Exogenous antigens enter the body via the oral, respiratory, and parenteral routes. In general, exogenous antigen are immunogenic structures expressed on extracellular bacteria, fungi, viruses, and pollens. Exogenous antigens are ingested by macrophages, and epitopes are presented in the context of class II molecules to Th2 cells. In some cases, exogenous antigens may be secretory products of bacteria or liberated on the death of the bacterium. For example, secreted protein exotoxins are both immunogenic and toxic to mammalian tissue. Lipopolysaccharide endotoxins are an integral part of the gram-negative cell wall and are released into the circulation following bacterial death.
Endogenous antigens are generated by cells infected by viruses, intracellular parasites, or tumor cells. These antigens are produced internally, processed in the cytosol, and loaded onto HLA class I molecules for presentation to CD8 cells. Antigen-specific CD8 cells then destroy the tumor cells.
Autoantigens are the result of mutation, neoantigen formation, or exposure of previously hidden self-antigens. Genes producing self-proteins can mutate and create a new immunogenic protein called neoantigen. Viral infections and drugs can create neoantigens that stimulate an immune response. In some cases, auto-reactive proteins found in organs that develop late in gestation (e.g., eyes, testes) are not present when lymphocytes undergo positive and negative selection in the thymus. Therefore, auto-reactive T cells are not selected for destruction in the thymus and enter peripheral blood. Under normal circumstances, autoantigens are protected from the immune system by anatomic barriers (e.g., testes), a lack of blood vessels, or cellular structures that force immunocompetent cells to undergo apoptosis (e.g., eyes). Trauma or infection can expose autoantigens, and the resulting immune response damages the tissue.