Rheumatoid arthritis is a common and debilitating autoimmune disease whose cause and mechanism remain a mystery. We recently described a T cell receptor transgenic mouse model that spontaneously develops a disease with most of the clinical, histological, and immunological features of rheumatoid arthritis in humans. Disease development in K/BxN mice is initiated by systemic T cell self-reactivity; it requires T cells, as expected, but B cells are also needed, more surprisingly. Here, we have identified the role of B cells as the secretion of arthritogenic immunoglobulins. We suggest that a similar scenario may unfold in some other arthritis models and in human patients, beginning with pervasive T cell autoreactivity and ending in immunoglobulin-provoked joint destruction.

The mb1 gene encodes the Ig-␣ signaling subunit of the B cell antigen receptor and is expressed exclusively in B cells beginning at the very early pro-B cell stage in the bone marrow. We examine here the efficacy of the mb1 gene as a host locus for cre recombinase expression in B cells. We show that by integrating a humanized cre recombinase into the mb1 locus we obtain extraordinarily efficient recombination of loxP sites in the B cell lineage. The results from a variety of reporter genes including the splicing factor SRp20 and the DNA methylase Dnmt1 suggest that mb1-cre is probably the best model so far described for pan-B cell-specific cre expression. The availability of a mouse line with efficient cre-mediated recombination at an early developmental stage in the B lineage provides an opportunity to study the role of various genes specifically in B cell development and function.Dnmt1 ͉ SRp20 ͉ loxP ͉ enhanced yellow fluorescent protein ͉ lymphocyte T he bacteriophage recombinase cre can efficiently delete DNA sequences that are flanked by loxP sites (floxed) even in eukaryotic cells (1). This feature has led to the frequent use of transgenic cre mice for the tissue-specific deletion or modification of floxed genes to access the function of a gene in a specific tissue (2).Development of a B lymphocyte can be separated into several ordered steps encompassing commitment to the B lineage, somatic recombination and expression of its heavy chain and light chain Ig genes, and selection of the B cell antigen receptor repertoire (for reviews, see refs. 3-5). In the B cell system there are several transgenic mouse lines available that express cre in defined stages of B lymphocyte development. For example, CD19-cre mice (6) express cre from the pre-B cell stage on, whereas CD21-cre mice (7) express cre only in mature B cells. However, a cre transgenic mouse line with efficient cre-mediated deletion from the earliest pro-B cell stage was missing so far. We asked whether expression of the cre recombinase from the murine mb-1 locus would provide an even more efficient model for studying gene function specifically in B cell precursors. The mb1 gene encodes the Ig-␣ signaling subunit of the B cell antigen receptor (8, 9). It is strongly expressed in the B cell lineage beginning at the very early pro-B cell stage in the bone marrow and continues to be expressed in all later stages except plasma cells (10). The mb1-cre line was tested by intercrossing it to a floxed enhanced yellow fluorescent protein (EYFP) reporter mouse line. The analysis showed a very efficient and B cell-specific recombination. To further test the mb1-cre line, we bred it to several different lines bearing floxed genes, some of which are believed to be essential genes in all cell types. We show results for the splicing factor SRp20 and the DNA methylase Dnmt1. SRp20 belongs to a family of serine-arginine-rich proteins important for a variety of cellular functions surrounding mRNA including constitutive and alternative splicing, transport, translation, an...

The maintenance of mature B cells hinges on signals emitted from the BAFF-R cell-surface receptor, but the nature of these signals is incompletely understood. Inhibition of canonical NF-kappaB transcription factor activity through ablation of the essential scaffold protein NEMO arrests B cell development at the same stage as BAFF-R deficiency. Correspondingly, activation of this pathway by constitutively active IkappaB Kinase2 renders B cell survival independent of BAFF-R:BAFF interactions and prevents proapoptotic PKCdelta nuclear translocation. In addition, canonical NF-kappaB activity mediates differentiation and proper localization of follicular and marginal zone B cells in the absence of BAFF-R, but not CD19. By replacing BAFF-R signals, constitutive canonical NF-kappaB signaling, a hallmark of various B cell lymphomas, causes accumulation of resting B cells and promotes their proliferation and survival upon activation, but does not per se induce lymphomagenesis. Therefore, canonical NF-kappaB activity can substitute for BAFF-R signals in B cell development and pathogenesis.

Mice carrying transgenic rearranged V region genes in their IgH and Igkappa loci to encode an autoreactive specificity direct the emerging autoreactive progenitors into a pre-B cell compartment, in which their receptors are edited by secondary Vkappa-Jkappa rearrangements and RS recombination. Editing is an efficient process, because the mutant mice generate normal numbers of B cells. In a similar nonautoreactive transgenic strain, neither a pre-B cell compartment nor receptor editing was seen. Thus, the pre-B cell compartment may have evolved to edit the receptors of autoreactive cells and later been generally exploited for efficient antibody diversification through the invention of the pre-B cell receptor, mimicking an autoreactive antibody to direct the bulk of the progenitors into that compartment.

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