Show simple item record

dc.contributor.advisorStüve, Olafen
dc.creatorMayeux, Jessicaen
dc.date.accessioned2016-09-01T19:35:08Z
dc.date.available2016-09-01T19:35:08Z
dc.date.created2014-08
dc.date.issued2014-07-25
dc.date.submittedAugust 2014
dc.identifier.urihttps://hdl.handle.net/2152.5/3597
dc.description.abstractSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nuclear antigens. Hyperactive B cells are present in SLE patients and murine models of lupus, many of which have defects in inhibitors of B cell receptor (BCR) signaling or plasma cell differentiation. Autoantibodies against a wide range of self antigens contribute to the pathogenesis of SLE and are used to diagnose SLE, determine prognosis, and predict specific disease manifestations. Autoantibodies form immune complexes which deposit in the kidney and joints, resulting in glomerulonephritis and arthritis, respectively. Autoantibodies against antigens in the CNS can cause Neuropsychiatric SLE manifestations, such as psychosis, memory loss, seizures, strokes, and mood disorders. Human SLE patients and murine models of lupus are used here to identify novel autoantibodies in SLE and to better understand the mechanisms by which autoantibodies accumulate in SLE. Protein arrays can be used to identify autoantibodies and autoantigens that are targeted in SLE patients. Using this approach, we identified Stress Induced Phosphoprotein 1 (STIP1) as an autoantigen in a subset of SLE patients. Those patients with elevated levels of anti-STIP1 IgG autoantibodies in their serum were less likely to have parameters associated with more severe disease, suggesting a protective role for anti-STIP1 IgG. In addition, I defined a genetic interaction between the src tyrosine kinase, Lyn, and the Ets family transcription factor, Ets1, in autoimmunity. Lyn is both a positive and negative regulator of BCR signaling; however its net effect is inhibitory. Lyn deficiency results in hyperactive B cells and Lyn-/- mice serve as a murine model of SLE. Ets1 is a regulator of plasma cell differentiation, and Ets1-/- mice have a similar phenotype to Lyn-/- mice. Lyn and Ets1 are in a shared pathway in which Lyn maintains Ets1 levels, thus limiting plasma cell accumulation. Compound heterozygotes of Lyn and Ets1 were used to determine whether partial loss of Lyn and Ets1 results in accelerated autoimmunity. Lyn and Ets1 were found to synergize in limiting the accumulation of activated and memory T cells, myeloid dendritic cells, age associated B cells, and IgM, but not IgG autoantibodies.en
dc.format.mimetypeapplication/pdfen
dc.language.isoenen
dc.subjectAntibodiesen
dc.subjectLupus Erythematosus, Systemicen
dc.subjectProtein-Tyrosine Kinasesen
dc.subjectProto-Oncogene Protein c-ets-1en
dc.subjectsrc-Family Kinasesen
dc.titlePathogenic and Protective Potential of B Cell Dysregulation in Systemic Lupus Erythematosusen
dc.typeThesisen
dc.date.updated2016-09-01T19:10:07Z
dc.type.materialtexten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.nameDoctor of Philosophyen
thesis.degree.levelDoctoralen
thesis.degree.disciplineImmunologyen
dc.contributor.committeeMemberSatterthwaite, Anne B.en
dc.contributor.committeeMemberMohan, Chandraen
dc.contributor.committeeMemberMonson, Nancy L.en
dc.contributor.committeeMemberDavis, Laurieen
dc.identifier.oclc957676348


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record