Browsing by Subject "Autoantibodies"
Now showing 1 - 7 of 7
- Results Per Page
- Sort Options
Item Autoantibodies as diagnostic tools and therapeutic targets in Systemic Lupus Erythematosus(2005-04-21) Reimold, AndreasItem Evidence of B Cell Dysregulation in Early Multiple Sclerosis Patients(2017-04-04) Rivas, Jacqueline Ruth; Satterthwaite, Anne B.; Monson, Nancy L.; Stowe, Ann; Cowell, Lindsay G.; Greenberg, Benjamin M.Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For many patients experiencing partial transverse myelitis symptoms, plasmablasts are elevated in the blood and cerebrospinal fluid (CSF) at the first clinical presentation of disease. Plasmablasts are a transient subset, representing the portion of B cells currently participating in an antibody-mediated immune response. However, it has not been investigated whether these cells have the potential to participate in the autoimmune response through the expression of autoreactive receptors. In these studies, we found genetic evidence of B cell dysregulation in early MS patients, likely from a loss of peripheral tolerance, and the development of affinity maturated, autoreactive plasmablasts. Plasmablasts from these early MS patients over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, exhibit excess light chain receptor editing, and have increased mutation accumulation in IgG utilizing VH4+ cells. Many highly mutated antibodies utilizing VH4 gene segments from both CSF B cells and peripheral plasmablasts recognize neurons and glial cells. Certain peripheral cells are polyreactive, while those in the CSF are typically specific for central nervous system antigens. Other V gene families have the potential for autoreactivity as well, although the strongest binding was observed in VH4+ antibodies. The peripheral plasmablast response is directed toward cytoplasmic neuronal antigens, and this autoreactivity is detectable in the serum IgG antibody pool. Interestingly, certain mutations in six key codons along the VH4 domain correlate with polyreactivity, neuron reactivity, or glial cell reactivity. Previous work identified that the prevalence of mutations at these codons in CSF B cells predicts conversion to MS, demonstrating their likely role in progression of disease. Plasmablasts may provide a useful biomarker of B cell activation in MS, or may be direct participants in autoimmunity. In either case, the study of plasmablasts provides insight to the development of the autoreactive B cell response in early MS patients.Item The fine specificity of rheumatic disease associated autoantibodies: an aging clinical immunologist's education in modern cell biology(1988-01-28) Sontheimer, Richard D.Item The genetic origin of autoantibodies(1988-06-30) Capra, J. DonaldItem The lupus anticoagulant-anticardiolipin antibody syndrome(1988-01-21) Jasin, Hugo E.Item Public health in rheumatology: are screening and prevention possible?(2014-09-12) Karp, David R.Item Targeting the Neonatal Fc Receptor, FcRn, to Treat Autoimmunity and Elucidation of Sites of FcRn Function(2016-10-13) Challa, Dilip Kumar; Eberhart, Robert C.; Ward, E. Sally; Greenberg, Benjamin M.; Satterthwaite, Anne B.; Stüve, OlafThe neonatal Fc receptor, FcRn, is expressed in many different cell types and serves several functions, some of which are cell type-specific. A function common to most cell types that express this receptor is salvage of IgG from cellular degradation which is responsible for the long in vivo half-life of IgG. This property of IgG is responsible for its indispensable role in humoral immunity and also contributes to the successful use of IgGs as therapeutics. In autoimmunity, however, autoantibodies are generated that can contribute to pathology. FcRn-mediated salvage is also responsible for the long half-life of autoreactive IgGs. Therefore, this study employed an engineered antibody (Abdeg, a novel FcRn inhibitor) that lowers endogenous IgG levels by competing for binding to FcRn, to directly assess the effect of decreased antibody levels in an autoantibody-dependent murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Essentially, Abdeg delivery reduced the accumulation of autoantibodies in the target organs and ameliorated the disease. Autoreactive CD4+ T cells are also known to play an important role in the pathogenesis of autoimmune diseases. Thus, with the goal of inducing antigen-specific T cell tolerance, the current study employed immunoglobulin Fc engineering to develop a novel platform for the delivery of peptide epitopes as Fc-peptide fusions with different dynamic properties. Using very low doses of these engineered antigens to avoid anaphylactic shock, the study demonstrates that the longevity of the peptide antigen is the primary determinant of tolerance induction in a murine EAE model that is driven by autoreactive CD4+ T cells. Long-lived Fc-antigen fusions are effective tolerogens in both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Further, to identify the FcRn-expressing cell types that mediate the effects of Abdegs and Fc-antigen fusions on autoantibodies and autoreactive T cells, respectively, cre-loxp technology was used to generate multiple cell type-specific FcRn knockout mice. This study indicates that macrophages are the primary sites among hematopoietic cells where IgG homeostasis occurs. Collectively, these studies have led to an improved understanding of FcRn function at both the level of its sites of functional activity and targeting this receptor for therapy.