Destruction of bone tissue by osteoclasts represents a severe pathological phenotype during inflammatory arthritis and results in joint pain and bone malformations. Previous studies have established the essential role of cytokines including TNFα and receptor–ligand interactions, such as the receptor activator of nuclear factor-kappa B–receptor activator of nuclear factor-kappa B ligand interaction for osteoclast formation during joint inflammation. Moreover, autoantibodies contribute to joint inflammation in inflammatory arthritis by triggering cellular fragment crystallizable (Fc)γ receptors (FcγR), resulting in the release of proinflammatory cytokines and chemokines essential for recruitment and activation of innate immune effector cells. In contrast, little is known about the expression pattern and function of different FcγRs during osteoclast differentiation. This would allow osteoclasts to directly interact with autoantibody immune complexes, rather than being influenced indirectly via proinflammatory cytokines released upon immune complex binding to other FcγR-expressing innate immune cells. To address this question, we studied FcγR expression and function on osteoclasts during the steady state and during acute joint inflammation in a model of inflammatory arthritis. Our results suggest that osteoclastogenesis is directly influenced by IgG autoantibody binding to select activating FcγRs on immature osteoclasts, resulting in enhanced osteoclast generation and, ultimately, bone destruction.

Neutrophil granulocyte biology is a central issue of immunological research, but the lack of animal models that allow for neutrophil-selective genetic manipulation has delayed progress. By modulating the neutrophil-specific locus Ly6G with a knock-in allele expressing Cre recombinase and the fluorescent protein tdTomato, we generated a mouse model termed Catchup that exhibits strong neutrophil specificity. Transgene activity was found only in very few eosinophils and basophils and was undetectable in bone marrow precursors, including granulomonocytic progenitors (GMPs). Cre-mediated reporter-gene activation allowed for intravital two-photon microscopy of neutrophils without adoptive transfer. Homozygous animals were Ly6G deficient but showed normal leukocyte cellularity in all measured organs. Ly6G-deficient neutrophils were functionally normal in vitro and in multiple models of sterile or infectious inflammation in vivo. However, Cre-mediated deletion of FcγRIV in neutrophils reduced the cells' recruitment to immune-complex-mediated peritonitis, suggesting a cell-intrinsic role for activating Fc receptors in neutrophil trafficking.

Intravenous immunoglobulin (IVIg) therapy is widely used to treat a variety of autoimmune diseases including immunothrombocytopenia, chronic inflammatory demyelinating polyneuropathy, and more recently autoimmune skin blistering diseases. Despite this well-documented clinical success, the precise molecular and cellular mechanisms underlying this immunomodulatory activity are discussed controversially. In particular, the clinically relevant therapeutic pathway of IVIg-mediated immune modulation has not been studied in detail. In the present study, we use four independent in vivo model systems of auto-Ab-mediated autoimmune disease to identify a common pathway explaining IVIg activity under therapeutic conditions in vivo. We show that irrespective of the in vivo model system, IVIg activity is strictly dependent on the presence of terminal sialic acid residues and the inhibitory FcγRIIB under preventive as well as therapeutic treatment conditions. In contrast, specific ICAM3 grabbing nonintegrin related 1, previously demonstrated to be essential under preventative treatment conditions, showed a disease-specific impact on IVIg-mediated resolution of established autoimmune disease.

A loss of humoral tolerance is a hallmark of many autoimmune diseases and the detection of self-reactive antibodies (autoantibodies) of the immunoglobulin G (IgG) isotype is widely used as a biomarker and diagnostic tool. However, autoantibodies might also be present in individuals without autoimmune disease, thus limiting their usefulness as a sole indicator of disease development. Moreover, while clear evidence exists of the pathogenic effects of autoantibodies in mouse model systems, the contribution of autoantibodies to the pathology of many autoimmune diseases has yet to be established. In this Review, the authors discuss the changes in total serum IgG and autoantibody glycosylation that occur during autoimmune disease and how these changes might help to predict disease development in the future. Furthermore, current knowledge of the signals regulating antibody glycosylation and how individual antibody glycoforms could be used to optimize current treatment approaches will be discussed.

Lehmann et al. targeted antigens to Fcγ receptors expressed on various antigen-presenting cells. Induced CD4+ and CD8+ T cell responses were solely dependent on CD11b+ and CD8+ DC subsets, respectively, but independent of receptor intrinsic ITAM or ITIM signaling domains.

Genetic differences between humans and in vivo model systems, including mice and nonhuman primates, make it difficult to predict the efficacy of immunoglobulin G (IgG) activity in humans and understand the molecular and cellular mechanisms underlying that activity. To bridge this gap, we established a small-animal model system that allowed us to study human IgG effector functions in the context of an intact human immune system without the interference of murine Fcγ receptors expressed on mouse innate immune effector cells in vivo. Using a model of B cell depletion with different human IgG variants that recognize CD20, we show that this humanized mouse model can provide unique insights into the mechanism of human IgG activity in vivo. Importantly, these studies identify the bone marrow as a niche with low therapeutic IgG activity.

BackgroundRheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. Estrogen (E2) may therefore have intrinsic immune-regulatory properties that vanish with menopause. Fc sialylation is a crucial factor determining the inflammatory effector function of antibodies. We therefore analyzed whether E2 affects immunoglobulin G (IgG) sialylation.MethodsPostmenopausal (ovariectomized) mice were immunized with ovalbumin and treated with E2 or vehicle. Total and ovalbumin-specific IgG concentrations, sialylation, and Fcγ receptor expression were analyzed. Postmenopausal women with RA receiving hormone replacement therapy, including E2, or no treatment were analyzed for IgG sialylation. Furthermore, effects of E2 on the expression of the sialylation enzyme β-galactoside α2,6-sialyltransferase 1 (St6Gal1) were studied in mouse and human antibody-producing cells.ResultsE2 treatment significantly increased Fc sialylation of total and ovalbumin-specific IgG in postmenopausal mice. Furthermore, E2 led to increased expression of inhibitory Fcγ receptor IIb on bone marrow leukocytes. Treatment with E2 also increased St6Gal1 expression in mouse and human antibody-producing cells, providing a mechanistic explanation for the increase in IgG-Fc sialylation. In postmenopausal women with RA, treatment with E2 significantly increased the Fc sialylation of IgG.ConclusionsE2 induces anti-inflammatory effector functions in IgG by inducing St6Gal1 expression in antibody-producing cells and by increasing Fc sialylation. These observations provide a mechanistic explanation for the increased risk of RA in conditions with low estrogen levels such as menopause.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1586-z) contains supplementary material, which is available to authorized users.

Intravenous immunoglobulins (IVIgs