Immunity and Molecular Signals

Clonal Selection and Tolerance

Clonal selection and tolerance select for survival of lymphocytes that will protect the host from foreign antigens.

Learning Objectives

Describe the importance of central and peripheral tolerance and distinguish between positive and negative clonal selection

Key Takeaways

Key Points

  • Clonal selection occurs after immature lymphocytes express antigen receptors.
  • Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self.
  • Both developing B cells and T cells are subject to negative selection during a short period after antigen receptors are expressed.
  • If, during embryonic development, it encounters its programmed antigen as part of a normal host substance (self), the lymphocyte is somehow destroyed or inactivated. This mechanism removes lymphocytes that can destroy host tissues and thereby creates tolerance for self.

Key Terms

  • lymphocyte: A type of white blood cell or leukocyte that is divided into two principal groups and a null group: B-lymphocytes, which produce antibodies in the humoral immune response, T-lymphocytes, which participate in the cell-mediated immune response, and the null group, which contains natural killer cells, cytotoxic cells that participate in the innate immune response.
  • antigens: In immunology, an antigen is a substance that evokes the production of one or more antibodies.
  • T cells: A lymphocyte, from the thymus, that can recognise specific antigens and can activate or deactivate other immune cells.
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Clonal Selection: clonal selection of the B and T lymphocytes:1. Hematopoietic stem cell 2. Immature lymphocytes with various receptors 3. “Self”-antigens from the body’s own tissues 4. Mature, inactive lymphocytes 5. Foreign antigen 6. Cloned activated lymphocytes.

Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. The concept of central tolerance was proposed in 1959 as part of a general theory of immunity and tolerance. It was hypothesized that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive. The theory that self-tolerance is ‘learned’ during lymphocyte development was a major conceptual contribution to immunology. It was experimentally substantiated in the late 1980’s when tools to analyze lymphocyte development became available. Central tolerance is distinct from periphery tolerance in that it occurs while cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery. Peripheral tolerance is generated after the cells reach the periphery. Regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self (or foreign)-reactive T cells in the thymus during T cell differentiation. However, they exert their immune suppression in the periphery on other self (or foreign)-reactive T cells.

Clonal selection occurs after immature lymphocytes express antigen receptors. The cells with useful receptors are preserved, and many potentially harmful, self antigen-reactive cells are eliminated by processes of selection induced by antigen receptor engagement. The preservation of useful specificities is called positive selection. Positive selection ensures maturation of T cells whose receptors bind weakly to self major histocompatibility complex molecules. Negative selection is the process that eliminates developing lymphocytes whose antigen receptors bind strongly to self antigens present in the lymphoid organs. Both developing B cells and T cells are subject to negative selection during a short period after antigen receptors are expressed. Negative selection of developing lymphocytes is an important mechanism for maintaining central tolerance.

Cytokines and Chemokines

Cytokines and chemokines are both small proteins secreted by cells of the immune system.

Learning Objectives

Summarize the role of cytokines and chemokines

Key Takeaways

Key Points

  • Cytokines and chemokines are important in the production and growth of lymphocytes, and in regulating responses to infection or injury, such as inflammation and wound healing.
  • Cytokines are the general category of messenger molecules, while chemokines are a special type of cytokine that directs the migration of white blood cells to infected or damaged tissues.
  • A cytokine and a chemokine both use chemical signals to induce changes in other cells, but the latter are specialized to cause cell movement.

Key Terms

  • cytokine: Any of various small regulatory proteins that regulate the cells of the immune system.
  • chemokine: Any of various cytokines, produced during inflammation, that organize the leukocytes.
  • chemotaxis: The movement of a cell or an organism in response to a chemical stimulant.

CYTOKINES

These are small cell-signaling protein molecules that are secreted by numerous cells, and are a category of signaling molecules used extensively in intercellular communication.

Cytokines can be classified as proteins, peptides, or glycoproteins. The term “cytokine” encompasses a large and diverse family of regulators produced throughout the body by cells of diverse embryological origin. The term has also been used to refer to the immunomodulating agents, such as interleukins and interferons.

Biochemists disagree as to which molecules should be termed cytokines and which hormones. As we learn more about each, anatomic and structural distinctions between the two are fading. Classic protein hormones circulate in nanomolar (10-9) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10-12) concentrations that can increase up to 1,000-fold during trauma or infection.

The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the interface with the external environment), are potent producers of IL-1, IL-6, and TNF-alpha. In contrast, classic hormones, such as insulin, are secreted from discrete glands (e.g., the pancreas).

As of 2008, the current terminology refers to cytokines as immunomodulating agents.

CHEMOKINES

These are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.

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Chemotaxis: Effect of chemokine concentration gradient on chemotaxis direction.

Proteins are classified as chemokines according to shared structural characteristics, such as small size (they are all approximately 8-10 kilodaltons in size), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape. However, these proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines.

Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development.

Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been described for other invertebrates. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.

Superantigens

Superantigens are a class of antigens that cause activation of T-cells and massive cytokine release.

Learning Objectives

Describe the mechanism of action for superantigens and the effects

Key Takeaways

Key Points

  • Superantigens (SAgs) are microbial products that have the ability to promote massive activation of immune cells, leading to the release of inflammatory mediators that can ultimately result in hypotension, shock, organ failure, and death.
  • They achieve this by simultaneously binding and activating major histocompatibility complex class II molecules on antigen -presenting cells and T-cell receptors on T lymphocytes bearing susceptible Vβ regions.
  • The resulting Th1 response may divert the immune system from effective microbial clearance and/or result in the cytokine -mediated suppression and deletion of activated T cells.

Key Terms

  • interferon: Any of a group of glycoproteins, produced by the immune system, that prevent viral replication in infected cells.
  • Kawasaki disease: A disease in which the medium-sized blood vessels throughout the body become inflamed. Symptoms include fever, lymphadenopathy, and elevated platelet count.
  • superantigen: an antigen, which has a powerful interaction with T-lymphocytes

Superantigens (SAgs) are proteins that cause the T-cells of the immune system to over-react to infection. They are produced by certain infectious bacteria and viruses. The immune system over-reaction to the antigen causes a group of diseases that manifest in fever and shock, such as food poisoning, toxic shock syndrome, and Kawasaki disease. Common bacterial species that may use a superantigen as part of their virulence strategy are staphylococci and streptococci.

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A Superantigen: Structure of a typical bacterial superantigen.

These bacteria usually live harmlessly on the body, but can cause infections in certain circumstances. The superantigens of each species are, like antigens, molecules the immune system recognizes as being foreign. Superantigens cause symptoms of illness by tricking the T-cells of the immune system into over-reacting to these molecules. Parts of a bacterium or a virus are usually recognized by the macrophage cells of the immune system. The macrophage ingests the foreign invaders and breaks them down. Then the macrophage takes parts of the broken-down invader or other molecules that it ingested and posts the fragments on the outside of the cell using a major histocompatibility complex (MHC) to hold the fragment.

The large number of activated T-cells generates a massive immune response which is not specific to any particular epitope on the SAg. This undermines one of the fundamental strengths of the adaptive immune system, that is, its ability to target antigens with high specificity. More importantly, the large number of activated T-cells secretes large amounts of cytokines, the most important of which is Interferon gamma. This excess amount of IFN-gamma is in turn what activates the macrophages.

The Complement System

The complement system helps antibodies and phagocytic cells clear pathogens from an organism.

Learning Objectives

Describe the function of the complement system

Key Takeaways

Key Points

  • The complement system has originally been identified as the part of the immune system called the innate immune system.
  • The complement system can also be recruited and brought into action by the adaptive immune system.
  • The three biochemical pathways that activate the complement system are the classical complement pathway, the alternative complement pathway, and the lectin pathway.
  • The complement system consists of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors. When stimulated by a trigger, proteases in the system cleave specific proteins to release cytokines that amplify further cleavages.
  • The end-result of this activation cascade is the massive amplification of the response and activation of the cell-killing membrane attack complex.

Key Terms

  • opsonization: the process of an antigen bound by antibody or complement to attract phagocytic cells.

The Complement System

The serum complement system, which represents a chief component of innate immunity, not only participates in inflammation but also acts to enhance the adaptive immune response. Specific activation of the complement via innate recognition proteins or secreted antibody releases cleavage products that interact with a wide range of cell surface receptors found on myeloid, lymphoid, and stromal cells. This intricate interaction among complement activation products and cell surface receptors provides a basis for the regulation of both B and T cell responses.

The complement system plays a crucial role in the innate defense against common pathogens. Activation of the complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of the complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now understood that the complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges.

Activation of the Complement System

The complement system can be activated through three major pathways: classical, lectin, and alternative. Initiation of the classical pathway occurs when C1q, in complex with C1r and C1s serine proteases (the C1 complex), binds to the Fc region of complement-fixing antibodies (generally IgG1and IgM) attached to pathogenic surfaces. Autocatalytic activation of C1r and C1s in turn cleaves C4 and C2 into larger (C4b, C2a) and smaller (C4a, C2b) fragments. The larger fragments associate to form C4bC2a on pathogenic surfaces, and the complex gains the ability to cleave C3 and is termed the C3 convertase.

Generation of the C3 convertase, which cleaves C3 into the anaphylatoxin C3a and the opsonin C3b, is the point at which all complement activation cascades converge. When C3 is cleaved into C3b, it exposes an internal thioester bond that allows stable covalent binding of C3b to hydroxyl groups on proximate carbohydrates and proteins. This activity underpins the entire complement system by effectively “tagging” microorganisms as foreign, leading to further complement activation on and around the opsonized surface and terminating in the production of anaphylatoxins and assembly of membrane attack complexes.

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Complement death: A complement protein attacking an invader.

Functions of the Complement System

The functions of the complement system, oposonization, lysis, and generation of the inflammatory response through soluble mediators, are paradigmatic and represent a well-characterized component of an innate host defense. It has become increasingly understood that complement functions in host defense extend beyond innate immune responses. The finding that B lymphocytes bound C3 raised the question as early as in the 1970s as to whether the complement system was involved in adaptive immune responses. Subsequent work demonstrated that depletion of C3 impaired humoral immune responses and provided direct evidence that efficient adaptive responses were contingent on an intact complement system in some cases.

Further study in animals bearing natural complement deficiencies implicated the classical pathway as a crucial mechanism for efficient antigen trapping and retention in lymphoid tissues (e.g., splenic follicles), suggesting that a major function of the complement system was to localize foreign antigens into immune sites important for lymphocytes responses.