What is the source of self-reactive B cells in the periphery? We have demonstrated that inflammation influences early B cell development by inducing early emigration into the blood and peripheral lymphoid tissues. This mobilization is mediated by IL-1 and TNFalpha and is correlated with increases in the frequency of auto-reactive peripheral B cells. Some evidence suggests that auto-antibody responses, even those characterized by lg class-switched (CSR) and hypermutated (SHM) antibody may bypass the germinal center (GC) reaction. In humans and mice, AID expression is generally believed to be restricted to B cells within GC where lg somatic hypermutation (SHM) and class-switch recombination (CSR) are most active. In birds, rabbits, and sheep AID expression in fetal tissues diversifies the primary antibody repertoire by gene conversion and/or SHM in the absence of activation by exogenous antigens. Recently, we and others demonstrated that immature and transitional B cells in mice constitutively express AID. AID levels are low in these developmental^ immature cells, but sufficient to drive CSR and SHM. We have now demonstrated similar levels of AID expression in human immature and transitional B cells, and most remarkably, in human fetal liver (FL). Indeed, the quantity of AID message (normalized to Igbeta) in FL is comparable to that of human tonsil, a tissue highly enriched for GC B cells. We shall investigate developmentally regulated AID expression in human pro-, pre-, and immature/transitional B cells to determine the consequences of early AID expression, and especially its role in the generation of auto-reactive, peripheral B lymphocytes. These experiments in normal subjects will be extended to patients with autoimmune disease and may reveal another pathway leading to mutated, self-reactive B cells that mature outside the normal boundaries of central tolerance.
We shall study the effects of inflammation on B-cell development and the acquisition self-reactivity. Our studies will be important in understanding pathogenesis of systemic auto-immune diseases, especially SLE, myasthenia gravis, and Goodpasture's syndrome.
|Su, Kuei-Ying; Watanabe, Akiko; Yeh, Chen-Hao et al. (2016) Efficient Culture of Human Naive and Memory B Cells for Use as APCs. J Immunol 197:4163-4176|
|Cui, Ang; Di Niro, Roberto; Vander Heiden, Jason A et al. (2016) A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data. J Immunol 197:3566-3574|
|Cao, Yonghao; Amezquita, Robert A; Kleinstein, Steven H et al. (2016) Autoreactive T Cells from Patients with Myasthenia Gravis Are Characterized by Elevated IL-17, IFN-Î³, and GM-CSF and Diminished IL-10 Production. J Immunol 196:2075-84|
|Haddon, David James; Jarrell, Justin Ansel; Diep, Vivian K et al. (2015) Mapping epitopes of U1-70K autoantibodies at single-amino acid resolution. Autoimmunity 48:513-23|
|Kountikov, Evgueni I; Poe, Jonathan C; Maclver, Nancie J et al. (2015) A spontaneous deletion within the desmoglein 3 extracellular domain of mice results in hypomorphic protein expression, immunodeficiency, and a wasting disease phenotype. Am J Pathol 185:617-30|
|Hall 3rd, R P; Fairley, J; Woodley, D et al. (2015) A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone. Br J Dermatol 172:760-8|
|Aranow, Cynthia; Kamen, Diane L; Dall'Era, Maria et al. (2015) Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus. Arthritis Rheumatol 67:1848-57|
|Nair, Nitya; Mei, Henrik E; Chen, Shih-Yu et al. (2015) Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy. Arthritis Res Ther 17:127|
|Ci, Xinxin; Kuraoka, Masayuki; Wang, Hongxia et al. (2015) TSC1 Promotes B Cell Maturation but Is Dispensable for Germinal Center Formation. PLoS One 10:e0127527|
|Labowsky, Michael; Lowenthal, Justin; Fahmy, Tarek M (2015) An in silico analysis of nanoparticle/cell diffusive transfer: application to nano-artificial antigen-presenting cell:T-cell interaction. Nanomedicine 11:1019-28|
Showing the most recent 10 out of 141 publications