A VH4-34+ myeloma protein with weak autoreactivity

Frøyland, Marianne; Thompson, Keith M.; Thorpe, Susan J.; Sahota, Surinder S.; Gedde‐Dahl, Tobias; Bogen, Bjarne

doi:10.3324/haematol.10850

Cited by 9 publications

(7 citation statements)

References 19 publications

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“…At a cellular level, despite the high frequency of 9G4 naïve B-cells, in healthy subjects 9G4 cells are markedly diminished (80–90%) in the IgG memory compartment and 9G4+ plasma cells are very hard to find (54, 65). The absence of 9G4+ plasma cell described in our laboratory using intracellular staining of magnetically purified CD138+ plasma cells from healthy bone marrow and tonsils is indeed striking and consistent with the virtual absence of 9G4 antibodies in more than 200 multiple myeloma tumors thus far analyzed by different groups (65–67). …”

Section: Introductionsupporting

confidence: 79%

B Cells and Immunological Tolerance

Manjarrez‐Orduño

Quách

Sanz

2009

Journal of Investigative Dermatology

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Work from multiple groups continues to provide additional evidence for the powerful and highly diverse roles, both protective and pathogenic, that B cells play in autoimmune diseases. Similarly, it has become abundantly clear that antibody-independent functions may account for the opposing influences that B cells exercise over other arms of the immune response and ultimately over autoimmunity itself. Finally, it is becoming apparent that the clinical impact of B cell depletion therapy may be to a large extent determined by the functional balance between different B cell subsets that may be generated by this therapeutic intervention. In this review, we postulate that our perspective of B cell tolerance and our experimental approach to its understanding are fundamentally changed by this view of B cells. Accordingly, we shall first discuss current knowledge of B cell tolerance conventionally defined as the censoring of autoantibody-producing B cells (with an emphasis on human B cells). Therefore, we shall discuss a different model that contemplates B cells not only as targets of tolerance but also as mediators of tolerance. This model is based on the notion that the onset of clinical autoimmune disease may require a B cell gain-of-pathogenic function (or a B cell loss-of-regulatory-function) and that accordingly, disease remission may depend on the restoration of the physiological balance between B cell pathogenic and protective functions.

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Section: Introductionsupporting

confidence: 79%

B Cells and Immunological Tolerance

Manjarrez‐Orduño

Quách

Sanz

2009

Journal of Investigative Dermatology

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“…We believe that newly diagnosed patients with HCL and leukocytosis, regardless of diagnosis of HCLv, should be tested for VH4-34 positivity either by PCR cloning, by flow cytometry, or by enzyme-linked immunoabsorbent assay using an anti-idiotype antibody such as 9G4. 44,46,56 In our study the incidence of VH4-34 positivity was 36% in HCL patients presenting with white blood cells greater than or equal to 5 ϫ 10 9 /L (Figure 3). Patients with VH4-34 ϩ HCL could be considered for alternative approaches, such as therapy with rituximab combined with purine analog, rather than with purine analog alone.…”

Section: Clinical Implications Of Vh4-34 ؉ Hclmentioning

confidence: 49%

“…[43][44][45] We and others have reported VH4-34 expression in isolated cases of HCLv and classic HCL, 18,24,25 but the 2 to 5 cases per study were insufficient for understanding the impact of VH4-34 in this disease.…”

Section: Vh4-34 Expression In Malignant Lymphocytesmentioning

confidence: 99%

VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy

Arons¹,

Suntum²,

Stetler‐Stevenson

et al. 2009

Blood

142

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Hairy cell leukemia variant (HCLv) presents with high disease burden, lack of typical antigens like CD25, and poor response to standard treatments like cladribine. Occasionally, patients with classic HCL respond poorly. Clinical and molecular features of HCL and HCLv has not been compared. Rearrangements expressing immunoglobulin VH chain were sequenced, including 22 from 20 patients with HCLv and 63 from 62 patients with classic HCL. Most patients were seeking relapsed/refractory trials, representing a poor-prognosis population. VH4-34, a gene commonly used in autoimmune disorders, was observed in 8 (40%) HCLv and 6 (10%) classic (P ‫؍‬ .004) HCL patients. Compared with 71 VH4-34 ؊ rearrangements, 14 VH4-34 ؉ rearrangements were more frequently (P < .001) unmutated, defined as greater than 98% homologous to germline sequence. VH4-34 ؉ patients had greater white blood cell counts at diagnosis (P ‫؍‬ .002), lower response rate (P < .001) and progressionfree survival (P ‫؍‬ .007) after initial cladribine, and shorter overall survival from diagnosis (P < .001). Response and survival were more closely related to VH4-34 status than to whether or not patients had HCLv. VH4-34 ؉ HCL is an important disorder that only partly overlaps with the previously described HCLv. Response to initial single-agent cladribine therapy is suboptimal; these patients should be considered for alternative approaches, including antibody-related therapy. IntroductionHairy cell leukemia variant (HCLv) is a B-cell disorder, recognized for nearly 30 years, which accounts for 10% of hairy-cell leukemia (HCL) cases. Morphology of variant cells was reported to be intermediate between that of classic HCL and prolymphocytic leukemias. [1][2][3] Patients typically present with leukocytosis rather than leukopenia and often lack the neutropenia, anemia, and/or thrombocytopenia with which classic HCL patients present. 1,2,4 By flow cytometry, B-cell antigens FMC7, CD11c, CD20, CD22, and surface immunoglobulin are strongly positive in both classic HCL and HCLv, whereas HCLv differs from classic HCL by lack of CD25, HC-2, and CD123 and by expression of CD27. [3][4][5][6][7] CD103 is usually positive in both but can be negative in HCLv. 2 HCLv lacking both CD25 and CD103 may be difficult to differentiate from splenic marginal zone lymphoma (SMZL)/splenic lymphoma with villous lymphocytes without also relying on morphologic differences between HCL and SMZL. 2,6,7 In contrast to the high complete remission and overall response rates of classic HCL to the administration of purine analogs pentostatin and cladribine, [8][9][10] response in patients with HCLv is limited to partial responses in approximately 50% of patients. [2][3][4]11,12 Several complete responses of HCLv to monoclonal antibody-based therapy with and without chemotherapy have been reported. [13][14][15][16][17] Like other mature B lymphocytes, the malignant cells in HCL patients have 1 or sometimes 2 different rearrangements for immunoglobulin heavy chain. Significant variability can be observ...

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“…It has been suggested that MM being a B‐cell malignancy is associated with a marked immune disturbance that may allow normally suppressed clones to develop and produce autoantibodies against red cell surface antigens . Counter selection of VH4‐36 segment in MM due to self‐tolerance mechanism has also been proposed to be a mechanism in development of AIHA . Several drugs have also been shown to be a causative agent for immune‐mediated hemolysis in MM such as lenalidomide and interferon‐α due to its immunomodulatory effects…”

Section: Discussionmentioning

confidence: 99%