Qualitative difference of anti-DNA antibody-producing cell precursors in the pre-immune B cell repertoire between normal and lupus-prone mice (original) (raw)
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Clinical and Experimental Immunology, 2008
SUMMARYPrecursor frequencies for anti-DNA-secreting B cells were estimated in six healthy donors and 18 SLE patients with active and inactive disease. Precursors for IgG anti-dsDNA-secreting B cells were exclusively detected in SLE patients (73% of active patients and one inactive patient, 0.01 – 0.99% of IgG-producing B cells). These frequencies were in the same order of magnitude as frequencies of precursors for IgG anti-tetanus toxoid, which were detectable in three healthy volunteers after booster vaccination (0.07–0.8% of IgG-producing B cells), but not before (<001%). Precursors for IgG anti-ss-DNA secreting B cells were observed in 33% of healthy donors and in 78% of SLE patients (0.01 – 0.32% of IgG-producing B cells). Only patient-derived IgG anti-DNA clones cross-reacted with (33%) or were monoreactive to dsDNA (12%). Precursors for IgM anti-DNA-secreting B cells were observed in healthy donors and SLE patients in comparable frequencies and with similar reactivities wit...
Immunology Today, 1983
B-cell hyperactivity is the general and cardinal feature of murine and human systemic lupus e~ythematosus (SLE), the prototype organ-non-specific autoimmune disease. The defect(s) responsible could be intrinsic to B cells, secondary to T-cell or macrophage abnormalities resulting in excessive help or deficient suppression, or could stem from qualitative/ quantitative abnormalities of autoantigens. Here Argyrios Theofilopoulos and his colleagues review the immunopathological and cellular abnormalities observed in murine lupus and the factors curren@ thought to play a role in normal B-cell proliferation, differentiation and Ig class switching. Next month, in a second article, they discuss abnormalities in B-cell response to and~or overproduction of T-cell-derived accessory signals which may explain the generalized B-cell hyperactivity associated with mouse and human lupus. Derivation of lupus strains and current conclusions The recent availability of two new strains of mice (MRL, BXSB) which, like the NZB and NZB/W F1 mice, spontaneously develop classical SLE-like syndromes, has added greatly to the potential value of murine SLE as an experimental model of generalized autoimmunity 1'2. Now this disease can be observed in mice of three quite different genetic backgrounds (Table I) and essential common denominators identified. In each kind of lupus mouse the disease occurs in two forms: a late-life variety (NZB, BXSB females, MRL/Mp-+/+) that appears during the second year of life; and an acute form (NZB/W F 1
Arthritis & Rheumatism, 1984
The cellular mechanism of anti-DNA antibody synthesis in patients with systemic lupus erythematosus (SLE) was studied by DNA-specific solid-phase radioimmunoassay. Anti-DNA antibody synthesis in response to DNA was T-dependent, and the experiments with reconstituted lymphocytes from identical twins discordant for SLE showed that B cells and T cells from SLE patients must cooperate to synthesize anti-DNA antibody. Anti-DNA antibody synthesis by lymphocytes from patients with inactive SLE was enhanced by T4 cells and suppressed by T8 cells in response to DNA. Although T4 cells from patients with active SLE could enhance anti-DNA antibody synthesis by autologous B cells, their T8 cells could not suppress anti-DNA antibody synthesis by autologous B cells. These results indicate that elevated anti-DNA antibody synthesis in response to DNA in patients with active SLE is due to abnormalities of both SLE B cells and SLE T cells. They further indicate that dysfunction of T8 cells from patients with active SLE may, in part, be responsible for deficient regulation of anti-DNA antibody synthesis.
Surface and functional characteristics of B cells from lupus-prone murine strains
Clinical immunology and immunopathology, 1982
B lymphocyte hyperactivity in systemic lupus erythematosus (SLE)-prone mice, originally considered a result of imbalances in T-cell subsets, more recently has been attributed to intrinsic abnormalities of B cells. In our experiments cited here, we used a variety of systems to assess the surface phenotypic and functional characteristics of B cells from several SLE strains (NZB, NZB/W, BXSB, MRL/Mp-lpr/lpr). Generation of Ig isotype diversity follows normal pathways in all these SLE strains. B cells from newborn BXSB and MRL/Mp-lprilpr mice, as in immunologically normal mice, do not reexpress surface Ig (sIg) after modulation with anti-Is. In contrast, B cells of newborn New Zealand mice do reexpress sIg after anti-Ig-induced modulation. The rates at which sIg-anti-Ig complexes cap and become endocytosed in all SLE strains are within normal limits. B cells from SLE strains are stimulated mitogenically by F(ab'), anti-y and lipopolysaccharide with indices no different from those of normal B cells. The ontogenic development of Ia+ and LybS+ cells is normal with the frequency of positive cells and density of alloantigens normal or slightly elevated, respectively. SLE and normal strains are much alike in expression of retroviral envelope gp70 antigen on surfaces of lymphocytes. Anti-gp70 antibodies fail to stimulate mitosis in cells of either SLE or normal strains. However, the frequency of B-cell colony-forming splenocytes is several fold higher in autoimmune mice compared to controls. Expression of acceptor sites for helper messages and of acceptor sites for suppressor messages on B cells is within normal limits in all SLE mice as revealed by the effects of immune response enhancing anti-Lyb3 serum and immune response suppressing anti-Lyb7 serum, respectively. As a whole, these results reaffum the generalized hyperactivity and advanced maturation of B cells of SLE mice but do not reveal any common surface or functional characteristics which might be responsible for the B-cell abnormality.
Journal of Experimental Medicine, 1999
The precise role of B cells in systemic autoimmunity is incompletely understood. Although B cells are necessary for expression of disease (Chan, O., and M.is unclear whether autoantibody production, antigen presentation, and/or other B cell functions are required for the complete pathologic phenotype. To address this issue, two experimental approaches were used. In the first, the individual contributions of circulating antibodies and B cells were analyzed using MRL/MpJ-Fas lpr (MRL/ lpr ) mice that expressed a mutant transgene encoding surface immunoglobulin (Ig), but which did not permit the secretion of circulating Ig. These mice developed nephritis, characterized by cellular infiltration within the kidney, indicating that B cells themselves, without soluble autoantibody production, exert a pathogenic role. The results indicate that, independent of serum autoantibody, functional B cells expressing surface Ig are essential for disease expression, either by serving as antigen-presenting cells for antigen-specific, autoreactive T cells, or by contributing directly to local inflammation.
Journal of Experimental Medicine, 1979
The frequencies and absolute numbers of B and T cells in the lymphoid organs of five murine strains (NZB, (NZB X NZW)F1, BXSB, MRL/l, and MRL/n) with SLE-like syndromes were examined. We assessed the frequencies of cells bearing surface Ig, C3d and IgG Fc receptors, and theta-antigen. The sequential expression of Ig isotopes on developing B cells and the Ig isotypes expressed on adult B cells were ascertained. In addition, the Ly subsets and the expression of Ia antigens coded for by the I-J subregion of the mouse H-2 complex were examined. Compared to normal, older mice, New Zealand mice had low frequencies and absolute numbers of B cells, BXSB mice had a moderate B-cell proliferation, and MRL/l mice had normal absolute numbers of B cells but a reduced frequency concomitant with a massive T-cell proliferation. Old New Zealand mice and BXSB mice had reduced frequencies and absolute numbers of T cells compared to old controls. The developmental Ig-isotype diversity during the 1st wk ...
Journal of Experimental Medicine, 1992
Disease activity in systemic lupus erythematosus is closely associated with the appearance of immunoglobulin (Ig)G antibody to native DNA in both humans and mice. Like normal antibody responses, the anti-DNA autoantibody first appears as IgM and then switches to IgG. Structural studies of IgG anti-DNA suggest that these antibodies are the products of clonally selected, specifically stimulated B cells. The origins of the IgM anti-DNA have been less clear. To determine whether the earlier appearing IgM anti-DNA antibody in autoimmune mice also derives from clonally selected, specifically stimulated B cells or B cells activated by nonselective, polyclonal stimuli, we have analyzed the molecular and serological characteristics of a large number of monoclonal IgM anti-DNA antibodies from autoimmune (NZB x NZW)F1 mice. We have also analyzed IgM and IgG anti-DNA hybridomas obtained from the same individual mice to determine how the later-appearing IgG autoantibody may be related to the ear...
Immunology, 2008
The role of natural killer (NK) T cells in the development of lupus-like disease in mice is still controversial. We treated NZB/W mice with anti-NK1.1 monoclonal antibodies (mAbs) and our results revealed that administration of either an irrelevant immunoglobulin G2a (IgG2a) mAb or an IgG2a anti-NK1.1 mAb increased the production of anti-dsDNA antibodies in young NZB/W mice. However, the continuous administration of an anti-NK1.1 mAb protected aged NZB/W mice from glomerular injury, leading to prolonged survival and stabilization of the proteinuria. Conversely, the administration of the control IgG2a mAb led to an aggravation of the lupus-like disease. Augmented titres of anti-dsDNA in NZB/ W mice, upon IgG2a administration, correlated with the production of BAFF/BLyS by dendritic, B and T cells. Treatment with an anti-NK1.1 mAb reduced the levels of interleukin-16, produced by T cells, in spleen cell culture supernatants from aged NZB/W. Adoptive transfer of NK T cells from aged to young NZB/W accelerated the production of anti-dsDNA in recipient NZB/W mice, suggesting that NK T cells from aged NZB/W are endowed with a B-cell helper activity. In vitro studies, using purified NK T cells from aged NZB/W, showed that these cells provided helper B-cell activity for the production of anti-dsDNA. We concluded that NK T cells are involved in the progression of lupus-like disease in mature NZB/W mice and that immunoglobulin of the IgG2a isotype has an enhancing effect on antibody synthesis due to the induction of BAFF/ BLyS, and therefore have a deleterious effect in the NZB/W mouse physiology.