Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma

N Engl J Med. 2016 Feb 11;374(6):555-61. doi: 10.1056/NEJMoa1508808.


Antigen-driven selection has been implicated in the pathogenesis of monoclonal gammopathies. Patients with Gaucher's disease have an increased risk of monoclonal gammopathies. Here we show that the clonal immunoglobulin in patients with Gaucher's disease and in mouse models of Gaucher's disease-associated gammopathy is reactive against lyso-glucosylceramide (LGL1), which is markedly elevated in these patients and mice. Clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC). Substrate reduction ameliorates Gaucher's disease-associated gammopathy in mice. Thus, long-term immune activation by lysolipids may underlie both Gaucher's disease-associated gammopathies and some sporadic monoclonal gammopathies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Gaucher Disease / complications
  • Gaucher Disease / immunology*
  • Glucosylceramides / analysis
  • Glucosylceramides / immunology*
  • Humans
  • Immunoglobulins / immunology*
  • Lysophosphatidylcholines / analysis
  • Lysophosphatidylcholines / immunology*
  • Mice
  • Multiple Myeloma / immunology*
  • Paraproteinemias / immunology*


  • Glucosylceramides
  • Immunoglobulins
  • Lysophosphatidylcholines