5.1). They can also recognize quaternary structures (formed by the juxtaposition of separate parts, if the molecule is composed of more than one protein subunit) (Figure 5.2).
Degradability
In contrast to B cells, in order for antigens to activate T cells to stimulate immune responses, interactions with MHC molecules expressed on antigen‐presenting cells (APCs) must occur (see Chapter 9). APCs must first degrade the antigen through a process known as antigen processing (enzymatic degradation of antigen) before they can express antigenic epitopes on their surface. Epitopes are also known as antigenic determinants. They are the part of an antigen that is recognized by the immune system and are the smallest unit of antigen that is capable of binding with antibodies and T‐cell receptors. Once degraded and noncovalently bound to MHC, these epitopes stimulate the activation and clonal expansion of antigen‐specific effector T cells.
A protein antigen’s susceptibility to enzymatic degradation largely depends on two properties: (1) it has to be sufficiently stable so that it can reach the site of interaction with B cells or T cells necessary for the immune response, and (2) the substance must be susceptible to partial enzymatic degradation that takes place during antigen processing by APCs. Peptides composed of D‐amino acids, which are resistant to enzymatic degradation, are not immunogenic, whereas their L‐isomers are susceptible to enzymes and are immunogenic. By contrast, carbohydrates are not processed or presented and are thus unable to activate T cells, although they can directly activate B cells.
In general, a substance must have all four of 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
