Siglecs, short for sialic acid-binding immunoglobulin-like lectins, are a family of proteins found on the surface of various cells, particularly those within the immune system. These specialized proteins act as recognition molecules. Their ability to bind to specific sugar molecules called sialic acids allows them to influence cellular interactions and signaling pathways.
What Are Siglecs and Where Are They Found?
Siglecs bind to sialic acids, sugar molecules found on cell surfaces and secreted proteins. These proteins are classified as type I transmembrane proteins, spanning the cell membrane with extracellular, transmembrane, and intracellular parts. Each Siglec contains an N-terminal V-type immunoglobulin domain for sialic acid binding, along with varying C2-type immunoglobulin domains.
There are 15 known human Siglec receptors, each with distinct expression patterns and functions. While primarily found on immune cells, their distribution varies. For example, Siglec-1 (Sialoadhesin or CD169) is predominantly on macrophages, which engulf foreign particles, while Siglec-2 (CD22) is largely expressed on B cells, a type of white blood cell involved in antibody production. Siglec-9 is more broadly expressed on various immune cells, including neutrophils, monocytes, and natural killer (NK) cells. In contrast, Siglec-8 is found almost exclusively on eosinophils and mast cells, immune cells involved in allergic reactions.
How Siglecs Influence Immune Responses
The interaction between Siglecs and sialic acids influences how immune cells respond to their environment. Many Siglecs contain specialized regions called immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within their intracellular part. When a Siglec binds to a sialic acid-containing ligand, these ITIMs activate, recruiting inhibitory SHP phosphatases. These phosphatases remove phosphate groups from other proteins inside the cell, dampening activating signals. This inhibitory role helps prevent an overactive immune response, acting like a “brake” to maintain immune balance.
Some Siglecs, however, promote activating signals. For instance, Siglec-14 and Siglec-15 lack ITIMs but associate with adapter proteins like DAP12, which contains immunoreceptor tyrosine-based activation motifs (ITAMs). When these Siglecs bind to their ligands, they can trigger a cascade of events leading to the activation or “boosting” of an immune response. This dual nature, with both inhibitory and activating roles, allows Siglecs to fine-tune immune responses based on the specific context and sialic acid type.
Siglecs also help maintain immune tolerance, the ability of the immune system to recognize and not attack the body’s own healthy cells and tissues. Since sialic acids are abundant on mammalian cells, Siglecs recognize these “self” glycans, distinguishing self from non-self. By dampening immune cell activation when encountering self-sialic acids, inhibitory Siglecs help prevent inappropriate immune reactions that could lead to autoimmune diseases. For example, Siglec-G in mice (similar to human Siglec-10) forms an inhibitory complex with CD24 on dendritic cells, suppressing inflammatory responses to certain self-molecules.
Siglecs and Their Role in Disease
Dysregulation of Siglec pathways or alterations in the sialic acid molecules they bind can contribute to various diseases. In autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues, a lack of inhibitory Siglec function can lead to overactive immune responses. For instance, Siglec-2 (CD22) on B cells normally provides inhibitory signals, helping maintain peripheral tolerance by suppressing autoreactive B cell responses. Reduced expression of sialic acid ligands for Siglec-1 and Siglec-2 has been observed in patients with rheumatoid arthritis and type 1 diabetes. An increase in Siglec-1 on monocytes and Siglec-10 on B cells has also been linked to the severity of systemic lupus erythematosus (SLE).
Cancer cells often exploit Siglecs to evade immune detection and destruction. Many tumor cells display increased sialic acids on their surface, a phenomenon known as hypersialylation. These abundant sialic acids can bind to inhibitory Siglecs on immune cells, such as Siglec-7 on natural killer (NK) cells and Siglec-9 on neutrophils, effectively “turning off” the immune cells’ ability to attack the cancer. This interaction creates an immunosuppressive environment within the tumor, allowing cancer cells to grow and spread. For example, Siglec-15 on macrophages can recognize tumor-associated sialyl-Tn antigen, promoting a macrophage profile that contributes to tumor progression.
Infectious diseases can also involve Siglecs, as pathogens have evolved strategies to interact with these receptors. Some pathogens can mimic host sialic acids or acquire them from the host, using these molecules to bind to Siglecs on immune cells. This binding can serve several purposes for the pathogen, including gaining entry into host cells or suppressing the host’s immune response. For example, Group B Streptococcus (GBS) uses sialic acids on its capsule to engage inhibitory Siglec-9 on human neutrophils, reducing the neutrophils’ ability to kill bacteria. Conversely, some viruses, like the porcine reproductive and respiratory syndrome virus, utilize Siglec-1 on macrophages for cell attachment and internalization, potentially interfering with the macrophage’s phagocytic activity.