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These cells are phenotypically heterogeneous, resembling either typical marginal zone (MZ<\/jats:styled-content>) B<\/jats:styled-content> cells (I<\/jats:styled-content>gM<\/jats:styled-content>+<\/jats:sup>I<\/jats:styled-content>gD<\/jats:styled-content>+<\/jats:sup>CD<\/jats:styled-content>27+<\/jats:sup>CD<\/jats:styled-content>21+<\/jats:sup>) or the exhausted CD<\/jats:styled-content>21low<\/jats:sup> B<\/jats:styled-content> cells that accumulate in HIV<\/jats:styled-content> infection or in common variable immunodeficiency. We show that both the MZ<\/jats:styled-content>\u2010like and the CD<\/jats:styled-content>21low<\/jats:sup> VH<\/jats:sub><\/jats:styled-content>1\u201069+<\/jats:sup> B<\/jats:styled-content> cells of MC<\/jats:styled-content> patients are functionally exhausted, since they fail to respond to TLR and BCR ligands. The proliferative defect of VH<\/jats:sub><\/jats:styled-content>1\u201069+<\/jats:sup> B<\/jats:styled-content> cells can be overcome by co\u2010stimulation of TLR<\/jats:styled-content>9 and BCR<\/jats:styled-content> in the presence of interleukin(IL)\u20102 and IL<\/jats:styled-content>\u201010. The MZ<\/jats:styled-content>\u2010like VH<\/jats:sub><\/jats:styled-content>1\u201069+<\/jats:sup> B<\/jats:styled-content> cells do not express the inhibitory receptors distinctive of CD<\/jats:styled-content>21low<\/jats:sup> B<\/jats:styled-content> cells, but display constitutive activation of extracellular signal regulated kinase (ERK<\/jats:styled-content>) and attenuated BCR<\/jats:styled-content>\/ERK<\/jats:styled-content> signaling. These cells also express abundant transcripts of S<\/jats:styled-content>tra13 (DEC<\/jats:styled-content>1, B<\/jats:styled-content>hlhb2, S<\/jats:styled-content>harp2, C<\/jats:styled-content>last5), a basic helix\u2010loop\u2010helix transcription factor that acts as a powerful negative regulator of B<\/jats:styled-content>\u2010cell proliferation and homeostasis. Our findings suggest that MZ B<\/jats:styled-content> cells activated by HCV<\/jats:styled-content> undergo functional exhaustion associated with BCR<\/jats:styled-content> signaling defects and overexpression of a key antiproliferative gene, and may subsequently become terminally spent CD<\/jats:styled-content>21low<\/jats:sup> B<\/jats:styled-content> cells. Premature exhaustion may serve to prevent the outgrowth of chronically stimulated MZ B<\/jats:styled-content> cells.<\/jats:p>","DOI":"10.1002\/eji.201142313","type":"journal-article","created":{"date-parts":[[2012,6,8]],"date-time":"2012-06-08T11:28:19Z","timestamp":1339154899000},"page":"1468-1476","source":"Crossref","is-referenced-by-count":44,"title":["Clonal B cells of HCV\u2010associated mixed cryoglobulinemia patients contain exhausted marginal zone\u2010like and CD21low<\/sup> cells overexpressing Stra13"],"prefix":"10.1002","volume":"42","author":[{"given":"Marcella","family":"Visentini","sequence":"first","affiliation":[{"name":"Department of Clinical Immunology Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Cagliuso","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology Sapienza University of Rome Rome 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