Editorial: The Role of Microorganisms in Multiple Myeloma

Abstract

Editorial on the Research TopicThe Role of Microorganisms in Multiple Myeloma Multiple myeloma (MM) is a bone marrow malignancy characterized by clonal, abnormal plasma cells that secrete large amounts of a single (monoclonal) immunoglobulin (Ig) (1). Despite great advances in knowledge and treatment, MM remains an incurable disease. MM is always preceded by a benign stage, called monoclonal gammopathy of undetermined significance (MGUS) (2). Recent studies suggested association of MGUS and MM with autoimmunity and with various microorganisms, including hepatitis C virus (HCV), human immunodeficiency virus (HIV), Epstein Barr virus (EBV), and other infectious pathogens (3-10). Indeed, chronic stimulation by self-or infectious antigens is recognized as an initial pathogenic event leading to chronic inflammation, cell proliferation, acquisition of genetic alterations, and cancer. This pathogenic model is proven in B-cell malignancies such as chronic lymphocytic leukaemia or lymphomas (11)(12)(13). Chronic antigen stimulation of B-cells triggers signaling pathways, increases proliferation and reduces apoptosis. Moreover, the complex and interactive balance between non-pathogenic microbes and the human immune system creates a steady state of coexistence, and disturbance of this balance may lead to illness. Direct links between the gut microbiota and MM have been suggested but its implication in the development of MGUS and MM remains poorly understood (14-16). In this collection of 1 original article and 3 reviews by 22 authors, the first section presents recent knowledge on the role of infectious pathogens in the initiation of MM, and the consequences for the therapy of this malignancy. The second section is devoted to the role played by the microbiota in MGUS and MM. ROLE OF INFECTIOUS PATHOGENSMany studies reported an increased prevalence of MGUS and MM in individuals with a prior history of auto-immunity or infections, supporting a role for chronic antigen stimulation in the pathogenesis of . Sigurbergsdottir et al. detail then summarize the reported links between autoimmune diseases, chronic inflammatory conditions, infections, and increased risk of MGUS and MM. The studies suggest that chronic stimulation by infectious antigens might trigger IgH-translocation in clonal plasma cells. The authors also carefully discuss the bias and

Role of the gut microbiota in hematologic cancer

“…Clostridium leptum regulates glucose concentration in the intestinal microenvironment by producing butyrate through the pyruvate and acetyl-coenzyme A pathway. Butyrate plays a role in increasing regulatory T cells and suppressing interleukin 17 (IL-17) (Linares and Hermouet, 2022). For instance, Calcinotto et al (2018) showed that a lack of IL-17 in MM mice, or treatment with antibiotics or antibodies that block IL-17/IL-17R interactions, leads toa delay in MM progression.…”

Impact of viral hepatitis therapy in multiple myeloma and other monoclonal gammopathies linked to hepatitis B or C viruses

“…For significant subsets of monoclonal gammopathies, including MM, the patient’s monoclonal Ig specifically recognizes an infectious pathogen, which implies that the clonal gammopathy was initiated by chronic stimulation by an antigen from this pathogen. 12 , 13 , 17-20 , 29 Moreover, patients with HCV-driven MGUS or MM (when the monoclonal Ig targeted HCV) benefited from AVT: MGUS or MM disease evolution improved after anti-HCV therapy, including a refractory MM for whom antiviral therapy led to long-term complete remission. 25 The present study strengthens and extends these findings to MGUS and MM linked to HBV: for over a third of HBV + patients whose monoclonal Ig could be studied, the monoclonal Ig targets HBV, which implies that HBV initiated the gammopathy in these individuals.…”

Determination of the target of monoclonal immunoglobulins: a novel diagnostic tool for individualized MGUS therapy, and prevention and therapy of smoldering and multiple myeloma

“…Fluorescent signals below the thresholds are considered negative. The MIAA assay has been used to analyse the specificity of recognition of purified monoclonal Igs from hundreds of patients: ~50% monoclonal Igs were found to target one of seven infectious pathogens (Figure 1A) (17,18,25,(32)(33)(34)(35), and unpublished data). The seven infectious agents thus associated with MGUS and MM are, by order of frequency: EBV, HSV-1, VZV, H. pylori, CMV, HCV and HBV (Figure 1B) (17,18,25,(32)(33)(34)(35).…”

“…These assays typically require ≥30 µg purified monoclonal Ig. The two Enterovirus VP1 coat protein sequences identified as monoclonal Ig targets, PALTAVETG and PALTAAETG, were reported to be recognized by monoclonal Igs from 8.4% MGUS patients and 2.0% MM patients (Figure 1B) (34,35).…”

“…Indeed, certain monoclonal Igs can cause organ lesions through autoantibody activity, for instance against collagen IV in the context of bullous skin disease, or anti-phospholipase A2 receptor in the context of glomerular nephropathy (48)(49)(50). It is also established that in the context of polyneuropathy, the monoclonal IgM of patients may target myelin-associated glycoprotein (MAG), chondroitin, or a ganglioside (34,(42)(43)(44)(45). In addition, GlcSph is the target of monoclonal Igs from ~15% of MGUS and MM patients with or without Gaucher's disease (Figure 1B) (19-21, 25).…”