Heritable factors shape natural human IgM reactivity to Ro60/SS-A and may predispose for SLE-associated IgG anti-Ro and anti-La autoantibody production

Ferreira, Ricardo C.; Barreto, Marta; Santos, Eugénia; Pereira, Clara; Martins, Berta; Andreia, Rita; Crespo, F.; Viana, João Faro; Vasconcelos, Carlos; Ferreira, Carlos; Vicente, Astrid M.; Fesel, Constantin

doi:10.1016/j.jaut.2005.05.004

Cited by 14 publications

(16 citation statements)

References 29 publications

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“…1 G,H,I,J). Anti-dsDNA and anti-Ro60/SS-A assays were already reported for a subset of the present samples in our previous heritability study [10].…”

Section: Resultssupporting

confidence: 64%

“…SLE-type autoantibodies accumulate and diversify over many years before SLE is diagnosed [7]. These autoantibodies, however, do not necessarily indicate manifest disease, and self-reactive IgG with specificities indistinguishable from SLE patients is frequently found in their healthy relatives [8]–[10]. These unaffected relatives obviously share a genetic disposition to produce SLE-associated autoantibodies [10], although they usually remain disease-free for life.…”

Section: Introductionmentioning

confidence: 99%

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Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL-2/CD25-Mediated Effects Suggested by Coreferentiality Modeling

et al. 2012

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In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We studied relations of IgG autoantibody profiles and peripheral blood activated regulatory T-cells (aTregs), represented by CD4+CD25bright T-cells that were regularly 70–90% Foxp3+. We found consistent positive correlations of broad-range as well as specific SLE-associated IgG with aTreg frequencies within unaffected relatives, but not patients or unrelated controls. Our interpretation: unaffected relatives with shared genetic factors compensated pathogenic effects by aTregs engaged in parallel with the individual autoantibody production. To study this further, we applied a novel analytic approach named coreferentiality that tests the indirect relatedness of parameters in respect to multivariate phenotype data. Results show that independently of their direct correlation, aTreg frequencies and specific SLE-associated IgG were likely functionally related in unaffected relatives: they significantly parallelled each other in their relations to broad-range immunoblot autoantibody profiles. In unaffected relatives, we also found coreferential effects of genetic variation in the loci encoding IL-2 and CD25. A model of CD25 functional genetic effects constructed by coreferentiality maximization suggests that IL-2-CD25 interaction, likely stimulating aTregs in unaffected relatives, had an opposed effect in SLE patients, presumably triggering primarily T-effector cells in this group. Coreferentiality modeling as we do it here could also be useful in other contexts, particularly to explore combined functional genetic effects.

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“…1 G,H,I,J). Anti-dsDNA and anti-Ro60/SS-A assays were already reported for a subset of the present samples in our previous heritability study [10].…”

Section: Resultssupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL-2/CD25-Mediated Effects Suggested by Coreferentiality Modeling

et al. 2012

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“…The healthy adult relatives of autoimmune patients have been reported to often have detectable anti-Ro60 IgM-antibodies [39], and it was hypothesized that this could predispose these individuals to later IgG class-switched anti-Ro60 responses and the development of overt clinical disease [39]. In an earlier report, 4–5 week old neonates from autoimmune mothers were found to have only low or non-detectable levels of IgM anti-Ro60 [40].…”

Section: Discussionmentioning

confidence: 99%

Modulation of natural IgM autoantibodies to oxidative stress-related neo-epitopes on apoptotic cells in newborns of mothers with anti-Ro autoimmunity

Grönwall

Clancy

Getu

et al. 2016

Journal of Autoimmunity

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At birth, the human immune system already contains substantial levels of polymeric IgM, with autoantibodies to neo-epitopes on apoptotic cells (ACs) that are proposed to play homeostatic and anti-inflammatory roles. Yet the biologic origins and developmental regulation of these naturally arising antibodies remain poorly understood. Herein, we report that levels of IgM-antibodies to malondialdehyde (MDA) protein adducts, a common type of in vivo generated oxidative stress-related neoepitope, directly correlate with the relative binding of neonatal-IgM to ACs. While levels of IgM to phosphorylcholine (PC), a natural antibody prevalent in adults, were relatively scant in cord blood, there was significantly greater relative representation of IgM anti-MDA antibodies in newborns compared to adults. To investigate the potential interrelationships between neonatal IgM with pathogenic IgG-autoantibodies, we studied 103 newborns born to autoimmune mothers with IgG anti-Ro (i.e., 70 with neonatal lupus and 33 without neonatal lupus). In these subjects the mean levels of IgM anti-Ro60 were significantly higher than in the newborns from non-autoimmune mothers. In contrast, levels of IgM anti-MDA in IgG anti-Ro exposed neonates were significantly lower than in neonates from non-autoimmune mothers. The presence or absence of neonatal lupus did not influence the total levels of IgM in the anti-Ro exposed newborns. Taken together, our studies provide evidence that the immune development of the natural IgM-repertoire may be affected, and become imprinted by, the transfer of maternal IgG into the fetus.

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“…It has been proposed that heritable differences in the autoreactive natural antibody repertoire at birth could contribute to predisposition to autoimmunity later in life [114]. For example, first-degree relatives of patients with SLE have similar levels of IgM anti-Ro antibodies [115]. In fact, there is evidence that disease-associated regulatory abnormalities can cause some IgM natural antibody-expressing B-cells to be recruited into T-cell dependent germinal center responses later in life, possibly changing their binding specificity through somatic hypermutation and class-switch to IgG.…”

Section: Natural Igg Antibodiesmentioning

confidence: 99%

Natural IgM: Beneficial Autoantibodies for the Control of Inflammatory and Autoimmune Disease

2014

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Natural IgM are highly represented in the circulation at birth, and these often autoreactive antibodies have been postulated to have innate-like properties and play crucial roles in apoptotic cell clearance, tissue homeostasis, and immune modulation. This review summarizes the known properties of these IgM autoantibodies, and the evidence that these anti-apoptotic cell IgM natural antibodies can regulate inflammatory responses through ancient pathways of the innate immune system that first arose long before the initial emergence of the adaptive immune system. While the regulatory contributions of these natural IgM autoantibodies are certainly not an essential and fundamental component of host defenses, these provide an additional layer to further protect the host. More importantly, these IgM antibody responses are highly inducible and their up-regulation can be a powerful means for the host to survive in a setting of chronic inflammation. The observed beneficial clinical associations for cardiovascular disease and autoimmunity, as well as opportunities for potential therapeutic implications are discussed.

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Heritable factors shape natural human IgM reactivity to Ro60/SS-A and may predispose for SLE-associated IgG anti-Ro and anti-La autoantibody production

Cited by 14 publications

References 29 publications

Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL-2/CD25-Mediated Effects Suggested by Coreferentiality Modeling

Compensatory T-Cell Regulation in Unaffected Relatives of SLE Patients, and Opposite IL-2/CD25-Mediated Effects Suggested by Coreferentiality Modeling

Modulation of natural IgM autoantibodies to oxidative stress-related neo-epitopes on apoptotic cells in newborns of mothers with anti-Ro autoimmunity

Natural IgM: Beneficial Autoantibodies for the Control of Inflammatory and Autoimmune Disease

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