ADAPTATIVE IMMUNITY

The immune system is able to generate specific responses against invaders through adaptive immunity. Adaptive immunity (immunite specifique/ immunità acquisita/ inmunidad específica) [I1], [E1], [E2], [F], develops throughout life and is mediated by lymphocytes and antibodies, but also requires the involvement of phagocytic cells, cytokines and of the complement system, which are components of innate immunity. Adaptive immunity is more effective than non-specific processes and has a memory component that improves response when the same type of pathogen is encountered again.
Depending on the components involved, the specific immune responses may be classified in two different types [E1], [E2], [F]:
- cell-mediated immunity is regulated by T-lymphocytes and directed against virus-infected or cancerous body cells, parasites, fungi, and protozoa;
- humoral (antibody-mediated) immunity is controlled by soluble circulating molecules (antibodies) produced by B-lymphocytes and defends against invading bacteria and viruses.

Adaptive immunity may also be divided into an active and a passive component.
• Active immunity develops slowly and includes all responses that are activated when the organism is exposed to a foreign antigen (contact with infection or vaccination).
• Passive immunity is "borrowed" from another source and determines a response in an organism that has never come in contact with a specific antigen. Passive immunity develops immediately, it is temporary, and affects all antigens to which the donor is immunized. It can be natural (for example, antibodies transferred from mother to child during pregnancy or breast feeding) or artificial (achieved by injection of gamma-globulins in order to confer a rapid resistance for example to snake poison). Moreover, passive immunity can be elicited through a lymphocyte transfer, leading to cell-mediated response.

Adaptive immunity has some characteristic properties:
- Specificity: the immune responses are highly specific for different antigens, and single lymphocytes are able to discriminate between very similar molecules.
- Diversity: the whole number of antigens that can be recognized by B- and T-cells is extremely large (more than 109). This property depends on the structural variability of antigen receptors, and is essential to defend the organism against the wide number of pathogens. Specificity and diversity of adaptive responses are explained by the “clonal selection hypothesis” [E], suggesting that every individual possesses a wide number of lymphocyte clones, each deriving from a single precursor and able to specifically recognize a particular antigen; later on, antigen stimulation selects a pre-existing clone, leading to cell proliferation and differentiation.
- Memory: the immune system memorizes the first contact with a foreign antigen (determining the primary response), so that the reaction to following exposures to the same antigen (secondary immune responses) is faster and more intense [I], . This is due to the fact that specific lymphocytes turn into “memory cells” and survive for long periods, eventually leading to more efficient responses. The immune memory is on the basis of immunization against infective diseases.
- Limitation: the immune response progressively switches off upon antigen removal, and the system returns to a resting condition, ready to react to other antigens.
- Self/non-self recognition: the immune system can distinguish among self and non-self components on the basis of a marker (the major histocompatibility complex, MHC): any cell not displaying this marker is considered non-self and attacked. The self-tolerance mechanism is achieved by counter-selecting and eliminating those lymphocytes that come in contact with the body’s own antigens during development [E] [ES]. Sometimes this process is impaired and the immune system attacks self-cells, causing autoimmune diseases.

Four main phases may be recognized in all specific immune responses:

• Recognition phase
• Activation phase
• Effector phase
• Suppressor phase

Recognition phase
The immune system is capable of recognizing foreign molecules both inside the cells of an organism and in the extracellular environment by means of MHC molecules (Major Histocompatibility Complex or Complexe Principal d’'Histocompatibilité/Complesso maggiore d’Istocompatibilità/Complejo Mayor de Histocompatibilidad)[E],[F1],[F2],[I],[ES]. MHC molecules are receptors expressed on the membrane of self cells and are capable of binding fragments of non-self molecules in order to “present” them to T lymphocytes. Specifically, there are two classes of MHC molecules: MHC class I molecules, which are only able to interact with cytotoxic T cells and MHC class II molecules, which are only able to interact with T helper cells. MHC class I molecules are expressed on 90% of the body’s nucleate cells and bind fragments of proteins synthesized inside the cells themselves. Each cell continuously synthesizes and degrades its own proteins in order to promote turn-over. In this way, proteins, which possibly are damaged, may be replaced. Under normal conditions, the fragments derived from the degradation of self proteins are bound to MHC class I molecules and expressed on the outer cellular surface; if a cytotoxic T cell interacts with these molecules, it does not become activated. When a virus infects a cell of our body, it is able to take over the host’s replication machinery and produce viral proteins; these proteins may also be degraded and exposed on the surface with MHC class I molecules; in this case cytotoxic T cells recognize a foreign fragment in association with MHC class I molecules and an immune response is triggered. This takes place also in the event of bacterial infection and tumors. All body cells may be infected or become cancerous and therefore express MHC class I molecules. MHC class II molecules are expressed, instead, only on APCs (Antigen Presenting Cells or Cellules présentatrices d'antigène/Cellule Presentanti l’Antigene/Células Presentadoras del Antígeno)[E1],[E2],[F], which are cells capable of endocyting extracellular molecules or small cells, reducing them to fragments and exposing these in association with class II MHC molecules. Dendritic cells, macrophages, B lymphocytes and epithelial cells have the function of APCs and are essential to signal the presence of foreign circulating cells or molecules to T helper cells.
The primary role of T lymphocytes (cytotoxic and T-helper cells) is therefore to continuously inspect the entire organism in order to recognize and signal the presence of non-self molecules in the extra- and intra-cellular environments.

Activation phase
The activation phase follows the recognition of non-self molecules.
In general, all lymphocytes (T and B) start dividing when activated, in order to enhance the immune response; in fact, when an increased number of leucocytes in comparison to normal values is revealed by blood tests, an immune response is usually in course. After proliferation, lymphocytes differentiate in two populations: effector cells, immediately active to eliminate the antigen, and memory cells [E], which do not participate to the immune response, but may become active when the same antigen invades the organism a second time.
During the immune response, all leucocytes are activated. Cytotoxic T cells are activated after the interaction with any cell of our body which exposes a class I MHC molecule in association with an antigen. The interaction between T-helper cells and APCs determines an activation both of T-helper cells and of APCs (macrophages and B lymphocytes). Moreover, active T-helper cells activate in turn other B lymphocytes and macrophages in two ways: by contact or by releasing substances (cytokines)[E], [F],[I] that enhance their defensive activities. Other immune cells may be attracted by chemiotaxis in the site of infection thanks to the secretion of specific substances (cytokines): it is possible to localize infected tissue by following growing concentrations of cytokines.

Effector phase
The functions of all cells involved in the effector phase are interconnected to enhance the immune response. When cytotoxic T cells localize infected cells, they directly eliminate them by lysis: they release proteins named perforins, which are introduced in the target cell’s membrane, they alter its osmotic equilibrium and lead it to death. Then, cytotoxic T cells proliferate and differentiate into memory cells and cytotoxic T cells, immediately active against other cells possibly infected by the same agent.
B lymphocytes, activated by direct contact with T-helper cells, proliferate and differentiate into memory cells and plasma cells, capable of secreting antibodies. Antibodies cover the surface of bacterial cells, parasites and foreign molecules rendering them more visible to macrophages and granulocytes, which cause local inflammation (infiammation/infiammazione/inflamación)[E],[F1], [F2]. Granulocytes secrete lytic substances capable of destroying the invaders membrane and macrophages phagocytic cells the fragments formed.

Suppressor phase
During the defensive response, self-cells can also be damaged, for example, by toxic substances secreted by granulocytes. It is therefore essential that, when the antigen activating the immune system has been completely removed, the immune response terminates, in order not to further damage self-tissues.
There are various mechanisms that serve to suppress the immune response, some of which are still in course of study. For example, through a negative feedback mechanism, antigen-activated lymphocytes and macrophages secrete a cytokine, TGF-b (Transforming Growth Factor)[I], capable of inhibiting the proliferation of T lymphocytes, which switches off the inflammatory response, preventing the activation of macrophages and the maturation of cytotoxic T cells. This cytokine, which is still in course of study, is perhaps produced by a specific subgroup of T lymphocytes, named T-suppressor. When the immune response has terminated, memory cells “recall the encounter” with the antigen; if this specific antigen penetrates in the organism a second time, memory cells differentiate immediately into effector cells and the response is much faster and effective [E]. Vaccination occurs exactly by this mechanism: it triggers a first immune response, which is harmless but allows the formation of memory cells.

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