TY - JOUR
T1 - Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients
AU - Rivas, Jacqueline R.
AU - Ireland, Sara J.
AU - Chkheidze, Rati
AU - Rounds, William H.
AU - Lim, Joseph
AU - Johnson, Jordan
AU - Ramirez, Denise M.O.
AU - Ligocki, Ann J.
AU - Chen, Ding
AU - Guzman, Alyssa A.
AU - Woodhall, Mark
AU - Wilson, Patrick C.
AU - Meffre, Eric
AU - White, Charles
AU - Greenberg, Benjamin M.
AU - Waters, Patrick
AU - Cowell, Lindsay G.
AU - Stowe, Ann M.
AU - Monson, Nancy L.
N1 - Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.
AB - Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.
KW - Antigen receptor genetics
KW - Autoantibody
KW - B cell
KW - Multiple sclerosis
KW - Plasmablast
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U2 - 10.1007/s00401-016-1627-0
DO - 10.1007/s00401-016-1627-0
M3 - Article
C2 - 27730299
AN - SCOPUS:84991098156
SN - 0001-6322
VL - 133
SP - 43
EP - 60
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 1
ER -