Humoral Immunity 9/5 Flashcards
Humoral Immunity
- Branch of adaptive immunity mediated by antibodies produced by B cells (Plasma cells). Humoral immunity is the principal defense against extracellular pathogens
- Abs are produced by plasma cells in the lymphoid tissues/organs. These Abs perform their functions at distant sites from production
- the effector functions of Abs are mediated by the Fc’ region. Different isotypes serve different effector functions
- Although the effector functions are mediated through the Fc’ region, all functions are triggered by the binding of Ag to Fab’ (V) region
Neutralization
- Many microbes gain entry into cells by binding the cell surface
- in neutralization, the Ab binds the microbe and thus neutralizes its infectivity and potential effects of infection by sterically hindering further binding
- neutralization only requires the binding of the Ag, thus any class of Ab will work. However, the higher the affinity, the better.
Opsonization and Phagocytosis
- Opsonization (binding) of microbe to an Ab occurs
- Binding of the opsonized microbe/Ab complex to phagocyte Fc receptors occurs
- Fc receptors signal activation of phagocyte
- The microbe is phagocytosed and is killed
Antibody Dependent Cellular Cytotoxicity (ADCC)
If the pathogen is coated with IgG, the IgG will bind to the Fc receptors on the NK cells. Through the binding a crosslinking, the NK cells will kill the pathogen that the Abs are attached to
IgE mediated reactions
- Th2 cell secreates IL-5 which stimulates the eosinophil
- IgE binds to the helminth worm. IgE also binds to Fc receptors present on mast cells
- The IgE binding to Fc receptors results in degranulation of the cell and helminth death
Why do we normally have more IgG in our bodies than IgM?
- IgG has a higher affinity (due to class switching and hypermutation)
- IgG can bind to Fc receptors on phagocytes and can activate the complement. IgM can only activate complement because it doesn’t bind to Fc receptors
Hyper-IgM Immunodeficiency
- five types with five genetic deficiency: all leading to the inability to class switch from IgM to IgG, IgA, or IgE
- 70% is due to CD40L deficiency (X linked HIGM)
- CD40L deficiency:
- have severely impaired production of IgG and IgA
- 1/2 normal - 1/2 elevated levels of IgM (indicating primary infection )
- no response to protein Ags
- TI Ag response only
- B memory cells absent or very reduced.
- CD40 is not only located on B cells but is also expressed on macrophages/monocytes/DC’s –> lack of this signalling leads to impaired handling of opportunistic pathogens
- CD40 is also expressed on platelets and endothelium and epithelial cells during inflammation
- prone to a variety of bacterial and opportunistic infections: pneumonia, neutropenia, failure to thrive, thrombocytopenia and anemia are common
- in charts, can see that the number of cells binidng soluble CD40 is very low, whereas number of cells binding anti-CD25 (IL-2 receptor on T cells, which stimulates survival and growht of T cells) is normal
Why are Abs to blood group Ag’s seen in patients with HIGM but not to tetanus toxoid Ags?
- T independent Ag’s are IgM - IgM’s to B and A exist because of cross-reactive sugars on pathogens – picked up and processed in mucosa –these secrete Abs that cross react on blood cell surfaces – DON’T need T cell help for this
- Tetanus Toxoid is a protein that requires T Cell Help
- The patient was given typhoid to look for primary reponse. Given Tdap to look for secondary response: looking for T cell responses.
Therapeutic Humoral Immunity
- some autoimmune/inflamatory diseases are treated with intravenous Ig (IVIG)
- throught to engage the inhibitory FcR on B cells and possibly DC’s and suppresses the immune responses. and though to provide Ab’s for people that can’t make Abs of the secondary response
Waste Management
–> opsonization allows for clearance of Immunce Complexes (ICs): which is mediated by C’ receptor CR1 on erythrocytes
- antibodies bind Ags in the circulation, forming small complexes
- activation of C’ leads tot he deposition of many molecules of C3b on the immune complex
- the C’ receptor CR1 on erythrocytes binds the immune complexes via bound C3b
- The RBC/Ag/Ab complex goes to the spleen and liver, where phagocytic cells remove the immunce complexes from the erythrocyte surface
Cryoglobulinemia
- Chronic Infection –> Immune-Complex Disease (ICD)
- chronic exposure to Ag
- polyclonal stimulation, B cell proliferation
- prolonged B cell survival
- organ/vessel damage due to increased amount of IC’s
- Can lead to malignancies and B cell lymphomas
- Persistant immune response to Ags can lead to formation of IC’s that themselves may become immunogenic
- Rheumatoid factor (anti-IgG IgM : patient is making IgM to their own IgG)
- Ags in IC can’t be cleared fast enough by the normal waste management process: thus they back up and start to block blood flow (esp in kidneys)
- Positive Cryoglobulinemia test results: indicates presence of IC’s deposited in the kidneys and small blood vessles of other organs (IC’s and proteins precipate at <37C)
- this requires a polyclonal B cell response: (Polyclonal by monoclonal Abs) meaning many different B cell clones bind to one pathogen via recognizing different Ag determinant (epitope) binding.
ICD Immunopathogenesis
1- circulating IC’s deposited in wall of very tiny capillaries where they activate C’.
2- They activate C’ and release C3a and C5a which are chemotactice for macrophages and neutrophils recruitment.
3- They come into area and release enzymes and granules and try to phagocytose the complex. When they can’t phagocytose they become frustrated, and dump all of ROS and NOS into area to try to kill what they can’t phagocytise –> resulting in erosion and bystander damage of healthy tissue and vasulitis.
CD20
- possible treatment for people with ICD???
a monoclonal Ab against CD20 has shown some benefit for cryoglobulinemia patients in clinical studies. This works because CD20 is a pan B cell marker, an Ab against them would target all B cells for death and would take out the Bcell population. –> however this would result in immuno-compromising
