Sialylated and de-sialylated immunoglobulin G anti-double-stranded DNA in lupus

Immunoglobulin G (IgG) is a major effector molecule in humoral immunity. IgG reacts to antigens, and its Fc fragment delivers various signals to Fc receptor (FcR)-containing cells, such as B cells, monocytes/macrophages, neutrophils, basophils, and dendritic cells.1 Although the significance of IgG in effective immunity has been long known, the impact of its glycan content on both positive and negative functions of the immune reaction was only identified 16 years ago.2 In this article, the authors conclusively demonstrated that de-sialylated (α-2,6-sialic acid [SIA]) IgG anti-platelet antibodies induced severe thrombocytopenia in vivo, in contrast to enriched sialylated IgG anti-platelet antibodies which induced markedly reduced or only marginal degree of thrombocytopenia.2 Moreover, enriched sialylated IgG (intravenous immunoglobulin, IVIg) reduced the severity of K/BxN-serum induced arthritis. However, no effect of de-sialylated or enriched sialylated IgG on nephritis had been reported2 until 2018.3 Then Pagan et al3 administered a construct containing a galactose and SIA supplement conjoined with a Fc fragment into nephrotoxic nephritis mice. The authors reported that the construct suppressed kidney pathology with reduced inflammatory cell infiltration3 in a manner similar to the IVIg effects described herein. Still, no effect of IgG anti-double-stranded DNA (dsDNA) antibodies on lupus nephritis in mice was reported. Later, Bartsch et al4 reported that sialylated antoantigen-reactive IgG antibodies reduced the development of mouse lupus nephritis. In particular, no inflammation was induced by sialylated IgG autoantibodies. Similarly, sialylated IgG cryoglobulins protected from cryoglobulin-mediated glomerulonephritis.5 These results indicate that sialylated IgG with non-specific or autoantigen-specific capacity does inhibit or reduce nephritis development in mice. Whether sialylated and de-sialylated IgG anti-dsDNA antibodies have similar effects on progress and severity of lupus nephritis was unknown until a recent publication describing the use of de-sialylated and sialylated IgG anti-dsDNA antibodies to explore their effects on pristane-induced lupus nephritis/proteinuria.6 The authors reported that de-sialylated IgG anti-dsDNA aggravated lupus proteinuria. In contrast, sialylated IgG anti-dsDNA relieved lupus proteinuria. In particular, different SIA contents of separate IgG anti-dsDNA antibodies were compatible with IgG's ability to mitigate (higher SIA content) or exacerbate (lower SIA content) lupus proteinuria.6 Intriguingly, SIA/IgG anti-dsDNA ratios (SIA content divided by amount of IgG anti-dsDNA antibodies) significantly and inversely correlated with lupus kidney pathology as represented by C3 staining. This finding indicates that SIA/IgG anti-dsDNA ratios in blood are potentially useful to specify the severity of lupus nephritis. Moreover, the observation that highly sialylated IgG deposited in the lupus kidney correlated with low urine protein further reinforces the vital role of sialylated IgG anti-dsDNA in relieving lupus proteinuria/nephritis.6 Whether such results in mice can be applied to human systemic lupus erythematosus (SLE) is a next central issue of concern. Very few related articles have been published. The monosialylated IgG percentage in total IgG reportedly decreased in association with the increasing number of symptoms/complications of human SLE.7 Recently, Han et al8 demonstrated that sialylated IgG1 anti-dsDNA levels increased with elevated SLE Disease Activity Index (SLEDAI) scores. Most recently, Liou et al9 revealed that SIA/IgG anti-dsDNA ratios in SLE patients were significantly lower than those in healthy controls. This finding indicates that SLE, being an autoimmune disease, actually has much lower SIA/IgG anti-dsDNA ratios than healthy people,9 similar to that reported earlier.10 The area-under-the curve (AUC) of SIA/IgG anti-dsDNA ratios in lupus patients against SLEDAI scores (inversely correlated) was comparable to the AUC of IgG anti-dsDNA levels in lupus patients against SLEDAI scores (positively correlated).9 Paired data from SLE patients whose blood was tested at least twice in a 6-month period were further assessed. Similarly, higher later SIA/IgG anti-dsDNA ratios were accompanied by corresponding lower successive SLEDAI scores. Moreover, medications increased SIA/IgG anti-dsDNA ratios together with decreasing SLEDAI scores.9 Importantly, SIA/IgG anti-dsDNA ratios in lupus patients without proteinuria were significantly higher than lupus patients with proteinuria; the same trend was also seen for serum IgG anti-dsDNA levels.9 These newly published results in human SLE suggest that SIA/IgG anti-dsDNA ratios are comparable to serum IgG anti-dsDNA levels in indicating SLEDAI scores and presence of proteinuria.9 The mechanism(s) of the IgG SIA effect on lupus nephritis/proteinuria or other outcomes is not uniform and remains unclear. For example, the markedly reduced affinity of enriched sialylated IgG anti-platelet antibodies to FcR, compared with their asialylated form, could be the reason for the low in vivo cytotoxicity of sialylated IgG.2 In particular, IVIg protects immune thrombocytopenia by increasing FcγRIIB expression of mouse splenic macrophages.11 The anti-inflammatory action of sialylated Fc fragments involves a specific C-type lectin, specific intercellular adhesion molecule-3 grabbing non-integrin-related 1 (SIGN-R1), which is expressed on spleen macrophages in the marginal zone.12 Bartsch et al4 reported lower frequency of pathogenic B, Th17, and Th1 cell reactions in the sialylated autoantigen-reactive IgG model (Table 1). Liou et al6 demonstrated that highly sialylated IgG anti-dsDNA induced higher interleukin (IL)-10/IL-12 ratios and transforming growth factor-β1 levels in vivo than their de-sialylated counterpart; in contrast, sialylated IgG anti-dsDNA elicited lower tumor necrosis factor-α levels than de-sialylated IgG anti-dsDNA (Table 1). Moreover, highly sialylated IgG anti-dsDNA stimulated IgG-anti-dsDNA-producing B cells to secrete more anti-inflammatory higher sialylated IgG anti-dsDNA in vitro, probably by increased expression of an important intracellular signaling molecule, Janus kinase 2.6 Likewise, chimeric IgG anti-dsDNA induced human lupus B cells to produce more anti-inflammatory higher sialylated IgG anti-dsDNA and IL-10 in vitro (Table 1).9 Concerning the basic immunologic effects of sialylated IgG, IgG Fc sialylation reportedly weakens complement-dependent cytotoxicity.13 IVIg elicits B-cell apoptosis by modulating B-cell receptor signaling through CD22 interaction.14 Furthermore, sialylated IgG anti-histone autoantibodies diminish the phagocytosis of late apoptotic (secondary necrosis) cells by monocytes.15 Until recently, all published articles on sialylated IgG in mouse nephritis and SLE patients employed mass spectrometry or related sophisticated machines/methods to examine IgG's SIA contents. In contrast, the 2 most recent articles6, 9 used enzyme-linked immunosorbent assay to detect SIA of isolated IgG against the autoantigen dsDNA. The 2 articles6, 9 examined the α-2,6-SIA of IgG anti-dsDNA in its natural configuration, in contrast to degraded IgG reported in all other publications. Intriguingly, sialylated IgG Fab is similarly related to anti-inflammatory activity of IgG,16 other than the Fc fragment.2 In summary, publications so far indicate that sialylated and de-sialylated IgG anti-dsDNA affect lupus in mice and humans with opposite effects on proteinuria and SLEDAI scores. In particular, rising sialylated IgG anti-dsDNA levels mitigate proteinuria and increased levels of de-sialylated IgG anti-dsDNA aggravate proteinuria in lupus mice. The same scenario also occurs in different clinical outcomes in human SLE patients. Hence, here are 2 key clinical issues on early detection of lupus complications. The first is whether the upsurge of de-sialylated IgG anti-dsDNA precedes the appearance of proteinuria in human SLE patients. The second is whether the escalation of sialylated IgG anti-dsDNA forecasts a significant improvement of proteinuria in human SLE patients. Both issues are fascinating and crucial topics that warrant further study. The author declares no conflict of interest.