What are immunogenetics? |

Genes, B Cells, and Antibodies

The fundamental question that led to the development of immunogenetics relates to how scientists are able to make the thousands of specific antibodies that protect people from the thousands of organisms with which they come in contact. Frank Macfarlane Burnet
proposed the clonal selection theory, which states that an antigen (that is, anything not self, such as an invading microorganism) selects, from the thousands of different B cells, the receptor on a particular B cell that fits it like a key fitting a lock. That cell is activated to make a clone of plasma cells, producing millions of soluble antibodies with attachment sites identical to the receptor on that B-cell surface. The problem facing scientists who were interested in a genetic explanation for this capability was the need for more genes than the number that was believed to make up the entire human genome.

It was Susumu Tonegawa who first recognized that a number of antibodies produced in the lifetime of a human did not have to have the equivalent number of physical genes on their chromosomes. From his work, it was determined that the genes responsible for antibody synthesis are arranged in tandem segments on specific chromosomes relating to specific parts of antibody structure. The amino acids that form the two light polypeptide chains and the two heavy polypeptide chains making up the IgG class of antibody are programmed by nucleotide sequences of DNA that exist on three different chromosomes. Light-chain genes are found on chromosomes 2 and 22. The specific nucleotide sequences code for light polypeptide chains, with half the chain having a constant amino acid sequence and the other half having a variable sequence. The amino acid sequences of the heavy polypeptide chains are constant over three-quarters of their length, with five basic sequences identifying five classes of human immunoglobulins: IgG, IgM, IgD, IgA, and IgE. The other quarter length has a variable sequence that, together with the variable sequence of the light chain, forms the antigen-binding site. The nucleotide sequence coding for the heavy chain is part of chromosome 14.

The actual light-chain locus is organized into sequences of nucleotides designated variable (V), joining (J), and constant (C) segments. The multiple options for the different V and J segments and mixing the different V and J segments cause the formation of many different DNA light-chain nucleotide sequences and the synthesis of different antibodies. The same type of rearrangement occurs between a variety of nucleotide sequences related to the V, diversity (D), and J segments of the heavy-chain locus. The recombination of segments appears to be genetically regulated by recombination signal sequences downstream from the variable segments and recombination activating genes that function during B-cell development. Genetic recombination is complete with the immature B cell committed to producing one kind of antibody. The diversity of antibody molecules is explained by the fact that the mRNA transcript coding for either the light polypeptide chain or the heavy polypeptide chain is formed containing exons transcribed from recombined gene segments during B-cell differentiation. The unique antigen receptor-binding site is formed when the variable regions of one heavy and one light chain come together during the formation of the completed antibody in the endoplasmic reticulum of the mature B cell. The B-cell antigen receptor is an attached surface antibody of the IgM class. Binding of the antigen to the specific B cell activates its cell division and the formation of a clone of plasma cells that produce a unique antibody. If this circulating B cell does not contact its specific antigen within a few weeks, it will die by apoptosis. During plasma cell formation, the class of antibody protein produced normally switches from IgM to IgG through the formation of an mRNA transcript containing the exon nucleotide sequence made from the IgG heavy-chain C segment rather than the heavy-chain C segment for IgM. The intervening nucleotide sequence of the IgM constant segment is deleted from the chromosome as an excised circle reminiscent of the transposon or plasmid excision process. The result of this switch is the formation of an IgG antibody having the same antigen specificity as the IgM antibody, because the variable regions of the light and heavy polypeptide chains remain the same. Although the activation and development of B cells by some antigens may not need T-cell involvement, it is believed that class switching and most B-cell activity are influenced by T-cell cytokines.

Major Histocompatibility Genes

In humans, the major histocompatibility genes encoding “self antigens” are also called the HLA complex and are located on chromosome 6. The nucleotides that compose this DNA complex encode for two sets of cell surface molecules designated MHC Class I and MHC Class II antigens. The Class I region contains loci A, B, and C, which encode for MHC Class I A, B, and C glycoproteins on every nucleated cell in the body. Because the A, B, and C loci comprise highly variable nucleotide sequences, numerous kinds of A, B, and C glycoproteins characterize humans. All people inherit MHC Class I A, B, and C genes as a haplotype from each of their parents. Children will have tissues with half of their Class I A, B, and C antigens like those of their mother and half like those of their father. Siblings could have tissue antigens that are identical or totally dissimilar based on their MHC I glycoproteins. Body surveillance by T lymphocytes involves T cells recognizing self glycoproteins. Cellular invasion by a virus or any other parasite results in the processing of an antigen and its display in the cleft of the MHC Class I glycoprotein. T cytotoxic lymphocytes with T-cell receptors specific for the antigen-MHC I complex will attach to the antigen and become activated to clonal selection. Infected host cells are killed when activated cytotoxic T cells bind to the surface and release perforins, causing apoptosis.

MHC Class II genes are designated HLA-DPA1 and HLA-DPB1, HLA-DQA1 and HLA-DQB1, and HLA-DRA and HLA-DRB1. These genes encode for glycoprotein molecules that attach to the cell surface in α and β pairs. A child will inherit the six genes as a group or haplotype, three α and β glycoprotein gene pairs from each parent. The child will also have glycoprotein molecules made from combinations of the maternal and paternal α and β pairings during glycoprotein synthesis.

The Class II MHC molecules are found on the membranes of macrophages, B cells, and dendritic cells. These specialized cells capture antigens and attach antigen peptides to the three-dimensional grooves formed by combined α and β glycoprotein pairs. The antigen attached to the Class II groove is presented to the T helper cell, with the receptor recognizing the specific antigen in relation to the self antigen. The specific T helper cell forms a specific clone of effector cells and memory cells.

Genes, T Helper Cells, and T Cytotoxic Cells

The thousands of specific T-cell receptors (TCR) available to any specific antigen one might encounter in a lifetime are formed in the human embryonic thymus from progenitor T cells. The TCR comprises two dissimilar polypeptide chains designated α and β or γ and δ. They are similar in structure to immunoglobulins and MHC molecules, having regions of variable amino acid sequences and constant amino acid sequences arranged in loops called domains. This basic structural configuration places all three types of molecules in a chemically similar grouping designated the immunoglobulin superfamily. The genes of these molecules are believed to be derived from a primordial supergene that encoded the basic domain structure.

The exons encoding the α and γ polypeptides are designated V, J, and C gene segments in sequence and associate with recombination signal sequences similar to the immunoglobulin light-chain gene. The β and δ polypeptide genes are designated VDJ and C exon segments in sequence associating with recombination signal sequences similar to the immunoglobulin heavy-chain genes. Just as there are multiple forms for each of the immunoglobulin variable gene segments, so there are multiple forms for the variable TCR gene segments. Thymocytes, T-cell precursors in the thymus, undergo chance recombinations of gene segments. These genetic recombinations, as well as the chance combination of a completed α polypeptide with a completed β polypeptide, provide thousands of completed specific TCRs ready to be chosen by an invading antigen and to form a clone of either T helper cells or T cytotoxic cells.

Immunogenetic Disease

The HLA genes of the major histocompatibility complex identify every human being as distinct from all other things, including other human beings, because of the MHC Class I and Class II antigens. Surveillance of self involves B- and T-cell antigen recognition because of MHC self-recognition. How well individual human beings recognize self and their response to antigen in an adaptive immune response are determined by MHC haplotypes as well as the genes that make immunoglobulins and T-cell receptors. These same genes can explain a variety of disease states, such as autoimmunity, allergy, and immunodeficiency.

Because immunoglobulin structure and T-cell receptor formation are based on a mechanism of chance, problems involving self-recognition may occur. It is currently believed that thymocytes with completed T-cell receptors are protected from apoptosis when they demonstrate self-MHC molecule recognition. Alternatively, it is believed that thymocytes are also presented with self-antigens processed by specialized macrophages bearing MHC Class I and Class II molecules. Thymocytes reacting with high-affinity receptors to processed self-antigens undergo apoptosis. There also appears to be a negative selection process within the bone marrow that actively eliminates immature B cells with membrane-bound autoantibodies that react with self-antigens. In spite of these selective activities, it is believed that autoreactive T cells and B cells can be part of circulating surveillance, causing autoimmune disease of either single organs or multiple tissues.

It has long been recognized that autoimmune diseases occur in families, and there is growing evidence that an individual with a certain HLA haplotype has a greater risk for developing a particular disease. For example, ankylosing spondylitis develops more often in individuals with HLA-B27 than in those with another HLA-B allele, and rheumatoid arthritis is associated with several common HLA-DRB1 alleles. Myasthenia gravis and multiple sclerosis are two neurological diseases caused by autoantibodies, and there is evidence that they are related to restricted expression of T-cell variable genes. Genomic studies are providing evidence for the possibility that autoimmune induction occurs because of molecular mimicry between human host proteins and microbial antigens. Among the cross-reacting antigens that have been implicated are papillomavirus E2 and the insulin receptor, and poliovirus VP2 and the acetyl choline receptor.

The genetics of immunity also involves the study of defective genes that cause primary immunodeficiency infectious disease. The deficiency can result in a decrease in an adaptive immune response involving B cells, T cells, or both, as is the case with severe combined immunodeficiency disorder (SCID). There is evidence that SCID can demonstrate either autosomal recessive or X-linked inheritance. One such defect has been located on the short arm of chromosome 11 and involves a mutation of recombination-activating genes that are necessary for the rearrangement of immunoglobulin gene segments and the T-cell receptor gene segments. The inability to recombine the VD and J variable segments prevents the development of active B cells and T cells with the variety of antigen receptors. SCID is essentially incompatible with life and characterized by severe opportunistic infections caused by even normally benign organisms.

Allergies are widely understood to have a genetic component, with the understanding that atopy, an abnormal IgE response, is common to certain families. There is evidence that children have a 30 percent chance of developing an allergic disease if one parent is allergic, while those children with two allergic parents have a 50 percent chance. The genetic control of IgE production can be related to TH2 lymphocyte cytokine stimulation of class switching from the constant segment of IgG to the constant segment of IgE on chromosome 14 in an antigen selected cell undergoing clonal selection.

Impact

Understanding the genetic basis for immune reactions is resulting in novel approaches to protection against disease and improvements in health. Researchers are pursuing the development of therapeutics aimed at controlling B cell responses in autoimmune diseases and IgE responses in allergic reactions. Clinical laboratories are providing detailed histocompatibility and immunogenetics testing for solid organ and stem cell transplantation and blood and platelet transfusions to reduce the incidence and severity of graft-versus-host disease.

Immunotherapy is increasingly used to capitalize on a person’s immune system to fight cancers or infectious diseases, either by actively stimulating the production of natural antibodies or by passively introducing antibodies specifically engineered in a laboratory. With active stimulation, specific immunity may be induced with vaccines or nonspecific immunity may be induced with interferons or interleukins. Passive stimulation is achieved with monoclonal antibodies that target specific cell-surface antigens. Several therapeutic monoclonal antibodies have been approved for use in humans by the US Food and Drug Administration (FDA), particularly in the treatment of colorectal cancer, non-Hodgkin lymphoma, and some types of leukemia. Conversely, other therapeutic monoclonal antibodies have been produced and marketed to suppress immune responses in diseases such as rheumatoid arthritis and allergic asthma. Using related technology, researchers are trying to develop biomarkers that will track the progression of immune disorders and measure their response to various treatment modalities.

Immunogenetics has led to new fields of study in public health, such as medical anthropology, which includes attempting to determine how people of certain races or ethnicities are genetically predisposed to certain diseases. Another new field of study is the immunology of aging, which includes attempting to determine the effect of genetic variation on the natural aging process. One noteworthy issue in this field is how to boost the immune response in the elderly to vaccines, especially those for influenza and pneumonia.

Key Terms




apoptosis


:

cell death that is programmed as a natural consequence of growth and development through normal cellular pathways or through signals from neighboring cells





cytokines


:

soluble intercellular molecules produced by cells such as lymphocytes that can influence the immune response




downstream

:

describes the left-to-right direction of DNA whose nucleotides are arranged in sequence with the 5′ carbon on the left and the 3′ on the right; the direction of RNA transcription of a genetic message with the beginning of a gene on the left and the end on the right




haplotype

:

a sequential set of genes on a single chromosome inherited together from one parent; the other parent provides a matching chromosome with a different set of genes





monoclonal antibodies


:

antibodies with one highly specific target that have been generated in large quantities from a single hybrid parent cell formed in a laboratory





transposon


:

a sequence of nucleotides flanked by inverted repeats capable of being removed or inserted within a genome





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