Genetics of the Immune System and Transplantation Genetics

1 The immune system defends us against armies of microorganisms that, numerically, dwarf the human population. In order to understand the inherited disorders of immunity we must look at the fundamentals of the genetic basis of immunity. Immune defense mechanisms can be divided into two main types:   innate immunity specific acquired or adaptive immunity 2 innate immunity, which includes a number of nonspecific systems that do not require or involve prior contact with the infectious agent specific acquired or adaptive immunity, which involves a tailor-made immune response that occurs after exposure to an infectious agent  Both types can involve either   humoral immunity, which combats extracellular infections cell-mediated immunity, which fights intracellular infections. 3 The first simple defense against infection is the mechanical barrier of the skin, which functions most of the time as an impermeable barrier but in addition, the acidic pH of sweat is inhibitory to bacterial growth. Mucus membranes line the respiratory and gastrointestinal tracts, and the respiratory tract is further protected by ciliary movement. 4 Two types of response: - Humoral immune response - Cellular immune response 5 The main mediators of humoral specific acquired immunity are immunoglobulins, or antibodies. Antibodies are able to recognize and bind to surface antigens of infecting microorganisms. 6 The immunoglobulins, or antibodies, are one of the major classes of serum protein. Secreted by B lymphocytes Great diversity and specificity: >1011 different antibodies; can distinguish between very similar molecules 7 Papain, a proteolytic enzyme, splits the immunoglobulin molecule into three fragments.   Two of the fragments are similar, antigen-binding fragment or Fab. The third fragment can be crystalized and was called Fc, and this component determines the secondary biological functions of antibodies, binding complement and Fc receptors on different cell types involved in the immune response. 8 9 the V regions show four regions that vary little from one antibody to another, known as framework regions (FR 1–4), and three markedly variable regions interspersed between these, known as hypervariable regions (HV I–III) 10 There are five different types of heavy chain, designated respectively as γ, μ, α, δ, and ε, one each for the five major antibody classes—the isotypes—IgG, IgM, IgA, IgD, IgE. The L chains are of two types—kappa (κ) or lambda (λ), and these occur in all five classes of antibody, but only one type occurs in each individual antibody. Thus, the molecular formula for IgG is λ2γ2 or κ2γ2. 11     there are four IgG subclasses—IgG1, IgG2, IgG3, and IgG4 two IgA subclasses—IgA1 and IgA2 The subclasses differ in their amino acid sequence and interchain disulfide bonds. Individual antibody molecules that recognize specific antigens are known as idiotypes. 12 13 monomer pentamer dimer J chain J chain IgG, IgD, IgE IgA IgM 14 In 1965 Dreyer and Bennett proposed that an antibody could be encoded by separate ‘genes’ in germline cells that undergo rearrangement or, as they termed it, ‘scrambling’, in lymphocyte development. Light Chain 1. Variable region 2. Junctional region 3. Constant region Heavy Chains plus 4. Diversity region 15 The genes for the κ and λ L-chains and the H-chains are located on chromosomes 2, 22, and 14, respectively. Only one of each of the relevant types of DNA segment is expressed in any single antibody molecule. The DNA coding segments for the various portions of the antibody chains on these chromosomes are separated by DNA that is non-coding. 16 There is a normal switch of antibody class produced by B cells on continued, or further, exposure to antigen—from IgM, the initial class of antibody produced in response to exposure to an antigen, to IgA or IgG. This class switching retains specificity of the antibody to the same antigen. 17 Analysis of class switching in a population of cells derived from a single B cell has shown that both classes of antibody have the same antigen-binding sites, having the same V region but differing only in their C region. Class switching occurs by a somatic recombination event that involves DNA segments, designated S (for switching), that lead to looping out and deletion of the intervening DNA. The result is to eliminate the DNA segment coding for the C region of the H-chain of the IgM molecule, and to bring the gene segment encoding the C region of the new class of H-chain adjacent to the segment encoding the V region 18 19 14q23 2P13 22q11 20 21 22 The MHC plays a central role in the immune system. Its role is to bind antigen peptides processed intracellularly and present this material on the cell surface, with costimulatory molecules, where it can be recognized by T cells. MHC molecules occur in three classes:    class I occur on virtually all cells and are responsible for presenting cytotoxic T cells; class II occur on B cells and macrophages and are involved in signaling T-helper cells to present further B cells and macrophages; the nonclassic class III molecules include a number of other proteins with a variety of other immunological functions 23 MAJOR HISTOCOMPATIBILITY COMPLEX is a large group of genes on chromosome 6 24 Structural analysis of class I and II MHC molecules reveal them to be heterodimers with homology to immunoglobulin. The genes coding for the class I (A, B, C, E, F, and G), class II (DR, DQ, and DP) and class III MHC molecules, or what is also known as the human leukocyte antigen (HLA) system, are located on chromosome 6. 25 Class I molecules are made up of one heavy chain (45 Kd) and a light chain called ß2microglobulin (12 KD) that contributes to the overall structure of the protein 26 27   Class II molecules do not contain ß2microglobulin and consist of two alpha and ß chains of similar size (34 and 30 kD) Both classes of MHC molecule fold up to produce very similar 3-D structures 28 29 Organ transplantation has become routine in clinical medicine and, with the exception of corneal and bone grafts, success depends on the degree of antigenic similarity between donor and recipient. The closer the similarity, the greater the likelihood that the transplanted organ or tissue (the homograft), will be accepted rather than rejected. Homograft rejection does not occur between identical twins or between non-identical twins where there has been mixing of the placental circulations before birth 30 In all other instances, the antigenic similarity of donor and recipient has to be assessed by testing them with suitable antisera or monoclonal antibodies for antigens on donor and recipient tissues. These were originally known as transplantation antigens but are now known to be a result of the MHC. As a general rule, a recipient will reject a graft from any person who has antigens that the recipient lacks. HLA typing of an individual is carried out using PCR based techniques 31 The HLA system is highly polymorphic. A virtually infinite number of phenotypes resulting from different combinations of the various alleles at these loci are theoretically possible. Two unrelated individuals are therefore very unlikely to have identical HLA phenotypes 32 any individual will have a 25% chance of having identical HLA antigens with a sibling, as there are only four possible combinations of the two paternal 33 • In any mating, four possible combinations of haplotypes can be found in the offspring; thus siblings are also likely to differ in the MHC allele they express. • Halplotype: The particular combination of MHC alleles found on a given chromosome 6. 34 35 The immune system reacts to grafted tissue recognized as foreign by trying to destroy it Graft versus host disease - Occurs in bone marrow transplants - Immune cells of the grafted bone marrow recognize host body as foreign and attack it 36 In a number of different animal species Tissue grafts from males were rejected by females of the same inbred strain. Due to a histocompatibility antigen known as H-Y.  H-Y seems to play little part in transplantation in humans. The H-Y antigen, aka Müllerian Inhibiting Factor (MIF), which is not the SRY gene, is important for testicular differentiation and function, but its expression does not correlate with the presence or absence of testicular tissue. 37 38