- Humoral Immunity is the arm of the Adaptive Immune Response which results in the release of antigen-specific Antibodies that target an invading microbe. This response is largely carried out by B-cells but requires the help of CD4+ T-cells and thus in part depends on successful Cell-mediated Immunity. Here we outline the steps of Humoral Immunity and organize this section according to the "Basic Architecture" common to all arms of the Adaptive Immune Response (see page).
|Random Generation and Selection|
- The Random Generation and selection of large numbers of B-cells, each expressing a unique antigen-specific antibody which does not bind self-antigens is described in B-cell Development. The end result of these stages is a large pool of peripheral, mature B-cells which continuously circulate through the blood and lymph nodes waiting to encounter antigen that can bind their surface B-cell Receptor. Recall that the B-cell Receptor is simply a membrane bound form of Antibody that can induce signal transduction cascades within the B-cell following antigen binding. If a B-cell does not encounter its antigen, it will eventually die within a few months only to be replaced by freshly-generated B-cells. However, if a B-cell does encounter its antigen, it will undergo proliferation and differentiation into an antibody-secreting cell as described below.
|Proliferation and Differentiation|
- B-cells undergo intense proliferation and differentiation into antibody-secreting cells after they encounter their respective antigens. For most antigens, these processes require additional stimuli from CD4+ T-cells and thus these are termed "Thymus-dependent Antigens".
- FYI: A smaller set of antigens can induce proliferation and differentiation of B-cells without additional T-cell stimuli and these are termed "Thymus-independent Antigens"; however, since most antigens are Thymus-dependent, we will only discuss this class here
- Antigen Binding and Presentation
- Following binding of antigen to the B-cell Receptor, the B-cell internalizes the attached microbe, degrades the organism, and presents peptide degradation products of the microbe on its surface with MHC II molecules. Consequently, in this limited sense, activated B-cells are in fact considered Antigen Presenting Cells.
- Encounter with Helper T Cell
- Like all B-cells, activated B-cells circulate through lymph nodes where they enter the Outer Cortex of the lymph node and interact with CD4+ Helper T-cells, especially of the Th2 sub-type. These CD4+ T-cells survey the MHC II displayed on entering, activated B-cells and determine if their T-cell Receptor can recognize the microbial peptides displayed on B-cell MHC II. If no CD4+ T-cell recognizes the peptides displayed on the B-cell's MHC II, the B-cell will simply move on to the next lymph node. However, if one of the peptides displayed by the B-cell is recognized by a CD4+ T-cell then the T-cell stimulates the B-cell to undergo intense proliferation as described below.
- T-cell-induced Proliferation
- CD4+ T-cells whose T-cell Receptor recognizes microbial peptides displayed on activated B-cells will shower the B-cell with a variety of cytokines, such as IL-4 and IL-5, that induce intense proliferation of the B-cell. It should be noted that the microbial peptide which the T-cell recognizes may not be the same region of the microbe that the B-cell's B-cell Receptor recognizes. This is because the B-cell displays peptides from the degradation of the entire microbe, including intracellular regions of the organism, whereas the B-cell Receptor can only recognize a single antigen on the microbial surface. At this point, one population of the proliferated B-cells will differentiate into Plasma Cells and begin secreting antibody which has not undergone isotype-switching and will thus be of the IgM isotype. Consequently, the earliest indication of a Humoral Immune Response to a microbe will be rising titers of IgM. However, a second population will proceed through the Affinity Maturation and Isotype Switching steps described below. These steps generate other isotypes of antibody and modify the antibody so that it has substantially increased affinity for the antigen.
- Affinity Maturation
- The process of Affinity Maturation allows activated B-cells to significantly improve the affinity of their B-cell Receptor for the antigen. Affinity Maturation occurs within the Germinal Centers of Lymphoid Follicles observed in certain areas of the lymph node outer cortex (See: Lymph Node Histology). Here, B-cells begin to intensely mutate the antigen-binding pocket of their antibody genes in a process known as "Somatic Hypermutation". Mutated antibodies are expressed as B-cell Receptors and are tested for increased affinity to the microbial antigen. Those B-cells whose B-cell Receptors display increased affinity are maintained, induced to proliferate, and undergo further rounds of somatic hypermutation while those whose B-cell Receptor loses affinity are instructed to die. The source of microbial antigen which is used for this process is currently not clear but may be derived from depositions of microbial material present on specialized Follicular Dendritic Cells present in the lymphoid follicles. The end result of this process, known as "Affinity Maturation", is a population of B-cells which synthesize antibodies with significantly higher affinity to the microbial antigen.
- Isotype Switching
- Through mechanisms that are currently not clear, B-cells are induced to switch the isotype of their antibody following Affinity Maturation. Isotype switching, also known as Class Switching, appears to require stimulation of the CD40 receptor on the B-cells by CD40-Ligand present on CD4+ T-cells. In most cases, B-cells are instructed to switch isotype to IgG; however, immune responses to mucosal antigens generally result in isotype switching to IgA. In a few cases, isotype switching to IgE occurs and this is an important step in the sequence of events that lead to allergic responses and Type I Hypersensitivity.
- Ultimately, affinity matured and isotype switched B-cells undergo one of two paths of differentiation. Some differentiate into antibody-secreting Plasma Cells while other differentiate into quiescent Memory B Cells. Recall that Plasma Cells are specialized types of B-cells which secrete enormous amounts of their antibody. Differentiation of large numbers of microbe-specific Plasma Cells during a successful humoral immune response results in high concentrations of anti-microbial antibodies within the plasma. These antibodies bind the organisms and either directly interfere with microbial proliferation or direct other immune cells to phagocytose and destroy the bound microbe.
- Humoral memory results in the long-lived presence of microbe-neutralizing antibodies within the plasma as well as the capacity to rapidly proliferate antigen-specific B-cells following re-infection. These two aspects of humoral immunity are the result of two different cellular pools.
- Long-lived Plasma Cells
- Certain Plasma Cells that develop following a humoral immune response are quite long-lived and continue to synthesize and secrete antibody for years largely from locations within the bone marrow. These long-lived Plasma Cells are responsible for maintaining the titers of neutralizing antibodies to many microbes and are the basis for long-lived immunity to extracellular pathogens. In some cases, however, these long-lived Plasma Cells eventually die explaining why immunity to certain pathogens wanes with time.
- Memory B Cells
- Following a successful humoral immune response, a certain set of B-cells with affinity matured and isotype-switched antibodies differentiate into quiescent Memory B Cells. Although these Memory B Cells do not secrete antibody, they likely roam the body primed to re-encounter their specific antigen. If antigen is re-encountered these Memory B cells immediately proliferate, likely without the aid of Th2 Cell help, and begin secreting their highly specific affinity-matured antibody. Thus, because of Memory B Cells the entire process of affinity maturation can be skipped following re-infection, saving several days.