Guillain Barré Syndrome (GBS) is a symmetrical ascending paralysis that often follows viral or bacterial infection. The foodborne pathogen Campylobacter jejuni is the most common infection that triggers GBS, but C. jejuni is mainly linked to one variant within a complex syndrome: Acute Motor Axonal Neuropathy (AMAN). One third of AMAN patients have IgG autoantibodies against neurogangliosides GM1 and GD1a; binding of these antibodies to peripheral nerves is thought to initiate nerve damage. Other GBS variants include Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Acute Motor and Sensory Axonal Neuropathy (AMSAN), and Miller Fisher Syndrome (MFS). The triggers for these disorders are not known and a large number of potential infectious and noninfectious initiating causes have been implicated. In addition to C. jejuni, bacteria such as Mycoplasma pneumonia and Haemophilus influenzae and viruses such as Cytomegalovirus and Influenza have been associated with GBS. GBS disease is monophasic; recurrence is rare, but has been reported. Patients in the initial stages of GBS report headache and joint pain. Tingling and numbness of extremities is followed by segmental ascending paralysis. Pain involving the extremities occurs later in the course of the disease and can be directly correlated with disease severity. The worst manifestation is paralysis of the muscles of respiration necessitating artificial respiration. Some GBS cases resolve, however, recent reports indicate that 20% of patients struggle with continuing disabilities. There is no cure and the death rate is 5%0303. Currently, treatment is symptomatic and consists of plasmapharesis and assisted ventilation for those patients with respiratory distress demonstrating the need for new approaches. In the AMAN form of GBS, molecular mimicry is thought to play a role in the production of anti-ganglioside antibodies, which bind to and trigger attack on host nerve tissue. Both in humans and in animal models, the immune response to the bacterium results in production of anti-ganglioside antibodies that leads to damage of nerves and Wallerian-like degeneration; such "autoantibodies" have been shown to bind to motor neurons, nodes of Ranvier, and neuromuscular junctions. Little progress has been made in understanding the pathogenesis of GBS and even less in developing effective therapies, largely because of the lack of tractable animal models that mimic natural human disease. Susceptible inbred mice would provide the ideal model in which the interplay of host and pathogen genetics in GBS pathogenesis could be explored. Non-Obese Diabetic (NOD) inbred mice have been documented to develop autoimmune diabetes mediated by auto-reactive T cells infiltrating the pancreas as well as autoimmune diseases of the salivary glands and thymus. Additionally, NOD mice deficient for the co-stimulatory molecule B7-2-/- are largely protected from autoimmune diabetes but develop a spontaneous autoimmune peripheral polyneuropathy (SAPP) called chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) that resembles GBS. A mouse model of Spontaneous Autoimmune Peripheral Polyneuropathy (SAPP) that mimics many aspects of human GBS has been identified. The short term goal of this body of work is to characterize the inflammatory responses that result in this spontaneous murine GBS with peripheral nerve lesions and to begin to determine mechanisms leading to this endpoint. The overarching goal is to use this mouse model to manipulate the onset and clinical severity of the disease, and screen new potential treatments for GBS that could reduce morbidity and mortality in human patients.
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