Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes

Abstract

Antibodies are critical for defence against a variety of microbes but may also be pathogenic in some autoimmune diseases. Many effector functions of antibody are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs). DCs are important antigen presenting cells and play a central role in inducing antigen-specific tolerance or immunity1,2. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via lymphatics to present antigen to T cells. In this study we demonstrate that FcγR engagement by IgG immune complexes (IC) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated murine and human DCs showed enhanced directional migration in a CCL19 gradient and increased CCR7 expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilisation. We confirmed that dermal DC migration to lymph nodes was CCR7-dependent and increased in the absence of the inhibitory receptor, FcγRIIb. These observations have relevance to autoimmunity, because autoantibody-containing serum from mice and humans with SLE also increased dermal DC migration to lymph nodes in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localisation of autoantigen-bearing DCs.

Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease

“…"Off-target" effects of autoantibodies were also observed in a model for systemic lupus erythematosus. There, immune complexes formed by AAbs derived from systemic lupus erythematosus patients were elegantly shown to promote the migration of dendritic cells into LNs and thereby enable efficient autoantigen-specific T-cell responses within the immune specialized LN environment (46). Our data, however, indicate that immune complexes unrelated to CNS-antigens are alone not sufficient to substantially accelerate or enhance CNS autoimmune disease.…”

Immune Monitoring of Trans-endothelial Transport by Kidney-Resident Macrophages

“…To probe uptake of circulating proteins and small immune complexes by tissue macrophages and blood leucocytes in vivo , we initially followed the uptake of fluorescent bovine serum albumin (BSA) or chicken ovalbumin (OVA), and small immune complexes (SIC) prepared by incubating rabbit polyclonal immunoglobulin G (IgG) against bovine serum albumin (RaBSA) or chicken ovalbumin (RaOVA) with an excess of BSA or OVA (Clatworthy et al, 2014; Stokol et al, 2004) (Figure S1A). Rabbit IgG bind FcγRI and FcγRIV with K D of 10 −7 –10 −8 and FcγRIIb/III with K D of 10 −5 , and ~20% of IgG was bound to albumin to form ~700 kDa SIC (Figures S1A and S1B).…”

Dendritic cell recruitment and activation in autoimmunity

“…By contrast, IFN-a priming and LPS stimulation significantly upregulated CCR7 in moDCs from SLE patients [128]. Similarly, immune complexes upregulated CCR7 and increased dermal DC migration in a mouse model of SLE [129]. Thus, these may represent additional mechanisms that promote autoimmune responses in SLE through the altered localization of autoantigenbearing DC.…”