Abstract
As a lymphoid organ, the spleen hosts a wide range of immune cell populations, which not only remove blood-borne antigens, but also generate and regulate antigen-specific immune responses. In particular, the splenic microenvironment has been demonstrated to play a prominent role in adaptive immune responses to enveloped viral infections and alloantigens. During both types of immunizations, antigen-specific immunoglobulins G (IgGs) have been characterized by the reduced amount of fucose present on N-linked glycans of the fragment crystallizable (Fc) region. These glycans are essential for mediating the induction of immune effector functions. Therefore, we hypothesized that a spleen may modulate humoral responses and serve as a preferential site for afucosylated IgG responses, which potentially play a role in immune thrombocytopenia (ITP) pathogenesis. To determine the role of the spleen in IgG-Fc glycosylation, we performed IgG subclass-specific liquid chromatography–mass spectrometry (LC–MS) analysis of Fc glycosylation in a large cohort of individuals splenectomized due to trauma, due to ITP, or spherocytosis. IgG-Fc fucosylation was consistently increased after splenectomy, while no effects for IgG-Fc galactosylation and sialylation were observed. An increase in IgG1- and IgG2/3-Fc fucosylation level upon splenectomy has been reported here for the first time, suggesting that immune responses occurring in the spleen may be particularly prone to generate afucosylated IgG responses. Surprisingly, the level of total IgG-Fc fucosylation was decreased in ITP patients compared to healthy controls. Overall, our results suggest a yet unrecognized role of the spleen in either the induction or maintenance of afucosylated IgG responses by B cells.
Highlights
As a lymphoid organ, the spleen hosts a wide range of immune cell populations, which remove blood-borne antigens, and generate and regulate antigen-specific immune responses
We investigated the role of the spleen on immunoglobulin G (IgG)-fragment crystallizable (Fc) glycosylation in a large cohort of individuals splenectomized due to trauma, or due to immune thrombocytopenia, or spherocytosis, to test the hypothesis that the spleen is a primary driver of afucosylated IgG responses in humans
We studied the impact of splenectomy on IgG-Fc N-linked glycosylation by comparing patients who had undergone splenectomy to control groups with an intact spleen
Summary
The spleen hosts a wide range of immune cell populations, which remove blood-borne antigens, and generate and regulate antigen-specific immune responses. The splenic microenvironment has been demonstrated to play a prominent role in adaptive immune responses to enveloped viral infections and alloantigens During both types of immunizations, antigen-specific immunoglobulins G (IgGs) have been characterized by the reduced amount of fucose present on N-linked glycans of the fragment crystallizable (Fc) region. Total serum IgG-Fc glycosylation is skewed, mostly with lowered galactosylation, and this is associated with increased disease progression, activity and symptoms s everity[16,17,18,19] Why this occurs is unclear, as elevated galactosylation of antigen-specific IgG is known to elevate their complement activity potential[14,15,20]. We found no biologically significant changes in IgG-Fc glycosylation were observed after CD20targeted rituximab treatment in immune thrombocytopenia (ITP)[23]
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