Splenic immunoglobulin-secreting cells and their regulation in autoimmune mice.

Theofilopoulos, Argyrios N.; Shawler, Daniel L.; Eisenberg, Robert A.; Dixon, Frank J.

doi:10.1084/jem.151.2.446

Cited by 148 publications

(41 citation statements)

References 34 publications

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“…The absence of antibodies that react with BAFF-R-Fc would explain the different results with this form of BLyS blockade (14). Nonspecific immune stimuli induce increased autoantibody production in young (NZB ϫ NZW)F 1 mice (35). The development of antibodies to the therapeutic TACI could also occur in human lupus.…”

Section: Discussionmentioning

confidence: 99%

Control of spontaneous B lymphocyte autoimmunity with adenovirus‐encoded soluble TACI

Liu¹,

Szalai²,

Zhao³

et al. 2004

Arthritis & Rheumatism

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Objective. Serum B lymphocyte stimulator (BLyS) is increased in autoimmune diseases, both in animal models and in humans. This study examined the effect of BLyS blockade in 3 animal models of lupus.Methods. Antibodies and lupus-like disease manifestations were examined in mice after administration of a single injection of an adenoviral construct for the transmembrane activator and CAML interactor receptor (AdTACI) that produces high serum levels of TACI-Fc fusion protein.Results. In C57BL/6 (B6) lpr/lpr mice (B6.lpr/lpr), which were used to model autoimmunity in the absence of severe disease, treatment of younger mice with Ad-TACI prevented the development of hypergammaglobulinemia. In contrast, use of AdTACI for BLyS blockade had only transient effects on the levels of IgG in normal B6 mice. AdTACI blocked the development of autoantibodies in younger B6.lpr/lpr mice and reversed the production of autoantibodies in older B6.lpr/lpr mice, and also reduced the numbers of splenic plasma cells. In MRL.lpr/lpr mice, which were used to examine disease manifestations, AdTACI reduced the extent of glomerulonephritis and proteinuria and improved survival, but had little effect on T cell infiltration and interstitial nephritis. However, in (NZB ؋ NZW)F 1 mice, AdTACI induced neutralizing anti-TACI antibodies and failed to reduce the numbers of B cells.Conclusion. BLyS blockade has little effect on IgG levels in normal mice, but reverses the production of spontaneously produced IgM and IgG autoantibodies in the setting of established autoimmunity. Blockade of BLyS ameliorates B cell-dependent disease manifestations even in the MRL.lpr/lpr model, but its effectiveness on autonomous T cell aspects of the disease is limited. Moreover, its effectiveness is neutralized by anti-TACI antibodies when present. These results provide a basis for understanding the potential effects of BLyS blockade in human disease.

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Section: Discussionmentioning

confidence: 99%

Control of spontaneous B lymphocyte autoimmunity with adenovirus‐encoded soluble TACI

Liu¹,

Szalai²,

Zhao³

et al. 2004

Arthritis & Rheumatism

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“…Ig secreting cells (IgSC) were quantitated with a reverse hemolytic plaque assay as previously described (6). IgSC were counted after 4 d of culture.…”

Section: Preparation Of T Cell-depleted Populations and Culture Condimentioning

confidence: 99%

“…Both B and T cell abnormalities have been reported, and the relative importance of a given defect varies from strain to strain (1,2,5,6). For example, T helper cell hyperfunction plays a dominant role in the disease of MRL/1 mice (6-10), whereas primary B cell abnormalities have been identified in BXSB, NZB, and (NZB × NZW)F1 (NZB/W) mice (1,2,6,(11)(12)(13)(14). In fact, these latter mice, unlike MRL/1 mice (7,9), develop SLE despite neonatal thymectomy (1,2,7,15).…”

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confidence: 99%

B cell dependence on and response to accessory signals in murine lupus strains.

Prud’homme¹,

Balderas²,

Dixon³

et al. 1983

The Journal of Experimental Medicine

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B cell hyperactivity, a feature common to all lupus-prone murine strains, may be caused by hyperresponsiveness to, overproduction of, or bypassing of certain signals required for B cell activation, proliferation, and differentiation. In this study, we have compared the responses of B cells from three lupus-prone strains of mice (BXSB males, MRL and NZB/W females) and normal strains in a number of assays for which two or more signals are required to obtain a response. In medium to low density cultures of B cells from BXSB and NZB/W but not MRL/l lupus mice, the cells' proliferation induced by bacterial lipopolysaccharide (LPS) or anti-mu antibody was much higher than that of B cells from normal controls. At low B cell density, polyclonal activation by these substances and subsequent Ig secretion were dependent on accessory signals present in supernatants of concanavalin A-treated normal lymphocytes (CAS) or on the MRL/l proliferating T cell-derived B cell differentiation factor (L-BCDF) in both lupus-prone and immunologically normal mice. However, the responses of B cells from BXSB and NZB/W, but not MRL/l, mice to these accessory signals were higher than those of normal mice. Ig synthesis by fresh B cells of BXSB and NZB/W mice cultured in the absence of mitogens but in the presence of CAS or L-BCDF was higher than by similar cells from other strains, suggesting an increased frequency of B cells activated in vivo in these two autoimmune strains of mice. The patterns of IgG subclass secretion in response to LPS (without added CAS or L-BCDF) were abnormal in all lupus strains, with a predominance of IgG2b and/or IgG2a and low levels of IgG3, contrary to normal B cells for which IgG3 synthesis predominated. However, IgG1 synthesis in vitro by autoimmune and normal B cells alike was highly dependent on T cell-derived soluble mediators. Antigen-specific responses to SRBC in vitro of B cells from all lupus strains, like those of B cells from normal strains, required a minimum of three signals (antigen, LPS, T cell-derived antigen nonspecific helper factors). Yet, once triggered, B cells of BXSB and NZB/W mice gave higher responses than those of the other strains. We conclude that B cells of lupus mice have signal requirements similar to those of normal mice. Nevertheless, B cells of BXSB and NZB/W, but not MRL/l, lupus mice hyperrespond or process some accessory signals abnormally.

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“…Though MRL-+/+ mice have much less severe autoimmune disease than do congenic MRLlprllpr (19,27,28), both mouse strains had similar levels of 8.4-kb MCF RNA. Thus, lpr did not increase 8.4-kb MCF expression on an autoimmune background.…”

Section: Discussionmentioning

confidence: 94%

Expression of an endogenous retroviral transcript is associated with murine lupus

Krieg¹,

Khan²,

Steinberg³

1989

Arthritis & Rheumatism

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We have been investigating whether murine lupus is associated with endogenous type C retroviral expression. We used Northern blot analyses and oligonucleotide probes, which are able to distinguish the envelope genes of the xenotropic and mink cell focusforming (MCF) classes of type C retroviruses. Xenotropic expression in the spleen varied markedly among inbred mouse strains; although all strains expressed a 1.8‐kb transcript, only one‐half expressed one or more larger transcripts (8.4, 7.2, and/or 3.0 kb). Autoimmune disease did not correlate with expression of any of the xenotropic transcripts. Xenotropic and MCF transcripts were expressed independently among the mouse strains studied. Splenic RNA from all strains contained 7.2‐, 3.0‐, and 1.8‐kb MCF transcripts. Some strains also expressed 8.4‐kb MCF splenic RNA. There was a strong association between murine lupus and expression of 8.4‐kb MCF transcripts: 6 of 6 lupus‐prone strains, but only 2 of 11 nonautoimmune strains, had detectable 8.4‐kb MCF RNA. The xid and Yaa mutations had minimal effects on expression of 8.4‐kb MCF‐related transcripts, despite their major and opposite effects on disease. Moreover, New Zealand black mice highly expressed this RNA from day 1 of life, before disease development. The data suggest that expression of 8.4‐kb MCF endogenous retroviral transcripts is a primary feature of murine lupus and is not secondary to disease expression.

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Splenic immunoglobulin-secreting cells and their regulation in autoimmune mice.

Cited by 148 publications

References 34 publications

Control of spontaneous B lymphocyte autoimmunity with adenovirus‐encoded soluble TACI

Control of spontaneous B lymphocyte autoimmunity with adenovirus‐encoded soluble TACI

B cell dependence on and response to accessory signals in murine lupus strains.

Expression of an endogenous retroviral transcript is associated with murine lupus

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