Biased IGH VDJ gene repertoire and clonal expansions in B cells of chronically hepatitis C virus-infected individuals

Felicia A. Tucci, Simo Kitanovski, Patricia Johansson, Ludger Klein-Hitpass, Alisan Kahraman, Jan Dürig, Daniel Hoffmann and Ralf Küppers

Key points

  • Chronic HCV infection leads to extensive BCR IG gene repertoire alterations with pathological features even in absence of mixed cryoglobulinemia.

  • Many large B cell clones are consistently found, mainly among IgM+ memory B cells, showing a massive influence of HCV on this compartment.


Patients chronically infected with hepatitis C virus (HCV) frequently develop mixed cryoglobulinemia (MC), a monoclonal expansion of IgM+ autoreactive B cells, and also have an increased B cell lymphoma risk. Whether HCV infection also impacts the B cell compartment and the B cell receptor repertoire in patients not affected by MC or lymphomas is poorly understood. Flow cytometric analysis of peripheral blood B cells of 30 MC-negative HCV-infected patients and 15 healthy controls revealed that frequencies of class-switched memory B cells were increased in the patients, whereas frequencies of transitional and naive B cells were decreased. For 22 HCV+ patients and 7 healthy controls, we performed high throughput sequencing of immunoglobulin heavy chain VDJ rearrangements of naive, mature CD5+, IgM+ memory, and class-switched memory B cells. An increased usage of several IGHV genes, including IGHV1-69 and IGHV4-59, which are closely linked to MC and HCV-associated lymphomas, was specifically seen among IgM+ memory B cells of the patients. Moreover, many, and partly very large, expanded clones were seen predominantly among IgM+ memory B cells of all HCV-infected patients analysed. Thus, chronic HCV infection massively disturbs the B cell compartment even in patients without clinically detectable B cell lymphoproliferation and generates many large B cell clones, especially among non-class-switched memory B cells. Since B cell clones in MC and lymphomas derive from this B cell subset, this establishes IgM+ memory B cells as a general target of lymphoproliferation in HCV+ patients, affecting apparently all patients.

  • Submitted September 8, 2017.
  • Accepted December 11, 2017.