Induction of primary immunological responses

Induction of a primary immunological response begins when an antigen penetrates epithelial surfaces. It will eventually come into contact with macrophages or certain other classes of Antigen Presenting cells (APCs), which include B cells, monocytes, dendritic cells, Langerhans cells and endothelial cells. Antigens, such as bacterial cells, are internalized by endocytosis and "processed" by the APC, then "presented" to immunocompetent lymphocytes to initiate the early steps of the immunological response. Processing by a macrophage (for example) results in attaching antigenic materials to the surface of the membrane in association with MHC II molecules on the surface of the cell . The antigen-MHC II complex is presented to a T-helper (TH2) cell which is able to recognize processed antigen associated with a class II MHC molecule on the membrane of the macrophage. This interaction, together with stimulation by Interleukin 1 (IL-1), produced by the macrophage, will activate the TH2 cell. Activation of the TH2 cell causes it to begin to produce Interleukin 2 (IL-2), and to express a membrane receptor for IL-2. The secreted IL-2 auto stimulates proliferation of the TH2 cells. Stimulated Antigen stimulated TH2 cells produce a variety of lymphokines including IL-2, IL-4, IL-6, and gamma Interferon, which mediate various aspects of the immune response. For example, IL-2 binds to IL-2 receptors on other T cells (which have bound the Ag) and stimulates their proliferation, while IL-4 causes B cells to proliferate and differentiate into antibody-secreting plasma cells and memory B cells. IL-4 activates only B cells in the vicinity which themselves have bound the antigen, and not others, so as to sustain the specificity of the immunological response.

As previously mentioned, B cells themselves behave as APCs. Antigens bound to antibody receptors on the surface of a B cell cause internalization of some of the antigen and expression on the B cell membrane together with MHC II molecules. The TH2 cell recognizes the antigen together with the Class II MHC molecules, and secretes the various lymphokines that activate the B cells to become antibody-secreting plasma cells and memory B cells. Even if the antigen cannot cross-link the receptor, it may be endocytosed by the B cell, processed, and returned to the surface in association with MHC II where it can be recognized by specific TH2 cells which will become activated to initiate B cell differentiation and proliferation. In any case, the overall B-cell response leads to antibody-mediated immunity (AMI).

The antigen receptors on B cell surfaces bear the specificity of antibodies that they are genetically-programmed to produce. Hence, there are thousands of sub-populations of B cells distinguished only by their ability to produce a unique (reactive) type of antibody molecule. A B-cell can react with a homologous antigen on the surface of the macrophage or with soluble antigens. When a B-cell is bound to Ag, and simultaneously is stimulated by IL-4 produced by a nearby TH2 cell, the B cell is stimulated to grow and divide to form a clone of identical B cells, each capable of producing identical antibody molecules. The activated B cells further differentiate into plasma cells which synthesize and secrete large amounts of antibody, and into a special form of B cells called memory B cells.

The antibodies produced and secreted by the plasma cells react specifically with the homologous antigen that induced their formation. Many of these reactions lead to host defense and to prevention of reinfection by pathogens. Memory cells a role in secondary immune responses.

Plasma cells are relatively short-lived (about one week) but produce large amounts of antibody during this period. Memory cells, on the other hand, are relatively long-lived and upon subsequent exposure to Ag they become quickly transformed into Ab-producing plasma cells.

Generation of cell mediated immunity (CMI) begins when (for example) a Tc cell recognizes a processed antigen associated with MHC I on the membrane of a cell (usually an altered self cell, but possibly a transplanted tissue cell or a eucaryotic parasite). Under stimulation by IL-2 produced by TH2 cells the Tc cell becomes activated to become a cytotoxic T lymphocyte (CTL) capable of lysing the cell which is showing the new (foreign) antigen on its surface, a primary manifestation of CMI.

The interaction between an antigen-presenting macrophage and a TH cell stimulates the macrophage to produce and secrete a cytokine called Interleukin-1 (IL-1) that acts locally on the TH cell. The IL-1 stimulates the TH cell to differentiate and produce its own cytokines (which in this case might be called lymphokines because they arise from a lymphocyte). These lymphokines have various functions. Interleukin-4 has an immediate effect on nearby B-cells. Interleukin-2 has an immediate effect on T cells as described above.

Time is required before a primary immunological response to be effective as a host defense. Antigens have to be recognized, taken up, digested, processed and presented by APCs; a few select TH cells must react with Ag and respond; preexisting B or T lymphocytes must encounter the Ag and proliferate and differentiate into effector cells (plasma cells or CTLs). In the case of AMI, antibody level has to build up to an effective physiological concentration to render its host resistant. It may take several days or weeks to reach a level of effective immunity, even though this immunity may persist for many months, or years, or even a lifetime due to the presence of the antibodies. In natural infections, the inoculum is small, and even though the antigenic stimulus increases during microbial replication, only small amounts of antibody are formed within the first few days, and circulating antibody is not detectable until about a week after infection.

Induction of a secondary immunological response

On re-exposure to microbial antigens (secondary exposure to antigen), there is an accelerated immunological response, the secondary or memory response. Larger amounts of antibodies are formed in only 1-2 days. This is due to the activities of specific memory B cells and memory T cells which were formed during the primary immune response. These memory cells, when stimulated by homologous Ag, "remember" having previously seen the Ag, and are able to rapidly divide and differentiate into effector cells. Stimulating memory cells to rapidly produce very high (effective) levels of persistent circulating antibodies is the basis for giving regular "booster"-type vaccinations to humans and pets.
 

Figure 4. Primary and Secondary Immunological Responses. Following the first exposure to an antigen the immune response (as evidenced by following the concentration of specific antibody in the serum, called "titer") develops gradually over a period of days, reaches a low plateau within 2-3 weeks, and usually begins to decline in a relatively short period of time. When the antigen is encountered a second time, a secondary (memory) response causes a rapid rise in the concentration of antibody, reaching a much higher level in the serum, which may persist for a relatively long period of time. This is not to say that a protective level of antibody may not be reached by primary exposure alone, but usually to ensure a high level of protective antibody that persists over a long period of time, it is necessary to have repeated antigenic stimulation of the immune system.