Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens
Adrien Bosseboeuf, Delphine Feron, Anne Tallet, Cédric Rossi, Cathy Charlier, Laurent Garderet, Denis Caillot, Philippe Moreau, Marina Cardó-Vila, Renata Pasqualini, Wadih Arap, Alfreda Destea Nelson, Bridget S. Wilson, Hélène Perreault, Eric Piver, Pierre Weigel, François Girodon, Jean Harb, Edith Bigot-Corbel, Sylvie Hermouet
Adrien Bosseboeuf, Delphine Feron, Anne Tallet, Cédric Rossi, Cathy Charlier, Laurent Garderet, Denis Caillot, Philippe Moreau, Marina Cardó-Vila, Renata Pasqualini, Wadih Arap, Alfreda Destea Nelson, Bridget S. Wilson, Hélène Perreault, Eric Piver, Pierre Weigel, François Girodon, Jean Harb, Edith Bigot-Corbel, Sylvie Hermouet
View: Text | PDF
Research Article Immunology

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

Abstract

Subsets of mature B cell neoplasms are linked to infection with intracellular pathogens such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), or Helicobacter pylori. However, the association between infection and the immunoglobulin-secreting (Ig-secreting) B proliferative disorders remains largely unresolved. We investigated whether the monoclonal IgG (mc IgG) produced by patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) targets infectious pathogens. Antigen specificity of purified mc IgG from a large patient cohort (n = 244) was determined using a multiplex infectious-antigen array (MIAA), which screens for reactivity to purified antigens or lysates from 9 pathogens. Purified mc IgG from 23.4% of patients (57 of 244) specifically recognized 1 pathogen in the MIAA. EBV was the most frequent target (15.6%), with 36 of 38 mc IgGs recognizing EBV nuclear antigen-1 (EBNA-1). MM patients with EBNA-1–specific mc IgG (14.0%) showed substantially greater bone marrow plasma cell infiltration and higher β2-microglobulin and inflammation/infection–linked cytokine levels compared with other smoldering myeloma/MM patients. Five other pathogens were the targets of mc IgG: herpes virus simplex-1 (2.9%), varicella zoster virus (1.6%), cytomegalovirus (0.8%), hepatitis C virus (1.2%), and H. pylori (1.2%). We conclude that a dysregulated immune response to infection may underlie disease onset and/or progression of MGUS and MM for subsets of patients.

Authors

Adrien Bosseboeuf, Delphine Feron, Anne Tallet, Cédric Rossi, Cathy Charlier, Laurent Garderet, Denis Caillot, Philippe Moreau, Marina Cardó-Vila, Renata Pasqualini, Wadih Arap, Alfreda Destea Nelson, Bridget S. Wilson, Hélène Perreault, Eric Piver, Pierre Weigel, François Girodon, Jean Harb, Edith Bigot-Corbel, Sylvie Hermouet

×

Figure 11

Confirmation of the specificity of HSV-1 recognition of purified mc IgGs.

Options: View larger image (or click on image) Download as PowerPoint
Confirmation of the specificity of HSV-1 recognition of purified mc IgGs...
(A, left): The purified monoclonal (mc) IgG from herpes simplex virus-1–positive (HSV-1+) index patient P56 was immobilized on Protein A/G beads and used for 4 rounds (R1–R4) of phage display peptide purification, with a CX7C library; the Fd-tet lacking peptide inserts served as a negative control. After the fourth round of selection, bacterial colonies were picked at random for sequencing. Results are expressed as mean ± SEM of duplicate wells. (A, right) Alignment of 14 related sequences, used for a BLAST alignment identifying the sequence VPALR from HSV-1 tegument protein, UL36 (in blue, aa 1498–1510). (B) Dot blotting with HSV-1 lysate and relevant (EAVLHLSEDLGGVPALRQYVP) and irrelevant (EAVLHLSEDLGGRPAERQYVP) HSV-1–derived peptides was performed for serum and purified mc IgG from the 7 patients found to have HSV-1–specific mc IgG with the multiplex infectious-antigen array (MIAA) assay. Patient P1, whose mc IgG did not recognize HSV-1 using the MIAA assay, was used as a negative control. Amino acids of the relevant epitope are in bold and underlined. The modified amino acids of the irrelevant peptide are in blue. Dot blots were performed at least twice.