CONTENTS:
Glycosylation and Immune Thrombocytopenia (ITP)
Dr. Nora V. Butta
Edited by Jennifer DiRaimo and Alexandra Kruse
If I say “sugar,” it is likely that your immediate association will be the white granules used to sweeten tea and coffee, candies, and cakes. In short, it is the flavor that evokes pleasant moments. Sugars are, however, far more than that. Among their numerous manifestations, sugars cover the surfaces of all cells in the body. In fact, the cell surface could be compared to a forest of trees, with varying arrangements of different shaped branches and leaves. These “trees” with varying characteristics and structures are actually long chains of sugars called “glycans.”
What are glycans, and glycosylation, and what does that have to do with the immune system?
Glycans (long sugars) are involved in the fine tuning of the immune system and its intricacies. They play a role in immune system activation (causing an immune response) or tolerance (preventing an immune response). Glycosylation (the process where a glycan is attached to a protein) is one of the most common and complex modifications of proteins. Glycans are essential for an organism’s health, and problems with glycosylation are significant contributors to human disease. Glycans that are part of proteins (glycoproteins) and fats (glycolipids) or pathogens are increasingly being recognized as key molecules in regulating immunity versus tolerance. Glycans modify proteins required for regulating immune cells (through glycosylation). For example, specific glycans regulate T cell activation and immunoglobulin functions.
One of the key features of the immune system is its extraordinary capacity to discriminate between self (the body’s own made biomolecules) and non-self (foreign biomolecules, like viruses or antigens) and to respond accordingly. Several molecular interactions enable the initiation of immune responses when a foreign antigen is recognized, while others regulate the resolution of inflammation and the process of tolerance to self-antigens.
Glycans are recognized by receptors expressed on immune cells. Sialic acids are a different form of sugar usually at the ends of glycoproteins and glycolipids on the cell surface. These acids play important roles in cell communication, in infection, and in the survival of pathogens (bacteria, viruses, or other microorganisms that cause illness). When pathogens attempt to escape immune recognition, they express sialic acids on their surface, effectively tricking the host immune system into thinking the pathogen is not an invader, and consequently avoiding immune system activation. Similarly, cancer cells increase their production of these glycans in order to make them invisible to the immune system, preventing their recognition as foreign. This is part of the reason why cancer can be difficult to treat.
How does this relate to ITP?
Immune thrombocytopenia (ITP) is a bleeding disorder characterized by low platelet counts due to decreased platelet production and increased platelet destruction by autoimmune mechanisms. Our research group previously identified platelet sugar residues and observed that
platelets from patients with ITP showed a consistent increase in structures that had a loss of sialic acids. We demonstrated that the loss of sialic acid could be explained by an increase in the activity of platelet’s neuraminidase, the enzyme (specialized protein) that mediates the release of sialic acid. In other words, ITP patients have more proteins that cut off the acid which signals to the immune system that our platelets are “ours,” and not a danger to the immune system. Furthermore, this loss of sialic acid from sugars on platelet surfaces contributes to both platelet counts and the platelets’ ability to prevent bleeding in ITP patients.
Our Research – What did we do?
To determine whether changes in the glycosylation pattern of platelets from patients with ITP trigger the immune system, we studied three groups of patients with ITP and one group of healthy controls.
Group 1 - Untreated ITP patients in remission after having chronic ITP
Group 2 - ITP patients who responded to TPO agents (Promacta®, Revolade™, and Nplate®)
Group 3 - ITP patients who do not respond to any ITP treatments
Control - People without ITP or other illnesses
We found that platelets from patients with untreated and non-responding ITP (groups 1 and 3), had a reduced amount of sialic acid residues. In these patients, increased loss of sialic acid residues on platelets correlated with increased platelet destruction. Moreover, we observed an inverse relationship between the loss of sialic acid and regulatory T cell count, which is responsible for suppressing the immune response, inhibiting the inflammatory response of the immune system, and plays a critical role in preventing autoimmunity. This observation suggests a relationship between glycan composition on the platelet surface and the immune response. Of note, patients with ITP treated with TPO-RA had a regulatory T cell count similar to that of healthy controls.
The other major component of the “self-tolerance” portion of the immune system are regulatory B cells, immunosuppressive cells that support immunological tolerance through the production of specific anti-inflammatory cells and prohibit the production of pro-inflammatory cells. No association was seen between the loss of sialic acid and regulatory B cell count.
What our research means for individuals with ITP
Our data suggests that specialized sugar complexes, such as glycoside residues, on the surface of platelets play a role in determining the overall platelet count and function in patients with ITP. Moreover, our results encourage further studies to better characterize the participation of the platelet glycome (all the sugars and their role in platelets) in the pathogenesis of ITP, given that the presence of sialic acid is a good sensor for the discrimination of “self” and “non-self” signals that regulate innate and adaptive immune system responses. This provides a novel explanation for the immune system’s detection for whether to destroy platelets in patients with ITP, providing a potential new target for immunotherapies.
Our work was performed thanks to the support of ISCIII-Fondos Feder (PI19/00772) and the Platelet Disorder Support Association.
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