Peter Parham The Immune System Second Edition Chapter 9 Failures of the Body’s Defenses Copyright © 2005 by Garland Science Publishing Failures of the body’s defenses. Two general ways in which the body’s defenses fail to protect against infection: 1. Microorganism can escape immune response. 2. The immune system itself can fail (immunodeficiency disease). Pathogens can evade the immune system through antigenic variation. There are three main forms of antigenic variation used by pathogens. 1. existence as multiple serotypes 2. antigenic drift and antigen shift 3. gene rearrangements Streptococcus pneumoniae exists in at least 90 known serotypes Figure 9-1 Antigenic drift-The development of mutations in an antigen that alters its ability to be recognized by antibodies. Figure 9-2 part 1 of 3 Cause of flu epidemics occurring every 2-3 years Antigenic shift-genetic recombination between different strains generates new viruses with different epitopes. Figure 9-2 part 1 of 3 Occurs in influenza type A strains with a wide host range (B is human specific and doesn’t undergo antigenic shift). Can cause worldwide pandemics (every 10-15 years) Gene rearrangements – rearrangement of DNA to allow expression of different surface proteins (express different epitopes) 1. Strategy used by trypanosomes. Protozoan parasites responsible for sleeping sickness (carried by Tse Tse fly). 2. Salmonella typhimurium – causes food poisoning - expresses 1 of 2 antigenically distinct flagellins. 3. Neisseria gonorrhoeae – causes STD gonorrhea-has several variable antigen genes. Of particular importance is the pilin gene-encoded by a family of genes of which only 1 at a time is expressed. (genetic recombination occurs in a manner somewhat similar to VSG shown above but occurs mainly within a single hypervariable region) Latency-used by many viruses-strategy is to hide in the cell in an inactive state while the initial immune response dies down. Normally, a virus infects a cell and, as it replicates, some of the viral peptides are presented by MHC class I molecules. Cells are killed by CD8 cytotoxic T cells. virus infected cell CD8 T cell Some viruses enter a quiescent state called latency. Don’t generate enough virus-derived peptides to elicit a response. Virus can be reactivated and cause an episode of disease. Herpes viruses often enter latency. Herpes Simplex causes cold sores – infects epithelial cells-infection is cleared by a normal adaptive immune response. Virus spreads to sensory neurons where it persists in a latent state (neuronal cells have low levels of MHC I and the virus is making very little viral protein. The virus can be reactivated in response to stress-travels down nerve axons and reinfects the epithelial cells. Varicella-Zoster-causes chicken pox (varicella). Virus can hide in dorsal root ganglia (cell bodies for sensory branches of spinal neurons (near spinal cord)). Can be reactivated later in life to cause shingles (Zoster). Usually only occurs one time per lifetime of an individual. Epstein-Barr virus. Most people are infected with EBV at a young age, symptoms are mild, but some virus remains in B lymphocytes in a latent state for life. If infected as an adolescent or adult symptoms are much worse-causes infectious mononucleosis-infection causes the B cells to proliferate and make new virus until immune system can catch up and eliminate infected cells. Subversion of the immune system lysosome phagolysosome phagosome Mycobacterium tuberculosis – blocks fusion of the phagosome with the lysosome to protect itself. Lives inside the cell in this vesicular system. Listeria monocytogenes - escapes from the phagosome to live in the cytoplasm (makes a virulence factor called lysteriolysin). Toxoplasma gondii – generates its own vesicle inside the cells that won’t fuse with the lysosome to protect it and its peptides from being available for presentation via MHCI. Over stimulation of immune system Staphylococci produce toxins that function as superantigens like enterotoxin or toxic shock syndrome toxin-1. These molecules bind to TCR’s on many CD4 T cells and, at the same time, bind to MHC II molecules on APC’s. Immunosuppression HIV is a good example, will consider in detail later. Leprosy is an interesting example. Caused by a bacterium, Mycobacterium leprae, that infects macrophages. Tends to suppress one arm of the T cell response, either TH1 or TH2 (depending on what initial conditions are like during early phase of infection). The outcome of the infection depends on the type of immune response that is elicited during the initial infection. Suppression of the antibody response, leaving a cell-mediated TH1 response leads to a condition known as tuberculoid leprosy. TH1 cells control the infection in macrophages pretty well. Damage is localized and is largely due to inflammation. Suppression of the cell-mediated response is much more severe. The TH2-mediated antibody response is ineffective in controlling the infection and the bacteria grow in the host macrophages in an uncontrolled fashion. Causes Lepromatous leprosy.