Monoclonal B cell lymphocytosis in hepatitis C virus infected individuals

Fazi, Claudia; Dagklis, Antonis; Cottini, Francesca; Scarfò, Lydia; Bertilaccio, Maria Teresa Sabrina; Finazzi, Renato; Memoli, Massimo; Ghia, Paolo

doi:10.1002/cyto.b.20545

Cited by 49 publications

(51 citation statements)

References 45 publications

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“…At 24 and 72 h, cultured cells were analyzed with a FC500 cytometer (Beckman Coulter), acquiring at least 10 000 events and using the following monoclonal antibodies: anti-CD19, anti-CD20, anti-CD5, anti-CD38, anti-CD80 (Becton and Dickinson, San Jose, CA, USA), anti-CD95 (Caltag Laboratories San Francisco, CA, USA) 37 and ZAP70 expression was analyzed using the anti-ZAP70 antibody (Caltag, Burlingame, CA, USA) as previously described. 38 In parallel, cell viability was also assessed using the Annexin V-based apoptosis detection kit (R&D Systems, Flanders, NJ, USA).…”

Section: Cytometric Analyismentioning

confidence: 99%

The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia

et al. 2011

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Malignant B lymphocytes from chronic lymphocytic leukemia (CLL) patients maintain the capacity to respond to CD40 ligation, among other microenvironmental stimuli. In this study, we show that (i) leukemic CLL cells stimulated with the soluble form of CD40L in vitro show differential responses in terms of upregulation of surface markers (CD95 and CD80) and induction of chemokines (CCL22 and CCL17) expression/secretion, and that (ii) these changes are mirrored by a distinct activation of intracellular signalling pathways including increase in IKKalpha/beta phosphorylation and upregulation of antiapoptotic proteins (BCL-2 and MCL-1). CLL patients can then be segregated into two distinct functional subsets. We defined the responsive subset of cases CD40L dependent, considering the capacity to respond as a sign of persistent need of this stimulation for the leukemic expansion. Conversely, we named the unresponsive cases CD40L independent, considering them less dependent on this microenvironmental signal, presumably because of a higher autonomous proliferative and survival potential. Importantly, we report that (iii) the two functional subsets show an opposite clinical outcome, with CD40L-independent cases having a shorter time to progression. This indicates that the functional differences observed in vitro may reflect a different leukemic potential in vivo likely responsible for a distinct clinical course.

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Section: Cytometric Analyismentioning

confidence: 99%

The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia

et al. 2011

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“…2,7 V1-69-RF, V3-7-RF, RF-WOL and V4-59-RF rearrangements are also frequently expressed in HCV-associated lymphomas, splenic marginal zone lymphomas and in individual cases of ocular MZBCLs and diffuse-large B-cell lymphomas. 5,6,[8][9][10] Recently, Kostareli et al 10 reported 12 cases of B-cell chronic lymphocytic leukemia (CLL) expressing V4-59-RF and Fazi et al 11 reported two cases of V3-7-RF in monoclonal B-cell lymphocytosis.In this study, we analyzed HCDR3 amino acid sequences of 81 IGHV3-7-expressing CLL and identified 3 cases with strong homology to 25 previously reported V3-7-RFs from both healthy and malignant B-cells (Table 1, Supplementary Table 1). These 25 V3-7-RF cases include 9 with proven RF-activity in vitro.…”

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confidence: 99%

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confidence: 99%

A novel chronic lymphocytic leukemia subset expressing mutated IGHV3-7-encoded rheumatoid factor B-cell receptors that are functionally proficient

et al. 2012

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Rheumatoid factors (RFs) are auto-antibodies, mostly of the IgM isotype, that specifically bind to the Fc portion of IgG. RFs are transiently produced in healthy individuals in response to infections and after immunization with mismatched red blood cells (RBCs). RFs are chronically produced in patients suffering from rheumatoid arthritis, Sjö gren's syndrome and in hepatitis C virus (HCV)-induced type-II mixed cryoglobulinemia (MC-II) (reviewed in Newkirk 1 ). Analyses of RFs in MC-II and in donors immunized with mismatched RBCs revealed four groups of stereotyped immunoglobulin (Ig) V H -D H -J H rearrangements, each with distinct heavy-chain complementary-determining region 3 (HCDR3) amino acid sequences: two with IGHV1-69/JH4 rearrangements, designated V1-69-RF and RF-WOL, and two with IGHV3-7/JH3 and IGHV4-59/JH2 rearrangements, designated V3-7-RF and V4-59-RF, respectively. [2][3][4] Remarkably, similar stereotyped RF-rearrangements are frequently expressed in malignant B-cell lymphomas. 2,5,6 Previously, we have shown that recombinantly produced V1-69-RF, V3-7-RF and RF-WOL, derived from gastric and salivary gland marginal zone B-cell lymphomas (MZBCL), bind with high-affinity to IgG in vitro. 2,7 V1-69-RF, V3-7-RF, RF-WOL and V4-59-RF rearrangements are also frequently expressed in HCV-associated lymphomas, splenic marginal zone lymphomas and in individual cases of ocular MZBCLs and diffuse-large B-cell lymphomas. 5,6,[8][9][10] Recently, Kostareli et al. 10 reported 12 cases of B-cell chronic lymphocytic leukemia (CLL) expressing V4-59-RF and Fazi et al. 11 reported two cases of V3-7-RF in monoclonal B-cell lymphocytosis.In this study, we analyzed HCDR3 amino acid sequences of 81 IGHV3-7-expressing CLL and identified 3 cases with strong homology to 25 previously reported V3-7-RFs from both healthy and malignant B-cells (Table 1, Supplementary Table 1). These 25 V3-7-RF cases include 9 with proven RF-activity in vitro. The three newly found CLL cases, CLL81, CLL311 and CLL416, utilized the IGHD3-22 gene segment and the IGHJ3 segment shared by 15/24 and 22/24 of V3-7-RFs, respectively. The CLL V3-7-RFs displayed 470% of homology with a V3-7-RF HCDR3 consensus sequence, defined by the amino acids used by the majority of V3-7-RF cases (Table 1). Of note, the V3-7-RFs also shared amino acids encoded by non-templated N-region nucleotides (Figure 1a). Two of the newly identified CLL V3-7-RF cases (CLL81 and CLL416) expressed the stereotyped IGKV3-15 Ig light chain (IgV L ) reported in 10/10 V3-7-RF cases (Table 1). In CLL311, the V3-7-RF Ig heavy chain (IgV H ) was paired with an IGKV3-20-encoded IgV L . Remarkably, similar IGKV3-20 rearrangements were found in the other groups of stereotyped RFs.The CLL V3-7-RFs were heavily mutated (94.5±1.9% average homology to the IGHV3-7 germline) and shared replacement mutations Q58P, Y66F and Q90E (Figure 1a and Supplementary Table S2). Identical somatic mutations are also frequent among

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“…This finding can be considered an incidental observation of monoclonal B-cell expansion with a very low probability of developing systemic disease, as reported by Rawstron. 20 Although 480% of all monoclonal B lymphocytosis expressed CD5 antigen in healthy HCVnegative individuals, 12 monoclonal B lymphocytosis cases were CD5 À in our series. Interestingly, two of the marginal zone lymphomas described here expressed CD5.…”

Section: Discussionmentioning

confidence: 57%

“…Absence of lymphoma infiltration by physical examination or histology. 12 (D) Tissue-based monoclonal B-cell and plasma cell proliferations of uncertain type:…”

Section: Pathological Findingsmentioning

confidence: 99%

Hepatitis C virus-related lymphoproliferative disorders encompass a broader clinical and morphological spectrum than previously recognized: a clinicopathological study

et al. 2014

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We describe a retrospective series of B-cell lymphoproliferative disorders associated with hepatitis C virus infection. In addition to splenic marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, all of which showed some specific features, we found two poorly described groups of cases. The first featured disseminated marginal zone lymphoma without splenic marginal zone lymphoma features, defying the current marginal zone lymphoma classification; the other consisted of monoclonal B lymphocytes in the peripheral blood, bone marrow or other tissues, with no clinical or histological evidence of lymphoma, and exhibiting a pattern that requires proper identification in order to avoid the misdiagnosis of the lymphoma. Diagnosis of hepatitis C virus infection-associated lymphoproliferative disorders requires the integration of clinical, pathological and molecular findings to establish an adequate diagnosis and decide the appropriate therapy to be applied.

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Monoclonal B cell lymphocytosis in hepatitis C virus infected individuals

Abstract: Results: MBL were identified in 35/123 (28.5%), at significantly higher frequency than in the general population. Sixteen/thirty-five were atypical-chronic lymphocytic leukemia (CLL) MBL (CD5

Cited by 49 publications

References 45 publications

The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia

The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia

A novel chronic lymphocytic leukemia subset expressing mutated IGHV3-7-encoded rheumatoid factor B-cell receptors that are functionally proficient

Hepatitis C virus-related lymphoproliferative disorders encompass a broader clinical and morphological spectrum than previously recognized: a clinicopathological study

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