Chapter 23 Immunogenetics

The immune response in mammals involves three steps: 1.Recognition of the foreign substance 2.Communication of this recognition to the responding cells 3.Elimination of the invading agent

Figure 23.1 A phagocyte stalking a rod-shaped bacterium. Nonspecific immune responses: -Inflammation of the infected tissues resulting in increased blood flow -Recruitment of phagocytes to ingest and destroy microorganisms

Antigen: A substance that is bound by an antibody or T cell receptor is called an antigen (antibody-generating substance) Immunogen: An antigen that elicits an immune response is called immunogen B lymphocyte (B cell): Lymphocyte that differentiate in the bone marrow T lymphocyte (T cell): Lymphocyte that differentiate in the thymus

B lymphocyte (B cell): -Upon receiving signal, B cells differentiate into plasma cells which produce antibodies -Upon receiving signal, B cells differentiate into memory B cells which facilitate a more rapid production of antibodies during a later exposure to the same antigen T lymphocyte (T cell): -Cytotoxic (killer) T cells carry T cell receptor on their cell surface and kill cells displaying the appropriate antigen -Helper T cells stimulate B and T cells to differentiate -Suppressor T cells assist in down-regulating the activity of plasma cells and cytotoxic T cells -Memory T cells “remember” the antigen and provide for a rapid production of cytotoxic T cells subsequent encounters with the same antigen

The mammalian immune response has two major components: 1.The antibody-mediated or humoral response -Production and secretion of antibody into circulatory system -The antibody/antigen complex are ingested and destroyed by a special class of white blood cells -response to foreign cells (e.g. bacteria and fungi) and free viruses before they infect host cells. 2. T cell-mediated or cellular response -Production of T cell receptor that coat the surfaces of cytotoxic T cells -The cytotoxic T cells recognize and kill infected cells of the host organism -Responsible for protecting mammals from viral infection

Figure 23.2 The most important cells of the immune system are derived from bone marrow stem cells by three separate cell lineages.

Figure 23.3 (a) Diagram and (b) space-filling model of antibody structure. Human IgG molecule Lock-and-key interaction between an antigen and an antibody Effector function domain: interaction of the antibody with other immune components

Complement: -about 20 soluble proteins that circulate in the bloodstream and form large protein complexes in response to antibody/antigen complexes -Kill cells by a variety of mechanisms, e.g. punching holes in the cell membrane -The proteins called complement because it complements the activity of antibodies in fighting pathogenic foreign cells Five Classes of Antibodies

Figure 23.5 Structure of a T cell receptor anchored in the cell membrane. Cytotoxic T cell Helper T cells

Major Histocompatibility Antigen: Distinguishing Self from Non-self -Major histocompatibility complex (MHC) proteins are cell surface macromolecules -In human, MHC proteins are called HLA antigen (human leukocyte-associated antigen) -Initial studied in the immune rejections of transplanted tissues -Primary function is to distinguish self from non-self antigens to protect pathogenic microorganisms -Highly polymorphic, with some genes having up to 100 or more different alleles

Three different classes of MHC proteins MHC (HLA) class I genes -Transplantation antigens -Glycoproteins present on virtually all cells of an organism -Provide cytotoxic T cells with a mechanism for distinguishing “foreign” from “self’ MHC (HLA) class II genes -Polypeptides present on surface of B cells and macrophages -Binding and present antigens to helper T cells MHC (HLA) class III genes -Complement proteins -Interact with antibody/antigen complex and help destroy them by proteolysis

Figure 23.6 Organization of the major histocompatibility complex (HLA) on human chromosome 6.

Figure 23.7 Summary of the immune response in mammals. Clonal selection Clonal selection: stimulation of a B cell producing an antibody that recognize the antigen to multiply and differentiate into plasma cells all producing the same antibody. Cytotoxic T cells secrete perforins to kill the target

Figure 23.8 Antibody/antigen complexes are eliminated by two major pathways. Naïve cells: B and T cells that have never encountered a foreign antigen

Figure 23.9 Lysis of a target cell displaying a foreign antigen by a killer T cell Target cell T cell

Genome Rearrangements during B Lymphocyte Differentiation Lambda light chain genes assembled from two different segments L V   leader peptide and variable region  51 L V (30 functional) J C  (joining segment and constant region), 7 J C (4 functional) Kappa light chain genes assembled from three different segments Heavy chain genes assembled from four different segments L  V   leader peptide and variable region  76 L  V  (40 functional) J  (joining segment), 5 J  C  (constant region), 1 C  L H V H  leader peptide and variable region  123 L H V H (44 functional) D H (diversity), 27 D H (25 functional) J H  (joining segment), 6 J H C H  (constant region), 9 C H

Figure The genetic control of human antibody lambda light chains. 51 L V   30 functional  7 J C  (4 functional)

Figure The genetic control human antibody heavy chains.

Figure Abbreviated model of V  -J  joining. Sequence-specific recombination: complementary RSS sequences RSS, Recombination signal sequences Heptamer-spacer-nonamer RAG, recombination-activating gene, endonuclease Artemis, repair DNA double strand break

Figure Antibody diversity at the V  -J  junction is produced by variation in the exact position of the joining reaction. Additional Diversity of Antibody: Variable joining sites V  J  V J V H D H J H Somatic hypermutation Variable region (2%)

Figure Antibody class switching may occur by alternate pathways of transcript splicing. Antibody Class Switching - B cells can switch from the production of one class of antibody to another class - Genome rearrangement (Figure 23.11) - Alternative splicing (Figure 23.14)

Allelic Exclusion: Only One Functional Rearrangement per Cell Each plasma cell produces only one type of antibody One of the allele is excluded from being expressed in the diploid B cells Only one productive genome rearrangement of light chain and heavy chain coding sequences occur during the differentiation of each B cell. Both alleles are sometimes arranged in the same cell, but only one allele has undergone a productive rearrangement to a functional gene.

Figure Activation of heavy chain gene transcription by movement of a heavy chain gene promoter into proximity with a tissue-specific enhancer during gene assembly in B lymphocytes. Heavy Chain Gene Transcription: A Tissue-Specific Enhancer

Figure 1 The production of monoclonal antibodies by hybridoma cell clones. In 1975, Dr. Cesar Milstein Dr. Georges Kohlor