Project Leaders: Sylvie Hermouet, Edith Bigot-Corbel, Jean Harb

This line of research aims to validate the hypothesis that latent infection may initiate certain hematological diseases, notably MGUS and MM.

Monoclonal Gammopathies of Undetermined Siginificance (MGUS) prevalence increases with age and concerns 3-5% of the general population aged over 50. Diagnosis of MGUS usually occurs during routine bood tests, when a monoclonal immunoglobulin (mc Ig) is detected, in the absence of other biological or clinical symptom. It is now established that the presence of a mc Ig gfor more than 6 months (MGUS) is a pre-cancerous stage, of variable length, that precedes all cases of MM. The risk of transformation into multiple myeloma (MM) for a MGUS patient is estimated to be 1% per year. In France, at least 2000 new cases of myeloma are diagnosed every year. At the MGUS stage, B lymphocytes may present genetic alterations whereas in MM, clonal plasma cells that produce the mc Ig accumulate in the bone marrow, often presenting numerous genetic defects. MM patients often present with clinical symptoms, such as anemia, fever, bone lesions, or kidney deficiency or failure. Despite numerous studies, the physiopathology of MGUS and evolution toward MM remain obscure, and despite great improvements in therapy, there is still no cure for MM and the median survival of patients remains short.

Multiple Myeloma (MM): Two main pathogenic models have been described for MM. The first model states that the disease is initiated in B-progenitor cell in the bone marrow, without antigenic stimulation. The second model, disease is initiated in lymph nodes, via the chronic antigenic stimulation of a mature B-lymphocyte. Our hypothesis is that an  abnormal B-lymphocyte responseto chronic infection (chronic antigenic stimulation by an infectious pathogen) may initiate certain cases of MGUS and over the years, after acquisition of genetic defects, to MM. The normal immune response to infection includes the synthesis of polyclonal Ig. In case of chronic infection, the polyclonal Ig response may become oliglonal then monoclonal; in the latter case, the mc Ig persists as long as the infection. In fact, MGUS and MM are frequently associated with chronic, (maibly viral) infection. Chronic antigenic stimulation inducd by infection is a processus known to lead to the malignant transformation of the cells from the B-lymphoid lineage (various types of lymphoma, B-cell chronic lymphocytic leukemia). In contrast, infection and chronic antigen stimulation have been relatively neglected in the context of MGUS and MM.

Chronic Infection ⇒ Polyclonal B cell response ⇒ oligoclonal ⇒monoclonal response ⇒ MGUS
MGUS ⇒ accumulation of genetic defects ⇒ Smoldering Myeloma ⇒ Multiple Myeloma

Using custom-made multiplexed protein micro-arrays designed and developped in the laboratory (collaboration with the IMPACT platform, Nantes) that carry panels of antigens, peptides and proteins from viruses, bacteria and parasites known to cause latnt infection in humans, we analyse the specificity of purified mc Ig from cohorts of patients diagnosed with MGUS or MM in several French university hospitals. Our multiplexed infectious antigen micro-array (MIAA) assay includes antigens from 9 infectious pathogens: EBV, hepatitis C virus (HCV), cytomegalovirus (CMV), herpes simplex viruses 1 et 2 (HSV1, HSV2), varicella-zoster virus, Helicobacter pylori (H. pylori), toxoplasma gondii, Borrelia burgdorferii. Using this assay, we analysed in parallel the serum and purified mc Ig from >340 MGUS and MM patients and showed that in case of HCV infection associated with MGUs or MM, the mc Ig is always specific for a HCV protein, usually the core protein. We also found that the purified mc Ig of >25% of MGUS and MM patients is specific for an infectious pathogen of the MIAA assay. Altogether, these studies suggest that infection, particularly by EBV, may initiate certain MGUS and MM. A systematic analysis of the specificity of mc Ig could in term become part of the diagnostic work-up of MGUS and MM patients. Identification of the infectious pathogen targeted by the mc Ig could lead to personalized treatment that would associate eradication of the latent infection (and MGUS) in addition to classical chemotherapy of MM.

These studies are being extended to large cohorts of patients, searching for additional infectious pathogens and antigens potentially involved in the pathogenesis of MGUS and MM.

We gratefully acknowledge financial support from the Institut national contre le cancer (INCa) (2010-2012), Ligue Nationale contre le Cancer (2012 and 2019), Bpi-France (2013), Cancéropôle Grand Ouest (CGO), Region Pays de la Loire (HII-GO project) (2015-2016) and Janssen USA (2016-2018).

Five representative publications

1. Hermouet S, Corre I, Gassin M, Bigot-Corbel E, Sutton CA, Casey JW. Hepatitis C virus, human herpesvirus-8 and the development of plasma cell leukemia. New Engl J Med (2003)
2. Bigot-Corbel E, Gassin M, Corre I et al. Hepatitis C virus (HCV) infection, monoclonal immunoglobulin specific for HCV core protein, and plasma-cell malignancy. Blood (2008)

3. Feron D, Charlier C, Gourain V, Garderet L, Coste-Burel M, Le Pape P, Weigel P, Jacques Y, Hermouet S, Bigot-Corbel E. Multiplexed infectious protein microarray immunoassay suitable for the study of the specificity of monoclonal immunoglobulins. Analytical Biochem (2013)

4. Bosseboeuf A, Feron D, Tallet A, Rossi C, Charlier C, Garderet L, Caillot D, Moreau P, Cardo-Vila M, Pasqualini R, Arap W, Nelson AD, Wilson BS, Perreault H, Piver E, Weigel P, Girodon F, Harb J, Bigot-Corbel E, Hermouet S. Monoclonal IgG in MGUS and multiple myeloma target infectious pathogens. J Clin Invest Insight (2017)
5. Bosseboeuf A, Allain S, Mennesson N, Tallet A, Rossi C, Garderet L, Caillot D, Moreau P, Piver E, Girodon F, Perreault H, Brouard S, Bigot-Corbel E, Hermouet S, Harb J. Pro-inflammatory state in MGUS and Myeloma is characterized by low sialylation of pathogen-specific and other monoclonal and polyclonal immunoglobulin G. Frontiers Immunology (2017)