What is the immune system?
The Immune system is a network of cells that organize themselves to defend our body against external organisms, such as microbes. This defense is achieved by directly eliminating the aggressor by specific cells (white blood cells) by devouring the intruder (phagocytosis), or by producing different defense substances such as enzymes, cytokines, or antimicrobial peptides.
The two types of immune system
There are two types of immune systems: the innate immune system (natural or nonspecific) and the acquired immune system(adaptive or specific). The innate immune system is present in virtually all living beings, even simple unicellular organisms such as bacteria have enzymatic systems that protect against viral infections .
1. Innate immunity
Innate immunity is the first line of defense against infectious and pathogenic agents that surround us. It is put into play immediately and is functional.
It involves different defense modules :
- Of component modules such as skin-mucosal barrier.
- Of induced modules such as phagocytosis and the inflammatory response, which requires the phagocytic cells and cytokines.
The innate immune Response is induced by a hazard signal issued after the specific interaction between the self receptors called PRR (for “Pattern Recognition Receptors” ) and molecules nonself called PAMP (for “Pathogen Associated Molecular Patterns” ) present at the level of microorganisms whether they are pathogenic or not.
PRRs are groups of receptors, whose genes are not polymorphic, they are all the same within a species. These receptors are expressed in different cells: macrophages, dendritic cells (CD), NK cells ( “natural killer” ), polynuclear cells, mast cells and resident cells (fibroblasts, muscle cells, epithelial cells).
I) The constituent modules
The mucocutaneous barrier is in contact with viruses, parasites and bacteria. It prevents their adhesions by mechanical, chemical or biological mechanisms, and has two elements: skin and mucous membranes.
1) The skin
The skin is a keratinized multi-stratified epithelium surrounding the entire external surface of man and is a very effective barrier against intrusions of any type; she plays the role of:
- Mechanical barrier to bacterial, viral and parasitic development, thanks to low permeability and flaking of the skin.
- Chemical barrier with antimicrobial proteins and peptides. Peptides have three modes of action, in fact they can lead to: a mechanical rupture of bacterial membranes, enzymatic destructuring of bacterial membranes and sequestration of nutrients.
- Biological barriers presenting a commensal flora which is a set of bacteria located on the skin and the mucous membranes and playing an important role of barrier.
2) The mucous membranes
The mucous membranes have a uni- or multi-stratified epithelium not keratinized and are therefore more sensitive to different infectious attacks. They therefore had to develop an additional defense: mucus.
The mucus contains sugars, which is called lures , since they are soluble bacterial receptors. It also acts as a mechanical barrier in the sense that it forms a viscous substance that traps foreign elements and is then eliminated by sputum. Finally the mucus contains antimicrobial substances just like the skin.
II) The induced modules
Once the infectious agent in the body, the induced modules take over. Indeed, once recognized (PRR-PAMP interaction), the infectious agent will be phagocytized by a phagocytic cell which will be at the origin of the formation of the danger signal , and which will thus activate the inflammatory reaction at the place where it is come into contact with the pathogen. The activation of the inflammatory reaction will be done through cytokines.
1) Phagocytosis & opsonization
The phagocytes and phagocytic cells are the scavengers of the body, capable of endocytosing bacteria and dead cells; we talk about phagocytosis . Phagocytosis is an induced phenomenon that can be done in two different ways, depending on the resistance of the bacterium considered:
- without opsonization , we then face a direct interaction between the receptor and the antigen. The recognition is made thanks to membrane PRRs: MMR receptors (for “Macrophage Mannose Receptor”), lectin receptors, and scavenger receptors (see PRR course ).
- with opsonization , the interaction this time requires an intermediary molecule that acts as an adapter, we call them opsonins . The opsonins are often associated with the antibodies, but there are also the complement components, the MBP proteins (for “Mannan Binding Protein” ), and the protein CRP (for “C-Reactive Protein” ).
Phagocytosis is achieved in different stages:
Phagocytosis is achieved in different stages:
- The opsonization (mandatory) corresponds to the attachment of opsonins around the bacterium.
- The chemotaxis can attract macrophages to the opsonized bacteria, and thanks to chemokines.
- The adhesion phase corresponds to the specific recognition of opsonins present on the surface of the bacterium by plasma membrane receptors of macrophages. This phase triggers phagocytosis itself.
- The rheological phase corresponds to the formation of cytoplasmic extensions, which are called pseudopodia, and completely envelop the bacterium. There is thus formation of a vacuole in which the bacterium is found; this vacuole is called the phagosome .
- The destruction phase corresponds to the digestion of the bacterium by fusion of the phagosome with lysosomes, thus forming the phago-lysosome. Digestion will be carried out by various mechanisms: acidification, hydrolysis by hydrolytic enzymes (lysozyme, protease), production of toxic derivatives of oxygen (superoxide ions), production of nitrates.
Phagocytes include macrophages, dendritic cells, and polynuclear cells
2) The inflammatory reaction
a) Liberation of cytokines
Cytokines are released following activation of the danger signal induced by PAMP-PRR interactions. This interaction will trigger the inflammatory response, corresponding to the secretion of soluble factors that allow the recruitment of cells to the site of inflammation:
- The pro-inflammatory cytokines : TNF-α, chemokines and interleukins IL-1, IL-6, IL-12 and IL18.
- The vasodilator substances : nitrogen monoxide (NO) and prostanoids.
- The anti-inflammatory cytokines : interleukin-10 and TNF-β, which play a role in regulating the inflammatory reaction, thus allowing it to not become exaggerated and therefore pathological.
b) Consequences of cytokine release
The consequences are of different types:
- Vasodilation , induced by nitric oxide (NO), allowing an increase in vascular permeability.
- Expression of adhesion molecules (selectins and immunoglobulins) on endothelial cells, induced by TNF-α and thus facilitating diapedesis ( see the continuation of the course ).
- Coagulation induced by TNF-α and allowed by the appearance on the endothelium of small molecules that will promote coagulation in the capillaries, thus inhibiting the spread of infectious micro-organisms. This propagation can however be done by the lymphatic circulation. Attention if TNF-α is present in too high concentration there is a risk of septic shock .
- Activation of the acute response phase of the inflammation which itself allows the synthesis of proteins of inflammation; here the pro-inflammatory cytokines will act at the level of organs more distant:
- IL-1 will act at the level of the hypothalamus , inducing the synthesis of prostaglandin at the origin of the fever.
- At the level of the bone marrow there will be induction of the synthesis of growth factors.
- The effect will however be the most important in the liver and will be activated mainly by IL-6 but also by IL-1 and TNF-α . This effect consists of induction of protein synthesis from the acute response phase of inflammation:
- CRP protein ( C-Reactive protein ) is part of soluble PRRs ( see chapter “PRR” ), and plays the role of opsonin by binding to pathogenic microorganisms. It is also used as a marker of acute, measurable inflammation in the blood. Indeed its concentration increases by 1000 times during an inflammation.
- The MBP protein also plays an opsonin role by attaching to mannose residues present on the surface of bacteria, and thus allows the activation of complement (see chapter “PRR” ).
- Synthesis of fibrinogen and complement factors , which is induced by interleukins IL-12 and IL-18 , and which allows modulation of T-cell activation.
- Recruitment of phagocytic cells by chemotaxis using chemokines . In fact, it is the macrophages and the resident cells that will usually first come into contact with the pathogen. There will be recruitment of other immune cells and especially dendritic cells that play a key role in the activation of the adaptive immune response ( see chapter From innate immunity to adaptive immunity ).
c) The diapedesis
The diapedesis corresponds to the passage of the immune cells blood to different target tissues. The polynuclear and monocytes will generally pass to the connective tissues, either constitutively or following an infection. The Lymphocytes in turn will preferentially to the lymphoid organs that do not have a conventional endothelium but so-called high endothelial venules ( HEV ) which have cubic cells whose junctions are relatively loose. It is done in several phases:
- The capture phase corresponds to the approximation of the cell to the endothelium.
- The labile and rolling adhesion phase (or rolling ) is due to linkages between selectins expressed by the immune cells and mucins (highly glycosylated proteins) presented on the surface of the endothelium. These interactions still allow the cell to perform bearings on the surface of the endothelial membrane.
- The strong adhesion phase blocks the rolling phase and is allowed by additional interactions between integrins (LFA-1) present on the surface of phagocytic cells or lymphocytes, and immunoglobulins (I-CAM) present on the surface of endothelium. But the integrins involved in this bond are normally inactive form, and pass in active form only after interaction between chemokines constitutively expressed in the endothelium membrane and their receptors on the surface of the cells wanting to pass through. ‘endothelium.
- The transmigration phase corresponds to the passage of the immune cell through two endothelial cells by local dissociation of the intercellular junctions. In the bone marrow the cells can cross the endothelium by meshes present at the level of the endothelial tissue.
2. Acquired immune system(adaptive or specific)
In order for the body to generate different types of immune responses, attention must be paid to the location of the antigens; since these can be exogenous , if they are in the extracellular space or within the phagocytic vacuoles; or endogenous if they are free in the cytosol.
The recognition of the antigens and the activation of the response occur in the lymph nodes , when the antigens come from the tissues through the lymph, and in the spleen when the antigen is in the blood circulation. The endogenous antigens are only recognized by the cytotoxic LT or CD8 + LT and the exogenous, by the cooperating LT or LT CD4 +. The recognition is direct in the case of B lymphocytes.
The activation of lymphocytes consists of the initiation of the synthesis of specific proteins and for this, two different signals are required. The first signal consists of the presence of the antigen, which ensures that the immune response is specific, while the second signal occurs when some manifestation of the innate immune response is specific, such as, for example, the secretion of cytokines. guarantees that the immune response is effective. Once both responses have been carried out, and the lymphocytes have been activated, they proliferate and differentiate.
Later, when the lymphocytes proliferate, they multiply by mitosis, in a process called clonal expansion, obtaining in this way a monospecific contingent of activated lymphocytes.
Finally, the differentiation process is carried out, where the activated lymphocytes are differentiated to effector cells and memory cells.
The whole process is regulated by cytokines, which direct the response according to the most efficient strategy to eliminate the antigen, and it takes between three and five days, therefore, as this process to mount the adaptive immunity is slow, the innate immunity It is vital to control skin and mucous infections and stimulate adaptive immunity.
In innate immunity the effector response is constituted by the elimination of the pathogen by phagocytosis, complement activation and NK cells. In adaptive immunity, the effector responses are of two fundamental types: humoral and cellular.
The humoral response is in charge of immunoglobulins or antibodies , which are complex multifunctional molecules synthesized by plasma cells that differentiate from activated B lymphocytes.
The antibodies circulate in the blood and other fluids of the body, recognizing specific microbial antigens, recognizing them and also being able to neutralize the infectious capacity of the pathogens, marking them to facilitate their elimination. Also, they are specific in terms of the type of response they induce, some of which can promote phagocytosis and others trigger the secretion of chemical mediators that participate in the inflammatory response and complement activation, for example. Humoral immunity is the main defense mechanism against extracellular microbes and their toxins.
On the other hand, intracellular pathogens, such as viruses and some bacteria, can survive and proliferate within phagocytes and other cells, where circulating antibodies can not reach, so in this case the defense against these pathogens is the responsibility of the cellular response , being able to distinguish the cytotoxic cellular response and the delayed hypersensitivity (DTH) type response. In the first CD8 LT participate and in the second CD4 LT.
The cytotoxic cell response is started when the antigen is synthesized by the affected cell, since the viral DNA has been incorporated into the cell genome and forces the cell to make viral proteins, or the cell has undergone changes in its genome and expresses proteins different from their own. When it has been activated, the T lymphocytes recognize the antigen on the cell surface, approach them, touch them and kill them by releasing perforins and granzymes, which induce apoptosis, that is, the death of the affected cells. In addition, the lymphocyte expresses a protein called fas ligand that binds to the fas protein located in the membrane of the cell that must die. When both molecules are contacted, cell death is induced. This response usually operates during tissue transplants.
What is the immunological memory?
Adaptive immunity together with being specific , manages to distinguish between different but closely related pathogens, so they have memory, since they can remember and respond to repeated exposures to the same microbe. The above is called immunological memory .
This memory is obtained when an adaptive immune response occurs against any antigen. It begins with the primary response, during which effector lymphocytes are generated, either T or B, which directly or indirectly eliminate the pathogen, in which a series of regulatory lymphocytes also participate. After completion of the primary response, memory T and B lymphocytes with specificity for the antigens of that pathogen remain circulating. With a second or later contact with the same antigen, these memory lymphocytes respond more quickly and efficiently, in a process called secondary response. The time it takes for the primary and secondary response to appear, which may be days or weeks, varies depending on the antigen used, the route of admission and the presence or absence of inflammation.vaccination.
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