Objective Fucosylation catalyzed by fucosyltransferases (FUTs) is an important post-translational modification involved in a variety of biological processes. The purpose of the current study is to determine the roles of fucosylation in rheumatoid arthritis (RA) and the efficacy of reestablishing the immune homeostasis by using 2-Deoxy-D-galactose (2-D-gal), a fucosylation inhibitor. Methods Q-PCR was performed to determine the expression of fucosyltransferases (FUTs) in RA and osteoarthritis (OA) synovial tissues and FACS sorted cells from RA synovial fluids. The in vivo inhibitory effect of 2-D-gal was evaluated in a collagen-induced arthritis (CIA) model. The in vitro effects of 2-D-gal on inflammatory macrophage differentiation, cytokine production, antigen uptake, processing, and presenting functions were analyzed. Results FUTs that are involved in terminal or sub-terminal, but not core or O-fucosylation, were upregulated in RA, compared to OA synovial tissues. The expression of terminal FUTs was highly positively correlated with that of TNF encoding for tumor necrosis factor α. Terminal FUTs were predominately expressed in M1 macrophages. In vivo, 2-D-gal treatment precluded CIA development with reduced inflammatory macrophages and Th17 in draining lymph nodes, decreased TNF-α, IL-6 and antibodies to type II collagen in the serum. In vitro, 2-D-gal skewed the differentiation of M1 macrophages to IL-10 producing M2 macrophages. Furthermore, 2-D-gal significantly inhibited antigen presenting function of M1 macrophages. Conclusion Terminal fucosylation is a novel hallmark of inflammatory macrophages. Inhibition of terminal FUTs reshapes the differentiation and functions M1 macrophages, leading to resolution of inflammation in arthritis.
The first line of defense against pathogens that enter the host by the oral route appears to involve the gut-associated lymphoreticular tissues e.g., Peyer's patches (PP). Although animals can readily be immunized by orally administered antigen that mobilizes the secretory immune system, there is a total lack oflocal antibody synthesis in the PP and the cellular basis for this deficiency remains a mystery. A lymphoreticular cell population, obtained when murine PP were treated with a neutral protease (Dispase), consisted of accessory cells [macrophages (MC)] and T and B lymphocytes. In vitro cultures of these PP cell preparations with the thymic-dependent antigen sheep erythrocytes (SRBC) resulted in good anti-SRBC plaque-forming cell (PFC) responses. The time courses of these responses were identical to those seen with spleen cell cultures. Submitogenic concentrations of concanavalin A (Con A) and optimal doses of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) (5) in GALT, local antibody production does not occur (6, 7). Instead, sensitized lymphocytes leave PP via efferent lymphatics, enter the blood circulation, and selectively populate mucosal sites (8, 9). The lack of local antibody synthesis in PP has been attributed to a deficiency (or architectural separation) of at least one of the three cell types required for immune responses to thymic-dependent (TD) antigens-namely, T and B lymphocytes and macrophages (MF) (see ref. 10 for review).Kagnoff and associates (1,11,12) have reported that dissociated PP cells lack an accessory (Mb) cell population required for in vitro responses to TD antigens. PP from athymic, nude mice lacked both MbD and T cells, and this B cell population was unresponsive to the B-cell mitogen lipopolysaccharide (LPS); responses to the mitogen were restored by exogenously supplied T cells and Mb or 2-mercaptoethanol (11
Polyclonal IgA secretion is inducible in murine B cells when DC-T from Peyer's patches (PP) provide the inducing stimulus. PP DC-T, which are composed predominantly of dendritic cells and Lyt-1+ T cells, are capable of dramatic augmentation of IgA secretion by PP or spleen B cells with minimal induction of IgM secretion. DC-T from spleen, however, are incapable of augmenting IgA secretion by either PP or spleen B cells. The level of IgA secretion is dependent upon the dose of DC-T providing the inducing stimulus and reaches a plateau with DC-T:B ratios of less than 1:1. This system for preferential induction of IgA responses should permit elucidation of cellular mechanisms involved in regulation of IgA secretion.
Previous studies have suggested that in vitro and in vivo immune responses are defective in Peyer's patch (PP) as a result of a deficiency in accessory cell number or function. However, we report here that enzymatic dissociation of PP does release a cell population with accessory activity in oxidative mitogenesis, i.e., the proliferation of periodate-modified T cells. The accessory activity present in PP is quantitatively similar to that of spleen. Accessory function is mediated by a cell type(s) that has the following characteristics: low buoyant density, lack of adherence to plastic or glass surfaces, lack of Fc receptors, and presence of surface Ia and the 33D1 dendritic cell (DC)-specific determinants. This PP accessory cell was markedly enriched by a novel technique. PP cells formed large aggregates when cultured for 16 h with irradiated, periodate-treated spleen cells. From the clusters we obtained a low density cell population that was 60% Ia positive, 33D1 positive, non-T and non-B, Fc receptor-negative, and dendritic in morphology. The DC-enriched populations were 60-80-fold enriched in accessory function relative to unfractionated PP. We can now compare PP accessory cells with accessory cells from other organs, and try to determine how PP dendritic cells contribute to the unique functions of this lymphoid organ.
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