Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll-like receptors 7 and 9

Abstract

SummaryPatients with common variable immunodeficiency (CVID) have reduced numbers and frequencies of dendritic cells (DCs) in blood, and there is also evidence for defective activation through Toll-like receptors (TLRs). Collectively, these observations may point to a primary defect in the generation of functional DCs. Here, we measured frequencies of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) in peripheral blood of 26 CVID patients and 16 healthy controls. The results show that the patients have reduced absolute counts of both subsets. However, the decreased numbers in peripheral blood were not reflected in reduced frequencies of CD34 + pDC progenitors in the bone marrow. Moreover, studies at the single cell level showed that DCs from CVID patients and healthy controls produced similar amounts of interferon-α or interleukin-12 and expressed similar levels of activation markers in response to human cytomegalovirus and ligands for TLR-7 and TLR-9. The study represents the most thorough functional characterization to date, and the first to assess bone marrow progenitor output, of naturally occurring DCs in CVID. In conclusion, it seems unlikely that CVID is secondary to insufficient production of naturally occurring DCs or a defect in their signalling through TLR-7 or TLR-9.

Common variable immune deficiency: Dissection of the variable

“…A number of other cellular defects have been described in CVID, including defective dendritic cells (DC). Reduced circulating monocyte derived DC (mDCs) and plasmacytoid (pDCs) have been reported by a number of different laboratories . Activation of mDCs results in deficient expression of CD86, CD40 and major histocompatibility (MHC) class II, demonstrating lack of appropriate maturation markers potentially relevant to the defective induction of T‐cell proliferation found in this study .…”

“…Reduced circulating monocyte derived DC (mDCs) and plasmacytoid (pDCs) have been reported by a number of different laboratories. [100][101][102] Activation of mDCs results in deficient expression of CD86, CD40 and major histocompatibility (MHC) class II, demonstrating lack of appropriate maturation markers potentially relevant to the defective induction of T-cell proliferation found in this study. 103,104 While excess monocyte production of intracellular IL-12 had previously been suggested, 105 mDCs of CVID subjects were found to have a significantly reduced capacity to secrete IL-12 when cultured with the physiologic simulators, LPS, TNFα, or CD40-L fusion protein.…”

Toll‐like receptor signaling in primary immune deficiencies

“…IFN‐α secretion by pDCs following stimulation through TLR3 mirrored controls, as did upregulation of activation markers on pDCs, conventional DCs, monocytes, and NK cells following stimulation of TLR2, TLR4, or TLR9 . Furthermore, normal secretion of TNF‐α, IL‐6, and IL‐12 from PBMCs stimulated through TLRs 1, 2, 3, 4, 5, 7, or 9 was seen in patients, as were levels of intracellular IL‐12 in myeloid DCs stimulated through TLR9 . Interestingly, a recent report did not find defects in pDC production of IFN‐α following TLR9 stimulation; instead similar levels of intracellular IFN‐α were found when gating on pDCs in PBMC cultures, unlike earlier studies examining isolated pDCs .…”

“…Furthermore, normal secretion of TNF‐α, IL‐6, and IL‐12 from PBMCs stimulated through TLRs 1, 2, 3, 4, 5, 7, or 9 was seen in patients, as were levels of intracellular IL‐12 in myeloid DCs stimulated through TLR9 . Interestingly, a recent report did not find defects in pDC production of IFN‐α following TLR9 stimulation; instead similar levels of intracellular IFN‐α were found when gating on pDCs in PBMC cultures, unlike earlier studies examining isolated pDCs . This discrepancy suggests increased fragility of CVID pDCs, a pDC defect in IFN‐α secretion but not intracellular accumulation, or the possibility of correction of the pDC defect by a PBMC component.…”

“…Given the hallmark of hypogammaglobulinemia, B cells have been heavily studied in this disorder, with defects reported in proliferation, class switch recombination, differentiation, and immunoglobulin (Ig) secretion. In addition, T cell cytopenia, clonality, and defects of (TLR‐independent) cytokine production have been described, as have reduced numbers of DCs and increased activation of monocytes in vivo …”