By Levi Clancy for Student Reader on
Antibody production by activated B cells is the core the humoral response: antibody effects, such as complement activation by IgM and certain IgGs, opsonization via F(c)Rs and pathogen/toxin neutralization by high-affinity IgG and IgA; and processes related to B cell activation, such as TH2 activation and cytokine production, germinal center formation, isotype switching, affinity maturation and memory cell production. The F(c) region of IgG binds to F(c) receptors, playing a critical role (along with receptors for complement byproducts) in clearing extracellular bacteria. Intracellular bacteria are cleared by cell-mediated immunity.
Antigens are grouped into thymus-dependent antigens and thymus-independent antigens. Activation by thymus-dependent antigens requires two signals: first, binding of the antigen itself to the B cell; second, binding of of a thymocyte to the B cell. Thymus-independent antigens, conversely, activate B cells on their own; in some cases, however, TH cytokine secretion (but not binding) is needed for maximum B cell activity.
Activation of naïve B cells by thymus-dependent and -independent antigens leads to the primary humoral response. The primary response is characterized by a lag phase -- during which naïve B cells undergo clonal selection, clonal expansion and differentiation into memory or antibody-secreting cells -- followed by an exponential increase in circulating antibodies that peaks, plateaus and declines. The lag ranges from ∼4-10 days and the peak antibody titer can occur as late as ∼14 days later. IgM is secreted initially, but the B cell population usually undergoes class switching to secrete increasing amounts of IgG. Memory B cells formed during the primary response enter the G0 phase and can live through the patient's entire life.
Activation of memory cells (both B and T type) by thymus-dependent antigens leads to the secondary humoral response. The secondary humoral response lasts longer and is highly effective due to class-switching (secretion of non-IgM antibodies), affinity maturation (antibodies with higher affinity), a shorter lag of ∼1-4 days and a ∼100-1000x greater magnitude. Memory B cells are responsible for secretion of high levels of high-affinity antibodies, and for class-switching to antibody isotypes best suited for clearing the pathogens. Original antigenic sin results in an apparent secondary response to a primary infection -- if the primary infection has any epitopes encountered before, then those epitopes will elicit a secondary response.
|Property||Primary response||Secondary response|
|Responding B cell||Naïve B cell||Memory B cell|
|Lag Period||∼4-7 days||∼1-3 days|
|Length of Response||∼7-10 days||∼3-5 days|
|Magnitude||Varies based on antigen||∼100-1000x greater than 1° response|
|Isotype Produced||Initially IgM, then IgG||Mostly IgG|
|Antigens||Thymus-dependent and -independent||Thys-dependent|
The thymus-dependent response requires linked recognition (aka associative recognition) whereby TH and B cells must both recognize a given molecule as an antigen for it to activate the B cell. This was demonstrated in the cell-transfer experiment. Antigens in the blood are concentrated in the spleen, while antigens accessible by lymph are concentrated in the nearest lymph nodes and nodules. Lymph nodes trap more than 90% of all antigens which flow through them, whether those antigens are bound to free-floating antibodies or antibodies bound to antigen-transporting cells (such as Langerhans or dendritic cells) or macrophages.
T and B cell epitopes are not necessarily identical; for example, T cells respond well to internal viral proteins while B cells produce neutralizing antibodies to viral coat proteins. (Once virus-infected cells have been killed and unassembled virus proteins released, B cells specific for internal proteins can also be activated to make opsonizing antibodies to those proteins.) Attaching a carbohydrate to a protein can convert the carbohydrate into a T-dependent antigen; the carbohydrate-specific B cell internalizes the complex and presents peptides to Th2 cells, which in turn activate the B cell to make antibodies specific for the carbohydrate.