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Published in final edited form as: Mol Aspects Med. 2022 Aug 30;90:101140. doi: 10.1016/j.mam.2022.101140

Impact of Siglecs on autoimmune diseases

Katarzyna Alicja Brzezicka a,b, James C Paulson a,b,*
PMCID: PMC9905255  NIHMSID: NIHMS1833418  PMID: 36055802

Abstract

Autoimmune diseases affect tens of millions of people just in the United States alone. Most of the available treatment options are aimed at reducing symptoms but do not lead to cures. Individuals affected with autoimmune diseases suffer from the imbalance between tolerogenic and immunogenic functions of their immune system. Often pathogenesis is mediated by autoreactive B and T cells that escape central tolerance and react against self-antigens attacking healthy tissues in the body.

In recent years Siglecs, sialic-acid-binding immunoglobulin (Ig)-like lectins, have gained attention as immune checkpoints for therapeutic interventions to dampen excessive immune responses and to restore immune tolerance in autoimmune diseases. Many Siglecs function as inhibitory receptors suppressing activation signals in various immune cells through binding to sialic acid ligands as signatures of self.

In this review, we highlight potential of Siglecs in suppressing immune responses causing autoimmune diseases. In particular, we cover the roles of CD22 and Siglec-G/Siglec-10 in regulating autoreactive B cell responses. We discuss several functions of Siglec-10 in the immune modulation of other immune cells, and the potential of therapeutic strategies for restoring immune tolerance by targeting Siglecs and expanding regulatory T cells. Finally, we briefly review efforts evaluating Siglec-based biomarkers to monitor autoimmune diseases.

Keywords: Autoimmune diseases, Siglec-2, Siglec-1, Siglec-G/10, Autoreactive B cells, Regulatory T cells

1. Introduction

The autoimmune diseases affect over 5–8% of the entire world’s population (Dinse et al., 2020; Fugger et al., 2020). It is estimated that over 50 million people suffer from autoimmune conditions just in the United States alone and their prevalence is constantly increasing (Dinse et al., 2020; Rosenblum et al., 2012). There are over 80 different autoimmune disorders with thyroid diseases and type 1 diabetes being the most common (Fugger et al., 2020; Wang et al., 2015). It is not known what triggers autoimmunity, but both environmental and genetic factors seem to be important (Bogdanos et al., 2012), including gender with women being generally more susceptible than men (Angum et al., 2020; Sohn, 2021).

Individuals with autoimmune diseases suffer from an imbalance between tolerogenic and immunogenic functions of their immune system. The immune system has an ability to ignore self-produced antigens and only become activated when the foreign antigen is encountered. In healthy individuals, the activation of immune system shifts the balance from a tolerogenic state to an inflammatory one. Once the foreign antigen is cleared from the body, the homeostatic regulatory mechanisms bring the system back to its initial tolerogenic state. Autoimmune diseases develop when the homeostatic mechanisms that maintain the balance between regulatory and effector functions become impaired (Horwitz et al., 2019). As a consequence, the overactive immune system responds to some self-antigens as foreign antigens, leading to damage of otherwise healthy tissues and chronic inflammation (Marshall et al., 2018). Many autoimmune disorders involve antibodies to self-antigens that mediate disease pathology, requiring antigen specific B cells that produce them. In some cases, autoantibodies are directed against a single autoantigen (Table 1) (Elkon and Casali, 2008; Peakman and Dayan, 2001; Sármay, 2021). Patients suffering from Graves’ disease for example, produce antibodies to the thyroid-stimulating hormone (TSH) receptor (McLachlan et al., 2007) whereas in the case of rheumatoid arthritis antibodies that target citrullinated proteins present in joints contribute to the characteristic swelling of these inflamed tissues (Janeway et al., 2001a; Smolen et al., 2018).

Table 1.

Selected human autoimmune diseases caused by known autoantigen(s).

Autoimmune disease Autoantibody target Affected tissue/organ Mouse model (examples) Treatment Age (a) and sex (b) related Ref
Rheumatoid arthritis (RA) Rheumatoid factor (RF), citrullinated proteins Synovium, cartilage, bone (joints in hands, wrists, knees) (a) K/BxN (spontaneous) (b) Collagen-induced mouse model (induced) (a) Managing symptoms: DMARDs (methotrexate) pain killers (ibuprofen) and NSAIDs (b) Treatment options: Rituxan + methotrexate (c) Clinical trials: IL-2 + methotrexate (a) Likelihood increases with age; middle-aged women (time of menopause) (b) Female-to-male ratio 2:1 or 3:1 (Grasshoff et al., 2021; Monach et al., 2007, 2008; Smolen et al., 2018; Zhang et al., 2022)
Type 1 diabetes (T1D) Pancreatic islet β-cells, insulin, IA-2, ZNT8 Pancreatic islet β- cells producing insulin The nonobese diabetic (NOD) Managing symptoms: insulin injections (a) Childhood or adolescence (b) Male-to-female ratio 1.8 (Katsarou et al., 2017; Östman et al., 2008; Pearson et al., 2016)
Grave’s disease Thyroid-stimulating hormone receptor (TSHR) Thyroid gland (hyperthyroidism), eyes, skin (dermopathy) Administration of: (a) TSHR expressing cells (b) TSHR coding plasmids (c) Recombinant adenovirus expressing TSHRA domain gene (a) Managing symptoms: antithyroid drugs, radioiodine (b) Surgery (a) All ages (b) Especially in women of reproductive age (Davies et al., 2020; Diana et al., 2020; Eckstein et al., 2020)
Systemic lupus erythematosus (SLE) dsDNA, phospholipids, ribonucleoproteins (Ro/SSA, La/SSB, Sm) Skin, joints, multiple organs (a) NZB/NZWF1 (BW), MRL/lpr (spontaneous) (b) Pristane injections, resiquimod cream administration (induced) (a) Managing symptoms: glucocorticoids, immunosuppressants, prednisolone (b) Clinical trials: rituximab, belimumab, blisibimod, tabalumab (c) Future: stem cell transplantation (a) Likelihood increases between puberty and menopause in females (b) Female-to-male ratio 3:1 (children), 9:1 (adults) (Ippolito et al., 2011; Kaul et al., 2016; Oliveira et al., 2018; Richard and Gilkeson, 2018)
Sjogren syndrome (SS) SjS-related antigen A (Ro/SSA, La/SSB) Exocrine glands (salivary and lacrimal glands), nose, upper respiratory tract (a) The nonobese diabetic (NOD): 2ndSS (b) NOD.Bl0. H2b (c) NFS/sld (a) Managing symptoms: tear substitution therapy, oral mucolytic agents, topical anti-inflammatory agents (b) Clinical trials: rituximab, epratuzumab, belimumab (a) Predominantly affects middle-aged women (b) Female-to-male ratio 9:1 (Brito-Zerόn et al., 2016; Gao et al., 2020; Toker, 2004)
Hashimoto’s thyroiditis Thyroid (thyroglobulin) Thyroid gland (hypothyroidism) Experimental autoimmune thyroiditis (EAT): injections with (a) TG protein (b) Adenovirus vector encoding human TG (induced) Managing symptoms: thyroid hormone replacement therapy (a) Adults 30–50 years old (b) Female-to-male ratio 10:1 (at least) (Faustino et al., 2020; Kong, 2007; Stassi and De Maria, 2002)
Guillain-Barré syndrome (GBS) Gangliosides (axolemma and other components of the peripheral nerves) Peripheral nerves, nerve roots Experimental autoimmune neuritis (EAN): injections with (a) peripheral nerve homogenate (b) PNS myelin proteins (c) gangliosides (GD1 b) Managing symptoms: intravenous immunoglobulin and plasma exchange (a) Incidence increases with age (b) More frequent in males than females (Alborzian Deh Sheikh et al., 2021; Leonhard et al., 2019; Soliven, 2014)
Multiple sclerosis (MS) Yet to be confirmed. Suggested: myelin antigens (MBP, MOG, lipids), potassium channel KIR4.1 White and grey matter of the brain (Central nervous system, CNS) (a) Experimental autoimmune encephalomyelitis (EAE) (b) Theiler’s Murine Encephalitis Virus-Induced Demyelinating Disease (a) Managing symptoms: corticosteroids, plasmapheresis (b) Some cases: B cell depletion therapy (e.g. anti-CD20 ocrelizumab) (a) Young adults (20–40 years old) (b) Female-to-male ratio 3:1 (Filippi et al., 2018; Greenfield and Hauser, 2018; Hunter et al., 2014; Kuerten et al., 2020)
Systemic sclerosis (SSC) Centromere proteins (limited cutaneous systemic sclerosis); topoisomerase I-, RNA polymerase III (diffuse cutaneous systemic sclerosis) Fibrosis and scaring in multiple organs (skin, lungs, gastrointestinal tract, kidneys, heart) (a) Tight skin 1/2 mouse model (spontaneous) (b) Bleomycin treated mice; HOCl-injected mice, Sclerodermatous GVHD (induced) (c) Endothelin-1 .FRA-2 (transgenic) (a) Managing symptoms: immunosuppressive drugs (b) Selected patients: immunomodulation followed by hematopoietic stem cell transplantation (HSCT) (a) Peak of onset in the fifth decade of life (b) Higher prevalence in women (Allanore et al., 2015; Artlett, 2014; Henrique-Neto et al., 2021; Yue et al., 2018)
Neonatal lupus erythematosus (NLE) In mothers: Ro/SSA, La/SSB (less often Ul-ribonucleoprotein) Skin (lesion), heart less often: lungs, CNS, spleen N/A Mild topical corticosteroids, pacemaker (if heart problems) (a) Newborn infants (b) Female-to-male ratio 2:1 Lun Hon and Leung (2012)
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Current treatments of autoimmune diseases include anti-inflammatory or immunosuppressive drugs or low-dose chemotherapeutics that generally treat symptoms but do not cure the underlying disease (Rosenblum et al., 2012). Such immunosuppressive treatments can also compromise the overall immune system and consequently increase the risk of opportunistic infections and contribute to other health complications (Rosenblum et al., 2012). One promising but high risk option in development is stem cell transplantation (Kaul et al., 2016), which has been explored for patients affected with different autoimmune conditions, including systemic sclerosis (Collins and Gilkeson, 2013). First, autoreactive T and B-cells are eliminated with high-dose immunosuppressive drugs followed by transplantation with hematopoietic stem cells to restore the immune repertoire (Kaul et al., 2016). An attractive alternative being pursued by many laboratories are antigen-specific therapies to induce long-lasting immune tolerance to autoantigen while preserving protective immunity (Kelly et al., 2021; Pozsgay et al., 2017; Richardson et al., 2020; Sármay, 2021; Serra and Santamaria, 2019; Wraith, 2018).

In this regard, members of the Siglec family have been considered as attractive targets for inducing antigen specific immune tolerance with potential application to autoimmune disease. The Siglecs are members of the immunoglobulin (Ig) superfamily with an N-terminal V-set Ig domain that recognizes sialic acid-containing glycans of glycoproteins and glycolipids, and contain regulatory motifs in their cytoplasmic domains (Crocker et al., 2007). Several recent comprehensive reviews discuss the roles of Siglecs in regulation of immune cell signaling in immune cell mediated diseases (Bochner and Zimmermann, 2015; Crocker et al., 2007; Duan and Paulson, 2020; Läubli et al., 2021; Läubli and Varki, 2020; Lubbers et al., 2018; Macauley et al., 2014; Meyer et al., 2018; Müller and Nitschke, 2014; O’Sullivan et al., 2020; Pillai et al., 2012; Smith and Bertozzi, 2021). In this review, we cover evidence for the roles of Siglec family members in regulation of immune responses relevant to autoimmune diseases.

2. B cell Siglecs in autoimmune responses

B cells are key players in adaptive immunity by producing antibodies that provide protection against microbial pathogens. The B cell repertoire is developed by somatic rearrangement in the bone marrow producing B cells with highly diverse antibody specificities (Janeway CA Jr, 2001). Because the gene rearrangement is random, both self- and non-self-reactive clones are generated (Musette and Bouaziz, 2018). Most B cells producing self-reactive antibodies are deleted in the bone marrow by mechanisms of receptor editing and clonal deletion. However, it is estimated that 20% of mature naive B cells that reach the periphery have receptors with the capacity to bind self-antigens and the potential for harmful autoimmune responses (Wardemann et al., 2003). In the periphery, additional mechanisms suppress autoreactive B cells that include apoptosis of B cells with high affinity to self-antigen and anergy of B cells with low affinity to self-antigen (Janeway CA Jr, 2001). Self-reacting B cells that are able to escape above mentioned mechanisms, produce autoantibodies that can result in autoimmune disease (Müller and Nitschke, 2014). Siglecs are now recognized to play a role in the enforcement of peripheral tolerance and suppressing autoimmune responses of B cells (Crocker et al., 2007; Macauley et al., 2014). In the sections below we review the roles of B cell Siglecs in maintaining peripheral B cell tolerance and two therapeutic approaches targeting CD22 for treatment of autoimmune disease.

2.1. Siglecs in regulation of B cell tolerance to self-antigens

CD22 (Siglec-2) and Siglec-G/Siglec-10 are the most abundant members of the Siglec family expressed on B cells. CD22 is not present at early stages of B cell development but is expressed on all mature B cell subsets and then is lost upon differentiation of activated B cells to plasma cells (Erickson et al., 1996). CD22 is conserved between mouse and human whereas Siglec-G and Siglec-10 are murine and human orthologs, respectively (Pillai et al., 2012). Both of these Siglecs are inhibitory co-receptors of the B cell antigen receptor (BCR) (Crocker et al., 2007; Duong et al., 2010b; Macauley et al., 2014). CD22 interacts specifically with ligands carrying α2–6-linked sialic acids whereases Siglec-G also recognizes α2–3 linked sialic acids (Duong et al., 2010a). Both Siglecs can independently regulate B cell signaling (Nitschke et al., 1997; Pfrengle et al., 2013; Pillai et al., 2012), and thus the different ligand specificities are relevant to regulation of B cell signaling in the context of self-recognition of cells that express different sialic acid linkages. Both Siglecs regulate signaling through immunoreceptor tyrosine-based inhibitory (ITIM) and switch (ITSM) motifs located in their cytoplasmic domains. ITIMs are activated by kinase Lyn-mediated phosphorylation, resulting in recruitment of inhibitory phosphatases such as SHP-1, dephosphorylation of active signaling molecules and downregulation of signaling factors (Crocker et al., 2007; Duan and Paulson, 2020; Pillai et al., 2012). Siglec-G is preferentially expressed on peritoneal B1 cells and may play a more dominant role in regulation of BCR signaling in these cells (Jellusova et al., 2010). B1 cells are a unique B-cell population producing most of the natural IgM antibodies and play an important role in the immune response to T-independent antigens, including bacterial polysaccharides and other common pathogens (Hoffman et al., 2016).

The importance of CD22 and Siglec-G in maintaining the B cell tolerance has been analyzed in mice with targeted gene inactivation (Hoffmann et al., 2007; Nitschke et al., 1997; O’Keefe et al., 1999). Several laboratories demonstrated that B cells from CD22−/− mice are hyper-responsive and show increased signaling and calcium influx (Nitschke et al., 1997; O’Keefe et al., 1996; Otipoby et al., 1996; Sato et al., 1996). Similar observations were made in Siglec-G deficient mice (Hoffmann et al., 2007). These animals show an expansion and hyper-responsiveness of their B1 cell population, enhanced calcium signaling and high IgM sera titers (Hoffmann et al., 2007). These results suggests that Siglec-G might regulate homeostasis of the B1 cell population.

Importantly, despite all the changes observed, neither CD22-deficient, nor Siglec-G–deficient mice developed spontaneous autoimmune disease (Hoffmann et al., 2007; Jellusova et al., 2010; Nitschke et al., 1997). Interestingly, lack of CD22 can increase the susceptibility to autoimmune disorder when crossed to mice of certain genetic background or autoimmune-prone strains (Nitschke et al., 2006; O’Keefe et al., 1999). For example, when CD22-deficient mice (129xC57BL/6) age, a high autoantibody titers are detected in their sera (O’Keefe et al., 1999). 8-months old animals develop high affinity autoreactive IgGs directed against double stranded DNA (O’Keefe et al., 1999). Similar observation was made in lupus-prone mouse strains (Nitschke et al., 2006). An aberrant form of CD22 (CD22a) which is unable to bind cis ligands, enhances B-cell activation and spontaneous production of autoantibodies favoring the development of autoimmune responses (Nitschke et al., 2006).

In contrast to mice missing either CD22 or Siglec-G alone, mice lacking both Siglecs exhibit more significant autoimmune phenotypes (Jellusova et al., 2010). In these animals, B cells hyper-proliferate and spontaneously produce anti-DNA and antinuclear autoantibodies. Moreover, as they age, mice develop a systemic lupus erythematosus (SLE)-like disease (Jellusova et al., 2010). Thus, it appears that Siglec-G and CD22 have synergistic functions in maintaining the B cell tolerance that is revealed when both are missing.

Further insights into the mechanism of Siglec mediated antigen tolerance were obtained in experiments involving adoptive transfer of B cells from transgenic mice with a BCR specific for hen egg lysozyme (IgMHEL) on a wild type background or missing either CD22, Siglec-G or both Siglecs (Macauley and Paulson, 2014). B cells specific for HEL antigen (IgMHEL B cells) were adoptively transferred to non-transgenic mice followed by the second adoptive transfer of B cells expressing membrane bound HEL (mHEL) on their surface (Macauley and Paulson, 2014). After 5 days, wild type IgMHEL B cells were depleted, while IgMHEL cells missing either CD22 or Siglec-G were less depleted, and cells missing both Siglecs showed no significant depletion. Depletion was shown to result from recruitment of Siglecs to the immunological synapse between the IgMHEL B cells and mHEL cells by sialic acid ligands on the mHEL cell, resulting in a tolerogenic signal produced by dephosphorylation of the AKT survival pathway and induction of the proapoptotic factor BIM. Thus, Siglecs appear to have a direct role in peripheral tolerance to membrane bound ‘self’ antigens as originally proposed by Lanoue et al. (2002), through a mechanism of inducing apoptosis of the B cell recognizing the antigen (Macauley and Paulson, 2014).

While Siglecs present on B cells are also likely to play a role in peripheral tolerance in humans, there is little evidence to date that their impaired expression is a cause of human autoimmune diseases (Clark and Giltiay, 2018; Nitschke, 2009). A potential link between single nucleotide polymorphisms (SNPs) in the CD22 gene and susceptibility to limited cutaneous systemic sclerosis (Hitomi et al., 2007) and SLE (Hatta et al., 1999) have been proposed. However, genome-wide association studies have not identified the CD22 as a susceptibility locus for SLE (Criswell, 2008; Rhodes and Vyse, 2008). Since ligands on the antigen presenting cell are also required for CD22 mediated B cell tolerance to the antigen (Lanoue et al., 2002; Macauley et al., 2014; Macauley and Paulson, 2014), a deficiency in cis or trans sialic acid ligands could also in principle impact B cell responses. In this regard, B cell ligand deficiencies due to loss of function in the 9-O-acetyl-N-acety-neuraminic acid esterase (SIAE) was identified as a risk factor to common human autoimmune diseases, and reduced expression of CD22 ligands on B cells was linked to type 1 diabetes and autoimmune polyglandular syndrome (Surolia et al., 2010). Moreover, growing evidence suggests that Siglec-10 has an important regulatory function in some of human autoimmune diseases (Alborzian Deh Sheikh et al., 2021; Smith and Bertozzi, 2021). In particular, Alborzian Deh Sheikh et al. investigated the function of Siglec-10 on B cells in development of Guillain-Barré syndrome (GBS) (Alborzian Deh Sheikh et al., 2021). GBS is an acute peripheral neuropathy and a rare autoimmune disorder in which a person’s own immune system damages the nerves, causing muscle weakness and in some cases, paralysis (Leonhard et al., 2019). Patients with GBS produce autoantibodies to gangliosides (GGs), sialic acid-containing glycosphingolipids. By analyzing sequences of Siglec-10 genes in patients with GBS, researchers identified a GBS-associated rare variant of SIGLEC10 that impairs its binding to gangliosides (Alborzian Deh Sheikh et al., 2021). As a result, it was proposed that Siglec-10 regulates development of GBS by inhibition of B cells responses to GGs and suppression of autoantibody production. Since CD22 and Siglec-G/10 play complementary roles in regulation of B cell responses to membrane antigens, their role in preventing autoimmune responses may only be revealed in the context of deficiencies in both genes. Further investigation is clearly warranted.

2.2. Antibodies targeting Siglec-2 on B cells for treatment of autoimmune diseases

CD22 was originally discovered as an antigen highly expressed on B cells, making it a target for treatment of B cell lymphomas that express CD22 (Chen et al., 2010, 2012). While it was identified early on as a B cell specific target, the first monoclonal antibody approved for treatment of B cell lymphomas was rituximab (Rituxan™) which targets CD20 on the B cell surface (Smith, 2003). Rituximab works by depleting B cells using antibody dependent cellular cytotoxicity (ADCC). Based on the importance of B cells in autoimmune disease, rituximab has also been tested and found to provide benefit in several autoimmune diseases (Randall, 2016) including multiple sclerosis (MS) (Greenfield and Hauser, 2018) and rheumatoid arthritis (RA) (Lopez-Olivo et al., 2015). Indeed, Rituxan™ in combination with methotrexate, has been FDA approved for the treatment of patients with moderate to severe RA who have had an inadequate response to other therapies (Lopez-Olivo et al., 2015).

In light of the success with rituximab treatment, several anti-CD22 antibodies have been pursued in the clinics for treatment of B cell mediated diseases. Two of them (BL22 and CMC-544) are immunotoxins and were approved by FDA for a lymphoma treatment (Shah and Sokol, 2021). This approach utilizes the well documented function of CD22 as an endocytic receptor that would deliver the toxin intracellularly, a property not shared with CD20 which does not undergo endocytosis. Another anti-CD22 monoclonal antibody, epratuzumab, has been considered as a potential treatment for SLE based on its function as an inhibitory co-receptor (Geh and Gordon, 2018). Epratuzumab has a different mode of action from rituximab (Carnahan et al., 2007). It provides only moderate B-cell depletion and is a non-blocking antibody that does not hamper ligand binding by CD22. One proposed mechanism of epratuzumab action is that it unmasks CD22 on B cells by inhibiting its cis interactions and thus facilitating binding with trans CD22 ligands expressed on other cells (Chang et al., 2015). Consequently, upon binding to CD22, epratuzumab selectively modulates B cells by disruption of BCR-signaling, reduction in plasma cell generation and inhibition of the pro-inflammatory cytokines production. Even though the initial trials on SLE patients showed promising effects, including reduction in peripheral B cell numbers (30–50%), all randomized controlled trials have failed to show a significant difference in primary endpoints between epratuzumab and placebo groups (Geh and Gordon, 2018). However, the post hoc analysis of data from EMBODY1 and EMBODY2 clinical trials revealed possible benefit of epratuzumab in SLE patients with associated Sjogren’s syndrome (Gottenberg et al., 2018). Although primary Sjogren syndrome develops independently, associated Sjogren syndrome is linked to coexisting autoimmune diseases, such as SLE. This could potentially open the door for new clinical trials investigating the role of epratuzumab in the management of Sjogren’s syndrome and the subgroup of patients with SLE and Sjogren’s syndrome in whom B cell modulation by epratuzumab may be most effective (Geh and Gordon, 2018).

2.3. Exploiting CD22 and Siglec-G/10 to induce antigen specific B cell tolerance

Based on the knowledge that glycan ligands of CD22 (CD22L) presented on the same membrane together with a foreign antigen, suppress antigen-specific B cell activation, several groups demonstrated that synthetic polymeric antigens displaying CD22L can prevent B cell responses to T-independent antigens, preventing plasma cell differentiation and induce tolerance to subsequent challenge with immunogenic antigen (Courtney et al., 2009; Duong et al., 2010a; Lanoue et al., 2002). This concept was expanded to T dependent protein antigens using a liposomal formulation known as Siglec tolerizing antigenic liposomes (STALs) (Chen et al., 2010; Macauley et al., 2013). STALs display both the antigen of interest and synthetic high affinity glycan ligands of murine CD22, 9-biphenylacetyl substituted N-glycolyl-neuraminic acid (BPANeuGc) α2–6 linked to N-acetyl-lactosamine (9-BPA-NeuGcα2–6Galβ1–4GlcNAc; 6′-BPANeuGc) (Collins et al., 2006). On resting B cells, CD22 localizes to clathrin-rich domains and binds self-ligands (cis) forming CD22 homo-oligomers (Han et al., 2005). Multivalent and high affinity CD22L on STALs can compete with cis ligands on B cells, enforcing ligation and colocalization of several CD22 with the BCR. The balance of activating and inhibitory signals in the immunological synapse ultimately determines if the B cell will be activated, and so multivalent constructs optimize the potential for recruiting sufficient CD22 to suppress B cell activation. STALs have the potential to both prevent B-cell activation, but also induce apoptosis of the antigen-reactive B cells resulting in immunological tolerance due to depletion of the antigen-specific cells from the B-cell repertoire (Macauley and Paulson, 2014; Macauley et al., 2013). Apoptosis of the antigen-reactive B cells causes decreased in antibody secreting plasma cells (Crocker et al., 2007; Macauley et al., 2013, 2014; Macauley and Paulson, 2014; Pfrengle et al., 2013). Because STALs can be formulated with any antigen of choice, they can be applied to variety of immunological conditions. For example, Orgel et al. examined the potential of STALs displaying peanut allergen Ara h 2 (Ah2) in prevention of undesired B-cell responses to a food allergen (Orgel et al., 2016, 2017). It was concluded that liposomes displaying CD22 ligand and the BCR specific for Ah2, can be used to prevent sensitization to the major peanut allergen (Orgel et al., 2017).

There are several antigen-specific autoimmune diseases in which autoantibodies can be detected in sera. For example, Grave’s disease is characterized by the production of autoantibodies to the thyroid-stimulating hormone (TSH) receptor in the thyroid gland whereas in Hashimoto’s thyroiditis by antibodies to thyroid peroxidase (McLachlan et al., 2007). Individuals suffering from type I diabetes produce anti-pancreatic islet β-cells antibodies and patients with arthritis produce antibodies targeting citrullinated proteins present in joints (Janeway et al., 2001a; Smolen et al., 2018). Therefore, use of CD22-targeting therapeutics, could in principle deplete the antigen-specific B cells from the B cell repertoire and decrease population of autoantibodies secreting plasma cells and thus be beneficial for the treatment of patients with above mentioned conditions. To investigate this possibility, Bednar et al. used CD22L-STALs to selectively target the citrulline-specific B-cells present in the rheumatoid arthritis (RA) patients (Fig. 1A) (Bednar et al., 2019). They show that co-presentation of synthetic citrullinated antigen (CA) and CD22 glycan ligand on STALs (CCP STALs) can prevent anticitrullinated protein autoantibodies production from RA patients’ memory B-cells in vitro. These CCP STALs were also effective in inducing CA-specific tolerance in SJL/J mice that spontaneously produce antibody responses against citrullinated antigens. Overall, authors demonstrated that STALs-based therapeutic strategy exhibits potential for control of autoreactive B cells for the treatment of RA. Like CD22, Siglec-G/Siglec-10 is also expressed on B cells, and as mentioned above plays a role in suppressing autoimmune responses to self-antigens (Hoffmann et al., 2007; Jellusova et al., 2010; Nitschke et al., 1997). B cells that are predominately regulated by Siglec-G belong to the B1 cell population. Siglec-G can regulate BCR signaling and suppress antigen mediated activation independently from CD22 (Pfrengle et al., 2013). Natural ligands of Siglec-G comprise of α2,3-linked or α2,6-linked sialic acid abundantly expressed on glycoproteins and glycolipids (Duong et al., 2010a). The independent role of Siglec-G in suppressing BCR signaling was explored by Pfrengle et al. (2013). First, selective and a high-affinity ligand of Siglec-G was developed by addition of a 9-biphenylacetyl substituted N-glycolyl-neuraminic acid (BPANeuGc) to N-acetyl-lactosamine in α2–3 linkage (BPANeuGcα2–3Galβ1–4GlcNAc; 3′-BPANeuGc) (Pfrengle et al., 2013). Next, liposomes decorated with 3′-BPANeuGc and antigen were tested in vitro and in vivo and showed excellent targeting to Siglec-G–expressing cells and inhibition of BCR signaling in both B1 and B2 B cells. Additionally, these liposomes not only inhibited B cell activation but also induced robust tolerance toward T-independent and T-dependent antigens (Duong et al., 2010a).

Fig. 1. CD22L STALs for suppressing autoantibodies in rheumatoid arthritis.

Fig. 1

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(A) CCP-STALs displaying citrullinated antigen (CA) and CD22 glycan ligand inhibit BCR signaling and prevent anticitrullinated protein autoantibodies production (Bednar et al., 2019) (B) Co-administration of liposomal STALs displaying GPI antigen and CD22 glycan ligand to inhibit BCR signaling with rapamycin-loaded PLGA nanoparticles to promote DC mediated expansion of regulatory T cells (Srivastava et al., 2021).

2.4. Suppressing B cell and T cell immune responses in autoimmune disease

Although autoreactive B cells generate pathogenic autoantibodies in many autoimmune diseases, their activation and differentiation requires ‘help’ from T cells that are autoreactive to the same antigen (Janeway, 2001b). Thus, an attractive strategy for treatment of autoimmune diseases where the antigen is known would control both autoreactive B cells and T-cells. An established strategy for suppressing T cell immune responses is to restore the balance between immune tolerance and activation by induction or/and expansion of regulatory T cells (Tregs) (Arellano et al., 2016; Sakaguchi et al., 2008; Vignali et al., 2008).

Tregs are generated during normal thymocyte differentiation (natural Tregs) or they are induced from naïve Foxp3−CD4+ T cells in the periphery (induced Tregs) when exposed to antigen in a tolerogenic environment or with suboptimal co-stimulation (Workman et al., 2009). Most regulatory T cells are characterized by expression of the X-linked transcription factor forkhead box p3 (Foxp3) that is critical for their development, function, and homeostasis (Fontenot et al., 2003; Hori et al., 2003). Mice deficient in Foxp3 (scurfy mice) develop a profound autoimmune-like lymphoproliferative disease, showing its importance in maintaining tolerance (Brunkow et al., 2001). There are several mechanisms by which regulatory T cells can limit excessive immune responses, including suppression of effector/autoreactive T cells proliferation by interleukin 2 (IL-2) sequestering or anti-inflammatory cytokines and finally, dampening antibody production by B cells that require T cell help (Romano et al., 2019; Vignali et al., 2008). More detailed description of the suppressive mechanisms of Tregs will be given in section 3.

Several approaches to generate Tregs to suppress autoimmune responses have shown promise. For example, daily administration of low doses IL-2 has been linked to expansion of Treg cells and induction of remission in systemic lupus erythematosus (SLE) and type I diabetes (Grasshoff et al., 2021). The mechanism is believed to result from engagement of heterotrimeric high affinity IL-2 receptor complex that is constitutively expressed on T regs (Malek, 2008; Malek and Castro, 2010). This is not an antigen specific mechanism but relies on the expansion of existing Tregs. Another strategy to induce antigen-specific immune tolerance to a variety of antigens is a co-administration of antigen with the immunosuppressive drug rapamycin-loaded poly(lactic-co-glycolic acid) nanoparticles (PLGA-RAPA) (Kelly et al., 2021; Maldonado et al., 2015). Tolerance induction relies on nanoparticles being non-specifically phagocytosed by antigen presenting cells (APCs) such as dendritic cells, that then acquire a tolerogenic phenotype (tDCs). tDCs promote the differentiation of antigen-specific regulatory T cells (Treg) (Taner et al., 2005) that suppress T cell help effector functions and thus reduce secretion of autoantibodies. Using this approach Moldanado et al. were able to prophylactically and therapeutically suppress disease pathology in a model of experimental autoimmune encephalomyelitis (EAE) (Maldonado et al., 2015).

Based on requirement of both B cells and T cells in generating autoimmune antibodies, Srivastava et al. investigated an approach to combine liposomal STALs (antigen-LP-CD22L) targeting B cells with rapamycin-loaded poly(lactic-co-glycolic acid) nanoparticles (PLGA-RAPA; Fig. 1B) (Srivastava et al., 2021) to generate Tregs. In pilot experiments, co-administration of ovalbumin decorated STALs (OVA-LP-CD22L) with PLGA-RAPA not only reduced OVA-specific IgG1 titers in wild type mice challenged with soluble OVA/Alum but also increased population of OVA-specific CD4+CD25+Foxp3+ regulatory T cells measured two weeks after the treatment. In contrast, administration of OVA-LP with PLGA-RAPA had minimal suppression of the production of anti-OVA antibodies.

The strategy for combining STALS and PLGA-RAPA was tested in transgenic K/BxN mice that spontaneously develop autoimmune arthritis (Ditzel, 2004; Monach et al., 2007, 2008). Autoantibodies generated in K/BxN mice are directed to the ubiquitously expressed self-antigen, glucose-6-phosphate isomerase (GPI). The combination of GPI-LP-CD22L and PLGA-RAPA exhibited improved immune tolerance over either particle alone, delayed the progression of disease and reduced anti-GPI IgG1 antibody responses (Srivastava et al., 2021). The results suggested potential for combining treatments that induced antigen specific tolerance in both B cells and T cells.

3. Siglecs expressed on innate immune cells in induction of regulatory T cells

As mentioned above, regulatory T cells are believed to be fundamental regulators of autoimmunity (Romano et al., 2019). They can limit excessive immune responses by different suppressive mechanisms acting on various immune cells, like T cell, B cells or DCs (Romano et al., 2019). For example, Tregs can produce anti-inflammatory cytokines, including transforming growth factor TGFβ and IL-10 that actively suppress effector T cells. In addition, Tregs release perforin and granzyme leading to apoptosis of target cells and can also sequester IL-2 from the microenvironment (Vignali et al., 2008). IL-2 starvation reduces T cells and natural killer cells proliferation and their effector functions. Tregs have been observed to have a direct effect on B-cells via PDL1/PD-1 interaction limiting autoantibody production (Gotot et al., 2012) and on DCs via CTLA-4 and CD80/CD86 (Onishi et al., 2008). Interactions with CTLA-4 on Tregs blocks co-stimulation and down-regulates expression of CD80/CD86 on antigen presenting cells (Cederbom et al., 2000; Onishi et al., 2008). To demonstrate protective functions of regulatory T cells in autoimmune diseases, Foxp3 deficient K/BxN arthritic mice lacking Tregs were developed. These animals exhibited more aggressive arthritis with an early disease onset (Monte et al., 2008; Nguyen et al., 2007). Similar results were observed in collagen induced arthritis (CIA) mice model. Animals depleted of CD25+ regulatory cells developed significantly more severe disease than control mice following collagen immunization. Therapeutic potential of Tregs was also demonstrated by adoptively transferring CD4+CD25+ T cells into depleted mice which shown to reverse the heightened severity (Morgan et al., 2003).

A potential role for Siglecs in the induction of regulatory T cells was explored by Perdicchio et al. (2016). Inspired by a mechanism used by tumor cells for creating immune suppression in their microenvironment, authors used sialylated antigens to target Siglec-E on dendritic cells (DCs). Loading of DCs with sialylated antigens resulted in antigen-specific induction of de novo Tregs and the inhibition of auto-reactive T cells in mice.

Suppression of Tregs proliferation in various autoimmune conditions has been directly linked to macrophages expressing CD169/sialoadhesin/Siglec-1 (Wu et al., 2009, 2021). CD169/sialoadhesin is the largest members of the Siglec family (Crocker et al., 2007; Hartnell et al., 2001). It is composed of one N-terminal V-set domain, followed by the unusually large number of 16 C2-set domains, a feature that may be important for its cell adhesive functions (Crocker et al., 1994; Hartnell et al., 2001). Unlike CD22 or Siglec10/G, Siglec-1 lacks ITIM signaling motif in its relatively short cytoplasmic domain (Crocker et al., 2007). CD169 has been detected in high levels on a subpopulation of tissue-resident macrophages in hematopoietic and secondary lymphoid organs and inflammatory macrophages in the tissues obtained from patients suffering from autoimmune diseases, including rheumatoid arthritis (Hartnell et al., 2001).

Siglec-1 can also mediate a crosstalk between macrophages and various immune cells including neutrophils (Crocker et al., 1995), dendritic cells (Van Dinther et al., 2018) and regulatory T cells (Wu et al., 2009, 2021) by interacting with sialic acid molecules on the ligands on their surfaces. In the context of autoimmune diseases macrophages expressing Siglec-1 were shown to suppress the expansion of regulatory T cells (Tregs) and therefore promoting an inflammatory condition (Fig. 2) (Wu et al., 2009). In a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), it was shown that Siglec-1-expressing macrophages are closely associated with activated CD4+Foxp3+ Tregs and that the binding is sialic acid-dependent (Wu et al., 2009). Co-culture of CD169-positive macrophages and T regs isolated from diseased mice suppressed their expansion. In contrast, Siglec-1-KO mice had increased numbers of Tregs and reduced levels of Th17 cells, leading to attenuated severity of EAE and slowing its progression. These results suggest that Siglec-1 participates in the mechanism of Treg proliferation, but the specific role of Siglec-1 was not defined.

Fig. 2. Schematic illustration of the interaction between Siglec-1+ macrophages and regulatory T cells.

Fig. 2

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The binding of macrophages to activated regulatory T cells (Tregs) is mediated via Siglec-1. This is proposed to suppress expansion of T regs and thereby promote effector T cell proliferation and resulting inflammation (Wu et al., 2009, 2021).

In another study, Wu et al. investigated the basis for Siglec-1 binding to Tregs using in vitro-induced cells as a model system (Wu et al., 2021). They provided evidence that binding of CD169-positive macrophages to Tregs depends completely on the activation status of regulatory T cells. Siglec-1 bound only to activated, but not resting Tregs. They concluded that differential binding of Siglec-1 to these cells may be due to changes in glycosylation that occur in activated Tregs. Finally, by proximity labeling of intact regulatory T cells they identified glycoprotein counter-receptors for Siglec-1. These included a wide range of glycoproteins involved in T cell functions, like the regulation of T cell activation and proliferation, such as CD80, PD-1, PD-L1, CD166 (adhesion molecule) and CD25. The latter one, CD25, is one of the subunits of heterotrimeric protein IL-2 receptor. Binding of Siglec-1 to CD25 may alter its function and as a result affect its capability in receiving IL-2, which is necessary for Treg cell expansion and proliferation (Wu et al., 2021). How these glycoprotein counter receptors can suppress Treg proliferation remains to be determined.

Given the importance of CD169+ tissue macrophages in autoimmune disease, targeting therapeutics to these cells may have the potential to alter disease pathology. Several studies target CD169 directly to deliver antigens (Edgar et al., 2019; Kawasaki et al., 2013). Liposomal nanoparticles displaying a high-affinity synthetic CD169/Siglec-1 ligand, 9-N-(4H-thieno[3,2-c]chromene-2-carbamoyl)-Neu5Acα2−3Galβ1−4GlcNAc (TCCNeu5Ac) (Nycholat et al., 2012) efficiently deliver antigen to CD169 expressing macrophages, resulting in enhanced presentation of antigen natural killer T cells (Kawasaki et al., 2013) or to CD8+ T cells (Edgar et al., 2019). Such strategies could in principle be explored to modulate CD169+ macrophage/regulatory T cells interactions and promote proliferation of Tregs in autoimmunity.

4. Roles of Siglec 10 on macrophages and T cells in autoimmunity

In addition to its role in regulation of B cell signaling, Siglec-10 is also expressed on human innate immune cells and regulates immune cell signaling (Chen et al., 2009; Liu et al., 2011). Several recent studies demonstrated the importance of Siglec-10/CD24 interactions in enhanced immune tolerance (Aroldi et al., 2021; Sammar et al., 2017, 2021). CD24 is a mucin-like sialylated glycoprotein expressed on hematopoietic cells and diverse tumor cells, which was also recognized as an important player in fetomaternal tolerance (Sammar et al., 2017, 2021). Interactions between CD24 on placenta with maternal cells expressing Siglec-10 is proposed to mediate immune tolerance between the fetus and the mother, preventing maternal immune system recognizing fetus as a foreign antigen (Sammar et al., 2017). Accordingly, reduced expression of CD24 was linked to reduced immune tolerance and preeclampsia, a major pregnancy complication (Sammar et al., 2021).

CD24 is also expressed on some tumor cells (Aroldi et al., 2021; Barkal et al., 2019). Therefore, not surprisingly, Siglec-10/CD24 interactions were identified as a “don’t eat me” signal (DEMs) that reduce inflammation and autoimmune responses but are also utilized by certain cancers to evade immunorecognition (Altevogt et al., 2021; Aroldi et al., 2021). CD24 overexpressed on ovarian and breast cancer bind to Siglec-10 on macrophages suppressing macrophage-mediated phagocytosis and thus promoting immune evasion of cancer (Barkal et al., 2019). The CD24 blocking antibody developed in that study enhanced phagocytosis of CD24 positive tumor cells giving a promise for a new cancer immunotherapy (Barkal et al., 2019). Consequently, based on the nature of Siglec-10/CD24 interactions, OncoImmune developed Siglec-10 agonist, CD24 fusion protein (CD24Fc) in which two CD24 units are conjugated to an immunoglobulin Fc domain. CD24Fc is currently being tested in several clinical trials for prevention of acute graft-versus-host disease (phase III; NCT04095858), COVID-19 associated inflammation (phase III; NCT04317040) (Ghasempour Dabaghi et al., 2021) and immune-related adverse events associated with checkpoint inhibitor therapy (phase I/II; NCT04060407) (Smith and Bertozzi, 2021).

Finally, while Siglec-10 is not expressed on naïve peripheral T cells, its expression has been demonstrated on tissue infiltrating T cells that have been found to protect mice from type 1 diabetes (T1D) (Bandala-Sanchez et al., 2013). T1D can be initiated in the nonobese diabetic (NOD) mouse strain by mucosal administration of the pancreatic islet autoantigen glutamic acid decarboxylase (GAD65) (Pearson et al., 2016). In healthy human and mice, antigen activated CD4+ T cells express high levels of CD52 surface marker, which is released in its soluble form (sCD52) to the bloodstream. sCD52, naturally decorated with α2–6-sialyllactosamine containing oligosaccharides (Treumann et al., 1995), binds to Siglec-10 on T cells, leading to their suppression and regulation of proliferation. In the people with or at risk of type 1 diabetes, the generation and function of GAD64 activated CD4+CD52high T cells is impaired, leading to disruption of regulatory mechanisms controlling T cells proliferation (Bandala-Sanchez et al., 2013). That finding was confirmed in the NOD mouse model in which depletion of CD52high lymphocytes led to a substantial acceleration of diabetes onset. This observation suggests that Siglec-10 agonists may be useful to modulate adaptive immune system responses and protect humans from autoimmune disease (Bandala-Sanchez et al., 2013; Smith and Bertozzi, 2021).

5. Siglecs-based biomarkers of autoimmune disorders

Biomarkers of autoimmune disorders have a high diagnostic and monitoring value. They may predict response to the therapy and the severity of the disease. Three Siglec-based biomarkers including Siglec-1, Siglec-10 and Siglec-5 which have been proposed as biomarkers for autoimmune disease will be discussed (Biesen et al., 2008; Clancy et al., 2019; Ju et al., 2022; Lee et al., 2019; Oliveira et al., 2018).

Siglec-1 is expressed by circulating blood monocytes in systemic lupus erythematosus (SLE) patients and was identified as a useful biomarker for monitoring the disease severity and treatment efficacy (Biesen et al., 2008; Oliveira et al., 2018). Most patients with SLE have a significantly increased frequency of Siglec-1–positive inflammatory and resident monocytes (Biesen et al., 2008) and a high concentration of soluble Siglec-1 (sSiglec-1) circulating in plasma samples (Oliveira et al., 2018). The frequency of Siglec-1 positive resident monocytes in patients with SLE also significantly correlates with serum levels of antinuclear antibody targeting double stranded DNA (anti-dsDNA) and upregulation of IFN and type I IFN–stimulated genes (Biesen et al., 2008). Anti-dsDNA autoantibodies are present in 43–92% of systemic lupus erythematosus cases and are generally linked with the disease activity (Didier et al., 2018). The treatment of SLE patients with a high-dose of glucocorticoid results in a dramatic reduction of Siglec-1 expression on inflammatory monocytes, highlighting the monitoring value of CD169 (Biesen et al., 2008).

The upregulation of IFN and type I IFN–stimulated genes is a prominent feature of SLE (Baechler et al., 2004; Rönnblom et al., 2006) and patients with Sjogren’s Syndrome (Marketos et al., 2019). The potential mechanism of interferon pathway activation in SLE has been proposed by several groups (Baechler et al., 2004; Crow, 2003; Pascual et al., 2003; Ronnblom and Alm, 2001). An environmental trigger, like microbial infection stimulates plasmacytoid DCs to produce IFN via TLR signaling. IFN promotes differentiation of SLE monocytes into activated DCs which present self-antigens to autoreactive CD4+ T cells. In turn, activated T cells stimulate self-reactive B cells to produce autoantibodies specific for nucleic acid and other nuclear constituents, like anti-dsDNA or anti-Smith (anti-Sm) antibodies (Ahn et al., 2019). These autoantibodies bind endogenous nucleic acids and chromatin derived from apoptotic material to form immune complexes that stimulate further IFN production by pDCs and B cell proliferation (Baechler et al., 2004). Given that autoimmune diseases associated with antinuclear autoantibodies are linked with an upregulation of IFN and type I IFN–stimulated genes, recent attention has been also focused on a potential role of Siglec-1 in the pathogenesis of congenital heart block (CHB) in neonatal lupus erythematosus (NLE) affected offspring (Clancy et al., 2019). NLE is a passively acquired autoimmune disease that is initiated by in utero exposure to maternal anti–Sjogren’s-syndrome-related antigen A autoantibodies (anti-SSA/Ro). The expression of CD169 on maternal cells was identified as a risk factor for the development of CHB in offspring, indicating Siglec-1 as a diagnostic marker and a disease-provoking factor leading to a pathological, persistently activated macrophages.

In another study of patients with SLE, Ju et al. measured the population of Siglec-10+ B cells and its correlation with disease activity (Ju et al., 2022). It was confirmed that Siglec-10 was selectively expressed in CD19+B cells from peripheral blood of SLE patients and that the proportion of CD19+Siglec-10+B cells was significantly elevated. Furthermore, the increased levels of Siglec-10 B cells positively correlated with the disease severity and efficacy of the treatment. Patients that received hydroxychloroquine had significantly attenuated proportion of CD19+Siglec-10+B cells detected in the peripheral blood mononuclear cells. Overall, the study demonstrated the value of Siglec-10 as a biomarker of the treatment efficacy and SLE progression.

Very recently, soluble siglec-5 (sSiglec-5) was identified as a novel biomarker for primary Sjogren’s Syndrome (pSS) (Lee et al., 2019). pSS is a systemic autoimmune disease that is characterized by lymphocytic infiltration in the exocrine glands, which results in oral and ocular dryness (Jung et al., 2021). Siglec-5 is expressed on the surface of neutrophils, monocytes, and macrophages, and its cytoplasmic tail has immunoreceptor tyrosine-based inhibitory motifs (ITIM), inhibiting cell activation. The level of sSiglec-5 was elevated in the saliva of pSS patients than in controls, which reflects the severity of hyposalivation and ocular surface damage in this condition. Even though the biological function of sSiglec-5 in pSS remains uncertain, the ease to obtain salivary biomarker could provide benefits for the diagnosis of Sjogren’s Syndrome.

In summary, sensitive Siglec-based biomarkers of autoimmune diseases can facilitate monitoring of disease severity and response to treatment. Consequently, easier, and more precise determination of treatment responses can greatly facilitate early decision-making around futility of treatment strategy, dose selection and give and opportunity to switch to alternatives for an optimal outcome.

6. Summary and conclusions

In this review we have summarized current evidence for the roles of Siglecs in regulation of innate and adaptive immunity as they relate to the development of autoimmune disease. A deeper understanding of their roles in regulation of immune responses has led to development of therapeutic strategies for targeting Siglecs to treat of autoimmune diseases. Given the central role of B cells in the generation of autoantibodies that mediate pathogenesis, increasing attention has been given to targeting B cell Siglecs. The anti-CD22 antibody epratuzumab is currently being evaluated for the management of Sjorgen Syndrome. Nanoparticles targeting inhibitory receptors CD22 and Siglec-G/Siglec-10 have been documented to promote antigen specific B-cell tolerance, and in combination with nanoparticle therapies that induce Tregs show promise for treating autoimmune diseases. An important relationship has been identified between CD169/Siglec-1 positive macrophages and expansion of Tregs in inflamed tissues. The upregulation of Siglec-1 on macrophages appears to suppress the expansion of regulatory T cells and promote the inflammatory condition. Conversely blocking Siglec-1 could potentially disrupt the interactions between macrophages and Tregs, promoting proliferation of regulatory T cells to limit immune responses to self-antigens.

Finally, several Siglecs have been shown to be suitable biomarkers of autoimmune disease. For example, over-expression of Siglec-1 on monocytes or Siglec-10 on B cells positively correlates with the severity of SLE and treatment efficiency. Consequently, monitoring of Siglecs can help to diagnose autoimmune diseases and determine the best treatment strategies available for patients.

Overall, Siglecs have a great potential as targets for novel therapeutic approaches to restore tolerance in autoimmune diseases and to monitor diseases progression and treatment outcome.

Acknowledgments

This work was funded in part by NIH grants R01AI050143 and R01AI132790. Open-source graphics for nanoparticle’s lipid monolayer and immune cells were provided by Servier Medical Art.

Footnotes

The authors have filed patent applications proposing to suppress autoimmune diseases by targeting Siglecs. They could potentially benefit financially if patents are issued and cover commercial treatments of disease.

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