A soluble form of the mannose receptor (sMR) has been found in conditioned medium of primary macrophages in vitro and in mouse serum. sMR was released as a single species, had a smaller size than the cellassociated form, and accumulated in macrophage-conditioned medium, in a cytokine-regulated manner, to levels comparable with those found for cell-associated mannose receptor. Pulse-chase experiments showed that sMR production in culture occurred by constitutive cleavage of pre-existing full-length protein. A binding assay was developed to determine the sugar specificity of sMR and its ability to interact with pathogens and particulate antigens (i.e. Candida albicans and zymosan). Protease inhibitor studies suggested that sMR was produced by cleavage of an intact mannose receptor by a matrix metalloprotease or ADAM metalloprotease. A role for sMR in the immune response is proposed based on its binding properties, regulation by cytokines, and the previous discovery of putative ligands for the cysteine-rich domain of the mannose receptor in lymph nodes and spleen.
The mannose receptor (MR)1 is a type I integral membrane glycoprotein expressed on many macrophage (MØ) subtypes, monocyte-derived dendritic cells, and hepatic endothelium (1-4). MR is the founding member of a family of molecules sharing the same basic domain structure: an NH 2 -terminal cysteinerich domain; a fibronectin type II domain; and a variable number of C-type lectin carbohydrate recognition domains (CRDs), eight in the case of MR, followed by a transmembrane domain and a COOH-terminal intracellular domain (5-7). The other members of the family are: (i) the phospholipase A 2 receptor, which contains eight CRDs and is widely distributed (8 -10); (ii) the receptor DEC-205, which contains 10 CRDs and is expressed mostly by dendritic cells in T-cell areas of secondary lymphoid organs and by thymic and intestinal epithelia (11-13); and (iii) a recently described molecule found by its homology to the C-type lectin domain of E-selectin (14).Mannosylated molecules and particles can be endocytosed and phagocytosed through their interaction with the MR (3, 4, 15-19). The domains likely to be involved in this process are the CRDs and the transmembrane and the COOH-terminal intracellular domains. Neither the cysteine-rich domain nor the fibronectin type II domain seems to be required (18,20). MR synthesis and function are regulated by MØ maturation, lipopolysaccharide (LPS) (3), and cytokines; inhibited by interferon (IFN)-␥ (6); and up-regulated by 22).Using as a probe a chimeric protein containing the cysteinerich domain of the MR fused to the Fc region of human IgG1 (CR-Fc), we found putative ligand(s) for this domain of the MR in marginal zone metallophilic and subcapsular sinus MØ in naive mice and in the germinal centers of immunized mice. CR-Fc ϩ cells with dendritic morphology migrated toward the follicular areas and paracortex of lymph nodes during a secondary immune response (23). We hypothesized a role for a soluble form of the MR in the transport...
Corneal confocal microscopy identifies corneal cellular and small nerve fiber pathology in young patients with type 1 diabetes without retinopathy, which increases in severity in those with retinopathy. Corneal confocal microscopy appears to have considerable use as an imaging biomarker for early subclinical pathology in young patients with type 1 diabetes mellitus.
Phagocytic and killing capacities of resident and cytokine-activated human macrophages against group B Streptococcus (GBS) type III were studied. Evidence is presented that monocyte-derived macrophages from cord and adults ingest serum-opsonized GBS but that killing of bacteria was negligible in resident cells. Treatment of adult macrophages with recombinant human gamma interferon (rhIFN-␥; 100 U/ml) or recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 200 U/ml) resulted in significant increases of killing of GBS (P < 0.01 for each). The killing capacity of cord macrophages treated with rhGM-CSF was also enhanced compared to that of untreated cells (P < 0.01). However, treatment with rhIFN-␥ resulted in only a moderate increase in the capacity of cord macrophages to kill GBS (P > 0.1). These results mirrored the effect of rhIFN-␥ on candidacidal capacities of cord and adult macrophages, reported earlier from our laboratory. These data indicate differential modulation of neonatal macrophages by rhGM-CSF and rhIFN-␥. We suggest that administration of rhGM-CSF to neonates with invasive GBS disease may enhance host resistance to these bacteria.Group B streptococci (GBS) are the most common cause of deep-seated bacterial infection and sepsis in neonates (4,20). Over the last decade, the burden of invasive GBS disease in immunocompromised children and adults has also been increasing (24). In adults, common predisposing conditions for severe GBS infection and sepsis include malignant neoplasms, diabetes mellitus, human immunodeficiency virus type 1 infection, trauma, and older age (6,8,18). The mortality of invasive GBS disease in both newborns and adults remains high despite advances in intensive care and the susceptibility of the pathogen to penicillin (4,18,20).The propensity of GBS to cause invasive neonatal infections might be related to inappropriate opsonization due to the lack of maternally derived, type-specific antibodies (20). Polymorphonuclear neutrophil granulocytes play a key role in phagocytosis and eventual killing of streptococci and other extracellular pathogens. We reported earlier that a clinical isolate of GBS type III was rapidly ingested and killed by cord and adult granulocytes in the presence of serum opsonins (13). In contrast to what is found for granulocytes, the capacity of cord monocytes to kill GBS was decreased compared to that of adult blood monocytes (13). To gain more insight into the newborn's ability to resist infection by GBS, we studied various interactions between these bacteria and monocyte-derived macrophages isolated from the cord. Experiments were performed to study the effect of recombinant human gamma interferon (rhIFN-␥) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on phagocytosis and the bactericidal capacities of cord and adult macrophages. We show here that cord macrophages efficiently phagocytose serum-opsonized GBS but that the ingested bacteria survive inside the cells. Bacterial killing was augmented b...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.