Case 6: A Summer Project to Forget
Karen had had an exciting summer working with a wildlife biologist studying the impact of urbanization on deer populations in rural Connecticut, but she was glad to be back in Tucson for her last year of undergraduate study. As the semester progressed she became bothered by headaches, mood swings, and muscle aches that seemed to move from place to place, and several times she forgot things on exams that she knew she had studied. By winter break her knees were too swollen and painful for her daily run. Karen visited her family physician when she was home for the holidays.
Karen did not have a fever and her blood cell counts were normal. She did not have anti-nuclear antibodies or rheumatoid factor, making rheumatoid arthritis and systemic lupus erythematosus (SLE) less likely. Her knee joints were inflamed, but no tendon or muscle damage could be detected. After taking an extensive history and learning Karen had spent her summer in Connecticut, the physician suspected Lyme disease and ordered an ELISA test for serum antibodies to Borrelia burgdorferi, which were detected. Live organisms could not be isolated; although they can be cultured in vitro, B. burgdorferi are usually present in numbers too low to detect.
Borrelia burgdorferi (Bb) is a Gram negative spirochete, a corkscrew-shaped bacterium 20-30 mm long x 0.2-0.3 mm wide. It is transmitted by Ixodes ticks from its reservoir in white-footed mice and deer. The mice and deer have Bb in their blood but show no signs of disease. Bb can be transmitted by both tick nymphs and adults as they feed on humans (the figure below shows an adult male, and adult female, a nymph, and a larva). Feeding for 48-72 hours must occur for efficient spirochete transmission. Since the nymphs are colorless and the size of a pencil point, they transmit the disease more often than the adult Ixodes, even though fewer of them carry the Borrelia. The CDC has a Lyme Disease web site at http://www.cdc.gov/ncidod/dvbid/lyme/index.htm from which this photo was taken.
Bb enter the skin and multiply at the site of the bite; later they spread to the spleen, kidneys, liver, CSF, brain, and joints. Borrelia burgdorferi contains linear plasmids but does not change its antigens like its relative Borrelia recurrentis, cause of relapsing fever. Bb is invasive, using host cell integrin receptors to bind to (and possibly penetrate) host cells to move into tissues. Whether Borrelia burgdorferi lives intracellularly is uncertain.
Lyme disease was first identified in Lyme, Connecticut in 1975. Stage 1 of Lyme disease is characterized by a spreading "bull's-eye" rash at the site of the bite, which fades in 3-4 weeks. There may also be a low grade fever, chills, muscle pain and regional lymph node swelling. Some patients never get the characteristic rash. An early IgM response to flagellar protein occurs; this protein is shared by other spirochetes and Gram negative bacteria, and the antibodies do not appear to protect from infection. IgG antibody may not be detectable until Stage 2 of infection. Antibodies to outer surface proteins Osp-1 and Osp-2 appear to be protective and persist long after the infection is gone. Stage two of Lyme disease is characterized by neurological or cardiac symptoms which occur 1-4 months after the bite and usually resolve within a few months; symptoms include mood swings, memory loss, and fainting. Stage 3 Lyme disease is characterized by arthritis. Six percent of patients develop a chronic progressive arthritis that is incurable; there appears to be a genetic association between arthritis progression and HLA DR4. Because she was in Stage 3, Karen's physician prescribed intravenous penicillin G treatments. Karen developed fever, chills, and nausea immediately after the antibiotic therapy was begun, but then improved.
1. List in chronological
order beginning with infection the immune responses that Karen would make to
Borrelia burgdorferi, assuming that the bacterium remains extracellular.What
kinds of effector cells and/or effector molecules would be involved and how would
they attempt to remove Bb from Karen's body? You don't need to discuss in this
answer how these effectors are activated or produced; concentrate on what they
do and how they do it (a bulleted list is fine).
2. IgG antibodies to Osp-1 become detectable late in Stage 1 or early in Stage 2 of Lyme disease and can persist for years.
3. Is OSP a T-dependent or T-independent antigen? What information in the case leads you to that conclusion?.
4. Think about antibody production.
5. Read about the ELISA (Enzyme-Linked ImmunoSorbent Assay) to detect antibody in the Toolbox (http://microvet.arizona.edu/Courses/MIC419/ToolBox/elisa.html) and visit some of the links that illustrate the assay.
6. Read about integrins.
7. Why did Karen become ill soon after antibiotic therapy was begun? [Hint: the antibiotic would kill large numbers of bacteria and release their molecules in high amounts in the tissues and the blood - what would those molecules be? do?]
8. Describe the immune effector mechanisms that are probably responsible for Karen's arthritis. Can the same mechanisms be responsible for the skin rash and neurologic symptoms often seen in Stage 1 and Stage 2 Lyme disease? Where you can, include the following information about several cytokines which have been implicated in the progression of Lyme disease in your explanation:
Answer the questions with as much detail as possible and save as a Word document entitled YourNameCase6.doc. Send to jdecker@u.arizona.edu as an attachment by 9 AM Thursday June 24. Make sure your name is in the document as well as in the title.
Supplementary Materials : Humoral Immunity, Complement, ToolBox