Virological analysis and phenotypic characterization of peripheral blood lymphocytes of hepatitis C virus-infected patients with and without mixed cryoglobulinaemia

Sansonno, Domenico; Lauletta, Gianfranco; Montrone, Michele; Tucci, Felicia Anna; Nisi, L.; Dammacco, Franco

doi:10.1111/j.1365-2249.2005.02987.x

Cited by 36 publications

(26 citation statements)

References 43 publications

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“…Our data, 36 combined with those from the literature, [37][38][39] indicate a significant expansion of CD5 ϩ B cells in the peripheral blood of these patients. It can be speculated that the increased frequency of t(14;18) in blood leukocytes of either cryoglobulinemic or non-cryoglobulinemic HCV-infected patients does not reflect a true increase of its incidence, but may be a confounding factor related to the increased proportion of circulating B cells in these patients.…”

Section: Discussionmentioning

confidence: 65%

HCV-Associated B Cell Clonalities in the Liver Do Not Carry the t(14;18) Chromosomal Translocation *

Sansonno

Tucci

et al. 2005

Hepatology

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H epatitis C virus (HCV), a positive-strand enveloped RNA virus belonging to the Flaviviridae family, genus Hepacivirus, causes acute and chronic liver damage. 1 The mechanisms responsible for the tissue injury are poorly understood. 2 HCV often leads to hepatocellular carcinoma and, less frequently, to B-cell non-Hodgkin lymphoma (B-NHL). [3][4][5] HCV is mainly characterized by the failure to generate an effective immune response. Derangement of the B cell immune response has recently been explored by analyses of the size and sequence of complementarity determining region-3 (CDR-3) in the variable diversity joining (VDJ) segment of immunoglobulin heavy chain (IgH), which provide a molecular footprint of the overall B cell receptor (BCR) repertoire. 6 CDR H 3 is the segment of the Ig molecules that most closely interacts with the foreign immunogenic peptides and triggers the adaptive B cell immune response. BCRs of different specificities are generated by different combinations of V, D, and J gene segments to maximize CDR H 3 diversity and to provide the unique specificity of BCR. 7 Because of the lack of an efficient cell culture system for HCV, functions of most virus-encoded proteins have been established by analogy to other viruses and by homology to known proteins. HCV core protein modulates gene transcription, cell proliferation, and cell death. 8 NS3-encoded protein shows numerous interactions with cellular components, including protein-kinases, p53, and histones. 9 NS5A protein has been found to contain a Bcl-2 (B-cell lymphoma-2) homology domain capable of protecting cells against apoptosis. 10 Ability of HCV to prolong the life span of the cells it infects is believed to be of etiological significance, because it enhances the risk of accumulating genetic errors.

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Section: Discussionmentioning

confidence: 65%

HCV-Associated B Cell Clonalities in the Liver Do Not Carry the t(14;18) Chromosomal Translocation *

Sansonno

Tucci

et al. 2005

Hepatology

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“…2 Conflicting results have been published on the optimal b value for hepatic fibrosis staging. 3 This was also remarkably reflected in the great variation of b values used in the studies of the meta-analysis.…”

Section: Tesla Diffusion-weighted Mri For Assessing Liver Fibrosis Inmentioning

confidence: 99%

“…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.…”

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confidence: 96%

Reply: B-cell frequency in HCV-related mixed cryoglobulinemia

et al. 2013

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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 þ Bcell 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 6 277 cells/lL in cryoglobulinemic and 1,280 6 196 cells/lL in noncryoglobulinemic patients. As shown in Fig. 1, the results demonstrate a significant enrichment of circulating B cells in MC patients.As a measure of range values, MC patients showed a CD19 þ 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. Reply: B-cell Frequency in HCV-Related Mixed CryoglobulinemiaWe appreciate the interest of Sansonno et al. in our recent article. 1 Sansonno et al. correctly state that we observed a reduction in the total number of B cells and in the size of the naïve B cell subset in patients with mixed cryoglobulinemia (MC) compared with hepatitis C virus (HCV)-infected patients without MC and healthy cont...

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Section: Tesla Diffusion-weighted Mri For Assessing Liver Fibrosis Inmentioning

confidence: 99%

“…Algorithms for combined use of serum markers and elastography have been proposed, with specific cut-off values being used in the decision trees. [3][4][5] However, a cut-off value for staging always involves a compromise between sensitivity and specificity. The use of Bayesian prediction to stage liver fibrosis involves calculating the stage based on elastographic or serum biomarker measures (see Appendix).…”

Section: Bayesian Prediction For Liver Fibrosis Staging: Combined Usementioning

confidence: 99%

3 Tesla diffusion-weighted MRI for assessing liver fibrosis in nonalcoholic fatty liver disease

et al. 2013

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difficult. Nonetheless, previous work found no increased prevalence of cryoglobulinemia in patients with B cell frequencies of >20% of the lymphocyte population. 7 The decreased B cell numbers in our study do not contradict the large expansions in specific B cell clones observed in cryoglobulinemia. Clonal B cell populations in the activated/memory B cell subset drive MC, and we did not identify reductions in this subset. Rather, we found the percentage of these cells in the total B cell population to be increased and resistant to apoptosis.With regard to the comment that our observations may be related to changes in B cell homing, we observed differential chemokine receptor expression on B cells from healthy controls and HCV patients, but no significant difference among HCV patients with and without MC. Thus, there is no evidence of differential B cell homing.The high percentage of men in our study is indeed interesting, and the possibility that sex and perhaps hormonal differences may explain the differences reported among studies is worth exploring. Of note, a large retrospective cohort study of 146,394 patients of Veterans Affairs health care facilities in the United States, in which 97% of the patients were male, also demonstrated an increased risk of cryoglobulinemia for HCV-infected men. 8

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Virological analysis and phenotypic characterization of peripheral blood lymphocytes of hepatitis C virus-infected patients with and without mixed cryoglobulinaemia

Abstract: SummaryIn clinical and pathological terms hepatitis C virus (HCV)-infected patients can be subdivided into two main groups with and without mixed cryoglobulinaemia (

Cited by 36 publications

References 43 publications

HCV-Associated B Cell Clonalities in the Liver Do Not Carry the t(14;18) Chromosomal Translocation *

HCV-Associated B Cell Clonalities in the Liver Do Not Carry the t(14;18) Chromosomal Translocation *

Reply: B-cell frequency in HCV-related mixed cryoglobulinemia

3 Tesla diffusion-weighted MRI for assessing liver fibrosis in nonalcoholic fatty liver disease

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