Lecture 1: Immunogenetics Dr ; Kwanama Immunology II Lecture 1: Immunogenetics Dr ; Kwanama

Overview of immunogenetics Basic immunogenetics terminology Polymorphic molecules of the human immune system Immunoglobulins and Immunoglobulin genes Structure –function relationship of antibodies Unique features of immunoglobulin genes

Immunogenetics Specificity Specificity: Is a key feature of the adaptive immune system Ability of the immune system to distinguish between antigens It ensures that distinct antigens elicit specific responses

Polymorphism→ diversity The human genome contains an estimated 32,000 genes that encode mRNAs for proteins. To protect us, our immune system has the ability to produce about 1010-1011 different antibodies. How can our immune system produce so many different antibodies with so few genes? How is Ig diversity specified genetically? If each gene encoded a different antibody, they would encode only 1 millionth of the antibodies needed. Polymorphism→ diversity

Immunogenetics Specificity and polymorphism specificity is attributed to highly variable lymphocyte receptors ( BCR and TCR ) and immunoglobulins Unique specificity of antigen receptors and the ability to react selectively against a very broad range of foreign antigens is a result of polymorphism Polymorphism means existence of two or more alternative forms or variants of expressed proteins in a population

Immunogenetics immunoglobulin superfamily Polymorphic immune molecules belong to a large family of proteins that contain a globular structure motif - Ig domain. they all possess a domain known as an immunoglobulin domain or fold This group of proteins is called immunoglobulin super family

Immunogenetics There are about 40 members of immunoglobulin superfamily: Recognition and regulation molecules: Ig, BCR, TCR, MHC molecules, CD2, CD3, CD4, CD8 molécules, Fc receptors Adhesion molecules (e.g. ICAM-1, ICAM-2, VCAM-1, PECAM-1) Receptors for PDGFR (= platelet growth factor receptor) Transporter associated with antigens (TAPI and TAO2)

Immunogenetics Immunoglobulin gene superfamily Genes that encode immunoglobulins (antibodies) ; BCR, TCR on cell surface molecules ; and MHC molecules Appear to be evolutionary related genes Members of a family share a certain degree of sequence homology Are likely to have been derived from a common precursor gene

Immunogenetics as a discipline Immunogenetics can be defined as the study of genetic control of innate and adaptive host defenses against infectious microorganisms It is the study of the genetic control of the cells and molecules that mediate immune responses It focuses on: structure and organizations of genes mediating immune responses HLA antigens and their association with disease Generation of antibody diversity

Immunogenetics The most polymorphic molecules of the human immune system MHC molecules [membrane glycoproteins] Immunoglobulins [antibodies] Members of the immunoglobulin superfamily TCR (T-Cell Receptor) BCR (B-Cell Receptor)

GENES encoding Ig, BCR and TCR: germline organization Cell and Xsome carrying the genes Ig (BCR) Heavy chain locus B-cell, Chromosome # 14 Ig (BCR) Light chain locus B-cell, Xsome # 2 (k), 22 (l) TCR b chain T-cell, Xsome # 7 TCR a chain T-cell, Xsome # 14 MHC class I genes All nucleated Xsome # 6 MHC class II genes APC, Xsome # 6

Antibody Molecules Basic structure: 2 heavy chains plus 2 light chains, joined together by disulfide bridges between cysteine amino acids. The molecule has a "Y" shape, with the two ends of the fork being composed of both heavy and light chain regions. Variable regions form antigen binding sites which specifically bind particular antigens Each Ab molecule has two identical Ag binding regions, and thus the Ab molecules can bind together large groups of Ag's. This makes an insoluble complex that is easy for other cells in the immune system to find and eat.

Antibody Molecules contd.. Each light (L) chain has 2 domains, a variable (V) region and a constant (C) region. There are only a small number of C regions in each person, but there are very many different V regions. Note that the V and C regions are together on the same polypeptide chain! Each heavy (H) chain has 4 domains, a V domain followed by 3 C domains. The C domains determine the 5 classes of antibodies: IgM (early response), IgG (main blood Ig), IgA (in body secretions), IgE (allergic response), and IgD (mostly a cell surface molecule in the early response). In many cases, the constant class-specific regions of the H chains bind to receptors on the surface of specific cells. For instance, IgA binds to secretory cells so it gets secreted into tears, mucus, etc.

Immunogenetics Genes for immunoglobulin (antibodies) Expression of genes for Ig occurs in B-cells Antibody genes are composed of segments Gene of Ig heavy chain …chromosome 14 Genes for Ig kappa and lambda on chromosome 2 and 22 respectively

Immunogenetics Unique features of Ig genes Human beings and other vertebrates can respond to a limitless array of foreign proteins. Every Ab molecule contains a unique amino acid sequence in its V region, but only one of a limited number of invariable sequences in its C region. Germ-line DNA contains multiple coding sequences, called gene segments, which encode portions of a single Ig H or L chain. The gene segments are separated by noncoding regions The Ig gene segments carried in the germ cells can’t be transcribed & translated into H & L chains until they are rearranged into functional genes. Lymphocytes die during development if Ig/TCR recombination does not occur

Immunogenetics Unique features of Ig genes contd… During B-cell maturation in the bone marrow, Ig gene segments are rearranged and generated into more than 1010 combinations of V region. Each B cell has a unique combination and is antigenically committed to a specific epitope. Mature B cells no longer contain identical chromosomal DNA to germ-line DNA. After antigenic stimulation, further rearrangement of C-region gene segments can generate changes in isotypes without changing the specificity of Ig. Genomic rearrangement is an essential feature of lymphocyte differentiation, and no other vertebrate cell type has been shown to undergo this process.