IgM antibodies against malondialdehyde and phosphorylcholine in different systemic rheumatic diseases

Abstract

the pReciSeSADS clinical consortium*, Marta Alarcon-Riquelme 1,3 & Johan frostegård 1 ✉ igM antibodies against phosphorylcholine (anti-pc) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here compare these antibodies in systemic rheumatic conditions and study their properties. Anti-pc and anti-MDA was measured using ELISA in patients with SLE (374), RA (354), Mixed connective tissue disease (MCTD, 77), Systemic sclerosis (SSc, 331), Sjögren's syndrome (SjS, 324), primary antiphospholipid syndrome (PAPs, 65), undifferentiated connective tissue disease (UCTD, 118) and 515 matched healthy controls (HC). Cardiovascular score (CV) was broadly defined based on clinical disease symptoms. Anti-PC and anti-MDA peptide/protein characterization were compared using a proteomics de novo sequencing approach. anti-MDA and anti-PC were extracted from total IgM. The proportion of Treg cells was determined by flow cytometry. The maximal difference between cases and controls was shown for MCTD: significantly lower IgM Anti-PC but not anti-MDA among patients (median 49.3RU/ml vs 70.4 in healthy controls, p(t-test) = 0.0037). IgM low levels were more prevalent in MCTD, SLE, SjS, SSc and UCTD. IgM anti-PC variable region profiles were different from and more homologous than anti-MDA. Anti-PC but not anti-MDA were significantly negatively correlated with CV in the whole patient group. In contrast to IgM anti-PC, anti-MDA did not promote polarization of Tregs. Taken together, Anti-pc is decreased in MctD and also in SLe, SjS and SSc but not in other studied diseases. Anti-pc may thus differentiate between these. In contrast, anti-MDA did not show these differences between diseases studied. Anti-pc level is negatively correlated with cV in the patient group cohort. in contrast to anti-PC, anti-MDA did not promote Treg polarization. These findings could have both diagnostic and therapeutic implications, one possibility being active or passive immunization with pc in some rheumatic conditions.

Systemic lupus erythematosus and cardiovascular disease

“…Also in SLE, we reported that anti-PC is associated with protection and in relation to prevalence of atherosclerotic plaques and other disease manifestations [55][56][57][58]83], which has been confirmed by other researchers [59,60]. Among subclasses and isotypes, the protective properties of anti-PC are mainly present in IgM and IgG1 [57,61,142].…”

“…Traditional risk factors Age [25,27,45] Dyslipidemia (including different abberations in lipids) [25,39,49] Hypertension [25] Diabetes [25] Smoking [25] Nontraditional risk factors Antiphospholipid antibodies [25,[50][51][52][53][54] Other SLE manifestations (especially renal) [1,2,25,[27][28][29][30][31][32][33][34][35][36][37]45] Cortisone treatment [25,27,39,45] Low levels of natural antibodies including antiphosphorylcholine [55][56][57][58][59][60][61] Note: Commonly, in CVD in the general population, the risk factor concept is related to causation; for example, a risk marker is determined to be a risk factor when treatment of the risk marker decreases CVD (as defined by myocardial infarction (MI), stroke, peripheral artery disease, and angina). Since SLE is a rare disease, such treatment studies have not often been done, so risk markers with substantial human data are also included in the concept.…”

“…Also, anti‐MDA has protective properties in general and in SLE, though it is less described than anti‐PC in this context, and is also only a DAMP, not a PAMP [ 58 , 145 ].…”

Potential natural immunization against atherosclerosis in hibernating bears

“…IgM anti-PC promote polarization of T regulatory cells, from atherosclerotic plaques, another immunomodulatory and anti-inflammatory property of anti-PC with direct relevance for the present study 33 . Moreover, IgG1, more than IgG2, anti-PC has protective properties associated with less atherosclerosis progress, less vulnerable plaques and mortality in CKD 29 , 30 , 34 and IgA anti-PC is associated with favorable atherosclerosis progress 29 . It is likely that IgA anti-PC also shares at least some of these protective properties with other anti-PC subclasses and isotypes but more studies on IgA anti-PC are warranted.…”

Mini Review: Structure and Function of Nematode Phosphorylcholine-Containing Glycoconjugates

“…In addition, in the context of rheumatic disease, an inverse correlation between anti-PC antibodies and, organ damage and disease activity in SLE patients has been demonstrated (95,96). Although the exact mechanism(s) underlying the protective effects of anti-PC antibodies is still under investigation, anti-inflammatory and cardioprotective benefits of anti-PC antibodies in SLE and also Sjögren's syndrome and mixed connective tissue disease are associated with regulatory T cell polarisation, oxidised low density lipoprotein uptake inhibition and enhanced apoptotic cell clearance (96)(97)(98)(99). Interestingly, IgM anti-PC antibodies are greatly increased in response to ES-62 in murine models of lupus and in high calorie diet (HCD)-fed mice (82,89).…”