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Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG\u2010ODN capable of forming higher\u2010order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell\u2010activating factor, or simultaneous co\u2010engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine\/paracrine loop, which is dependent on IRF\u20101, IL\u20106 and IL\u201012 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self\u2010derived hypomethylated double\u2010stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co\u2010engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9\u2010induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.<\/jats:p>","DOI":"10.1002\/eji.200535734","type":"journal-article","created":{"date-parts":[[2006,6,22]],"date-time":"2006-06-22T11:09:23Z","timestamp":1150974563000},"page":"1951-1962","source":"Crossref","is-referenced-by-count":15,"title":["Higher\u2010order CpG\u2010DNA stimulation reveals distinct activation requirements for marginal zone and follicular B cells in lupus mice"],"prefix":"10.1002","volume":"36","author":[{"given":"Rachel","family":"Brummel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara\u2004L.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katryn\u2004J.","family":"Stacey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petar","family":"Lenert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,6,30]]},"reference":[{"key":"e_1_2_7_1_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.165.6.1755"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni0901-764"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.177.5.1367"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.2.387"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(08)60641-0"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1997.tb52047.x"},{"key":"e_1_2_7_7_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.4049\/jimmunol.160.1.51","article-title":"A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL\u2010lpr\/lpr mice.","volume":"160","author":"Chan O.","year":"1998","journal-title":"J. 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