Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies against nucleoproteins and DNA. Here we show that DNA-containing immune complexes (ICs) within lupus serum (SLE-ICs), but not protein-containing ICs from other autoimmune rheumatic diseases, stimulates plasmacytoid DCs (PDCs) to produce cytokines and chemokines via a cooperative interaction between Toll-like receptor 9 (TLR9) and FcγRIIa (CD32). SLE-ICs transiently colocalized to a subcellular compartment containing CD32 and TLR9, and CD32 + , but not CD32 -, PDCs internalized and responded to SLE-ICs. Our findings demonstrate a novel functional interaction between Fc receptors and TLRs, defining a pathway in which CD32 delivers SLE-ICs to intracellular lysosomes containing TLR9, inducing a signaling cascade leading to PDC activation. These data demonstrate that endogenous DNA-containing autoantibody complexes found in the serum of patients with SLE activate the innate immune system and suggest a novel mechanism whereby these ICs contribute to the pathogenesis of this autoimmune disease.

The type I interferon system in systemic lupus erythematosus

“…The ongoing production of IFN␣ in many patients with SLE suggests the presence of inducers that trigger expression of IFN␣ genes. Therefore, an important finding was that DNA-containing immune complexes in patients with SLE can induce IFN␣ production by NIPCs/PDCs, and that the occurrence of such interferogenic immune complexes is associated with active disease (5,6,70). When formed, these immune complexes are internalized via Fc␥RIIa and reach the endosomes of NIPCs/PDCs, with subsequent activation of the relevant TLR and induction of IFN␣/␤ production (20,70).…”

Genetic variation in toll‐like receptor 9 and susceptibility to systemic lupus erythematosus

“…Its recognition of CpG nucleotide sequences appears to enhance the activation of B cells via the B cell receptor (1)(2)(3). Subsequent studies in humans have shown that dendritic cells are activated by chromatin immune complexes and that this effect is mediated by a cooperation between TLR-9 and Fc␥ receptors (4,5). These observations suggest that genetic variation affecting the costimulatory function of TLR-9 could lead to differences in B cell response to autoantigens and dendritic cell response to chromatin immune complexes.…”

Antimalarial drugs inhibit IFNα-enhanced TNFα and STAT4 expression in monocytes: Implication for systemic lupus erythematosus

“…However, it is well known that both IFNa and TNFa are over-expressed in many patients with SLE and other autoimmune diseases, sometimes associated with disease activity [40,41]. In such patients, the presence of nucleic acid-containing immune-complexes induces plasmacytoid DCs, and probably other cell types, to produce IFNa [42] after stimulation across TLR-7/9 [9,43]. Similarly, immune-complexes can induce TNFa production [44].…”

“…Therefore, hydroxychloroquine blocks TLR-mediated activation of pDC in vitro, as shown by inhibition of IFNa synthesis, either after induction by immune-complexes [9] or upon stimulation with TLR9 agonists [48,49]. Recently, it has been observed that the significant clinical improvement in SLE patients after hydroxychloroquine therapy correlated with reductions in IFNa levels [50].…”

“…The pivotal role of IFNa in the pathogenesis of systemic lupus erythematosus (SLE) and other autoimmune diseases [4] is well established, since the majority of patients present increased production of type I IFN as well as IFNa-induced genes [5,6]. Moreover, Rönnblom and Alm demonstrated that immunocomplexes containing nucleic acids, characteristic of SLE serum, could trigger the production of high levels of IFNa [7] by plasmacytoid DCs through their interaction with the Toll-like receptor (TLR)-7 and TLR-9 [8,9].…”