De novo oligoclonal expansions of circulating plasmablasts in active and
relapsing IgG4-related disease
#MMPMID24815737
Mattoo H
; Mahajan VS
; Della-Torre E
; Sekigami Y
; Carruthers M
; Wallace ZS
; Deshpande V
; Stone JH
; Pillai S
J Allergy Clin Immunol
2014[Sep]; 134
(3
): 679-87
PMID24815737
show ga
BACKGROUND: IgG4-related disease (IgG4-RD) is a poorly understood, multiorgan,
chronic inflammatory disease characterized by tumefactive lesions, storiform
fibrosis, obliterative phlebitis, and accumulation of IgG4-expressing plasma
cells at disease sites. OBJECTIVE: The role of B cells and IgG4 antibodies in
IgG4-RD pathogenesis is not well defined. We evaluated patients with IgG4-RD for
activated B cells in both disease lesions and peripheral blood and investigated
their role in disease pathogenesis. METHODS: B-cell populations from the
peripheral blood of 84 patients with active IgG4-RD were analyzed by using flow
cytometry. The repertoire of B-cell populations was analyzed in a subset of
patients by using next-generation sequencing. Fourteen of these patients were
longitudinally followed for 9 to 15 months after rituximab therapy. RESULTS:
Numbers of CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts, which are largely IgG4(+),
are increased in patients with active IgG4-RD. These expanded plasmablasts are
oligoclonal and exhibit extensive somatic hypermutation, and their numbers
decrease after rituximab-mediated B-cell depletion therapy; this loss correlates
with disease remission. A subset of patients relapse after rituximab therapy, and
circulating plasmablasts that re-emerge in these subjects are clonally distinct
and exhibit enhanced somatic hypermutation. Cloning and expression of
immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak
of disease reveals that disease-associated IgG4 antibodies are self-reactive.
CONCLUSIONS: Clonally expanded CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts are a
hallmark of active IgG4-RD. Enhanced somatic mutation in activated B cells and
plasmablasts and emergence of distinct plasmablast clones on relapse indicate
that the disease pathogenesis is linked to de novo recruitment of naive B cells
into T cell-dependent responses by CD4(+) T cells, likely driving a self-reactive
disease process.
free
free
free
