Pro-inflammatory State in Monoclonal Gammopathy of Undetermined Significance and in Multiple Myeloma Is Characterized by Low Sialylation of Pathogen-Specific and Other Monoclonal Immunoglobulins

Abstract

Multiple myeloma (MM) and its pre-cancerous stage monoclonal gammopathy of undetermined significance (MGUS) allow to study immune responses and the chronology of inflammation in the context of blood malignancies. Both diseases are characterized by the production of a monoclonal immunoglobulin (mc Ig) which for subsets of MGUS and MM patients targets pathogens known to cause latent infection, a major cause of inflammation. Inflammation may influence the structure of both polyclonal (pc) Ig and mc Ig produced by malignant plasma cells via the sialylation of Ig Fc fragment. Here, we characterized the sialylation of purified mc and pc IgGs from 148 MGUS and MM patients, in comparison to pc IgGs from 46 healthy volunteers. The inflammatory state of patients was assessed by the quantification in serum of 40 inflammation-linked cytokines, using Luminex technology. While pc IgGs from MGUS and MM patients showed heterogeneity in sialylation level, mc IgGs from both MGUS and MM patients exhibited a very low level of sialylation. Furthermore, mc IgGs from MM patients were less sialylated than mc IgGs from MGUS patients (p < 0.01), and mc IgGs found to target an infectious pathogen showed a lower level of sialylation than mc IgGs of undetermined specificity (p = 0.048). Regarding inflammation, 14 cytokines were similarly elevated with a p value < 0.0001 in MGUS and in MM compared to healthy controls. MM differed from MGUS by higher levels of HGF, IL-11, RANTES and SDF-1-α (p < 0.05). MGUS and MM patients presenting with hyposialylated pc IgGs had significantly higher levels of HGF, IL-6, tumor necrosis factor-α, TGF-β1, IL-17, and IL-33 compared to patients with hyper-sialylated pc IgGs (p < 0.05). In MGUS and in MM, the degree of sialylation of mc and pc IgGs and the levels of four cytokines important for the anti-microbial response were correlated, either positively (IFN-α2, IL-13) or negatively (IL-17, IL-33). Thus in MGUS as in MM, hyposialylation of mc IgGs is concomitant with increased levels of cytokines that play a major role in inflammation and anti-microbial response, which implies that infection, inflammation, and abnormal immune response contribute to the pathogenesis of MGUS and MM.

Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms

“…Our study confirms that the three subtypes of MPNs present with a very high level of inflammation (26 cytokines produced in excess among 42 measured). The cytokine levels found in the blood of MPN patients were higher than those previously observed in patients with myeloma, although myeloma is a much more severe blood cancer than MPNs [ 45 ]. Of note, whereas EPO and TPO are low in MPNs, high levels of JAK2-activating G-CSF (and IL-6) were observed in MPN patients despite the fact that patients typically present with elevated neutrophil counts.…”

“…Forty cytokines and chemokines and two receptors linked to inflammation were measured in the blood serum of 75 MPN patients and 17 HDs using the Luminex technology and Bio-Plex Pro human cytokine panel kits, as previously described [ 45 ]. We found significantly high levels for 26 cytokines ( Table 2 , indicated in blue) in MPN patients, compared to HDs ( p < 0.05, Mann–Whitney t -test).…”

“…There are examples of hematological malignancies where inflammation precedes the acquisition of multiple genetic mutations and the subsequent expansion of the mutated clone. Our previous study of inflammation in the context of myeloma and its asymptomatic stage (MGUS) revealed that except for four cytokines found to be significantly higher in myeloma (HGF, IL-11, RANTES, SDF-1α), the levels of 38 inflammation cytokines were similar in MGUS and in myeloma [ 45 ]. Thus, a high level of inflammation is already present at the asymptomatic, benign stage of MGUS, and except for four molecules, the acquisition of multiple genetic alterations characteristic of progression toward myeloma did not significantly increase cytokine production.…”

Prevalence and prognostic value of monoclonal gammopathy in heart failure patients with preserved ejection fraction: A prospective study

“…All the diseases within the MG spectrum may show cardiac involvement, with myocardial deposits of paraprotein or its components, that generate a diastolic alteration leading to a restrictive pattern and HF [9][10][11][12][13]. MGs trigger a proinflammatory state [14] that could contribute to the development of diastolic alterations at a cardiac level.…”

“…Given the pathogenesis, both may rely on immune system activation and inflammation mechanisms [14,15], suggesting a possible link between them.…”