IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

STRUCTURE AND PRINCIPLES OF FUNCTIONING OF THE IMMUNE SYSTEM

Immunoglobulins

IMMUNOGLOBULINS (Antibodies). The products of the HUMORAL Immune Response are specific antibodies, namely immunoglobulins.

In the serum of a healthy human, about 65% of the total protein is albumin, while the rest consists of immunoglobulins (Ig). These are large, complex glycoprotein molecules composed of heavy and light polypeptide chains.

Biological properties of immunoglobulins. An immunoglobulin (antibody) molecule performs two MAIN TYPES OF Functions: antigen binding through specific recognition of an antigen epitope by the antibody paratope, and effector functions. The recognition and binding of antigenic epitopes are Functions of the variable Regions of the immunoglobulin, whereas effector functions are determined by the constant region. Antigen binding induces Conformational Changes in the constant region that affect the EFFECTOR FUNCTIONS OF antibodies, such as Complement activation, interaction with FcRs, expression of alloantigens, and others.

Physical, antigenic, and functional differences among the constant regions define 5 Major Classes of heavy chains—M, G, A, E, and D—and their corresponding 5 classes of immunoglobulins. Antibodies of all 5 classes are present in most higher vertebrate species.

IgM. In the course of evolution, IgM Class antibodies appeared first. They are also the first to be synthesized in response to primary antigenic stimulation, making IgM markers of the primary immune response. Because they possess a pentameric Structure with 10 active sites, they are highly effective in binding and agglutinating microorganisms, and are secreted by B lymphocytes on days 4–5 following antigen stimulation.

IgG - IgG class antibodies appear in the serum following IgM during an immune response. They have The ability to actively bind via their Fc region to C1q and phagocyte receptors. They enter extravascular spaces and cross the Placenta to the fetus. Most species possess several IgG subclasses. IgG are synthesized by mature T lymphocytes As a result of a specific adaptive immune response, appearing in the Blood 14–16 days after antigenic stimulation and peaking on days 21–24.

IgA - the principal antibodies found in secretions, including the Lungs, intestines, and urine. They feature an additional structure known as the secretory component, which protects the antibody molecule from degradation. The primary function of IgA is to prevent the penetration of Antigens from external surfaces into Tissues.

IgE are capable of binding to mast Cells via their Fc fragment and stimulating their degranulation.

IgD exist and function On the surface of B cells, performing regulatory roles. They appear to act as antigen-binding receptors for B lymphocytes.

Nonspecific (innate) Immunity. When the body needs protection, such as upon the invasion of an infectious pathogen, the factors of innate (natural) immunity come into play first.

Innate nonspecific (natural) immunity consists primarily of mechanical barriers and physiological factors that prevent infectious agents from entering the body.

Natural barriers are factors of the body's natural resistance that obstruct The entry of disease-causing pathogens. The main natural barriers in The Human Body include:

1. Skin and mucous membranes (including the exosecretions they produce).

2. Histohematic (blood-Brain, placental) and histolymphatic barriers, including the drainage function of Lymph Nodes. Their containment role involves preventing the hematogenous spread of pathogens into tissues during bacteremia in Sepsis; and protecting "immunologically privileged" Organs—such as the brain, Thyroid Gland, Testes, eyes, and the placenta-fetus complex—from immune system aggression.

3. Cellular barrier, provided by Cell membranes.

4. Nuclear barrier, which protects the Genetic information of cells.

Chemical factors that suppress the proliferation of pathogenic flora:

1. Low gastric juice pH.

2. Organic and Fatty acids contained in the secretions of sweat and Sebaceous Glands, which have a detrimental effect on most pathogenic Bacteria and Fungi. Furthermore, glandular secretions inhibit the adhesion of microorganisms to epithelial cells and facilitate their mechanical washout.

3. Nucleic acid depolymerases (DNases, RNases) capable of protecting genetic information by degrading foreign Nucleic Acids, primarily viral ones.

The filtering capacity of the Liver, Spleen, and lymph nodes. Nonspecific resistance factors also include physiological functions such as sneezing, vomiting, and diarrhea, which help eliminate pathogenic agents from the body. Other contributing physiological factors are body Temperature, oxygen concentration, and hormonal balance. For example, increased corticosteroid production suppresses inflammatory processes and reduces the body's resistance to infection. It is well known, for instance, that in autoimmune diseases or organ transplant rejection crises, Treatment with high doses of corticosteroids renders patients hypersensitive to infectious agents.

The next component (link) of innate immunity is the cellular link, which includes mononuclear phagocytes (monocytes, tissue macrophages), granulocytes—neutrophils, eosinophils, basophils (peripheral blood and tissue cells, or mast cells)—as well as killer cells: natural killer (NK) cells, conventional killer (K) cells, and lymphokine-activated killer (LAK) cells.

Peripheral blood monocytes and tissue macrophages originate from a pluripotent stem cell. Upon entering the bloodstream, monocytes migrate into tissues within 2-3 days, where they differentiate into tissue macrophages.

The primary function of tissue macrophages and, at the same time, an exceptionally important mechanism of innate immunity is phagocytosis.

Phagocytosis is The process of engulfing foreign material and damaged cells, destroying them, and eliminating them from the body. The most informative parameters of phagocytosis in an immunogram are the phagocytic number (PhN) and the percentage of phagocytosis (PhP).

Complete phagocytosis involves several stages: 1) activation of the phagocytic cell; 2) chemotaxis, i.e., its movement toward the target that triggered its activation; 3) attachment to this target (adhesion); 4) actual engulfment of the target; 5) Digestion, or Processing, of the ingested material.

Incomplete phagocytosis fails to digest microorganisms within the phagocyte. In this case, the phagocytosed microorganisms survive and can persist for a long time inside secondary Lysosomes.

During complete phagocytosis, following sufficiently tight attachment (adhesion) of the phagocytic cell to the target cell, it engulfs the phagocytic target. This forms a so-called phagosome, or phagocytic vacuole, created by the membrane of the phagocytic cell wrapping around the particle being ingested. This phagosome moves inside the Cytoplasm toward a lysosome, and the membranes of these two vacuoles fuse into a single vacuole, the phagolysosome. Once the phagolysosome is formed, the digestion of the ingested foreign material begins. The contents of lysosomal granules are crucial for destroying the internalized material and killing microorganisms. Lysosomal granules are of two types: a) primary, which contain numerous hydrolytic Enzymes, myeloperoxidase, Lysozyme, and cationic Proteins; b) secondary (specific), which are more abundant than primary ones and contain alkaline phosphatase, lactoferrin, and lysozyme.

The contents of Primary and secondary granules can spill into the interstitial space during the destruction of phagocytic cells. This process is called exocytosis and is characterized by tissue damage and inflammation.

The substance that enhances phagocytosis via opsonization is Fibronectin (CD29), a glycoprotein that binds to microorganisms and for which neutrophils and macrophages have surface receptors, facilitating the binding of opsonized microorganisms.

Killer cells play a major role in the mechanisms of innate immunity. These include natural killer cells (NK cells), killer cells (K cells), and lymphokine-activated killer cells (LAK cells).

A common feature of NK and K cells is their ability to lyse target cells without prior sensitization, distinguishing them from cytotoxic killer T lymphocytes. Morphologically, natural killer cells are large, with azurophilic granulation and low density, which is why they are classified as large granular lymphocytes.

NK cells. The target cells for NK cells include virtually all nucleated cells; however, NK activity is most pronounced against tumor and virus-infected cells. Because the destruction of target cells by NK cells does not require antibodies or the presence of complement, this type of lysis is termed spontaneous cell-mediated cytotoxicity.

The Role of NK cells in the body is to protect against tumor development and infectious diseases, which essentially constitutes the function of immune surveillance.

Killer K cells carry receptors for the Fc fragment of IgG on their surface and are capable of antibody-dependent cell-mediated cytotoxicity. K cells are involved in the Pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, Glomerulonephritis, and chronic hepatitis. K cells from patients with chronic hepatitis have the ability to destroy isolated hepatocytes. An important role of K cells has been established in salmonellosis, dysentery, oncological diseases, and graft rejection reactions. These findings formed the basis for defining a distinct type of immunological reactions mediated by antibodies and K cells.

The nonspecific defense system operates before the first barrier (nonspecific secretory immunoglobulins, lysozyme) and between the First and Second barriers (complement system, lysozyme, eosinophilic, K- and NK-cytotoxicity, phagocytosis).