Acute Lyme disease is characterized by fever, a migratory “bull’s eye” skin rash, muscle and joint pains, often with evidence of meningeal irritation. In a chronic form evolving over several years meningoencephalitis, myocarditis, and a disabling recurrent arthritis may develop. B.burgdorferi is transmitted to humans by Ixodes ticks.
B. burgdorferi existsin a complexcycle involvingticks, mice, and deer. Lyme diseaseoc-curs when the ticks feed on humans who enter their wooded habitat. The disease is en-demic in several regions of the United States, Canada, and temperate Europe and Asia. Approximately 90% of the 10,000 to 15,000 cases reported each year in the United States occur in areas along the northeastern and mid-Atlantic seaboard, including Old Lyme, Connecticut, where the disease was first recognized. The majority of cases probably go unreported, particularly outside the primary endemic regions.
The primary reservoir of B.burgdorferi is rodents, particularly white-footed mice. In-fection is transmitted by Ixodes ticks, whose complete life cycle involves rodents for the early stages and deer for adult maturation. In the spring, fertile female ticks, engorged from their blood meals, fall from their deer hosts to the ground and deposit their eggs. During the summer, the tick larvae seek out and obtain a blood meal from mice and the B.burgdorferi ingested by the larvae are maintained through the subsequent developmentstages of the tick. The following spring or summer, the small (1 to 2 mm) nymphs feed again on vertebrate hosts to obtain the blood required for maturation to adulthood. The engorged, satiated nymphs fall off their hosts and mature into adults by parasitizing avail-able deer, thus completing a life cycle that has occupied a full 2 years. Vertebrates other than deer can be infected by both the adult and nymph stages of the tick, but human Lyme disease is acquired primarily from nymphs, because they are active at the time of year when humans are most likely to invade their ecosystem. Deer are essential to the mating and survival of the tick and thus the disease does not occur in areas in which deer are not abundant.
Because Lyme disease is a recently discovered disease with a complex biology, it is not surprising that the pathogenic mechanisms in humans remain to be established clearly. Studies in ticks have shown changes in the antigenic makeup of B. burgdorferi as it migrates from the midgut and salivary glands and again after it reaches mam-malian tissue. OspA is the major outer surface protein expressed when B. burgdorferi resides in ticks, but its expression diminishes during tick engorgement, while OspC in-creases, so that by the time of transmission to hosts, OspC predominates. Although OspC has been shown to stimulate protective antibody in animals, its role in disease is unknown.
Some candidate adhesins of B. burgdorferi could be important in the early stages of human infection. These surface proteins and lipoproteins have been shown to medi-ate attachment to integrins, platelets, and collagen-associated elements of the extracel-lular matrix (ECM). Other molecules which bind plasmin to the spirochete surface may activate host proteolytic systems and facilitate spread through the ECM to adja-cent tissues. It is known that the outer membrane of the spirochete contains proteins and a toxic lipopolysaccharide that differs from the usual Gram-negative endotoxin. The spirochetal peptidoglycan has inflammatory properties, survives considerable pe-riods in tissues, and may contribute to arthritis when deposited in joint tissues.
Clinical investigations in patients with Lyme disease have noted modulation of im-mune responses, including inhibition of mononuclear and natural killer cell function, lymphocyte proliferation, and cytokine production. The ability of B. burgdorferi to downregulate deleterious immune responses could serve as a survival strategy or play a role in chronic disease. Chronic disease, particularly Lyme arthritis, has aspects of au-toimmunity. One candidate cross-reactive autoantigen is OspA. The sera of individuals with Lyme arthritis but not other forms of arthritis react with epitopes present in OspA and with homologous epitopes in human leukocyte antigens (HLAs). A genetic basis for this linkage is suggested by the statistical association between chronic arthritis and certain HLA types. Such theories must be reconciled with the downregulation of OspA in mammalian infection and clarification of the role of many other candidate virulence factors.
The immune response to B. burgdorferi infection develops slowly with IgM followed by IgG antibody over weeks to months. Although immune-mediated killing by the classical complement pathway has been demonstrated the molecular target is unknown. Host neu-trophils and macrophages can phagocytose opsonized spirochetes and induce a metabolic burst leading to spirochetal death. OspC elicits protective immunity in rodents, but this protection is short lived and ineffective against challenge with heterologous B. burgdorferi isolates. Antigens capable of eliciting broadly protective immune responses have not been identified.
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