Abnormal transcription factor induction through the surface immunoglobulin M receptor of B-1 lymphocytes.

Despite stringent regulation of disease-associated autoantibodies, a substantial proportion of circulating Abs in sera of healthy individuals exhibit self-reactivity. These Abs are referred to as naturally occurring or natural autoantibodies (NAAs). To understand the origin and function of NAAs, we have generated a new site-directed transgenic mouse model in which a prerearranged VDJ gene coding for the H chain of a typical polyreactive NAA, ppc1-5, is inserted into the IgH locus. This H chain, when combined with its original L chain, the λ1 L chain, yields a NAA that characteristically binds a variety of self and non-self Ags including ssDNA, actin, ubiquitin, and nitrophenyl phosphocholine. Despite their autoreactivity, B cells expressing ppc1-5H/λ1 NAA are not negatively selected, but rather are overrepresented in the transgenic mice. The shift toward λ1 expression mainly occurs during the transition of immature to mature B cells in the spleen, suggesting a BCR selection process. The ppc1-5H/λ1 B cells exhibit a phenotype that is different from those of the known mature B cell populations, and they are located predominantly in the lymphoid follicles of the spleen and the lymph nodes. These B cells are functionally active, producing high levels of Abs in vivo and responding well to BCR stimulation in vitro. The findings indicate that the ppc1-5/λ1 natural autoantibodies originate from a distinct B cell subset that may be positively selected by virtue of its poly/autoreactivity.

Section: The Ppc1-5h/ 1 B Cells Respond Well To Anti-bcr and Mitogen mentioning

confidence: 81%

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Tian¹,

Beardall²,

Xu³

et al. 2006

“…While aggregation of the BCR on these cells results in tyrosyl phosphorylation of many BCR proximal proteins, including phospholipase C-␥, the activation of this enzyme, measured by phosphatidylinositol 4,5P 2 hydrolysis, is markedly diminished compared with splenic B cells (25). And, unlike splenic B cells, translocation of the transcription factor NF-B to the nucleus does not occur following BCR aggregation on peritoneal B-1 cells (9). Interestingly, similar changes in BCR signal transduction have been reported in anergic B cells from the hen egg lysozyme (HEL)/anti-HEL model in which the peripheral B cells are constantly exposed to their cognate soluble Ag (26).…”

mentioning

confidence: 97%

“…CD5 ϩ B-1 cells have been shown to display an altered responsiveness to BCR ligation compared with their B-2 cohorts. This is marked by a diminished ability for intracellular Ca 2ϩ mobilization, aberrant proliferation, and increased apoptosis after BCR cross-linking (6,7,9,10). While B-1 cells only comprise a small percentage of all B cells, they are the primary source of the serum Ab in unimmunized mice, known as natural Ab (3,11,12).…”

mentioning

confidence: 99%

The Unique Antigen Receptor Signaling Phenotype of B-1 Cells Is Influenced by Locale but Induced by Antigen

Chumley

Porto

Cambier

2002

Normal animals contain an autoreactive B lymphocyte subset, the B-1 subset, which is controlled by undefined mechanisms to prevent autoimmunity. Using a VH11Vκ9 Ig transgenic mouse, with a specificity prototypic of the subset, we have explored conditions responsible for the previously reported Ag hyporesponsiveness of these cells. We report that peritoneal VH11Vκ9 B cells exhibit typical B-1 behavior with high basal intracellular free Ca2+ and negligible receptor-mediated calcium mobilization. However, splenic B cells from this mouse, while phenotypically similar to their peritoneal counterparts, including expression of CD5, mount robust B-2-like responses to Ag as measured by calcium influx and altered tyrosine phosphorylation responses. When these splenic cells are adoptively transferred to the peritoneal cavity and encounter their cognate self-Ag, they acquire a B-1 signaling phenotype. The ensuing hyporesponsiveness is characterized by increases in both basal intracellular calcium and resting tyrosyl phosphorylation levels and is highlighted by a marked abrogation of B cell receptor-mediated calcium mobilization. Thus, we show that self-Ag recognition in specific microenvironments such as the peritoneum, and we would propose other privileged sites, confers a unique form of anergy on activated B cells. This may explain how autoreactive B-1 cells can exist while autoimmunity is avoided.

“…Ex vivo B-1a cells fail to proliferate following BCR cross-linking, which drives B-2 cells into S phase (35,36). Conversely, B-1a cells enter S phase in response to PMA and do so unusually rapidly, whereas B-2 cells require the combination of PMA and a calcium ionophore (35,37).…”

mentioning

confidence: 99%

Disruption of Cyclin D3 Blocks Proliferation of Normal B-1a Cells, but Loss of Cyclin D3 Is Compensated by Cyclin D2 in Cyclin D3-Deficient Mice

Mataraza

Tumang

Gumina

et al. 2006

Peritoneal B-1a cells differ from splenic B-2 cells in the molecular mechanisms that control G0-S progression. In contrast to B-2 cells, cyclin D2 is up-regulated in a rapid and transient manner in phorbol ester (PMA)-stimulated B-1a cells, whereas cyclin D3 does not accumulate until late G1 phase. This nonoverlapping expression of cyclins D2 and D3 suggests distinct functions for these proteins in B-1a cells. To investigate the contribution of cyclin D3 in the proliferation of B-1a cells, we transduced p16INK4a peptidyl mimetics (TAT-p16) into B-1a cells before cyclin D3 induction to specifically block cyclin D3-cyclin-dependent kinase 4/6 assembly. TAT-p16 inhibited DNA synthesis in B-1a cells stimulated by PMA, CD40L, or LPS as well as endogenous pRb phosphorylation by cyclin D-cyclin-dependent kinase 4/6. Unexpectedly, however, cyclin D3-deficient B-1a cells proliferated in a manner similar to wild-type B-1a cells following PMA or LPS stimulation. This was due, at least in part, to the compensatory sustained accumulation of cyclin D2 throughout G0-S progression. Taken together, experiments in which cyclin D3 was inhibited in real time demonstrate the key role this cyclin plays in normal B-1a cell mitogenesis, whereas experiments with cyclin D3-deficient B-1a cells show that cyclin D2 can compensate for cyclin D3 loss in mutant mice.