Dedicator of cytokinesis 8–deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells

Abstract

Background Dedicator of Cytokinesis 8 (DOCK8) deficiency is typified by recurrent infections, elevated serum IgE levels, eosinophilia, and a high incidence of allergic and autoimmune manifestations. Objective We sought to determine the role of DOCK8 in the establishment and maintenance of human B cell tolerance. Methods Autoantibodies were measured in the plasma of DOCK8 deficient patients. The antibody coding genes from new emigrant/transitional and mature naive B cells were cloned and assessed for their ability to bind self-antigens. Regulatory T (Treg) cells in the blood were analyzed by flow cytometry, and their function was tested by examining their capacity to inhibit the proliferation of CD4+CD25− T effector (Teff) cells. Results DOCK8 deficient patients had increased levels of autoantibodies in their plasma. We determined that central B cell tolerance did not require DOCK8 as evidenced by the normal low frequency of polyreactive new emigrant/transitional B cells in DOCK8 deficient patients. In contrast, autoreactive B cells were enriched in the mature naïve B cell compartment, revealing a defective peripheral B cell tolerance checkpoint. In addition, we found that Treg cells were decreased and exhibited impaired suppressive activity in DOCK8 deficient patients. Conclusions Our data support a critical role for DOCK8 in Treg cell homeostasis and function and the enforcement of peripheral B cell tolerance. Clinical Implications DOCK8 deficient patients should be evaluated for autoantibodies, the possible emergence of autoimmunity, and end organ damage.

Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients

“…We conclude that the restoration of WASp expression in HSCs of WAS patients after GT leads to the normalization of the central B cell tolerance checkpoint. who displayed decreased frequencies of Tregs, nonfunctional Tregs, or both (24,26,27,29). In agreement with these data, the defective peripheral B cell tolerance checkpoint in WAS patients was associated with Tregs displaying an abnormal phenotype and showing defect in homeostasis regulation and suppressive capacities.…”

“…A central B cell tolerance checkpoint, which depletes many polyreactive and antinuclear clones in the BM, appears to be mostly controlled by B cell intrinsic factors, since decreased BCR signaling and Toll-like receptor (TLR) 7 and 9 function lead to an impaired counterselection of autoreactive B cells (22)(23)(24)(25). On the other hand, peripheral B cell tolerance is mostly regulated by B cell extrinsic factors, such as regulatory T cells (Treg) (24,(26)(27)(28)(29). We thus investigated if the absence of WASp could affect central and peripheral B cell checkpoints, by evaluating the frequency of B cells expressing autoreactive antibodies at a single-cell level.…”

Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint

“…In addition, the frequencies of antinuclear B cells were also elevated in AID-deficient patients (13.1% ± 5.4% in AID-deficient patients compared with 3.3% ± 2.2% in HDs, P < 0.001) ( Figure 1E). (2,18,20). In addition, both CD40L-and AID-deficient patients showed decreased peripheral blood Treg an incomplete correlation between serum BAFF concentration and B cell homeostatic expansion ( Figure 2C).…”

“…However, the impact of BAFF on the accumulation of autoreactive mature naive B cells remains unclear. While increased serum BAFF concentrations in CD40L-and AID-deficient patients as well as in CVID patients correlated with an altered peripheral B cell tolerance checkpoint, FOXP3-, SAP-, and DOCK8-deficient patients showed normal serum BAFF concentrations, despite increased frequencies of autoreactive mature naive B cells (2,7,8,15,16,18). We found that all CSR-D patients, who have no switched memory B cells, had a 2-fold increase in serum BAFF concentrations ( Figure 2B).…”

“…Decreased Treg numbers or function and elevated BAFF concentrations have both been reported to be associated with a dysregulated peripheral B cell tolerance checkpoint (2,14,16,18,20). Elevated serum BAFF concentrations can potentially impact the peripheral checkpoint due to the ability of BAFF to rescue autoreactive B cells from cell death in mice (33,34).…”