Plasma Cell Differentiation Pathways in Systemic Lupus Erythematosus
#MMPMID29556239
Malkiel S
; Barlev AN
; Atisha-Fregoso Y
; Suurmond J
; Diamond B
Front Immunol
2018[]; 9
(?): 427
PMID29556239
show ga
Plasma cells (PCs) are responsible for the production of protective antibodies
against infectious agents but they also produce pathogenic antibodies in
autoimmune diseases, such as systemic lupus erythematosus (SLE). Traditionally,
high affinity IgG autoantibodies are thought to arise through germinal center
(GC) responses. However, class switching and somatic hypermutation can occur in
extrafollicular (EF) locations, and this pathway has also been implicated in SLE.
The pathway from which PCs originate may determine several characteristics, such
as PC lifespan and sensitivity to therapeutics. Although both GC and EF responses
have been implicated in SLE, we hypothesize that one of these pathways dominates
in each individual patient and genetic risk factors may drive this predominance.
While it will be important to distinguish polymorphisms that contribute to a
GC-driven or EF B cell response to develop targeted treatments, the challenge
will be not only to identify the differentiation pathway but the molecular
mechanisms involved. In B cells, this task is complicated by the cross-talk
between the B cell receptor, toll-like receptors (TLR), and cytokine signaling
molecules, which contribute to both GC and EF responses. While risk variants that
affect the function of dendritic cells and T follicular helper cells are likely
to primarily influence GC responses, it will be important to discover whether
some risk variants in the interferon and TLR pathways preferentially influence EF
responses. Identifying the pathways of autoreactive PC differentiation in SLE may
help us to understand patient heterogeneity and thereby guide precision therapy.
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