Browsing by Subject "autoimmunity"
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Item Cellular requirements for antibody production in a novel LPS-enhanced model of autoimmune myasthenia gravis(2009-07-20) Windy Rose Allman; Premkumar Christadoss, M.D.; Stephen Higgs, Ph.D.; Socrates Tzartos, Ph.D.; Silvia Pierangali, Ph.D.; Gary Klimpel, Ph.D.Bacterial lipopolysaccharide (LPS) is a T cell-independent adjuvant known to abrogate peripheral tolerance. For the first time, the potential of LPS to induce antigenspecific B cell responses to acetylcholine receptor (AChR) in myasthenia gravis (MG) was evaluated in wild type (WT), CD4-/-, and CD8-/- C57BL/6 mice. Historically, MG\r\nhas been induced in mice by immunization with AChR emulsified in complete Freund’s\r\nadjuvant (CFA). WT mice immunized with AChR in LPS developed an MG-like disease\r\n(LPS-EAMG) similar to a disease induced by immunization with AChR in complete\r\nFreund’s adjuvant (CFA-EAMG). The CD4-/- mice were resistant to the development of\r\nCFA-EAMG, but had significantly higher frequencies of IgG expressing AChR-binding\r\nB cells than WT mice. However, CFA-AChR immunization of CD4-/- mice failed to\r\ndifferentiate these cells to secrete anti-AChR IgG. The CD4-/- mice were susceptible to\r\nthe development of LPS-EAMG and also had significantly higher frequencies of IgG\r\nexpressing AChR-binding B cells than WT mice. WT and CD4-/- mice in the LPSEAMG\r\nmodel had significant amounts of secreted high-affinity anti-AChR IgG2,\r\nimmune complex deposits (IgG, C3, MAC) in muscle, and elevated sera levels of the Bcell survival factor, BAFF. Our results indicate that LPS abrogated B cell differentiation\r\nto antibody secreting cells in the LPS-EAMG model. Furthermore, CD8-/- mice were\r\nalso susceptible to the development of LPS-EAMG, but were resistant to the development of moderate or severe signs of EAMG. While CD8 deficiency did not affect the quantity or avidity of secreted anti-AChR antibodies, it significantly reduced the\r\nsurvival of circulating IgG expressing AChR-binding B cells. The findings, accordingly\r\nhave allowed us to identify an alternate cellular mechanism for the development of EAMG.Item The effects of psychological stress on an animal model of multiple sclerosis, Theiler's virus induced demyelination(Texas A&M University, 2005-02-17) Sieve, Amy NicoleMultiple Sclerosis (MS) is the most common demyelinating condition of the central nervous system (CNS), resulting in paralysis and death. The etiology of MS is unknown. However, genetics, exposure to a pathogen, psychological stress and gender are all implicated in the onset and progression of the disease. An animal model of MS, Theiler?s virus (TMEV) infection, causes a biphasic disease. An early CNS viral infection, if allowed to persist within the CNS, is followed by a chronic CNS autoimmune demyelinating condition that is similar to MS. The development of Theiler?s Virus Induced Demyelination (TVID) is under genetic control: SJL mice are highly susceptible to viral persistence and TVID while CBA mice have an intermediate susceptibility. Chronic restraint stress (RST) administered during the first four weeks of TMEV infection influenced the subsequent development of TVID differentially across strain and sex of mice. TVID was exacerbated by RST in male and female SJL mice, but in the CBA strain, TVID was alleviated by RST in male mice only. This pattern of results in SJL and CBA mice could be seen in the chronic phase of TVID on multiple dependent measures: body weights, behavioral signs of the chronic phase, rotarod performance (an automated measure of motor abilities), and inflammation, demyelination, and axonal loss within the spinal cord. The exacerbation of TVID in SJL mice provides some of the first experimental evidence that coincides with reports of stress precipitating the onset of MS in human patients. The sex dependent alleviation of TVID in CBA mice illustrates the complex interaction between genetic predisposition, gender, stress, and exposure to a pathogen that has been proposed for the development of MS.