The doctrine of immunity

1. The doctrine of immunity

2. The name antigens (Gk. anti against, genos genus) is given to organic substances of a colloid structure (proteins and different protein complexes in combination with lipids or polysaccharides) which upon injection into the body are capable of causing the production of antibodies and reacting specifically with them. Antigens, consequently, are characterized by the following main properties: (1) the ability to cause the production of antibodies (antigenicity), and (2) the ability to enter into an interaction with the corresponding antibodies (antigenic specificity). The features of molecules that determine antigenicity and immuno- genicity are as follows. A. Foreignness:In general, molecules recognized as "self” are not immunogenic; ie, we are tolerant to those self-molecules. To be immunogenic, molecules must be recognized as "nonself," ie, foreign. B. Molecular Size:The most potent immunogens are proteins with high molecular weights, ie, above 100,000. Generally, molecules with molecujar weight below 10,000 are weakly immunogenic, and very small ones, eg, an amino acid, are nonimmunogenic. Certain small molecules, eg, haptens, become immunogenic only when linked to a carrier protein.

3. C. Chemical-Structural Complexity:A certain amount of chemical complexity is required; eg, amino acid homopolymers are less immunogftnic fhan heteropolymers containing two or three different amino acids. D. Antigenic Determinants (Epitopes):Epitopcs are - small chemical groups on the antigen molecule that can elicit and react with antibody. An antigen can have one or more determinants. Most antigens have many determinants; ie, they are multivalent. In general, i determinant is roughly 5 amino acids or sugars in size. The overall three-dimensional structure is the main criterion of antigenic specificity. The determinant group may be isolated in a relatively pure form, which makes it possible to improve the efficacy of vaccinal preparations significantly. Antigenic substances must have also certain properties: a colloid structure, and solubility in the body fluids. Antigenic properties are pertinent to toxins of a plant origin (ricin, robin, abrin, cortin, etc.), toxins of an animal origin (toxins of snakes, spiders, scorpions, phalangia, karakurts, bees), enzymes, native foreign proteins, various cellular elements of tissues and organs, bacteria and their toxins, rickettsiae and viruses.

7. Haptenis a molecule that is not immunogenic by itself but can react with specific antibody. Haptens are usually small molecules, but some high-molecular-weight nucleic acids, lipids, complex carbohydrates and other substances are haptens as well. Many drugs, eg, penicillins, are haptens, and the catechol in the plant oil that causes poison oak and poison ivy is a hapten. The addition of proteins to haptens even in a small amount gives them the properties of complete antigens. In this case the protein carries out the function of a conductor.

8. It is well known that the properties of chemical, structu- ral and functional specificity are inherent in all natural proteins. Proteins of different species of animals, plants, bacteria, rickettsiae and viru- ses can be differentiated by immunological reactions. The antigenic function of bacteria, rickettsiae and viruses is cha- racterized not only by species, but also by type specificity. Antigenic properties of bacte- ria, toxins, rickettsiae and viru- ses, used in the practice of reproducing artificial immu- nity against infectious disea- ses, are of most practical importance.

9. When the antigenic structures of the host are similar to those of the causative agent, the macroorganism is incapable of producing immunity, as the result of which the disease follows a graver course. It is possible that in individual cases the carrier state and inefficacy of vaccination are due to the common character of the microbial antigens and the antigens of the person's cells. It has been established that human erythrocytes have antigens in common with staphylococci, streptococci, the organisms of plague, E. coli. Salmonella paratyphi, Shigella organisms, smallpox and influenza viruses, and other causative agents of infectious diseases. Such a condition is called antigenic mimicry. Isoantigens. Isoantigens are those substances which have antigenic properties and are contained in some individuals of a given species. They have been found in the erythrocytes of animals and man. At first it was established that in human erythrocytes there are two antigens (A and B), and in the sera — beta- and alpha-antibodies. Only heterogenic antigens and antibodies (agglutinins) can be found in human blood. On the basis of antigenic structure the erythrocytes of all people can be subdivided into 4 groups.

10. Isoantigens of leukocytes, blood platelets, lymphocytes, granulocytes, blood sera, liver, and kidneys and inter-organ (cell nuclei, mitochondria, ribosomes, etc.) and pathological (cancerous, bum, radiation) isoantigens have been revealed. These data are taken into account during blood transfusion. Autoantigens are substances capable of immunizing the body from which they are obtained. Thus, they become modified and are capable of bearing an antigenic function. These substances include the eye lens, spermatozoids, homogenates of the seminal gland, skin, emulsions of kidneys, liver, lungs and other tissues. Under ordinary conditions they do not come in contact with the immunizing systems of the body, therefore antibodies are not produced against such cells and tissues. However, if these tissues are injured, then autoantigens may be absorbed, and may cause the production of antibodies which have a toxic effect on the corresponding cells. The origination of autoantigens is possible under the influence of cooling, radiation, drugs (amidopyrine, sulphonamides, preparations of gold, etc.), virus infections "(virus pneumonias and mononucleosis), bacterial proteins and toxins of streptococci, staphylococci, tubercle bacilli, paraproteins, aseptic autolysis of brain tissue, and other factors.

11. Major Histocompatibility Complex The success of tissue and organ transplants depends on the donor's and recipient's human leukocyte antigens (HLA) encoded by the HLA genes. These proteins are alloantigens; ic, they differ among members of the same species, If the HLA proteins on the donor's cells differ from those on the recipient's cells, an immune response occurs in the recipient. The genes for the HLA proteins are clustered in the major histocompatibility complex (MHC), located on the short arm of chromosome 6. Three of these genes (HLA-A, HLA-B, and HLA-C) code for the class I MHC proteins. Several HLA-D loci determine the class II MHC proteins, ie, DP, DQ, and DR. There are many alleles of the class I and class II genes. For example, there are at least 47 HLA-A genes, 88 HLA-B genes, 29 HLA-C genes, and more than 300 HLA-D genes, but any individual inherits only a single allele at each locus from each parent and thus can make no more than two class I and tl proteins at each gene locus. Expression of these genes is codominant, ie, the proteins encoded by both the paternal and maternal genes are produced. Each person can make as many as 12 HLA proteins: 3 at class I loci and 3 at class II loci, from both chromosomes.

12. Between the class I and class II gene loci is a third locus, sometimes called class III. This locus contains several immunologically important genes, encoding two cytokines (tumor necrosis factor and lymphotoxin) and-two complement components (C2 and C4). Class I MHC Proteins. These are glycoproteins found on the surface of virtually all nude ated cells. There are approximately 20 different proteins encoded by the allelic genes at the A locus, 40 at the B locus, and 8 at the C locus.

13. Class II MHC Proteins. These are glycoproteins found on the surface of certain cells, including macrophages, B cells, dendritic cells of the spleen, and Langerhans cells of the skin. BIOLOGIC IMPORTANCE OF MHC The ability of T cells to recognize antigen is dependent on association of the antigen with either class 1 or class II proteins. For example, cytotoxic T cells respond to antigen in association with class 1 MHC proteins. Thus, a cytotoxic Tcell that kills a virus-infected cell will not kill a cell in­fected with the same virus if the cell does not also express the appropriate class 1 proteins. MHC genes and proteins are also important in two other medical contexts. One is that many autoimmune diseases occur in people who carry certain MHC genes, and the other is that the success of organ transplants is, in large part, determined by the compatibility of the MHC genes of the donor and recipient

15. ANTIBODIES (IMMUNOGLOBULINS) Antibodies are globulin proteins (immunoglobulins) that react specifically with the antigen that stim­ulated their production. They make up about 20% of the protein in blood plasma.. There are five classes of antibodies: IgG, IgM, IgA, IgD, and IgE. IMMUNOGLOBULIN STRUCTURE Immunoglobulins are glycoproteins made up of light (L) and heavy (H) polypeptide chains. The terms "light" and heavy" refer to molecular weight; light chains have a molecular weight of about 25,000, whereas heavy chains have a molecular weight of 50,000-70,000. The simplest antibody molecule has a Y shape and consists of four polypeptide chains: two H chains and two L chains. The four chains are linked by disulfide bonds. An individual antibody molecule always consists of identical H chains and identical L chains.

16. If an antibody molecule is treated with a proteolytic enzyme such as papain, peptide bonds in the "hinge" region are broken, producing two identical Fab fragments, which carry the antigen-binding sites, and oneFc fragment,which is involved in placenta! transfer, complement fixation, attachment site for various cells, and other biologic activities

17. The Immune system includes 5 classes of Immunoglobulin (Ig). • Each class is secreted at specific stages of the immune process. • Each class can carry out different effector functions 1.    IgM2.    IgG3.    IgA4.    IgE5.    IgD

18. IMMUNOGLOBULIN CLASSES IgG. Each IgG molecule consists of two L chains and two H chains linked by disulfide bonds (molecular formula H2L2). Because it has two identical antigen-binding sites, it is said to be divalent. IgG is the predominant antibody in the secondary-response and constitutes an important defense against bacteria and viruses. IgG is the only antibody to cross the placenta only its Fc portion binds to receptors on the surface of placental cells. It is therefore the most abundant immunoglobulin in newborn. IgG is one of the two immunoglobulins that can activate complement; IgM is the other. IgG is the immunoglobulin that opsonizes.

19. IgM is the main immunoglobulin produced early in the primary response. It is present as a monomer on the surface of virtually all B cells, where it functions as an antigen-binding receptor In serum, it is a pentamer composed of 5 H2L2 units plus one molecule of J (joining) chain. Because the pentamer has 10 antigen-binding sites, it is the most efficient immunoglobulin in agglutination, complement fixation (activation), and other antibody reactions and is important in defense against bacteria and viruses. It can be produced by the fetus in certain infections. It has the highest avidity of the immunoglobulins; its interaction with antigen can involve all 10 of its binding sites.

20. IgA is the main immunoglobulin in secretions such as colostrum, saliva, tears, and respiratory, intestinal, and genital tract secretions. It prevents attachment of bacteria and viruses to mucous membranes. Each secretory IgA molecule consists of two H2L2 units plus one molecule each of J (joining) chain and secretory component. The secretory component is a polypeptide synthesized by epithelial cells that provides for IgA passage to the mucosal surface. It also prelects IgA from being degraded in the intestinal tract. In serum, some IgA exists as monomericH2L2.

22. IgE is medically important for two reasons: (1) it mediates immediate (anaphylactic) hypersensitivity, and (2) it participates in host defenses against certain parasites, eg, helminths (worms). The Fc region of IgE binds to the surface of mast cells and basophils. Bound IgE serves as a receptor for antigen (allergen), and this antigen-antibody complex triggers allergic responses of the immediate (anaphylactic) type through the release of mediators. Although IgE is present in trace amounts in normal serum (approximately 0.004%), persons with allergic reactivity have greatly increased amounts, and IgE may appear in external secretions. IgE does not fix complement and does not cross the placenta.

23. IgD. This immunoglobulin has no known antibody function but may function as an antigen receptor; it is present on the surface of many B lymphocytes. It is present in small amounts in serum.

27. Immunoglobulins

33. Cells of the Immune System White Blood Cells Phagocytes - Neutrophils Macrophages Lymphocytes

35. ORIGIN OF IMMUNE CELLS The capability of responding to immunologic stimuli rests mainly with lymphoid cells. During embryonic development, blood cell precursors originate mainly in the fetal liver and yolk sac; in post­natal life, the stem cells reside in the bone marrow. Stem cells differentiate into cells of the erythroid, myeloid, or lymphoid series. The latter evolve into two main lymphocyte populations: T cells and B cells. The ratio of T cells to B cells is approximately 3:1. T cells T cell precursors differentiate into immunocompetent T cells within the thymus. Stem cells lack antigen receptors and CD3, CD4, and CD8 molecules on their surface, but during passage through the thymus they differentiate into T cells that can express these glycoproteins. The stem cells, which initially express neither CD4 nor CD8 (double-negatives), first differentiate to express both CD4 and CD8 (double-positives) and then proceed to express either CD4 or CD8. A double-positive cell will differentiate into a CD4-positive cell if it contacts a cell bearing class II MHC proteins but will differentiate into a CD8-positive cell if it contacts a cell bearing class I MHC proteins.

37. B CELLS B cells perform two important functions; (1) They differentiate into plasma cells and produce anti­bodies, and (2) they are antigen-presenting cells (APCs). Origin. During embryogencsis, B cell precursors are recognized first in the fetal liver. From there they migrate to the bone marrow, which is their main location during adult life. Unlike T cells, they do not require the thymus for maturation. Pre-B cells lack surface immunoglobulins and light chains but do have μ heavy chains in the cytoplasm. The maturation of B cells has two phases: the antigen-independent phase consists of stem cells, pre-B cells, and B.cells, whereas the antigen-dependent phase consists of the cells that arise subsequent to the interaction of antigen with the B cells, eg, activated B cells and plasma cells. B cells display surface IgM, which serves as a receptor for antigens. This surface IgM is a monomer, in contrast to circulating IgM, which is a pentamer. Surface IgD on some B cells may also be an antigen receptor. Pre-B cells are found in the bone marrow, whereas B cells circulate in the blood stream. B cells constitute about 30% of the recirculating pool of small lymphocytes, and their life span is short, ie. days or weeks. Within lymph nodes, they are located in germinal centers; within the spleen, they are found in the white pulp. They are also found in the gut-associated lymphoid tissue, eg, Peyer's patches.

41. Humoral Immune response

50. HYPERSENSITIVITY (ALLERGY) When an immune response results in exaggerated or inappropriate reactions harmful to the host, the term hypersensitivity,or allergy,is used. The clinical manifestations of these reactions are typical in a given individual and occur on contact with the specific antigen (allergen) to which the individual is hypersensitive. Allergens are subdivided into household and epidermal (the dust of feather quilts and pillows, skin epidermis, dandruff of dogs, cats, and horses, etc.), occupational (library dust, dust of wool and cotton, certain dyes, soaps, varnishes, wood pulp, explosives and synthetic substances, etc.), plant (the pollen of plants during pollination of meadow grasses, garden and potted plants), food (eggs, strawberries, shellfish, citrus fruits, coffee, chocolate, and other foods), drug (codeine, acetylsalicylic acid, sulphanilamides, penicillin and other antibiotics). The activity of allergens is determined by their structure and the position of the determinant groups in their molecules. The allergens are of bacterial and fungal origin, protein-polysaccharide-lipid complexes. Different allergens have antigenic determinants in common (polyvalent character of allergic reactions).