The immune system has the purpose of defending the body from external invaders (viruses, bacteria, fungi and parasites), which can penetrate inside it through inhaled air, ingested food, sexual relations, wounds, etc.
The immune system has three main functions:
- protects the body from pathogens (external invaders that cause illness)
- removes damaged or dead cells and tissues and aged red blood cells
- recognizes and removes abnormal cells, such as cancer (neoplastic)
As a whole, the immune system represents a complex integrated network consisting of three essential components that contribute to immunity:
- the organs
- the cells
- chemical mediators
- organs located in different parts of the body (spleen, thymus, lymph nodes, tonsils, appendix) and lymphatic tissues. They are distinguished:
- Primary lymphatic organs (the bone marrow and, in the case of T lymphocytes, the thymus) constitute the site in which the leukocytes (white blood cells) develop and mature.
- secondary lymphatic organs capture the antigen and represent the site in which the lymphocytes can meet and interact with it; in fact they show a reticular architecture that traps foreign material present in the blood (spleen), in the lymph (lymph nodes), in the air (tonsils and adenoids) and in food and water (vermiform appendix and Peyer plaques in the intestine).
Deepening: lymph nodes play a very important role in the development of the immune response, since they are able to trap and destroy bacteria and malignant tumor cells transported by the lymphatic vessels along which they are distributed.
- isolated cells present in blood and tissues : the main ones are called white blood cells or leukocytes, of which we can recognize several subpopulations (eosinophils, basophils / mast cells, neutrophils, monocytes / macrophages, lymphocytes / plasma cells and dendritic cells).
Lymphocytes They mediate acquired immunity, fight specific viral agents and tumor cells (cytotoxic T lymphocytes) and coordinate the activity of the entire immune system (T helper lymphocytes) Monocytes They mature becoming macrophages with phagocytic activity and stimulation towards T lymphocytes Neutrophils They absorb bacteria and release cytokines basophils They release histamine, heparin (an anticoagulant), cytokines and other chemicals involved in the allergic and immune response mast cells Basophilic white blood cells involved in allergic response, asthma and resistance to parasites Eosinophils They fight parasites and participate in allergic reactions Dendritic cells White blood cells that activate the immune system by capturing the antigens and exposing them to the action of the "killer" cells (the T lymphocytes). Dendritic cells concentrate at the level of tissues that act as a barrier to the external environment, where they play the role of real "sentinels". After coming into contact with portions of foreign agents and having them exposed on their surface, they migrate to the level of the lymph nodes where the encounter with the T lymphocytes takes place. - chemical substances that coordinate and execute immune responses : through these molecules, the cells of the immune system are able to interact by exchanging signals that mutually regulate their activity level; this interaction is allowed by specific recognition receptors and by the secretion of substances, generally known as cytokines, which act as regulatory signals.
The very important protective activity of the immune system is exercised through a triple defensive line that guarantees immunity, or the ability to defend itself from the aggressions of viruses, bacteria and other pathogenic entities, to counteract damage or disease .
- Mechanical and Chemical Barriers
- Innate or unspecified immunity
- Immunity Acquired or Specific
Mechanical and Chemical Barriers
The body's first defense mechanism is represented by mechanical-chemical barriers, which have the purpose of preventing the penetration of pathogens into the body; let's see some examples in detail.
| Intact skin | The keratin present in the most superficial portion of the epidermis (stratum corneum) is neither digestible nor beyond the reach of most microorganisms. |
| Sweat | The acid pH of sweat, conferred by the presence of lactic acid, associated with a small amount of antibodies, has an effective antimicrobial action. |
| Lysozyme | Enzyme present in tears, nasal secretions and saliva, capable of destroying the cell membrane of bacteria. |
| Sebum | The oil produced by the sebaceous glands of the skin exerts a protective action on the skin itself, increasing its impermeability and exerting a slight antibacterial action (enhanced by the acid pH of sweat). |
| Mucus | Viscous, whitish substance, secreted from the mucous membranes of the digestive system, from the respiratory, urinary and genital ones. It protects us from microorganisms by incorporating them and masking the cellular receptors with which they interact to exercise their pathogenic activity. |
| Ciliated epithelium | It is able to fix and hold foreign bodies, filtering the air. Moreover, it facilitates the expulsion of the phlegm and the microorganisms incorporated in it. Cold viruses exploit the inhibiting action of the cold on the motility of these lashes, to infect the upper respiratory tract. |
| acid pH of the stomach | It has a disinfectant function, since it destroys many microorganisms introduced with food. |
| Commensal intestinal microorganisms: | They prevent the proliferation of pathogenic bacterial strains by subtracting their nourishment, occupying the possible sites of adhesion to the intestinal walls and producing active antibiotic substances that inhibit their replication. |
| spermine | Prostatic secretions have a bactericidal action. |
| Vaginal commensal microorganisms | Under normal conditions, a saprophytic bacterial flora is present in the vagina which, together with the slightly acidic pH, prevents the excessive growth of pathogenic germs. |
| Body temperature | The normal temperature inhibits the growth of some pathogens, which is even more hindered in the presence of fever, which also favors the intervention of immune cells. |
The immune response
If the first defensive barriers fail and the pathogen enters the body the internal immune response is activated. Two types of internal immune responses have been identified:
- innate (or non-specific ) immune response : general defense mechanism, present from birth, which acts quickly (minutes or hours) and indiscriminately against any external agent;
- acquired (or specific or adoptive) immune response : it develops slowly after the first encounter with a specific pathogen (over a few days), but retains a certain memory to act more quickly following further future exposures.
| INNATE IMMUNITY | SPECIFIC IMMUNITY |
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| Cells of innate immunity | Specific immunity cells |
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It should be pointed out immediately that both types of immune response are closely interconnected and coordinated; the innate response, for example, is reinforced by the acquired antigen-specific response, which increases its effectiveness. Overall, the resulting immune response proceeds according to the following basic steps:
- ANTIGEN RECOGNITION PHASE: identification and identification of the foreign substance
- ACTIVATION PHASE: communication of the danger to other immune cells; recruitment of other actors of the immune system and coordination of the overall immune activity
- EFFECTIVE PHASE: attack on the invader with destruction or suppression of the pathogen.
Innate immunity (either natural or non-specific)
As the name itself suggests, this mechanism is active towards all microorganisms (for example, it recognizes the lipopolysaccharide present in the Gram negative bacterial membrane) and exploits mechanisms present since birth.
The concept of antigen : the very functionality of the immune system implies the ability to distinguish harmless cells from dangerous ones, saving the former and attacking the latter. The distinction between the self (or self) and the non-self (or non-self), between the harmless and the dangerous, is permitted by the recognition of particular surface macromolecules, called antigens, which have a unique and well-defined structure. For example, as we have seen, the innate immune system is able to recognize the lipopolysaccharidic structure of the outer wall of bacteria.
Let's look at some important definitions.
- Antigens are substances recognized as foreign (not self) and therefore able to induce an immune response and to interact with the immune system.
- The epitope is the specific portion of an antigen, recognized by the antibody.
- The hapten is a small antigen capable of inducing an immune response only when conjugated to a carrier.
- The allergen is a foreign element in the body which is non-pathogenic in itself, but still capable of causing allergic disease in some individuals as a result of the induction of an immune response; examples are dust mites, pollens and molds.
- Autoantibodies are abnormal antibodies directed against the self, or against one or more of the body's own substances; they are a fundamental element of autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus.
Present since birth and therefore called innate, non-specific immunity has NO memory of any kind with respect to previous encounters with pathogens. Furthermore, it does NOT strengthen following new and further contact with the same pathogen.
As soon as the microorganisms manage to go beyond the mechanical-chemical barriers, the non-specific immunity activates QUICKLY and helps to neutralize them by blocking many infections and preventing their evolution into disease. This ability is related to the presence:
- on one side of particular cells, such as neutrophil granulocytes and monocytes;
- on the other hand, some particular substances they produce that recall other cells of the immune system.
1) CELL FACTORS
| THE CELLS OF INNATE IMMUNITY |
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- Phagocytes : recognize the invaders through specific surface receptors, incorporate them and destroy them by digesting them in lysosomes (phagocytosis); moreover, they recall other cells of the immune system by secreting cytokines.
The main phagocytes are tissue macrophages and neutrophils.
- Macrophages : with strong phagocytic activity, they derive from monocytes produced in the bone marrow and circulating in the blood. They are present in all tissues and particularly concentrated in those most exposed to possible infections, such as pulmonary alveoli. Neutrophils, on the other hand, circulate in the blood and only penetrate infected tissues.
In addition to phagocytic activity, in response to the presence of bacteria, macrophages secrete soluble proteins, called cytokines, chemical mediators that recruit other cells of the immune system:
- Chemotaxins: they attract other FAGOCYTES, some stimulate the proliferation of B and T lymphocytes, others produce drowsiness
- Prostaglandins: they produce an increase in body temperature to an intolerable level for pathogens and that stimulate the defenses: FEBRUARY.
- Neutrophil granulocytes or leukocytes (polymorphic) nucleated (PMN): they are blood cells able to exit the vessels to migrate into the tissues where the infection has occurred and engulf, destroying them, microorganisms, debris and cancer cells. They are able to act even in anaerobic conditions. They die at the site of infection forming pus.
- Macrophages : with strong phagocytic activity, they derive from monocytes produced in the bone marrow and circulating in the blood. They are present in all tissues and particularly concentrated in those most exposed to possible infections, such as pulmonary alveoli. Neutrophils, on the other hand, circulate in the blood and only penetrate infected tissues.
- NK - Synonyms Lymphocytes: natural Killer (NK) cells : thus the T Lymphocytes are defined which, once activated, emit substances capable of neutralizing virus-infected and tumor-infected cells. Stimulated by some cytokines, natural killer lymphocytes cause the virus-infected or abnormal cells to "commit suicide" according to a mechanism known as apoptosis.
NK lymphocytes also have the ability to secrete various antiviral cytokines, including interferons.
Unlike the other types of lymphocytes (B and T), characteristic of the acquired immune response, the NK lymphocytes do not specifically recognize the antigen (they do not have specific receptors) and for this reason they are part of innate immunity.
- Dendritic cells : unlike macrophages and neutrophils, they are not able to phagocytise the antigen, but they capture it and expose it on its surface following the interaction with it (for this reason they belong to the group of APC cells, presenting the antigen). In this way the externalized antigen is recognized as "killer" cells, the cytotoxic T lymphocytes that give away the specific immune response. Not surprisingly, dendritic cells concentrate at the level of those tissues that act as a barrier to the external environment, such as the skin and the internal lining of the nose, lungs, stomach and intestine.
NOTE: after having covered the role of "sentinels" (intercepting the antigens and exposing them on their surface), the dendritic cells migrate to the lymph nodes where the T lymphocytes meet.
PLEASE NOTE:
- Innate immunity cells express more receptors on their surface, each of which recognizes more than one well-defined microbial structure; hence their non-specific multiple recognition capabilities derive.
2) HUMOR FACTORS
- Complement system : plasma proteins produced by the liver, normally present in an inactive form; they are similar to messengers that synchronize communications between the various components of the immune system. The cytokines circulate in the blood and are sequentially activated, with a cascade mechanism (the activation of one triggers that of the others), in the presence of appropriate stimuli.
When activated, cytokines trigger a series of enzyme chain reactions that make certain components of the immune system acquire particular characteristics. For example, they attract phagocytes and B and T lymphocytes to the site of infection via a mechanism called chemotaxis. The complement system also has an intrinsic ability to damage the membranes of pathogens causing pores on them that lead to lysis. Finally, the complement covers the bacterial cells "labeling" them (opsonization) as pathogens, facilitating the action of phagocytes (macrophages and neutrophils) which recognize and destroy them.
Opsonins are macromolecules that, if they cover a microorganism, greatly increase the efficiency of phagocytosis as they are recognized by receptors expressed on the membrane of phagocytes. In addition to the opsonins deriving from the activation of the complement (the best known is the C3b), one of the most powerful opsonization systems is represented by the specific antibodies that cover the microorganism and which are recognized by the Fc receptor of the phagocytes. Antibodies (or immunoglobulins) represent the humoral defense mechanism of acquired immunity.
NOTE: complement activation is a common mechanism for both innate and acquired immunity. Indeed, there are three distinct complement activation pathways: 1) the classical pathway, mediated by antibodies (specific immunity); 2) the alternative way, activated directly by some proteins of microbial cell membranes (innate immunity); 3) the lectin pathway (uses mannose as a site of attachment to pathogen membranes).
- Interferon system (IFN) : cytokines produced by NK lymphocytes and other cell types, so called because of their ability to interfere with viral reproduction. Interferons facilitate the intervention of cells that participate in immune defense and inflammatory reactions.
There are various types of interferon (IFN-α IFN-β IFN-γ), produced by some T lymphocytes after the recognition of an antigen. Interferons are active against viruses, but do not directly attack them, but stimulate other cells to resist them; in particular:
- act on cells not yet infected by inducing a state of resistance to viral attack (interferon alpha and interferon beta);
- help activate Natural killer (NK) cells;
- stimulate macrophages to kill cancer cells or virus-infected cells (interferon gamma);
- inhibit the growth of some cancer cells.
- Interleukins : they act as "short range" chemical messengers, especially acting between adjacent cells:
- Tumor necrosis factors : secreted by macrophages and T lymphocytes in response to the action of interleukins IL-1 and IL-6; they allow you to raise your body temperature, dilate blood vessels and increase the catabolic rate.
Inflammation is a characteristic reaction of innate immunity, very important to fight infection in a damaged tissue:
- attracts immune substances and cells to the site of infection;
- produces a physical barrier that delays the spread of infection;
- at resolved infection, promotes repair processes of damaged tissue.
The inflammatory response is triggered by the so-called degranulation of mast cells, cells present in the connective tissue that release histamine and other chemical substances, which increase blood flow and capillary permeability and stimulate the intervention of white blood cells. The typical symptoms of inflammation are redness, pain, heat and swelling of the inflamed area.
NOTE: in addition to infections, the inflammatory response can also be triggered by stings, burns, injuries and other stimuli that damage the tissues.
The main cellular actors of the immune system involved in inflammation are neutrophils and macrophages.
Specific or acquired or adaptive immunity
The third defensive line is represented by specific immunity. Unlike the previous one, it is not present at birth, but is acquired over time. It is also specific for a specific microorganism, in particular towards some very specific molecules (antigens) of the pathogen.
The acquired immunity is strengthened following further contacts with the same pathogen (appearance of memory of the recognition carried out).
Acquired immunity intervenes only when the other lines of defense have failed to effectively counteract the pathogen. It overlaps innate immunity by enhancing the immune response: the inflammatory cytokines recall lymphocytes at the site of the immune reaction and the latter then release their cytokines by feeding and enhancing the specific inflammatory response.
Two types of acquired immune responses are distinguished:
- humoral immunity (or mediated by antibodies): it is mediated by B lymphocytes that transform into plasma cells that synthesize and secrete antibodies
- cell mediated (or cell-mediated ): mainly mediated by T lymphocytes that directly attack the invader antigen (intervention of helper and cyto-toxic T cells)
The acquired humoral immunity can also be divided into active (the body itself produces antibodies in response to exposure to pathogens) and passive (antibodies are acquired from another organism, for example by the mother during fetal life or by vaccination).
1) HUMOR FACTORS :
- Immunoglobulins (antibodies): some microorganisms have developed stratagems to alter their surface markers, becoming "invisible" to the eyes of the phagocytes and losing the ability to activate the complement. To combat these pathogens, the immune system produces specific antibodies against them, labeling them as dangerous to the eyes of phagocytes (opsonization). Antibodies coat the antigens facilitating their recognition and phagocytosis by immune clellules. The function of antibodies is therefore to transform unrecognizable particles into "food" for phagocytes.
The antibodies are part of the globulins (globular plasma proteins) present in the blood and are called immunoglobulins. They are cataloged in 5 classes, namely: IgA, IgD, IgE, IgG and IgM. Antibodies can also bind and inactivate certain bacterial toxins and contribute to fueling inflammation by activating complement and mast cells.
Immunogenic antigens are molecules capable of stimulating the synthesis of antibodies; in particular, all these molecules have a small part capable of binding to their specific antibody. This portion, called epitope, generally differs from antigen to antigen. It follows that each antibody recognizes and is sensitive only to one or more specific epitopes and not to the entire antigen.
2) CELL FACTORS
The cells mainly involved in the establishment of acquired immunity are the cells that present the antigen (the so-called APC, antigen-presenting cells) and the lymphocytes.
LYMPHOCYTES
- B and T lymphocytes: B lymphocytes originate and mature in the bone marrow, while T lymphocytes originate in the bone marrow, but migrate and mature in the Thymus. As we have seen, these organs are called primary lymphoid organs and, in addition to production, they are also responsible for the maturation of these lymphocytes.
During its development, each lymphocyte synthesizes a type of membrane receptor that can only bind to a particular antigen. The link between antigen and receptor therefore gives rise to the activation of the lymphocyte, which at that point begins to divide repeatedly; in this way lymphocytes are formed with receptors identical to the one that had recognized the antigen: these lymphocytes are called CLONES and the process by which they are formed is called CLONAL SELECTION.
PLEASE NOTE: following the activation of the lymphocytes, both EFFECTIVE CELLS that actively participate in the immune response and CELLS OF THE MEMORY are formed, which have the task of recognizing the antigen in the event of any subsequent invasion.
- EFFECTIVE CELLS: ready to face the enemy and destroy it
- MEMORY CELLS: they do not attack the foreign agent but enter a state of quiescence ready to intervene in a subsequent attack OF THE SAME IDENTICAL ANTIGEN
B lymphocytes express immunogobulins (antibodies, AB), while T lymphocytes express receptors; both act as membrane receptors.
- LYMPHOCYTES B : they directly recognize the antigen through surface antibodies; once activated, they partly undergo proliferation and maturation in specialized cells that secrete antibodies (called plasma cells, real "antibody factories") and partly in memory cells (which have the same function as the previous ones but are more long-lived). and for this reason they continue to circulate for much longer periods than plasma cells, sometimes even for the whole life of the organism). As we have seen, memory cells guarantee rapid production of antibodies if a certain pathogen occurs again for the second time.
Each B lymphocyte expresses on its membrane something like 150, 000 identical (specific) receptors for the same antigen. The antigen-antibody bond is extremely specific: there is an antibody for every possible antigen. A mature plasma cell can produce up to 30, 000 antibody molecules per second.
PLEASE NOTE: activation of B lymphocytes requires the stimulation of T helper lymphocytes. B lymphocytes recognize the antigen in its native form, while T lymphocytes recognize the antigen processed by accessory cells (APC)
- LYMPHOCYTES : they interact directly with the cells of our body that are infected or altered. They contribute to the elimination of the antigen:
- directly, cytotoxic activity against virus-infected cells;
- indirectly by activating B lymphocytes or macrophages.
- T helper lymphocytes govern the regulation of all immune responses by the release of cytokines that help B lymphocytes and cytotoxic T lymphocytes. They therefore have a COORDINATION FUNCTION:
- present CD4 membrane receptors;
- recognize antigens presented by the MHC II;
- induce differentiation of B lymphocytes into plasma cells (the latter producing antibodies);
- regulate the activity of cytotoxic T lymphocytes;
- activate macrophages;
- secrete cytokines (interleukins);
- there are several subtypes of helper T lymphocytes; for example, Th1 is important in the control of intracellular pathogenic bacteria by macrophage activation.
- Cytotoxic T cells (T C ) (CD8 +) preside over the cell-mediated immune response and exert a toxic action against their specific target cells (infected cells and tumor cells). They therefore have the function of DEMOLITION OF EXTRANEE CELLS:
- present the CD8 membrane molecule;
- recognize the antigens presented by the MHC I;
- selectively affect virus-infected and carcinogenic cells;
- regulated by the T Helper.
When an infection has been defeated, the activity of the B and T lymphocytes is blocked thanks to the action of other T lymphocytes called suppressors which, in fact, suppress the immune response: however, this process is not entirely clear and is currently the source of several studies
PLEASE NOTE: B lymphocytes recognize soluble phase antigens, while T lymphocytes cannot bind to antigens unless they exhibit class I MHC protein sequences on their cell membranes. T cells therefore recognize antigens presented by APCs "(antigen presenting cells).
The tools of the acquired immune system to recognize the specific antigens are therefore three:
- Immunoglobulins or Antibodies
- T cell receptors
- Major histocompatibility complex and APH MHC proteins (antigen presenting cells).
Antigen-presenting cells (APC)
- INTRODUCTION: phagocytes (macrophages and neutrophils) have a modest intrinsic ability to bind directly to bacteria and other microorganisms. However their phagocytic activity becomes particularly pronounced if the bacterium has activated the complement (thanks to the C3b opsonins). The microorganisms that do NOT activate complement are opsonized (labeled) by the antibodies that can bind to the Fc receptor of the phagocyte. The antibodies can also activate the complement and, if both the antibodies and the complement (C3b) opsonize the pathogen, the bond becomes even more solid (remember that opsonization, regardless of its origin, enormously increases the efficiency of phagocytosis).
- From the phagocytosis of foreign molecules originate fragments of antigen which, within the phagocyte, are combined with particular proteins belonging to the so-called "major complex of incompatibility" ( MHC, major histocompatibility complex, which in humans is called HLA, human leukocyte antigen ). The major histocompatibility complex - originally discovered because it is involved in engraftment and rejection of organ transplants - allows us to recognize self from non-self. These are ubiquitous proteins that have the ability to bind to molecules inside the cell and expose them to the outside of the membrane.
The molecular complexes (fragments of antigen + MHC II molecules) are exposed on the surface of some cells, which are called antigen-presenting cells (APCs). APC cells (dendritic cells, macrophages and B lymphocytes) can be compared to shuttles that present on the cell surface protein fragments derived from the digestion of proteins internalized by phagocytes combined with the major class 2 histocompatibility complex.
At this point it is necessary to specify that there are two types of MHC molecules:
- the class I MHC molecules are found on the surface of almost all the nucleated cells and make sure that the "abnormal" body cells are recognized by the CD8 receptors of cytotoxic T lymphocytes; it is therefore possible to "avoid a massacre" that is to prevent the cytotoxic lymphocytes from attacking the healthy cells of the body. For example, natural killer lymphocytes recognize cells with low expression of MHC-I (tumor cells) as non-self, while cytotoxic T lymphocytes attack only cells that present complex viral antigens - MHC-I.
- Class II MHC molecules, instead, are found only on the APC cells of the immune system, mainly on macrophages, B lymphocytes and dendritic cells. Class II MHCs have exogenous peptides (derived from antigen digestion) and are recognized by CD4 helper T lymphocyte receptors.
Peptides exposed on the cell surface thanks to MHCs are examined by the cells of the immune system, which intervene only if they recognize these complexes as "non self".
After exposure of the MHC-antigen complex, the cells migrate through the lymphatic vessels to the lymph nodes, where they activate other protagonists of the immune system; in particular:
- If a cytotoxic T cell encounters a target cell that exposes fragments of antigen on its MHC-I (tumor nucleated or virus-infected cells) it kills it to prevent reproduction;
- If a T helper cell encounters a target cell that exposes exogenous antigen fragments on its MHC-II (phagocytes and dendritic cells) it secretes cytokines by increasing the immune response (for example by activating the macrophage or the B lymphocyte that presented the antigen).
