Marquette University e-Publications@Marquette College of Nursing Faculty Research and Nursing, College of Publications 1-1-1995 The mmI une System Betty Bierut Gallucci University of Washington - Seattle Campus Donna O. McCarthy Marquette University, [email protected] Published version. "The mmI une System," in Biotherapy: A Comprehensive Overview. Ed. Paula Trahan Rieger. Boston: Jones and Bartlett ubP lishers, 1999: 15-42. Permalink. © 1999 Jones and Bartlett Publishers. Donna McCarthy was affiliated with the University of Wisconsin - Madison at the time of publication. CHAPTER 2 The lmmune System Betty Bierut Gallucci, PHD Donna McCarthy, PHD Modern biotherapy has been in use for sorne current concepts of oncogenesis, particularly 30 years. The first types of biotherapy were oncogenes and growth factors. Because re­ nonspecific stimulators of the immune re­ search efforts are beginning to identify many sponse, but advances in genetic engineering biological proteins as having a role in autoim­ are allowing the mass production of pure bio­ mune and other diseases, a brief introduction logical products which are now being tested to autoimmune diseases is also included at the as pharmaceutical agents. Biotherapy con­ end of the chapter. notes the administration of products (1) that are coded by the mammalian genome; (2) that modify the expression of mammalian genes; THE IMMUNE SYSTEM or (3) that stimulate the immune system. In Overview of this chapter the discussion of the immune sys­ the lmmune Response tem will be limited primarily to topics relevant to cancer or autoimmune diseases. The immune system is a complex, dynamic Because understanding the new biological system which evolved to protect the individ­ agents requires an understanding of both the ual against pathogenic organisms (Figure 2.1). immune response and the molecular basis of In addition to recognizing and destroying for­ oncogenesis, this chapter first presents a sum­ eign substances or antigens, immune re­ mary of the structure and function of the im­ sponses can also destroy altered and malig­ mune system. Following a discussion of im­ nant cells. This latter function of the immune mune responses, and the cells involved in system is called immune surveillance. The these responses, will be a discussion on the destruction of microorganisms and the de- 15 16 Biotherapy: Principies and Foundations Figure 2.1 The humoral branch and cell-mediated branches of the immune system . The humoral response involves interaction of B lymphocytes with antigen and their differentiation into antibody­ secreting plasma cells. The secreted antibody binds to the antigen and facilitates its clearance from the body. The cell-mediated response involves various subpopulations of T lymphocytes that recognize antigen p,resented on self-cells. T H-cells respond to antigen with the production of lymphokines and cytotoxic T lymphocytes (CTL) mediate killing of cells that have been altered by antigen (e.g., virus-infected cells). Antigens Foreign Viruses Bacteria Parasites Fungi proteins Vertebrate body Humoral response / Cell-mediated response B cells Tcells activated activated Tcell + Antigen *! + TH cell Plasma cells secrete antibodies ~ rf( rl\ Lymphokines Antigen elimination Altered *~~** self-cell Source: IMMUNOLOGY by )anis Kuby. Copyright (e) 1992 by W.H. Freeman and Company. Reprinted with permission. The lmmune System 17 Table 2.1 Functions of the lmmune System physicaJ barriers are breached, an inflamma­ tory response attempts to limit the coloniza­ Protection Recognition and destruction of tion of the microbe. The acute inflammatory pathogenic microorganisms Surveillance Destructio.p of malignant cells response involves the physiological processes Homeostasis Destruction of worn and damaged of capillary dilatation, exudation of fluid and ce lis plasma protein into the tissues, and accumula­ Tolerance Recognition of self components tion of neutrophils at the site of infection. Regulation Augmentation and depression of These responses are manifested clinica11y as immune responses the five cardinal signs of inflammation: heat, redness, swelling, pain, and loss of function. struction of tumor cells involve the same im­ The invading organism is then killed through munologic mechanisms. The mechanisms phagocytosis by neutrophils or soluble chemi­ used to fight viral diseases are particularly cal factors generated during the inflammatory important in immune responses to tumors. response (Figure 2.2). The influx of neu­ See Table 2.1 for a summary of functions of trophils is replaced by monocytes, which con­ the immune system. tinue to migrate to the inflammed area. The lmmune responses involve a number of activation of monocytes is the bridge between different cell types and their products. Be­ innate and adaptive immunity. Monocytes are cause it is impossible to discuss or study all capable of processing the antigen they pha­ the responses at the same time, they are di­ gocytize and presenting it to other white vided into two types, innate and adaptive. blood cells involved in adaptive or specific Innate immunity is also called natural or non­ immunity. specific immunity and includes the inflamma­ Thus, if this innate response fails and the tory response. Adaptive immunity is also organism colonizes the body, the adaptive im­ k.nown as specific or acquired immunity. For a mune system is stimulated and responds. The review of innate and adaptive immune re­ specific immune response on the next expo­ sponses, see Table 2.2. sure to the same antigen will be heightened Innate immunity is the first line of defense and more rapid. This secondary response is against pathogenic organisms; adaptive im­ called memory or anamnestic response. munity involves the recognition of specific Generally speaking, the white blood cells foreign determinants and a memory response. are responsible for immune responses; granu­ To recognize and destroy what is foreign also locytes (neutrophils, eosinophils, and baso­ implies that the immune system must be able phils), monocytes and their tissue counterparts to tolerate self, that is, to tolerate its own cells macrophages are involved in innate immunity, and their products. If the molecules on the whereas lymphocytes are responsible for spe­ microorganism or tumor cell are recognized cific immun~ responses. Lymphocytes have as foreign (nonself or altered self) and stimu­ two different ways of recognizing antigenic late a specific immune response, they are determinants. The first is by antibodies located called antigens. The small area of the antigen on the membrane of B lymphocytes and the that binds to the lymphocyte receptor is the second is by T-lymphocyte (or T-cell) recep­ antigenic determinant or epitope. tors. For the T-cell receptors to recognize the The cells and products of innate and antigenic determinants the antigen must be adaptive immune responses act in concert and present along with self molecules or major his­ are aH responsible for resistance to pathogens tocompatibility (MHC) molecules. Typically, and surveillance. For instance, the first line of both the innate and adaptive systems (both B defense against pathogenic organisms (e.g. and T lymphocytes) are needed to effect a Pseudomonas) are mechanical barriers such as response sufficient to contain and eliminate intact skin and mucous membranes. If these pathogens. 18 Biotherapy: Principies and Foundations Table 2.2 Features of innate and adaptive immunity System Hallmarks Features and Functions lnnate lmmunity Primary line of defense Mechanical Barriers Non-specific lntact Skin ·No memory Mucous Membranes Chemical Barriers lnflammatory response Fever Phagocytic Cells Soluble Factors Protects against pathogens Adaptive lmmunity Secondary line of defense Lymphocytes Specificity T-cells: Provide cell mediated Memory immunity Primarily protects against intracellular organisms, immune surveillance, responsible for rejection of transplanted organs and modulation of immune response B-cells: Provide humoral immunity Primarily protects against viruses and bacteria ANTIGENS The majar function of the immune system is to distinguish one individual from another indi­ distinguish between self molecules and non­ vidual of the same species. The A, B, and O self or altered-self molecules. Molecules that blood-type molecules and the histocompati­ induce a specific immune response are called bility antigens are examples of alloantigens. A immunogens. AJI immunogens are also anti­ bone marrow transplant between siblings is gens. Allergens are antigens that induce aller­ caBed an allogeneic transplant. gic responses. The epitope or antigenic deter­ The distinction between self molecules minant is that specific part of an antigen, and foreign molecules is a learned response. allergen, or immunogen that binds directly Exposure of the immune system to molecules with the immunoglobulin or T-cell receptor. in utero will generate tolerance to these mole­ For example, an antigenic protein may consist cules: the immune system will not respond to of hundreds of amino acids, but only six or these molecules, rather they will be consid­ seven of these bind directly with an immu­ ered self molecules (self antigens). The greater noglobulin. The binding area of the antigen is the difference between self molecules and ex­ the epitope. Tolergens are molecules that in­ ogenous or foreign molecules, the more likely duce a state of immunologic unresponsive­ it is that an immune response will be gener­ ness. Most