Abstract
Dermatan sulfate (DS) and autoantigen (autoAg) complexes are capable of stimulating autoreactive CD5+ B1 cells. We examined the activity of DS on CD5+ pre-B lymphoblast NFS-25 cells. CD19, CD5, CD72, PI3K, and Fas possess varying degrees of DS affinity. The three pre-BCR components, Ig heavy chain mu (IgH), VpreB, and lambda 5, display differential DS affinities, with IgH having the strongest affinity. DS attaches to NFS-25 cells, gradually accumulates in the ER, and eventually localizes to the nucleus. DS and IgH co-localize on the cell surface and in the ER. DS associates strongly with 17 ER proteins (e.g., BiP/Grp78, Grp94, Hsp90ab1, Ganab, Vcp, Canx, Kpnb1, Prkcsh, Pdia3), which points to an IgH-associated multiprotein complex in the ER. In addition, DS interacts with nuclear proteins (Ncl, Xrcc6, Prmt5, Eftud2, Supt16h) and Lck. We also discovered that DS binds GTF2I, a required gene transcription factor at the IgH locus. These findings support DS as a potential regulator of IgH in pre-B cells at protein and gene levels. We propose a (DS•autoAg)-autoBCR dual signal model in which an autoBCR is engaged by both autoAg and DS, and, once internalized, DS recruits a cascade of molecules that may help avert apoptosis and steer autoreactive B cell fate. Through its affinity with autoAgs and its control of IgH, DS emerges as a potential key player in the development of autoreactive B cells and autoimmunity.
Highlights
Autoimmunity, an immune response against the body self, is an intriguing phenomenon
We have proposed that the glycosaminoglycan dermatan sulfate (DS) is a key missing player in autoimmunity in that (i) self-molecules with affinity to Dermatan sulfate (DS) have a high propensity to be autoAgs and (ii) DSautoAg complexes work in concert to stimulate autoreactive B cells [1, 2]
We provide several lines of evidence to support DS as a regulator of autoreactive B cell development at the pre-B stage via interaction with the Ig heavy chain mu (IgH) μ chain of the pre-BCR
Summary
Autoimmunity is caused by autoreactive lymphocytes and/or autoantibodies that target autoantigens (autoAgs) present in single or multiple tissue types throughout the body, leading to over 80 recognized types of autoimmune diseases, ranging from systemic diseases such as lupus and rheumatoid arthritis to organ-specific diseases such as type 1 diabetes. Several hundred autoAgs have been identified across seemingly unrelated tissue locations or biologic functions. These different autoantigens can all elicit a similar autoimmune response such as clonal expansion of autoreactive cells or production of specific autoantibodies. Better understanding of these processes will greatly advance the field of autoimmunity
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