To The Editor:

We read with great interest the article by Holz et al.1 published in HEPATOLOGY. The authors provide information on immunophenotypic changes of peripheral B cells (PBLs) in 17 chronically hepatitis C virus (HCV)-infected patients with mixed cryoglobulinemia (MC). They underlined the primary role of B cells in the pathogenesis of MC. The occurrence of B-cell subpopulations biased toward anergy and/or apoptosis was demonstrated. As unexpected findings, they reported a significant reduction of total circulating B-cell number in MC patients as compared with control populations. They concluded that, naive B cells being more prone to apoptosis and representing the largest fraction of the major B-cell compartment, their reduced frequency may contribute to the observed reduction in CD19+ B-cell number in these patients.

These data, indeed, contradict many previously published observations showing an expanded number of PBLs in MC populations.2, 3 Stirred by these observations, we reassessed the results of immunophenotypic analyses of PBLs assessed in 100 HCV-related MC and in 100 HCV-infected patients without MC and in 50 healthy controls. In all patients, PBLs were obtained on the same day of liver biopsy and in no case were cells thawed after cryopreservation. All had histological diagnosis of chronic hepatitis without cirrhosis. The patient groups had a comparable total lymphocyte frequency of 1,435 ± 277 cells/μL in cryoglobulinemic and 1,280 ± 196 cells/μL in noncryoglobulinemic patients. As shown in Fig. 1, the results demonstrate a significant enrichment of circulating B cells in MC patients.

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Figure 1. Frequency distribution of CD19+ B cells in healthy subjects and in chronically HCV-infected patients with and without mixed cryoglobulinemia.

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As a measure of range values, MC patients showed a CD19+ B-cell frequency higher than 20% in almost 80%. These results are not in line with data reported by Holz et al., whose observations may support the notion of compartmentalization of lymphocyte subpopulations. An altered trafficking of B cells with an increased number of naive phenotype in circulation may be proposed, in that activated B cells are selectively retained. HCV induces changes regulating lymphocyte homing, migration, or adhesion to the extracellular matrix. Furthermore, the sharp prevalence of male sex in Holz et al.'s population accounts for a distinct subgroup of cryoglobulinemic patients. They found a 2.4 male/female ratio, which is a very unusual finding. The high prevalence of females in cryoglobulinemic patients is a long-standing observation. In this context remarkable differences in sex distribution within the patients considered by Holz et al. may suggest that hormone patterns may contribute to the modification of characteristics of the B-cell immune response.


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  • 1
    Holz LE, Yoon JC, Raghuraman S, Moir S, Sneller MC, Rehermann B. B-cell homeostasis in chronic hepatitis C virus-related mixed cryoglobulinemia is maintained through naive B-cell apoptosis. HEPATOLOGY 2012; 56: 1602-1610.
  • 2
    Curry MP, Golden-Mason L, Doherty DG, Deignan T, Norris S, Duffy M, et al. Expansion of innate CD5pos B cells expressing high levels of CD81 in hepatitis C virus infected liver. J Hepatol 2003; 38: 642-650.
  • 3
    Sansonno D, Lauletta G, Montrone M, Tucci FA, Nisi L, Dammacco F. Virological analysis and phenotypic characterization of peripheral blood lymphocytes of hepatitis C virus-infected patients with and without mixed cryoglobulinaemia. Clin Exp Immunol 2006; 143: 288-296.