The anti-inflammatory activity of intravenous Ig (IVIG) results from a minor population of the pooled IgG molecules that contains terminal ␣2,6-sialic acid linkages on their Fc-linked glycans. These anti-inflammatory properties can be recapitulated with a fully recombinant preparation of appropriately sialylated IgG Fc fragments. We now demonstrate that these sialylated Fcs require a specific C-type lectin, SIGN-R1, (specific ICAM-3 grabbing nonintegrin-related 1) expressed on macrophages in the splenic marginal zone. Splenectomy, loss of SIGN-R1 ؉ cells in the splenic marginal zone, blockade of the carbohydrate recognition domain (CRD) of SIGN-R1, or genetic deletion of SIGN-R1 abrogated the anti-inflammatory activity of IVIG or sialylated Fc fragments. Although SIGN-R1 has not previously been shown to bind to sialylated glycans, we demonstrate that it preferentially binds to 2,6-sialylated Fc compared with similarly sialylated, biantennary glycoproteins, thus suggesting that a specific binding site is created by the sialylation of IgG Fc. A human orthologue of SIGN-R1, DC-SIGN, displays a similar binding specificity to SIGN-R1 but differs in its cellular distribution, potentially accounting for some of the species differences observed in IVIG protection. These studies thus identify an antibody receptor specific for sialylated Fc, and present the initial step that is triggered by IVIG to suppress inflammation.autoimmune disease ͉ DC-SIGN ͉ rheumatoid arthritis ͉ sialylated IgG Fc ͉ SIGN-R1

Tumors are composed of multiple cell types besides the tumor cells themselves, including innate immune cells such as macrophages. Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells present in the tumor microenvironment (TME). Here, they contribute to immunosuppression, enabling the establishment and persistence of solid tumors as well as metastatic dissemination. We have found that the pattern recognition scavenger receptor MARCO defines a subtype of suppressive TAMs and is linked to clinical outcome. An anti-MARCO monoclonal antibody was developed, which induces anti-tumor activity in breast and colon carcinoma, as well as in melanoma models through reprogramming TAM populations to a pro-inflammatory phenotype and increasing tumor immunogenicity. This anti-tumor activity is dependent on the inhibitory Fc-receptor, FcγRIIB, and also enhances the efficacy of checkpoint therapy. These results demonstrate that immunotherapies using antibodies designed to modify myeloid cells of the TME represent a promising mode of cancer treatment.

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IgG antibodies can suppress more than 99% of the antibody response against the antigen to which they bind. This is used clinically to prevent rhesus-negative (Rh ؊ ) women from becoming immunized against Rh ؉ erythrocytes from their fetuses. The suppressive mechanism is poorly understood, but it has been proposed that IgG͞erythrocyte complexes bind to the inhibitory

Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169 + cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL lpr/lpr mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.inflammation | macrophage M acrophages (MΦ) are innate scavenging cells that are important in maintenance of tolerance to self. Mechanistically, it is unknown how MΦs contribute to self-tolerance although it is evident that clearance is necessary and must lead to regulation rather than adaptive immunity. In this vein it has been shown that interaction of apoptotic cells with MΦs results in the induction of an anti-inflammatory response dominated by TGF-β, which suppresses proinflammatory cytokine production (1, 2). However, the molecular mechanisms by which capture of apoptotic cells trigger immune suppression in vivo is unknown. Moreover, known mechanisms, such as exposure of phosphatidyl serine and TGF-β production, do not explain how tolerance is maintained at the molecular level.Apoptotic cells in circulation are trapped and removed in the marginal zone (MZ) of the spleen (3). The MZ is populated by specialized MΦs tightly associated with the reticular meshwork. These MΦ are defined by constitutive expression of either the scavenger macrophage receptor with collagenous structure, MARCO, or the metallophillic macrophage marker, MOMA-1 (4-6). The importance of MZ MΦs (MZMs) in apoptotic cell removal and tolerance was illustrated by our recent findings that their depletion significantly changed the immune response to apoptotic cells altering localization, increasing proinflammatory cytokine production, and enhancing phagocytosis and phagocyte activation (7). Similarly, in related studies deletion of MARCO + and MOMA-1 + MZMs retarded the clearance of apoptotic material and abrogated tolerance to apoptotic cell-associated antigens in a mouse model of experimental autoimmune encephalomyelitis (8). Thus, defective MZM-mediated apoptotic cell capture and removal appears to have sig...