High levels of antibodies against glutamic acid decarboxylase (GAD) are observed in patients with different neurological disorders, but cells producing these autoantibodies are largely unexplored. We detect circulating GAD‐reactive B cells in peripheral blood that readily differentiate into antibody‐producing cells. These cells are highly elevated in most patients with GAD‐antibody–associated disorders (n = 15) compared to controls (n = 19). They mainly produce GAD65 antibodies of the IgG1 and IgG4 subclasses and are as abundant as B cells reactive for common recall antigens. Bone marrow cells represent an additional source of GAD antibodies. The identification of GAD‐antibody–producing cells has implications for the selection of cell‐specific biologics. ANN NEUROL 2019;85:448–454.
Dendritic cells (DCs) are key players of the immune system and thus a target for immune evasion by pathogens. We recently showed that the virulence factors phenol-soluble-modulins (PSMs) produced by community-associated methicillin-resistant
Staphylococcus aureus
(CA-MRSA) strains induce tolerogenic DCs upon Toll-like receptor activation via the p38-CREB-IL-10 pathway
in vitro
. Here, we addressed the hypothesis that
S. aureus
PSMs disturb the adaptive immune response via modulation of DC subsets
in vivo
. Using a systemic mouse infection model we found that
S. aureus
reduced the numbers of splenic DC subsets, mainly CD4
+
and CD8
+
DCs independently of PSM secretion.
S. aureus
infection induced upregulation of the C-C motif chemokine receptor 7 (CCR7) on the surface of all DC subsets, on CD4
+
DCs in a PSM-dependent manner, together with increased expression of MHCII, CD86, CD80, CD40, and the co-inhibitory molecule PD-L2, with only minor effects of PSMs. Moreover, PSMs increased IL-10 production in the spleen and impaired TNF production by CD4
+
DCs. Besides,
S. aureus
PSMs reduced the number of CD4
+
T cells in the spleen, whereas CD4
+
CD25
+
Foxp3
+
regulatory T cells (T
regs
) were increased. In contrast, Th1 and Th17 priming and IFN-γ production by CD8
+
T cells were impaired by
S. aureus
PSMs. Thus, PSMs from highly virulent
S. aureus
strains modulate the adaptive immune response in the direction of tolerance by affecting DC functions.
Background and ObjectivesAntibodies (Abs) against the cytoplasmic protein glutamic acid decarboxylase 65 (GAD65) are detected in patients with neurologic syndromes together referred to as GAD65-Ab spectrum disorders. The response of some of these patients to plasma exchange or immunoglobulins indicates that GAD65-Abs could contribute to disease pathogenesis at least at some stages of disease. However, the involvement of GAD65-reactive B cells in the CNS is incompletely understood.MethodsWe studied 7 patients with high levels of GAD65-Abs and generated monoclonal Abs (mAbs) derived from single cells in the CSF. Sequence characteristics, reactivity to GAD65, and the role of somatic hypermutations of the mAbs were analyzed.ResultsTwelve CSF-derived mAbs were generated originating from 3 patients with short disease duration, and 7/12 of these mAbs (58%) were GAD65 reactive in at least 1 detection assay. Four of 12 (33%) were definitely positive in all 3 detection assays. The intrathecal anti-GAD65 response was polyclonal. GAD65-Abs were mostly of the IgG1 subtype and had undergone affinity maturation. Reversion of 2 GAD65-reactive mAbs to their corresponding germline-encoded unmutated common ancestors abolished GAD65 reactivity.DiscussionGAD65-specific B cells are present in the CNS and represent a sizable fraction of CSF B cells early in the disease course. The anti-GAD65 response in the CSF is polyclonal and shows evidence of antigen-driven affinity maturation required for GAD65 recognition. Our data support the hypothesis that the accumulation of GAD65-specific B cells and plasma cells in the CSF is an important feature of early disease stages.
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