Medical brain notes 12

  INTRODUCTION It is generally believed that the immune system evolved as the host’s defense against infectious agents, and it is well known that patients with deficiencies in the immune system generally succumb to these infectious diseases. However, as we shall see, it may well play a larger role in the elimina-tion of other foreign substances, including tumor antigens or cells and antibodies that attack self. An immune response may be conve-niently divided into two parts: (1) a specific response to a given antigen and (2) a more nonspecific augmentation to that response. An important feature of the specific response is that there is a quicker response to the antigen during a second exposure to that antigen. It is the memory of the initial response that provides the booster effect.   For convenience, the specific immune response may be divided into two parts: (1) the humoral response and (2) the cellu-lar response to a given antigen. As we shall see, however, both responses are medi-a

  ANTIGENS Antigens are any substances that are capable, under appropriate conditions, of inducing the formation of antibodies and reacting specifically with the antibodies so produced. They react with both T-cell recognition receptors and with antibodies. These antigenic molecules may have sev-eral antigenic determinants, called  epitopes , and each epitope can bind with a specific antibody. Thus, a single antigen can bind to many different antibodies with different binding sites. Some low-molecular-weight mol-ecules called  haptens  are unable to evoke an immune response but can react with existing antibodies. These molecules need to be coupled to a carrier molecule to be antigenic. For some molecules such as drugs, the molecule needs to be conjugated to a car-rier. The carrier may be a host protein. The tertiary structure of the molecule as well as the amino acid sequence is important in determining antigenicity. Certain struc-tures such as lipids and DNA are generally poor antigens

  ANTIBODY The basic structure of the antibody molecule is depicted in Figures 1.2A and B. It consists of a four- chain structure divided into two identical heavy (H) chains with a molecular weight of 25 kDa. Each chain is composed of  domains  of 110 amino acids and is connected in a loop by a disulfide bond between two cysteine residues in the chain. The amino acid N-terminal domains of the heavy and light chains include the anti-gen-binding site. The amino acids of these variable domains vary between different antibody molecules and are thus known as the  variable  (V) regions. Most of these dif-ferences reside in the  hypervariable  areas of the molecule and are usually only six to ten amino acid residues in length. When the hypervariable regions in each chain come together along with the counterparts on the other pair of H and L chains, they form the antigen-binding site. This part of the molecule is unique to the molecule and is known as the  idiotype determinant . In any individ

  T CELLS AND THEIR RECEPTORS Each T cell is also committed  to a given antigen and recognizes it by one of two TCRs. They may have TCR2s composed of gamma ( γ ) and delta ( δ ) chains or TCR2s composed of another heterodimer of alpha ( α ) and beta ( β ) chains. These TCR2s are associated with a group of transmem-brance proteins on the CD3 molecule, which takes the antigen recognition sig-nal inside the cell. Signal transduction via the CD3 complex is regulated by a series of kinases, which are associated with the tails of the CD3–TCR complex and regulate phosphorylation. Deficiencies or blocks in the T-cell signaling pathways either atthe cell-surface complex or at the level of the kinases may result in various forms of immunodeficiency. Two other important antigens present on TCR2 cells recognize histocompatibility antigens and will be discussed later. The genes for TCR chains are on different chromosomes with the  β  and  α  molecules on chromosome 7, while the  α  and  δ  are on c

  MAJOR HISTOCOMPATIBILITY COMPLEX Human histocompatibility antigens are also known as human leucocyte antigens (HLA), a term that is synonymous with the MHC complex. These antigens are cell-surface glycoproteins classified as type I or type II. They can produce genetic poly-morphism with multiple alleles at each site, thus permitting a great deal of genetic variability between given individuals (see Figure 1.6  Diagrammatic representation of class I and II MHC antigens with   B 2  microglobulins and CHO carbohydrate side chains. Figure 1.6). This extensive polymorphism is important when viewed in the context of an immune system that needs to cope with an ever-increasing range of pathogens. These pathogens in turn are extremely adept at evading the immune system. Thus, the battle between invading microbe and immune recognition is constant and ever changing. Recognition of antigen by T cells is MHC restricted. Therefore, any given individual is only able to recognize antigen as part of

  ADHESION MOLECULES In spite of the known MHC  complex consisting of binding of a TCR to the pro-cessed antigen, which in turn is bound to the class II molecule of APCs, this is not enough for T-cell activation. One must have additional stimuli that are provided by a series of adhesion molecules on the two cell surfaces. These molecules are composed of a diverse set of cell-surface glycoproteins and play a pivotal role in mediating cell-to-cell adhesion. Adhesion molecules are divided into four major groups, (a) integrins, (b) selectins, (c) immunoglobulin superfamily, and (d) caherins. β   Integrins are heterodimers: These are divided into  α  and  β  subunits. Depending on the substructure of the  β  unit, there are five families, but for convenience  β 1  and  β 2  integrins are   involved in leucocyte–endothelial inter-actions.  β 1  integrins, also known as very late activation proteins, are so named because they appear on lymphocytes   several days after antigenic stimula-tion a

  CYTOKINES This group of soluble molecules plays an extremely important role in clinical immunology. They are secreted by macrophages and may act as stimulatory or inhibi-tory signals between cells. Cytokines that initiate chemotaxis of leucocytes are called  chemokines .   Among the group of cytokines, there are a few of particular interest because of their stimulatory activity. Interleu-kins 1 (IL-1) and 2 (IL-2) are of particu-lar importance secondary to their role in amplifying the immune response. IL-1 acts on a wide range of cells including T and B cells. In contrast, IL-2 primarily acts on lymphocytes, although it has similar trophic effects on IL-receptor B cells and natural killer (NK) cells. (See Table 1.1 and functions.)

  INITIATION OF THE IMMUNE RESPONSE The effector cells are really divided into two types: B cells and T cells. B cells are primarily responsible for antibody produc-tion, whereas T cells act as effector cells and may function as both helpers and suppres-sors, depending on the stimulus provided by APCs. The first step in initiation of the immune response to an antigen must necessarily involve modification of the antigen, and these specialized cells are called APCs. Without such processing, T cells cannot recognize antigen. Thus, it is the secretion of cytokines by APCs activated by antigen presentation that further activates antigen- specific T cells. This interaction between APCs and T cells is strongly influenced by a group of molecules called co-stimulators. For example, it is CD80 (B7-1) and CD86 (B7-2) on the APC cells with receptors CD28 and CTLA-4 on the T cell that pro-vides this interaction. The absence of these co-stimulators leads to T-cell unrespon-siveness. The importance o

  ANTIBODY PRODUCTION To achieve antibody production, at least four types of cells are required: APC, B cells, and two types of regulating cells. B Cells Antibodies are produced by naïve B cells and are called  plasma cells . These cells express immunoglobulins on their sur-face. In the early stages, B cells first show intracellular µ-chains and then surface IgM. Through the process described ear-lier, these cells can later express IgG, IgA, or IgE, a phenomenon known as isotype switching. The final type of surface immu-noglobulin determines the class of anti-body secreted. Isotype switching is mediated through two important protein interactions: CD40 on the B cell interacts with CD40L on acti-vated T cells (IL-4 induced) to stimulate B  cells to switch from IgM molecules to other isotypes.   Deficiencies in either molecule lead to severe immunodeficiency states with only IgM produced but no IgG or IgA antibodies. This syndrome is called the hyper-IgM syndrome, and in this case of CD40