Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders.
In a previous study, it was shown that the Kaposi sarcoma-associated herpesvirus (KSHV) was specifically associated with monotypic (IgMlambda) plasmablasts in multicentric Castleman disease (MCD). The plasmablasts occur as isolated cells in the mantle zone of B-cell follicles but may form microlymphoma or frank plasmablastic lymphoma. To determine the clonality and cellular origin of the monotypic plasmablasts, the rearranged Ig genes in 13 patients with KSHV-related MCD, including 8 cases with microlymphomas and 2 with frank lymphomas, were studied. To investigate the role of the interleukin 6 (IL-6) receptor signaling in the pathogenesis of MCD and associated lymphoproliferative disorders, viral IL-6 and human IL-6 receptor expression was examined. KSHV-positive plasmablasts were polyclonal in MCD-involved lymphoid tissues in all cases and microlymphomas in 6 of 8 cases. Monoclonal KSHV-positive plasmablasts were seen in microlymphomas of 2 cases and in both frank lymphomas. Despite their mature phenotype, KSHV-positive plasmablasts did not harbor somatic mutations in the rearranged Ig genes, indicating origination from naive B cells. Viral IL-6 was expressed in 10% to 15% of KSHV-positive plasmablasts, whereas the human IL-6 receptor was expressed in most KSHV-positive cells. Thus, KSHV infects monotypic but polyclonal naive B cells and is associated with a range of lymphoproliferative disorders from polyclonal isolated plasmablasts and microlymphomas to monoclonal microlymphoma and frank plasmablastic lymphomas in MCD patients. Activation of the IL-6 receptor signaling pathway may play a role in differentiation of KSHV-infected naive B cells into plasmablasts and development of lymphoproliferative lesions. (Blood. 2001;97:2130-2136)
Department of Histopathology, Royal Free and University College Medical School, University College London, London, United Kingdom. m.du@ucl.ac.uk
M Q
MQ
Du
H
H
Liu
T C
TC
Diss
H
H
Ye
R A
RA
Hamoudi
N
N
Dupin
V
V
Meignin
E
E
Oksenhendler
C
C
Boshoff
P G
PG
Isaacson
D000956:Antigens, Viral; D016175:B-Lymphocyte Subsets / Q000737:chemistry / Q000473:pathology / Q000821:virology*; D015415:Biomarkers; D005871:Castleman Disease / Q000150:complications / Q000473:pathology / Q000821:virology*; D002999:Clone Cells / Q000737:chemistry / Q000473:pathology / Q000821:virology; D004279:DNA, Viral / Q000032:analysis; D015658:HIV Infections / Q000150:complications; D006566:Herpesviridae Infections / Q000150:complications / Q000473:pathology / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D019288:Herpesvirus 8, Human / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D007075:Immunoglobulin M / Q000032:analysis*; D007146:Immunoglobulin lambda-Chains / Q000032:analysis*; D017403:In Situ Hybridization; D015850:Interleukin-6 / Q000032:analysis; D016483:Lymphoma, AIDS-Related / Q000737:chemistry / Q000473:pathology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000473:pathology / Q000821:virology*; D009687:Nuclear Proteins / Q000032:analysis; D010950:Plasma Cells / Q000737:chemistry / Q000473:pathology / Q000821:virology*; D019947:Receptors, Interleukin-6 / Q000032:analysis; D014764:Viral Proteins / Q000032:analysis
D000956:Antigens, Viral; D015415:Biomarkers; D004279:DNA, Viral; D007075:Immunoglobulin M; D007146:Immunoglobulin lambda-Chains; D015850:Interleukin-6; D009687:Nuclear Proteins; D019947:Receptors, Interleukin-6; D014764:Viral Proteins; C109540:latency-associated nuclear antigen