The Emerging Role of DNA Vaccines

W. Michael McDonnell, MD, Western Washington Medical Group, and Frederick K. Askari, MD, PhD, University of Michigan.

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In This Article

MHC Class I and MHC Class II Antigen Processing Pathways

Antigen processing and therefore the immune response to vaccines is generally divided into two systems, although considerable cross-over exists.[11] The antibody pathway is the MHC class II system or the exogenous pathway (Fig. 1). This system processes exogenous antigens that are taken up by cells and presented in such a way as to stimulate helper T-cells, which then stimulate B lymphocytes and antibody production (the humoral pathway). MHC class II molecules are present in macrophages, neutrophils, some lymphocytes, dendritic cells and other antigen presenting cells. These cells take up foreign antigen by phagocytosis or endocytosis.

I. Presentation of antigens to the immune system. The MHC class I system mediates presentation of endogenous or intracellularly-produced proteins. The MHC class II system mediates presentation of exogenous or externally-produced antigens. The MHC I pathway is used predominantly for immune presentation of endogenously synthesized proteins such as would occur following DNA immunization. Intracellular or endogenously produced proteins (1) are broken down into peptides (8 to 12 amino acids long) by spliceosomes and then directed into the endoplasmic reticulum (ER) through transport associated protein (TAP) molecules (2). Once in the ER, the peptide antigens bind to activated MHC class I molecules (3), which subsequently transport the complexes through the Golgi toward the cell surface (4). This pathway generates an immune response biased toward cell-mediated/cytotoxic CD 8+ lymphocyte activation. II. Following endocytosis, the MHC II pathway presents peptide antigens which originated outside of the cell. Extracellular or exogenous antigens are taken up into specialized antigen presenting cells (APCs) by endocytosis (5). The antigen is degraded in a lysosome (6) into immunogenic peptides which bind to MHC class II molecules (7). To produce an antibody biased immune response, the MHC class II-peptide antigen complex is transported to the cell surface (8) where it binds to CD4+ helper T cells.

MHC molecules are the gene products of the major histocompatability complex (MHC) gene locus, which was initially discovered because of its critical role in the immune response to transplanted tissue in mice. In humans this region is known as the human leukocyte antigen (HLA) system. MHC molecules are much like antibodies in that they bind to antigens. Unlike antibodies, MHC class II molecules are heterodimers with one end anchored in the cell membrane and the other available to bind specific oligopeptides, rather than the large proteins to which antibodies bind. MHC class II molecules bind antigens that are brought into the cell exogenously. This system is well-suited for detecting bacterial infections, which are primarily extracellular. Viral infections are primarily intracellular and viruses require the host cellular machinery to replicate and synthesize viral proteins. These proteins are not "exogenous" and are not available for display by the MHC class II system.

The other system of antigen presentation to the immune system is the MHC class I system, or the endogenous pathway (Fig. 1). This pathway stimulates cell-mediated immunity. The system is designed to identify and display intracellular antigens -- those proteins that are either synthesized in cells or that enter the cell through some route other than endocytosis or phagocytosis. All nucleated cells in the body express class I MHC molecules, which are located on the smooth endoplasmic reticulum. In contrast, only specified antigen presenting cells express MHC class II molecules. Intracellular proteins are cleaved into 8 to 12 amino acid-long peptides by proteosomes in the cytosol. These short peptides then enter the smooth endoplasmic reticulum via MHC-linked TAPs (transporters associated with antigen processing) where they bind to MHC class I molecules. MHC class I molecules are unique in that the recognition site is closed at either end, so that only short amino acid sequences can bind to the molecule. Therefore this system only recognizes epitopes of short amino acid sequences (secondary protein structure) and does not recognize tertiary protein structure (the overall three-dimensional shape of the native protein), as do antibodies. The MHC-antigen complex then travels through the Golgi apparatus and is expressed on the cell surface.

Once there, this complex is recognized by MHC class I restricted CD8+ cytotoxic T-cells which in turn are activated, amplified and attack cells containing the antigen. This allows for a cell- mediated immune response to "see" foreign proteins within all nucleated cells. In this way, cells infected with a virus may be detected and destroyed. A DNA vaccine designed to activate the MHC I arm of the immune system may be uniquely suited to fight viral infections.

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