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.

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.

Hapten is 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.

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.

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.

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.

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.

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.

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 in fected 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

Disease HLA Frequency

of an antigene

at ill

persons

of a presence

at healthy persons

Antigene on which the immune answer

develops

Addison’s disease

DR5 70 20 Adrenal cortex

Behtyer’s disease

B27 89 9 Unknown

Hashimoto’s thyreoiditis

DR3, DR5 51 24 Thyroglobulin

Juvenile diabetes

DR3, DR4 72 24 Insulin receptor

Rheumatoid arthritis

DR7,

DR21 59 21 Colagen, Fc fragment

of IgG

Narcolepsy DR2 100 34 Unknown

Goodpasture’s syndrom

DR2 88 29 Basement membrane of a kidney and lung

 ANTIBODIES (IMMUNOGLOBULINS) Antibodies are globulin proteins (immunoglobulins) that react specifically with the antigen that stim ulated 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.

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 one Fc fragment, which is involved in placenta! transfer, complement fixation, attachment site for various cells, and other biologic activities

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

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.

IMMUNOGLOBULIN CLASSESIMMUNOGLOBULIN CLASSES

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.

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.

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.

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.

 

Immunoglo

bulin Major Functions

IgG Main antibody in the secondary response. Opsonizes bacteria, making them easier to phagocytize. Fixes complement, which enhances bacterial killing. Neutralizes bacterial toxins and viruses. Crosses the placenta.

IgA Secretory IgA prevents attachment of bacteria and viruses to mucous membranes Does not fix complement.

IgM Produced in the primary response to an antigen. Fixes complement. Does not cross the placenta. Antigen receptor on the surface of B cells.

IgD Uncertain. Found on the surface of many B cells as well as in serum.

IgE Mediates immediate hypersensitivity by causing release of mediators from mast cells and basophils upon exposure to antigen (allergen) Defends against worm infections by causing release of enzymes. frorn eosinophils. Does not fix complement. Main host defense against helminth infections.

Immunoglobulins

White Blood Cells Phagocytes - Neutrophils

Macrophages

Lymphocytes

Cells of the Immune SystemCells of the Immune System

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 post natal 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.

B CELLS B cells perform two important functions; (1) They differentiate into plasma cells and produce anti bodies, 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.

Humoral Immune response

HYPERSENSITIVITY (ALLERGYHYPERSENSITIVITY (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).

Peter Gell and Robert Coombs developed a classification system for reactions responsible for hypersensitivities in 1963. Their system correlates clinical symptoms with information about immunologic events that occur during hypersensitivity reaction. The Gell-Coombs clasification system divides hypersensitivity into four types:

Type I (Anaphylaxis) Hypersensitivity Type II (Cytotoxic) Hypersensitivity Type III (Immune Complex) Hypersensitivity Type IV (Cell-Mediated) Hypersensitivity

Allergic reactions are subdivided into two groups: (1) immediate and (2) delayed reactions, although it is difficult to draw a strict distinction between them. Allergic reactions of immediate action are associated with B-lymphocytes and antibodies circulating in the blood, allergic reactions of delayed action with T-lymphocytes.

TYPE I: IMMEDIATE (ANAPHYLACTIC) TYPE I: IMMEDIATE (ANAPHYLACTIC) HYPERSENSITIVITYHYPERSENSITIVITY

 An immediate hypersensitivity reaction occurs when antigen binds to

IgE on the surface of mast cells with the consequent release of several mediators. The process begins when an antigen induces the formation of IgE antibody, which binds firmly by its Fc portion to basophils and mast cells. Reexposure to the same antigen results in cross-linking of the cell-bound IgE and release of pharmacologically active mediators within minutes (immediate reaction). Cyclic nucteotides and calcium play essential roles in release of the mediators.

The clinical manifestations of type I hypersensitivity can appear in various forms, eg, urticaria (also known as hives), eczema, rhinitis and conjunctivitis (also known as hay fever), and asthma.

The most severe form of type 1 hypersensitivity is systemic anaphylaxis, in which severe bronchoconstriction and hypotension (shock) can be life-threatening.

No single mediator accounts for all the manifestations of type I hypersensitivity reactions. Some important mediators and their effects are as follows:

(1) Histamine occurs in granules, of tissue mast cells and basophils in a preformed state. Its release causes vasodilation, increased capillary permeability, and smooth-muscle contraction. Clinically, disorders such as allergic rhinitis (hay fever), urticaria, and angioedema can occur. The bronchospasm so prominent in acute anaphylaxis results, in part, from histamine release. (2) Slow-reacting substance of anaphylaxis (SRS-A) consists of several leukotrienes, which do not exist in a preformed state but are produced during anaphylactic reactions. Leukotrienes are formed from arachidonic acid by the lipoxygenase pathway and cause increased vascular permeability and smooth-muscle contraction. (3) Eosinophil chemotactic factor of anaphylaxis (ECF-A) (4) Serotonin is preformed in mast cells and blowl platelets. When released during anaphylaxis, it causes capillary dilation, increased vascular permeability, and smooth-muscle contraction (5) Prostaglandlns and thromboxanes are related to leukotrienes. Prostaglandins cause dilation and increased permeability of capilaries and bronchoconstriction. Thromboxanes aggregate platelets.

Stages of reaction Stages of reaction and mechanismand mechanism

Prevention therapyPrevention therapy

Allergen penetrates into individual

Avoid meeting allergen

IgE antibody is induced by allergen and binds to mast cells and basophils

Desensitization

When exposed to the al- lergen again, the allergen

cross-links the bound IgE,which induces degra-

nulation

Stabilization of mast cells (chromolyn sodium, theocine, caffeine)

Release of mediators Antagonists of mediators,

Antihistamine drugs

Local manifistations:

rhinitis, asthma, urticaria

Inhibitors of late stage.

Corticosteroides, indometacin

Atopy. Atopic disorders, such as hay fever, asthma, eczema, and urticaria, are immediate-hypersensitivity reactions that exhibit a strong familial predisposition and are associated with elevated IgE levels. Several processes seem likely to play a role in atopy, for example, failure of regulation at the T cell level (eg, increased production of interleukin-4 leads to increased IgE synthesis), enhanced uptake and presentation of environmental antigens, and hyperreactivity of target tissues. It is estimated that up to 40% of people in the United Stales have experienced an atopic disorder at some time in their lives.The symptoms of these atopic disorders are induced by exposure to the specific allergens. These antigens are typically found in the environment (eg, pollens and dust mite feces often found in bedding and carpet) or in foods (eg, shellfish and nuts).

Skin testing can be useed for identify the allergen responsible for allergies. These tests involve inoculating small amounts of suspect allergen into the skin. Sensitivity to the allergen is shown by a rapid inflammatory reaction characterizide by redness, swelling, and itching at the site of inoculation

Desensitization Major manifestations of anaphylaxis occur when large amounts of mediators are suddenly released as a result of a massive dose of antigen abruptly combining with IgE on many mast cells. This is systemic anaphylaxis, which is potentially fatal. Desensitization can prevent sys temic anaphylaxis.

Acute desensitization involves the administration of very small amounts of antigen at 15-minute intervals. Antigen-IgE complexes form on a small scale, and not enough mediator is released to pro duce a major reaction. This permits the administration of a drug or foreign protein to a hypersensi tive person, but hypersensitivity is restored days or weeks later.

Chronic desensitization involves the long-term weekly administration of the antigen to which the person is hypersensitive. This stimulates the production of IgG-blocking antibodies in the serum, which can prevent subsequent antigen from reaching IgE on mast cells, thus preventing a reaction.

TYPE II: CYTOTOXIC HYPERSENSITIVITYTYPE II: CYTOTOXIC HYPERSENSITIVITY

Cytotoxic hypersensitivity occurs when antibody directed al antigens of the cell membrane activates complement. This generates a membrane attack complex, which damages the cell membrane. The antibody (IgG or IgM) attaches to the antigen via its Fab region and acts as a bridge to complement via its Fc region. As a result, there is complement-mediated lysis as in hemolytic anemias, ABO transfusion reactions, or Rh hemolytic disease. In addition to causing lysis, complement activation attracts phagocytes to the site, with consequent release of enzymes that damage cell membranes.

Drugs (eg, penicillins, phena cetin, quinidine) can attach to surface proteins on red blood cells and initiate antibody for- mation. Such autoimmune an- tibodies (IgG) then interact with the red blood cell surface and result is hemolysis. Certain infec tions, eg, Mycoplasma paeumo- niae infection, can induce anti bodies that cross-react with red cell antigens, resulting in hemo- lytic anemia. In rheumatic fever, antibodies against the group A streptococci cross-react with cardiac tissue. Other drugs can attach to platelets and induce autoantibodies that lyse the platelets, producing thrombocy topenia and,

as a consequence, a bleeding tendency. Others (eg, hydralazine) may mo- dify host tissue and induce the production of autoantibodies directed at cell DNA. As a result, disease manifestations resembling those of syste- mic lupus erythematosus occur. In Goodpasture's syndrome, antibody to basement membranes of the kidneys and lungs bind to those membranes and activate complement.

TYPE III: IMMUNE-COMPLEX HYPERSENSITIVITYTYPE III: IMMUNE-COMPLEX HYPERSENSITIVITY

Immune-complex hypersensitivity occurs when antigen-antibody com- plexes induce an inflammatory response in tissues. Normally, immune complexes are promptly removed by the retticuloendothelial system, but occasionally they persist and are deposited in tissues, resulting in several disorders. In persistent microbial or viral infections, immune complexes may be deposited in organs, eg, the kidneys, resulting in damage. In auto- immune disorders, "self antigens may elicit antibodies that bind to organ antigens or deposit in organs as complexes, especially in joints (arthritis), kidneys (nephritis), or blood vessels (vasculitis).

Wherever immune complexes are deposi- ted, they activate the complement system. Polymorphonuclear cells are attracted to the site, and inflam- mation and tissue injury occur.

Two typical type III hypersensitivity reactions are the Arthus reaction and serum sickness.

Arthus Reaction. Arthus reaction is the name given to the inflamma -tion caused by the deposition of immune complexes at a localized site. It is named for Arthus, who first described the inflammatory, response that occurs under the following conditions. If animals are given an antigen repeatedly until they have high levels of IgG antibody and that antigen is then injected subcutaneously or intradermally, intense edema and hemor- rhage develop, reaching a peak in 3-6 hours. Antigen, antibody, and com- plement are deposited in vessel walls; polymorphonuclear cell infiltration inlravascular clumping or platelets then occur. These reactions can lead to vascular occlusion and necrosis. A clinical manifestation of the Arthus reaction is hypersensilivity pneumonitis (allergic alveolitis) associated with the inhalation of thermophilic actinomycetes ("farmer's lung").

Serum Sickness. In contrast to the Arthus reaction, which is localized inflammation, serum sickness is a systemic inflammatory response to the presence of immune complexes deposited in many areas of the body. Af- ter the injection of foreign serum (or, more commonly these days, certain drugs), the antigen is excreted slowly. During this time, antibody produc- tion starts. The simultaneous presence of antigen and antibody leads to the formation of immune complexes, which may circulate or be deposited at various sites. Typical serum sickness results in fever, urticaria, arthral- gia. lymphadenopathy, splenomegaly, and eosinophilia a few days to 2 weeks after injection of the foreign serum or drug.

Immune-Complex Diseases A. Glotnerulonephritis: Acute poststreptococcal glomerulonephritis is a

well-accepted immune-complex disease. B. Rheumatoid Arthritis: Rheumatoid arthritis is a chronic

inflammatory autoimmune disease of the joints seen commonly in young women.

C. Systemic Lupus Erythematosus: is a chronic inflammatory autoimmune disease that affects several organs,yespecially the skin of the face, the joints, and the kidneys.

TYPE IV: DELAYED (CELL-MEDIATED) TYPE IV: DELAYED (CELL-MEDIATED) HYPERSENSITIVITYHYPERSENSITIVITY

Delayed hypersensitivity is a function of T lymphocytes, not antibody. It can be transferred by immunologically committed (sensitized) T cells, not by serum. The response is "delayed"; ie, it starts hours (or days) after contact with the antigen and often lasts for days.

In certain contact hypersensitivities, such as poison oak, the pruritic, vesicular skin rash is caused by CD-8-positive cytotoxic T cells that attack skin cells that display the plant oil as a foreign antigen. In the tuberculin skin test, the indurated skin rash is caused by CD-4-positive helper T cells and macrophages that are attracted to the injection site.

The sensitized lymphocytes carry on their surface receptors which are antideterminants, specific to the given antigen. They bind with the foreign antigen by means of these receptors and destroy it with their enzymes and by producing special humoral factors, lymphokinins, which act as auxiliary vehicles of cellular immunity. Some types of lymphokinins may mobilize non-immune lymphocytes and include them in the reactions of cellular immunity.

A. Contact Hypersensitivity: This manifestation of cell-mediated hyper- sensitivity occurs after sensitization with simple chemicals (eg, nickel, for- maldehyde), plant materials (eg, poison ivy, poison oak), topically applied drugs (eg, sulfonamides, neomycin), some cosmetics, soaps, and other substances. In all cases, the small molecules acting as haptcns enter the skin, attach to body proteins, and become complete antigens. Cell-mediated hypersensitivity is induced, particularly in the skin.

Upon a later skin contact with the offending agent, the sensitized per-son develops erythema, itching, vesicles, eczema, or necrosis of skinwithin 12-48 hours. B. Tuberculin-Type Hypersensitivity: Delayed hypersensitivity to

antigens of microorganisms occurs in many infectious diseases and has been used as an aid in diagnosis. It is typified by the tuberculin reaction. When a patient previously exposed to Mycobacterium tuberculosis is injected with a small amount of tuberculin (PPD) intradermally, there is little reaction in the first few hours. Gradually, however, induration and redness develop and reach a peak in 48-72 hours. A positive skin test indicates that the person has been infected with the agent, but it does not confirm the presence of current disease. However, if the skin test converts from negative to positive, it suggests that the patient has been recently infected.

Cell-mediated hypersensitivity develops in many bacterial, viral, protozoan and helminthic infections.

A positive skin test response assists in diagnosis and provides support for chemoprophylaxis or chemotherapy.

ALLERGY DIAGNOSTIC TESTS. Many infectious diseases are associated with the development of the body's elevated sensitivity toward the causative agents and products of their metabolism. Allergy tests used for the diagnosis of bacterial, viral, and protozoal infections, as well as mycosis and helminthiasis, rely exactly on this phenomenon. Allergy tests are quite specific but not infrequently they can be observed in vaccinated individuals and in those with a history of the disease in question.All allergy tests are divided into two groups, namely, in vivo and in vitro tests.The first group (in vivo) consists of cutaneous tests made di rectly on the patient and revealing allergy of immediate (in 20 min) or delayed (in 24-48 hrs) type.

Cutaneous Tests. Infective allergens are most often administered either intracutaneously or epidermally by rubbing them into scarified sites of the skin, less commonly they are injected subcutaneously.

In Vitro Tests. These methods of investigation are safe for the patient, highly sensitive, and allow to carry out a quantitative assessment of the body's allergization. To date, a number of tests have become avail able in -which reactions with T- and B-lymphocytes, tissue basophils, neutrophil granulocytes, etc. are employed for this purpose. These tests include inhibition of leucocyte migration and lymphocyte blast transformation, specific rosette formation, the parameter of neutrophil granulocyte damage, Shelley's basophil test, reaction of tissue basophil degranulation. Still another test involves determination of IgE in blood serum.

Immunizations

2 artificial methods to make an individual immune to a disease

Active immunizationadministration of a vaccine so that the patient actively mounts a protective immune response

Passive immunization

individual acquires immunity through the transfer of antibodies formed by an immune individual or animal

The Chinese noticed that children who recovered from smallpox did not contract the disease a second timeYoung children were inoculated with material from a smallpox scab to induce immunity

process known as variolation

Edward Jenner found that protection against smallpox could be induced by inoculation with material from an individual infected with cowpox similar but much

milder disease

Brief history of immunologyBrief history of immunology

Relatively new science; origin usually

attributed to Edward Jenner, but has deep roots in folk medicine

Jenner discovered in 1796 that cowpox (vaccinia)

induced protection against smallpox

Jenner called his procedure

“vaccination”

It took almost two centuries for smallpox vaccination to become universal

Vaccination enabled the WHO to announce in 1979 that smallpox had been eradicated, arguably the greatest triumph in modern medicine.

Louis Pasteur developed a vaccine against Pasteurella multocida

Practice of transferring protective antibodies was developed when it was discovered that vaccines protected through the action of antibodies

• In the 1880s, Louis Pasteur devised a vaccine against cholera in chickens and developed a rabies vaccine that proved a spectacular success upon its first use in a boy bitten by a rabid dog

• These practical triumphs led to a search for the mechanisms of protection and the development of the science of immunology

• In 1890 Emil von Behring and Shibasaburo Kitasato discovered that the serum of vaccinated individuals contained “antibodies” that specifically bound to the relevant pathogen

3 general types of vaccines

attenuated (live) microbe “treated” to lose virulence but retain antigenicity

killed (inactivated)

Toxoidtoxin treated with heat or formaldehyde to lose toxicity but retain antigenicity

Also called modified live vaccinesUses pathogens that are living but have reduced virulence so they don’t cause disease

Attenuation is the process of reducing virulence

viruses often attenuated by raising them in tissue

culture cells for which they aren’t adapted until

they lose the ability to produce disease bacteria can

be made avirulent by culturing under unusual

conditions or through genetic manipulation

Attenuated Vaccines

Left: A Calmette, centre: a scanning electron micrograph of M tuberculosis, right: a comparison of the efficacy of the BCG vaccines in different populations and

areas of the world

How do we make attenuated viruses?

Rubella and Sabin polio vaccines were derived by passage through monkey kidney and duck embryo cells respectively.

Attenuated Vaccines

Can result in mild infections but no disease

Contain replicating microbes that can stimulate a strong immune response due to the large number of antigen molecules

Viral vaccines trigger a cell-mediated immune response dominated by TH1 and cytotoxic T cells

Vaccinated individuals can infect those around them, providing herd immunity

Problems with Attenuated Vaccines

Attenuated microbes may retain enough virulence to cause disease, especially in immunosuppressed individuals

Pregnant women should not receive live vaccines due to the risk of the modified pathogen crossing the placenta

Modified viruses may occasionally revert to wild type or mutate to a virulent form

Inactivated Vaccines

Can be either whole agent vaccines produced with deactivated but whole microbes, or subunit vaccines produced with antigenic fragments of microbes

Both types are safer than live vaccines since they cannot replicate or mutate to a virulent form

When microbes are killed must not alter the antigens responsible for stimulating protective immunity

Formaldehyde is commonly used to inactivate microbes by cross-linking their proteins and nucleic acids

Recognized as exogenous antigens and stimulate a T2H response that promotes antibody-mediated immunity

Problems with Inactivated Vaccines

Do not stimulate herd immunity Whole agent vaccines may stimulate a inflammatory response due to nonantigenic portions of the microbeAntigenically weak since the microbes don’t reproduce and don’t provide many antigenic molecules to stimulate the immune response

Administration in high or multiple doses, or the incorporation of an adjuvant, can make the vaccine more effective

adjuvants are substances that increase the antigenicity of the vaccineadjuvants may also stimulate local inflammationhigh and multiple vaccine doses may produce allergic reactions

General Properties of Attenuated (Live) and Inactivated Vaccines

InactivatedAttenuated (Live)

• Virulent pathogen grown under adverse conditions or continued passage through different hosts

• Single boost• Can be unstable• Induces both humoral and

cellular immunity• Reversion to virulent form

possible (eg. Sabin vaccine 1 case per 4 million doses)

• Contamination with other viruses (eg. SV-40 from Monkey present in Sabin Vaccine)

• Inactivation of virulent pathogen by chemicals (formaldehyde) or irradiation with X-rays

• Multiple boosts

• Stable (important for 3rd world)

• Induces primarily humoral immunity

• No reversion (provided the inactivation is complete)

Attenuated organisms confer better immunity but are less “safe”

Live attenuatedLive attenuated vaccines are the major class of vaccines for intracellular pathogens. As these agents lead to active infections and propagate in the

body, suitably attenuated strains require low doses of vaccine and lead to a lasting form immunity that is both antibody and cytotoxic. Live attenuated vaccines, therefore, are ideal vaccines if attenuation can be achieved and can be maintained, ie if attenuation is stable and reversion to the virulent

phenotype occurs.

 inactivated   attenuated

cost

higher (greater mass required)

lower (agent replicates in the body)

administration parenteral oral

adjuvant needed not needed

stability good  poor

reversion   absent possible

immunity mucosal immunity absent

antibody-mediated

short-lasting

mucosal immunity present

antibody-mediate and cytotoxic T cells

long-lasting

Toxoid Vaccines

Chemically or thermally modified toxins used to stimulate active immunity

Useful for some bacterial diseases

Stimulate antibody-mediated immunity

Require multiple doses because they possess few antigenic determinants

Modern Vaccine Technology

Research attempts to make vaccines that are more effective, cheaper, and safer

A variety of recombinant DNA techniques can be used to make improved vaccines

Left: in large areas of China hepatitis B has been endemic for a long time leading to high incidences of chronic liver disease and liver cancer. Right:

Incidence of human hepatitis in the USA (top) and liver cancer in children in Taiwan (bottom)

DPT vaccine:– Diphtheria: Purified diphtheria toxoid– Pertussis: Acellular fragments of B. pertussis– Tetanus: Purified tetanus toxoid

Meningococcal meningitis: Purified polysaccharide from N. meningitidis

Haemophilus influenzae type b meningitis: Polysaccharides conjugated with protein

Pneumococcal conjugate vaccine: S. pneumoniae antigens conjugated with protein

Principal Vaccines Used in the World to Prevent Bacterial Diseases in Humans

Smallpox: Live vaccinia virusPoliomyelitis: Inactivated virusRabies: Inactivated virusHepatitis A: Inactivated virusInfluenza: Inactivated or attenuated virusMeasles: Attenuated virusMumps: Attenuated virusRubella: Attenuated virusChickenpox: Attenuated virusHepatitis B: Antigenic fragments (recombinant vaccine)

Principal Vaccines Used in World to Prevent Viral Diseases in Humans