from reinfection and disease
Germinal center B cells will differentiate into either antibody secreting long lived plasma cells or memory B cells
- long lived plasma cells migrate to the bone marrow and secrete higher affinity and isotype switched antibody that is observed during the later part of primary response
- memory B cells maintain surveillance of secondary lymphoid tissues
Events in the _____ will determine life span of B cells once plasma cell has exited the bone marrow
Germinal center
What characteristics of the antibody response will be helpful in preventing disease
- antibody response occurs more rapidly (3-5 days)
- antibody levels will be higher than the level attained with the primary response
- antibodies produced will have a higher affinity for the antigen epitope
- antibody will consist of an isotype different from IgM
2 types of antigens encountered by B cells
Thymus dependent protein antigens
- requires T cell help - signal 2
Thymus independent non protein antigens
- antigen provides both signals
Thymus dependent antigen
Protein antigens require T cell help for B cell proliferation and differentiation
Thymus independent antigen
Polysaccharides from bacterial capsules and some viruses (antigen can provide both signal 1 and 2)
- repeated epitopes of these antigens can engage BCRs and TLRs
- multitude of signals is sufficient to induce B cell proliferation and differentiation to short lived plasma cells secreting IgM = early IgM response to infection
B cells recognize ___ and T cells recognize ___
Polysaccharide; protein portion of an antigen
Follicular B cells
Aka: mature naive B cells
- adaptive immunity
- diverse repertoire of antibody specificities that respond to thymus-dependent antigens
- require T cell help for activation (signal 2)
- location: secondary lymphoid tissues, recirculate between the blood and lymphatics
Marginal zone B cells
Respond to pathogens in the blood
- differentiate to short lived plasma cells secreting IgM
- location: marginal zone of the spleen where the blood is filtered
B-1 B cells
Respond to pathogens entering the major body cavities
- differentiate to short lived plasma cells secreting IgM
- location: peritoneal and pleural cavities
Why do we have different antibody isotypes?
We need different antibody effector functions because of different kinds of pathogens.
We also need to protect the different body compartments where pathogens invade
In what general ways do antibodies clear infections with extracellular pathogens and their products?
Focus defense mechanisms onto the pathogen itself
- antibody links the pathogen with the leukocytes and plasma proteins that will eliminate it
Effector functions of antibodies
- neutralization
- opsonization: phagocytes express Fc receptors for antibody bound to a pathogen
- activation of complement: phagocytes express complement receptors for C3b bound to a pathogen
Fc region
C terminus of antibody is also called Fc region
- Fc receptors for IgG, IgA, and IgM
- low affinity: cannot bind to free IgG or antibody from the plasma
IgM
Is confined to the bloodstream, but does enter tissue at a site of infection
- is not recognized by Fc receptors of phagocytes, but phagocytes express receptors for complement component C3b that is deposited onto surface of the pathogen
How does IgM clear an infection?
IgM is a potent activator of complement and is specialized to activate complement efficiently upon binding to the pathogen
C1q
First component of the classical complement pathway, must bind two or more antibody heavy chains to become activated –> requires multiple molecules of IgG bound to the pathogen
- a single molecule of IgM bound to the pathogen is sufficient for activation of complement due to pentameric structure of IgM
Effector function of IgG
Neutralization!
- prevents infection of cells by neutralizing bacterial and viral toxins
Opsonization!
- macrophages and neutrophils express Fc receptors for IgG
Antibody-dependent cell mediated cytotoxicity!
What is neutralization?
Antibodies can prevent infection by coating the surface of a pathogen and prevent the pathogen from binding to healthy cells
What is an opsonin?
A substance that enhances phagocytosis
- ex: IgG
Antibody dependent cell mediated cytotoxicity
Natural killer cells express Fc receptors for IgG
- NK cells use their Fc receptors to bind to antibody coated cells, which they kill by inducing apoptosis
Antibody-coated cells recognized by NK cells
- virus infected cells
- tumor cells
IgA
Formed after a primary response to a pathogen in the respiratory tract or upper intestinal tract
- germinal centers that form in the 2nd week of the response will produce memory B cells that have IgA as an antigen receptor and long-lived plasma cells which will secrete IgA
How does IgA provide the first line of defense against re-infection?
IgA is present in mucus secretions that cover the epithelial linings of the body
How does IgA protect the epithelial surfaces?
Neutralization
Does IgA activate complement?
No, IgA is a dimer that is unable to activate complement
Should complement be activated at epithelial surfaces?
No! Will result in tissue damage at intestinal surfaces due to cytokine storm, reason why you need an antibody potent in neutralization (IgA)
Migration of IgA to epithelial surface
Binding of IgA to receptor on basolateral face of epithelial cell –> receptor mediated endocytosis of IgA –> transport of IgA to apical face of epithelial cell –> receptor is cleaved, IgA is bound to mucus through the secretory piece
IgE
Second line of defense, behind IgA
- primary response to parasites results in long-lived plasma cells secreting IgE
- mast cells stimulate an anti-parasitic response –> IgE provides mast cells the ability to “sense” pathogens
Mast Cells
- located beneath the epithelial surfaces of the skin, respiratory tract, and GIT
- express Fc-receptors for IgE (high affinity, can bind free IgE that is not bound to an antigen)
- when an antigen binds IgE on the surface of mast cells = release of histamine stimulates an inflammatory response
Mast cells are found in ____ and respond to _____
tissues; parasite infection
Mast cell activation
Inflammation at the site of infection
- histamine: vascular permeability, peristalsis
- TNF alpha: vascular permeability, upregulation of cytokines
How does IgE provide a second line of defense against re-infection with pathogens that invade the intestinal epithelium and enter the underlying tissue?
IgE is bound to the surface of mast cells and is responsible for mast cell activation in response to pathogen invasion
Eosinophils
Express Fc receptors for IgE
- binding to IgE coated pathogen induces degranulation, release proteins that damage larvae membrane
- type of antibody-dependent cellular cytotoxicity
