Immunology. Richard Coico
these characteristics to be immunogenic; it must be foreign to the individual, have a relatively high molecular weight, possess a certain degree of chemical complexity, and be degradable.
Haptens
As noted earlier, substances called haptens fail to induce immune responses in their native form because of their low molecular weight and their chemical simplicity. These compounds are not immunogenic unless they are conjugated to high molecular weight, physicochemically complex carriers. Thus an immune response can be evoked to thousands of chemical compounds—those of high molecular weight and those of low molecular weight, provided the latter are conjugated to high molecular weight complex carriers.
Figure 5.1. Levels of protein organizational structure. The primary structure is indicated by the linear arrangement of amino acids (using a single‐letter code) and includes any intrachain disulfide bonds, as shown. The secondary structure derives from the folding of the polypeptide chain into α helices and β‐pleated sheets. The tertiary structure, shown as a ribbon diagram, is formed by the folding of regions between secondary features.
Source: Adapted with permission from Sun P, Boyington JC. Current Protocols in Protein Science. Hoboken, NJ: John Wiley and Sons, Inc.
Further Requirements for Immunogenicity
Several other factors play roles in determining whether a substance is immunogenic. The genetic make‐up (genotype) of the immunized individual plays an important role in determining whether a given substance will stimulate an immune response. Genetic guidance of immune responsiveness is largely controlled by genes mapping within the MHC. Another factor that plays a crucial role in the immunogenicity of substances relates to the B‐ and T‐cell repertoires of an individual. Acquired immune responses are triggered following the binding of antigenic epitopes to antigen‐specific receptors on B and T lymphocytes. If an individual lacks a particular clone of lymphocytes consisting of cells that bear the identical antigen‐specific receptor needed to respond to the stimulus, an immune response to that antigenic epitope will not take place. Finally, practical issues such as the dosage and route of administration of antigens play a role in determining whether the substance is immunogenic.
Insufficient doses of antigen may not stimulate an immune response, either because the amount administered fails to activate enough lymphocytes or because such a dose renders the responding cells unresponsive. The latter phenomenon induces a state of tolerance to that antigen (see Chapter 12). Besides the need to administer a threshold amount of antigen to induce an immune response, the number of doses administered also affects the outcome of the immune response generated. As discussed below, repeated administration of antigen is required to stimulate a strong immune response.
Figure 5.2. The quarternary structure of proteins results from the association of two or more polypeptide chains, which form a polymeric protein.
Source: Adapted with permission from Sun P, Boyington JC. Current Protocols in Protein Science. Hoboken, NJ: John Wiley and Sons, Inc.
Finally, the route of administration can affect the outcome of the immunization strategy, because this determines which organs and cell populations will be involved in the response. Antigens administered via the most common route, namely subcutaneously, generally elicit the strongest immune responses. This is due to their uptake, processing, and presentation to effector cells by Langerhans cells present in the skin, which are among the most potent APCs. Responses to subcutaneously administered antigens take place in the lymph nodes draining the injection site. Intravenously administered antigens are carried first to the spleen, where they can either induce immune unresponsiveness or tolerance or, if presented by APCs, generate an immune response. Orally administered antigens (gastrointestinal route) elicit local antibody responses within the intestinal lamina propria but often produce a systemic state of tolerance (antigen unresponsiveness) (see Chapter 12 for a detailed discussion about tolerance). Finally, administration of antigens via the respiratory tract (intranasal route) often elicits allergic responses (see Chapter 13).
Since immune responses depend on multiple cellular interactions, the type and extent of the immune response are affected by the cells populating the organ to which the antigen is ultimately delivered. The stringent requirements given above constitute a portion of the delicate control mechanisms, expanded and elaborated in subsequent chapters, which, on one hand, trigger the adaptive immune response and, on the other hand, protect the individual from responding to substances in cases where such responses are detrimental.
PRIMARY AND SECONDARY RESPONSES
The first exposure of an individual to an immunogen is referred to as the primary immunization, which generates a primary response. As we shall see in subsequent chapters, many events take place during this primary immunization: cells process antigen, triggering antigen‐specific lymphocytes to proliferate and differentiate; T‐lymphocyte subsets interact with other subsets and induce the latter to differentiate into T lymphocytes with specialized function; T lymphocytes also interact with B lymphocytes, inducing them to synthesize and secrete antibodies.
A second exposure to the same immunogen results in a secondary response. This may occur after the response to the first immune event has leveled off or has totally subsided (within weeks or even years). The secondary response differs from the primary response in many respects. Most notably and biologically relevant is the much quicker onset and the much higher magnitude of the response. In a sense, this secondary (and subsequent) exposure behaves as if the body remembered that it had been previously exposed to that same immunogen. In fact, secondary and subsequent responses exploit the expanded number of antigen‐specific lymphocytes generated in response to the primary immune response. Thus the increased arsenal of responding lymphocytes accounts, in part, for the magnitude of the response observed. The secondary response is also called the memory or anamnestic response, and the B and T lymphocytes that participate in the memory response are termed memory cells.
ANTIGENICITY AND ANTIGEN‐BINDING SITE
An immune response induced by an antigen generates antibodies or lymphocytes that react specifically with the antigen. The antigen‐binding site of an antibody or a receptor on a lymphocyte has a unique structure that allows a complementary fit to some structural aspect of the specific antigen. The portion of the immunoglobulin that specifically binds to the antigenic determinant or epitope is concentrated in several hypervariable regions of the molecule, which form the complementarity‐determining region (CDR). Additional structural features of the immunoglobulin molecule are described in Chapter 6.
Various studies indicate that the size of an epitope that combines with the CDR on a given antibody is approximately equivalent to 5–7 amino acids. These dimensions were calculated from experiments that involved the binding