Type IV: delayed hypersensitivity

Type IV: delayed hypersensitivity. Unlike the other types of hypersensitivity reactions, type IV reactions are not mediated by antibody. Delayed hypersensitivity reactions are mediated primarily by T lymphocytes (cell-mediated immunity). The classic examples are the tuberculin skin test reactions and contact dermatitis.

 

 

Type III: immune-complex-mediated reactions

Type III: immune-complex-mediated reactions. Immune complexes are formed when antigens bind to antibodies. They are usually cleared from the circulation by the phagocytic system. However, deposition of these complexes in tissues or in vascular endothelium can produce immune complex-mediated tissue injury. Two important factors leading to injury by this mechanism include increased quantity of circulating complexes and the presence of vasoactive amines, which increase vascular permeability and favor tissue deposition of immune complexes. Immune complex deposition leads to complement activation, anaphylatoxin generation, chemotaxis of polymorphonuclear leukocytes, phagocytosis, and tissue injury. Clinical examples are serum sickness, certain types of nephritis, and certain features of bacterial endocarditis.

 

 

Type II: cytotoxic reactions

Type II: cytotoxic reactions. Cytotoxic reactions involve the binding of either IgG or IgM antibody to cell-bound antigens. Antigen–antibody binding results in activation of the complement cascade and the destruction of the cell to which the antigen is bound. Examples of tissue injury by this mechanism include immune hemolytic anemia and Rh hemolytic disease in the newborn. Diseases such as autoimmune hyperthyroidism in which thyroid-stimulating antibodies stimulate the thyroid tissue, or thyroid-stimulating hormone (TSH)-binding inhibitory antibodies inhibit the binding of TSH to its receptor; or myasthenia gravis in which antibodies are directed to the acetylcholine receptor blocking this neuromediator from interacting with its receptor are also type II reactions. In this latter group of diseases, cytolysis is not a component of these reactions.

 

 

Type I: anaphylactic or immediate hypersensitivity

Type I: anaphylactic or immediate hypersensitivity. Antigen binding to preformed IgE antibodies attached to the surface of the mast cell or basophil causes release of inflammatory mediators, e.g., histamine, leukotrienes, cytokines, proteases, arachidonic acid metabolites, and enzymatic mediators (see Chapter 2), which produce the clinical manifestations. Examples of type I diseases include anaphylactic shock, allergic rhinitis, allergic asthma, and acute drug allergic reactions. 

 

Classification of Immunologic Reactions

Although the function of the immune system is protection of the host from foreign antigens, abnormal immune responses can lead to tissue injury and disease. Gell and Coombs classified the mechanisms of immune tissue injury into four distinct types of reactions, which allows for a better understanding of the immunopathogenesis of disease.

1. Type I: anaphylactic or immediate hypersensitivity.

2. Type II: cytotoxic reactions

3. Type III: immune-complex-mediated reactions.

4. Type IV: delayed hypersensitivity

 

 

Antigen–Antibody Interactions

An antigen is a substance that can stimulate an immune response and react with an antibody or a sensitized T cell. The capacity of an antigen to elicit an immune response is termed its immunogenicity; its ability to react with an antibody is termed its antigenicity. Low molecular weight substances (e.g., drugs) are not immunogenic by themselves unless combined with a carrier protein. These small molecules are called haptens. Although they cannot evoke an antibody response when injected alone, they can by themselves react with antibody. Immunogenicity is a complex phenomenon that depends not only on the physical properties of the antigen, but also on the biologic system, route of administration, and method of immunization.

 

The membrane attack complex (MAC)

After activated C5 binds to C6, C7 and C8 subsequently bind, forming the complex C5b678, which is then capable of binding multiple molecules of C9. This forms a cylindrical structure, C5b6789, termed the MAC. This structure is inserted through the cell membrane, breaching the osmotic barrier of the cell wall, ultimately resulting in death of the cell. 

 

Effector mechanism

The classic and alternative C3 pathways generate C3b, which serves a number of functions, including interaction of C4b2a (the classic C3 convertase) and C3bBb (the alternative pathway C3 convertase) to allow further activity on C5 and subsequent activation of the terminal sequence (Fig. 1.5). In the final steps, formation of membrane-bound C5b67 permits binding of C8 to the C5 fragment to cause a partial membrane lesion resulting in slow cell lysis. By complexing with C9, the cytolytic reaction is accelerated.

 

Amplification

Constituent proteins of the amplification pathway include C3b, factors B and D, and properdin. Under normal circumstances, an alternative pathway convertase, which amplifies the activation of this pathway, is quite unstable and rapidly decays. Properdin binds to this alter-native pathway convertase, stabilizing and retarding its decay and allowing it to perpetuate the complement cascade.

 

 

Alternative pathway activation

Microbial and mammalian cell surfaces can activate the alternative pathway in the absence of specific antigen– antibody complexes. This nonspecific activation offers a major physiologic advantage, because host protection can be generated before the induction of an antibody-mediated immune response. Factors capable of activating the alternative pathway include inulin, zymosan, bacterial polysaccharides, and aggregated immunoglobulins IgG4, IgA, and IgE. Proteins involved in this reaction include properdin, factor D, factor B, and C3.

 

The classic activation pathway

The classic activation pathway depends on the interaction of three complement proteins (C1, C4, and C2) with antigen-bound antibody to activate the initial cleavage of C3. C1, the first complement component, consists of three subcomponents, C1q, C1r, and C1s, which form a complex in the presence of calcium. Antigen–antibody complexes (containing IgG1, IgG2, IgG3, or IgM) can activate C1 to its enzymatically active form.

Activated C1 then cleaves its two complement substrates, C4 and C2, to form a bimolecular complex, C4b2ba. This complex, known as C3 convertase, is capable of cleaving C3 to initiate activation of the effector sequence. Once C3 is activated, there is subsequent activation of the terminal components of the pathway. Complement enhances the immune response. The attachment of C3 to an antigen has been demonstrated to affect various phases of the acquired immune response. C3 is involved in (i) the promotion of antigen uptake, processing, and presentation by B cells to antigen-specific T cells; (ii) direct activation of B cells; and (ii) facilitation of B cell interactions.

The complement system

The complement system is made up of more than 25 plasma and cell membrane proteins, which are activated sequentially, and play important roles in immunologic effector mechanisms and host defense. Complement promotes bacterial, viral, and cellular lysis. Complement also acts to promote phagocytosis by the process of opsonization involving the deposition of specific complement fragments onto the surface of foreign microbes or cells. Receptors for these complement fragments are on phagocytic cells, leading to enhanced recognition and binding of the cell membrane to the phagocyte. Complement regulates inflammatory and immune responses, and has also been shown to play a role in acquired immunity because it helps to ensure the retention of antigen by follicular dendritic cells (FDC) in germinal centers, thereby providing a constant source of antigenic stimulus to activated, antigen-specific B cells.

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Complement proteins can be grouped into four functional divisions according to their interaction with the third component (C3):
classic pathway activation,
alternative pathway activation,
the amplification mechanism, and
the effector mechanism.
An additional pathway of complement activation is the lectin pathway. Activation of this pathway is mediated by mannose binding lectin (MBL). The structure of MBL is similar to the C1q molecule of the classical complement pathway and is a pattern recognition receptor specific for mannose carbohydrates found only in bacteria and yeasts. MBL associates with two serine proteases (mannin binding lectin associated proteases 1 and 2 [ MASP-1 and -2]). This entire complex cleaves downstream components of complement.

Phagocytic immunity

Phagocytic immunity The phagocytic arm of the immune system can be divided into two major groups: the circulating and fixed components. Circulating cells with phagocytic capacity include all of the granulocytes (including eosinophils) and the monocytes. The fixed tissue phagocytes include cells of the monocyte/macrophage lineage, specifically Kupffer cells of the liver, splenic macrophages, pulmonary alveolar macrophages, lymph node macrophages, and the microglial cells of the brain. Together, the fixed-tissue phagocytes are referred to as the reticuloendothelial system. The ability of the granulocytes, monocytes, and macrophages to destroy foreign antigen by phagocytosis is crucial for host defense. Failure of either of these systems invariably results in an increased susceptibility to infection.

The following steps are necessary for adequate phagocytosis and destruction of foreign antigen:

• random movement ;
  
• neutrophil adherence to vascular endothelium;
  
• transmembrane migration (diapedesis) ;
  
• chemotaxis ;
  
• opsonization and fixation of the bacteria or foreign material;
  
• ingestion of the antigen;
  
• metabolic activation of the phagocytes to destroy the foreign material;
  
• destruction of the organism. Specific features of this system are as follows.
  

A. Phagocytic cells migrate either in a random manner or in response to biochemical signals. This directed movement is called chemotaxis. Known chemoattractants include the activated complement components C3a, C4a, C5a, bacterial products, various leukotrienes, and other arachidonic acid metabolites.

B. Opsonization is the process by which antibody coats a bacterial cell wall or foreign material and increases its susceptibility to phagocytosis.

C. Phagocytosis is the process of engulfing foreign material into the phagocytic cell. After an intracellular phagocytic vacuole, or phagosome, is formed around the foreign material, lysosomal enzymes are released into this vacuole, resulting in the degradation of the foreign material. Neutrophil-generated, oxygen free radicals also play an important role in the destruction of phagocytosed microbes. Stimulated neutrophils can use the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase directly to generate superoxide anion radicals, which are rapidly converted to hydrogen peroxide and hydroxyl radicals. The latter two metabolic products provide the majority of the microbicidal activity in the phagosome. When halides and myeloperoxidase are present in the phagosome, hypochlorous acid and free halides are generated. During this process an increased burst of metabolic activity, with increased oxygen consumption, can be measured and used to assess neutrophil- killing capacity.

T lymphocytes do not recognize antigens directly

T lymphocytes do not recognize antigens directly, but do so after the antigen is processed and presented on the surface of an antigen-presenting cell associated with a cell surface glycoprotein, which is coded for by the MHC. This glycoprotein is termed the MHC class II molecule. Histocompatibility molecules are classified into two major groups: class I molecules (which regulate interactions between CD8+ cells and target cells), and class II molecules (which regulate inter-actions between CD4+ cells and antigen-presenting cells).

The function of both class I and II MHC molecules is to present antigen to T cells, thus initiating the adaptive immune response. T cells are able to interact with the histocompatibility molecules only if they are genetically identical; this phenomenon is known as MHC restriction.

      1. In humans, the MHC is located on chromosome 6. It is divided into four major regions: A, B, C, and D. The A, B, and C regions code for class I molecules, and the D region codes for class II molecules. The histocompatibility leukocyte antigen (HLA) complex comprises more than 200 genes. The class I genes code for the a-polypeptide chain of the class I molecule, whereas the beta2-microglobulin gene, on chromosome 15, encodes for the b-chain of the class I molecule, and is the light chain of the class I molecule. The a-chain has four domains: two peptide-binding domains (a1 and a2); one immunoglobulin-like domain (a3), and the last domain is the cytoplasmic tail. The class II molecules contain a and b polypeptide chains, which are encoded by the class II genes. The class II genes are also found on chromosome 6 and have a special system used for designation and nomenclature of their loci. Specifically, three letters are used. The three letters signify class, family, and chain. The first letter is always a D and indicates the class. The second letter is an M, O, P, Q, or R and represents the family. The third letter in the series is an A or B and represents the a or b chain, respectively. In addition, each of the class II a and II b chains has four domains: the peptide-binding domain (a1 or b1), the immunoglobulin-like domain (a2 or b2), the transmembrane region, and the cytoplasmic tail.

With rare exception, class I genes are expressed on all cells of the body, whereas class II genes are primarily expressed by antigen-presenting cells, such as B cells, dendritic cells, macrophages, some activated T cells, and thymic epithelial cells. Class I and II molecules process antigen differently. Class I molecules process intracellular proteins that are marked by ubiquitin. The proteins unfold and enter proteosomes, where they are processed and degraded into peptides. Next, they enter the endoplasmic reticulum. The peptide is then transported to the outer surface of the cell and bound to the HLA I molecule. Class II molecules degrade extracellular proteins via a different pathway. These are taken into the cell via invaginations, which pinch off and form endocytic vesicles. These vesicles join with lysosomes and at this point, the peptides are exposed to proteolytic enzymes. The lysosome–endocytic vesicle complex becomes known as an endosome. Once digested, the peptides are placed on the outer surface of the cell and are bound to the HLA class II molecules. MHC class II molecules lacking the peptide ligands are unstable and disassemble at low pH. MHC class II molecules require a ligand to occupy the peptide-binding groove in order to remain stable. Therefore, a peptide can be regarded as the “third subunit” of a mature MHC class II molecule. HLA-DM has been shown to bind the empty class II dimers and thus stabilize the groove in the absence of peptides.

T-cell receptors discriminate between MHC class I and II molecules. In general, CD8 cells bind HLA class I and down-regulate the expression of CD4 molecules, whereas CD4 cells bind class II and down-regulate the expression of CD8 molecules. Generally, CD4+ T lymphocytes become helper T cells and CD8+ T lymphocytes become cytotoxic T cells. As thymocytes enter the thymic cortex, they attempt to match their receptors with HLA peptide complexes on the cortical epithelial cells. If the receptors and ligands do not match up, which happens in the majority of cases, the thymocytes die via apoptosis mechanisms. A minority of thymocytes undergoes positive selection, in which these cells engage HLA peptide complexes and bind with low affinity. This low-affinity binding is sufficient to block apoptosis. Next, at the corticomedullary junction, the thymocytes are given the opportunity to undergo negative selection. At this point, they encounter antigen-presenting cells that express costimulatory molecules and proteases (cathepsins). This expression allows for a high-affinity interaction between the T-cell receptor and the HLA peptide. This interaction creates a signal instructing the thymocyte to undergo apoptosis. This process is termed negative selection and takes place so that self-reacting (or autoreactive) T cells, which can cause autoimmune disease, can be destroyed. Of all the progenitor cells that enter the thymus and proliferate in it, fewer than 1% mature into T cells. The MHC gene products have important roles in clinical immunology. For example, transplanted tissues are rejected if transplants are performed across MHC barriers.

     2. The majority of cellular immunity is mediated by the CD4+ cell, which is responsible for the following immune phenomena:

1.Delayed hypersensitivity reactions (e.g., tuberculin skin test response).
2. Contact sensitivity (e.g., poison ivy dermatitis).
3. Immunity to intracellular organisms.
4. Immunity to viral and fungal antigens.
5. Tissue graft rejection.
6. Elimination of tumor cells bearing foreign antigens.
7. Formation of chronic granulomas.

Both CD4+ and CD8+ cells participate in the T helper1/T helper 2 paradigm

Both CD4+ and CD8+ cells participate in the T helper1/T helper 2 paradigm. There is increasing evidence that Th2-like CD8+ cells exist in both humans and mice, and can be derived under similar conditions. IL-12 and IFN-g facilitate differentiation of Th1 or cytotoxic type 1 (Tc1) CD8+ T cells, whereas IL-4 facilitates differentiation into Th2 or cytotoxic type 2 (Tc2) CD8+ T cells.

However, in order for these CD8+ Tc2 cells to become IL-4 secreting, they need to be exposed to require higher levels of IL-4 during the initial priming than do CD4+ Th2 cells. Once committed to a Tc2 lineage, these CD8+ cells secrete the Th2 cytokines IL-4, 5, 9, 10, and 13. Different types of infectious organisms can affect which subsets of CD8+ cells will predominate during an immune response to that infection. Tc2-like cells have been isolated from patients with lepromatous leprosy, human immunodeficiency virus (HIV), and Job syndrome. In contrast, Tc1-like cells have been isolated from patients with tuberculoid leprosy. Although the Tc2 cells function in a “helper” manner, by secreting the appropriate cytokines, they can be just as cytotoxic as Tc1 cells. Both cell subsets kill via Ca2+/perforin-dependent mechanisms and by activation of Fas. Although Tc2 cells can help B cells, they do not do so in a cognate manner. Cognate help by Tc2 cells is unlikely because these cells do not recognize antigen processed and presented by MHC class II cells, as Tc2 cells are restricted to recognizing MHC class I. However, it is possible that Tc2 cells can help B cells via bystander, or non-cognate mechanisms.

Phagocyte-dependent host responses

Phagocyte-dependent host responses are partially controlled by Th1 cells, whereas phagocyte-independent immune responses are controlled by Th2 cells. Specifically, Th1 cells promote the production of opsonizing and complement-fixing antibodies, macrophage activation, antibody-dependent cell cytotoxicity, and delayed-type hypersensitivity. Th2 cells primarily provide help for humoral immune responses such as IgE- and IgG1-isotype switching and mucosal immunity.

Th2 cells also provide signals that induce mast cell and eosinophil growth and differentiation and facilitate IgA synthesis. Moreover, some Th2-derived cytokines (such as IL-4, IL-10, and IL-13) inhibit certain macrophage functions. Recently, two activation markers have been identified that are associated with the two primary subsets of T helper cells. Lymphocyte activation gene-3 (LAG-3) is an activation marker associated with Th1 cells and is a member of the immunoglobulin superfamily. CD30 is an activation marker associated with Th2 cells, and is a member of the TNF receptor family.

T helper 1 and T helper 2 cells regulate cellular function

T helper 1 and T helper 2 cells regulate cellular function. Specific Th1 cytokines promote Th1 proliferation and differentiation, but these cytokines act to inhibit the differentiation and effector function of Th2 cells and cytokines. For example, IFN-g selectively inhibits Th2 proliferation, whereas IL-10 (a Th2 cytokine) inhibits Th1 cytokine production. Likewise, throughout the entire body, Th1 and Th2 cells interact to suppress each other. Pregnancy is a special condition in which there is systemic “immune tolerance” partly mediated through a shifting of the Th1/Th2 balance. During pregnancy, the Th1 system is suppressed while the Th2 system is enhanced. This facilitates fetal survival because Th1 cytokines can be harmful to the placenta, whereas IL-10 is protective against fetal loss.

T helper 1 and T helper 2 cells exhibit functionally distinct characteristics

T helper 1 and T helper 2 cells exhibit functionally distinct characteristics. For example, Th1 cells primarily are involved in cell-mediated inflammatory reactions and thus the cytokines they produce activate cytotoxic and inflammatory reactions. IFN-g, a Th1 cytokine, is often found at sites of delayed-type hypersensitivity reactions. Th1 cells mediate these reactions; likewise, Th2 cytokines augment antibody production, particularly IgE responses, and enhance eosinophil production. Therefore, the Th2 cytokines are often found in association with allergic and antibody-driven immune responses.

 

The T helper 1/T helper 2 paradigm

T-cell elaboration of cytokines contributes to both the regulation of immunoglobulin synthesis and secretion, and cell-mediated immunity. Subsets of CD4+ T lymphocytes are characterized on the basis of patterns of cytokine release: Th1 cells differ from Th2 cells in that Th1 cells produce IL-2 and IFN-g, whereas Th2 cells produce IL-4, IL-5, IL-9, IL-10, and IL-13, among other cytokines. Th2 cells promote preferential production of some immunoglobulin isotypes, whereas Th1 cells mediate delayed hypersensitivity responses and inhibit the proliferation of the Th2 cells. Unlike B cells, T cells must migrate to the sites within the body where antigen is found, because T-cell responses to pathogens are dependent on the T cell being in direct contact with the pathogenic antigen.

In adults, there are approximately 25 million to 100 million distinct “naïve” T cell clones that have never encountered antigen. In contrast, there are only several thousand T cells bearing receptors that recognize individual antigen. Naïve T cells are first given the task of determining whether or not antigen is present, and second, whether or not this antigen is a threat to the body. Dendritic cells are instrumental in presenting antigen to T cells and are found in secondary lymphoid organs. These organs collect and trap antigen that is present in other parts of the body. Naïve T cells begin to migrate to these lymphoid organs in a process known as “homing.” When a T cell encounters an antigen, a cascade is initiated that results in an approximate thousand-fold clonal expansion of T cells with identical antigen specificity. In time, the activated T cells acquire effector function and once again home a second time to areas of inflammation. At these sites of inflammation, the T cells interact with eosinophils, basophils, mast cells, and antigen-presenting cells. There is another set of effector cells that contact activated B cells in lymphoid tissue and facilitate humoral immune responses. Although most effector T cells die after the antigen is cleared, a few remain and become memory cells and are able to mount rapid immune responses when specific antigen returns.

In humans, Th1 cells produce IL-2, IFN-g, lymphotoxin, and possibly small amounts of IL-6, IL-10, and IL-13. Th2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. Both Th1 and Th2 cells produce TNF-a, granulocyte macrophage colony-stimulating factor (GM-CSF), and chemokines. In reality, there is significant overlap in the types of cytokines produced by these cell populations. A third subset of T helper cells exists and is termed Th0. Th0 cells express cytokines inherent to both Th1 and Th2 cells.

Cell-mediated immunity

Cell-mediated immunity consists of a set of immune phenomena distinct from antibody-mediated immunity. Several features distinguish the humoral and cellular arms of the immune system. Specifically, cell-mediated immunity is mediated by T cells and monocytic cells and requires either intact cells to carry out their immune functions by direct cell-to-cell contact or acts through production of soluble factors, or cytokines that control and/or regulate specific immunologic functions.

1. The T helper 1/T helper 2 paradigm
2. T helper 1 and T helper 2 cells exhibit functionally distinct characteristics.
3. T helper 1 and T helper 2 cells regulate cellular function
4. Phagocyte-dependent host responses
5. Both CD4+ and CD8+ cells
6. Histocompatibility