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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.