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Betty Diamond

Publications and source records attributed to Betty Diamond.

At least 37 records · Page 2Linked to original sources
PubMed2005

Expansion and hyperactivity of CD1d-restricted NKT cells during the progression of systemic lupus erythematosus in (New Zealand Black x New Zealand White)F1 mice.

CD1d-restricted NKT cells expressing invariant TCR alpha-chain rearrangements (iNKT cells) have been reported to be deficient in humans with a variety of autoimmune syndromes and in certain strains of autoimmune mice. In addition, injection of mice with alpha-galactosylceramide, a specific glycolipid agonist of iNKT cells, activates these T cells and ameliorates autoimmunity in several different disease models. Thus, deficiency and reduced function in iNKT cells are considered to be risk factors for the development of such diseases. In this study we report that the development of systemic lupus erythematosus in (New Zealand Black (NZB) x New Zealand White (NZW))F(1) mice was paradoxically associated with an expansion and activation of iNKT cells. Although young (NZB x NZW)F(1) mice had normal levels of iNKT cells, these expanded with age and became phenotypically and functionally hyperactive. Activation of iNKT cells in (NZB x NZW)F(1) mice in vivo or in vitro with alpha-galactosylceramide indicated that the immunoregulatory role of iNKT cells varied over time, revealing a marked increase in their potential to contribute to production of IFN-gamma with advancing age and disease progression. This evolution of iNKT cell function during the progression of autoimmunity may have important implications for the mechanism of disease in this model of systemic lupus erythematosus and for the development of therapies using iNKT cell agonists.

Animals↗
PubMed2005

B cell selection and susceptibility to autoimmunity.

Autoreactive B cells arise routinely as part of the naive B cell repertoire. The immune system employs several mechanisms in an attempt to silence these autoreactive cells before they achieve immunocompetence. The BCR plays a central role in B cell development, activation, survival, and apoptosis, and thus is a critical component of the regulation of both protective and autoreactive B cells. The strength of signal mediated by the BCR is determined by numerous factors, both B cell intrinsic and B cell extrinsic. Perturbations in the molecules that regulate the BCR signal strength or that activate pathways that engage in cross talk with the BCR-mediated signaling pathways can lead to the aberrant survival and activation of autoreactive B cells. In this review, we will discuss the some newly identified genetic loci and factors that modulate the BCR signal transduction pathway and, therefore, the regulation of autoreactive B cells. We will also provide evidence for a model of autoreactivity in which a reduction in the strength of the BCR signal allows the survival and the modulation of a naive B cell repertoire replete with autoreactivity.

Animals↗
PubMed2005

Receptor editing in peripheral B cell tolerance.

Receptor editing or secondary Ig gene rearrangement occurs in immature, autoreactive B cells to maintain self-tolerance. Here we show that nonspontaneously autoimmune mice immunized with a peptide mimetope of DNA develop peptide- and DNA-reactive antibodies. Antigen-specific B cells display a follicular B cell phenotype. As these cells move into the memory compartment, many express RAG protein and acquire expression of both kappa and lambda light chains. Thus, this study provides evidence for receptor editing occurring in a mature, antigen-activated B cell population. Because the receptor editing observed here occurred in an autoreactive response to antigen, it may function to maintain peripheral tolerance.

Animals↗
PubMed2005

Autoantibodies that bind glomeruli: cross-reactivity with bacterial antigen.

OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by the production of multiple autoantibodies. Anti-DNA antibodies are associated with glomerulonephritis in SLE. It has been shown that anti-DNA antibodies cross-react with bacterial polysaccharide and, thus, might be elicited by microbial exposure. Non-DNA-binding antibodies also contribute significantly to the pathogenesis of lupus nephritis. The goal of this study was to characterize non-DNA-binding, kidney-binding antibodies. METHODS: We generated a combinatorial library derived from spleen cells of a patient with SLE who had just previously received pneumococcal vaccine. The phage library was used in an in vivo biopanning technique to identify non-DNA-binding, kidney-binding antibodies. Antibodies were then analyzed for binding to bacterial polysaccharide and to renal antigens. RESULTS: Eight antibodies were characterized that bound glomeruli, but not DNA. All antibodies isolated by this protocol were IgG class, suggesting that there is affinity maturation for glomerular binding. Four of the antibodies cross-reacted with pneumococcal polysaccharide. Six of the antibodies bound to renal antigens that have previously been reported to be cross-reactive with DNA; the other 2 bound to histone. CONCLUSION: This study suggests that both DNA-binding and non-DNA-binding antibodies in SLE may be elicited by the same bacterial antigens.

Antibodies, Antinuclear↗
PubMed2005

Hormonal modulation of B cell development and repertoire selection.

Systemic lupus erythematosus is an autoimmune disorder characterized by the production of pathogenic autoantibodies, primarily to nuclear antigens. The etiology of SLE is not entirely understood, but it is well-appreciated that multiple factors such as genetics and environment contribute to disease progression and pathogenesis. There is also convincing evidence that gender plays an import role in SLE since the incidence of disease occurs with a female to male ratio of 9:1. While it is plausible that some sex-linked genes may contribute to the genetic predisposition for the disease, other likely culprits for this gender bias are the sex hormones estrogen and prolactin. The data implicating estrogen and prolactin in SLE, until recently, were largely circumstantial. However, within the last few years, data collected from both human and mouse studies have provided compelling evidence that alterations in sex hormone levels can alter tolerance of autoreactive B cells and exacerbate disease. In this review, we will discuss recent data demonstrating a role for estrogen and prolactin in SLE and the effect of these hormones on B cell maturation, selection and activation.

Animals↗
PubMed2005

Autoimmunity.

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Animals↗
PubMed2005

Overwhelming leukoencephalopathy as the only sign of neuropsychiatric lupus.

We describe a patient with diffuse leukoencephalopathy, a rare central nervous system complication of systemic lupus erythematosus, who died of brain herniation despite aggressive management. Brain magnetic resonance imaging revealed diffuse white matter hyperintensities consistent with vasogenic edema. Autopsy revealed only widespread cerebral edema. Early recognition and persistent, aggressive treatment will be required to avoid this fatal and rare manifestation of neuropsychiatric lupus.

Adult↗
PubMed2004

Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus.

B cell-activating factor belonging to the TNF family (BAFF) blockade prevents the onset of disease in systemic lupus erythematosus (SLE)-prone NZB/NZW F(1) mice. To determine the mechanism of this effect, we administered a short course of TACI-Ig with and without six doses of CTLA4-Ig to 18- to 20-wk-old NZB/NZW F(1) mice and evaluated the effect on B and T cell subsets and on anti-dsDNA Ab-producing B cells. Even a brief exposure to TACI-Ig had a beneficial effect on murine SLE; CTLA4-Ig potentiated this effect. The combination of TACI-Ig and CTLA4-Ig resulted in a temporary decrease in serum IgG levels. However, after cessation of treatment, high titers of IgG anti-dsDNA Abs appeared in the serum and IgG Abs deposited in the kidneys. Despite the appearance of pathogenic autoantibodies, the onset of proteinuria was markedly delayed; this was associated with prolonged depletion of B cells past the T1 stage, a decrease in the size of the spleen and lymph nodes, and a decrease in the absolute number of activated and memory CD4(+) T cells. TACI-Ig treatment normalized serum levels of IgM that are markedly elevated in NZB/W F(1) mice; this appeared to be due to a prolonged effect on the ability of the splenic microenvironment to support short-lived IgM plasma cells. Finally, a short course of combination TACI-Ig and CTLA4-Ig prolonged life and even reversed proteinuria in aged NZB/W F(1) mice, suggesting that BAFF blockade may be an effective therapeutic strategy for active SLE.

Abatacept↗
PubMed2004

Prolactin as a modulator of B cell function: implications for SLE.

Prolactin is not only a lactigenic hormone but also an immunomodulator involved in lymphocyte survival, activation and proliferation. There is increasing data implicating prolactin in autoimmunity, and specifically in SLE. Increased serum prolactin levels have been reported in lupus patients of both genders, and have been associated with accelerated disease expression and early mortality in lupus-prone mice. Furthermore, suppression of prolactin secretion with bromocriptine provides beneficial effects in murine lupus, and perhaps in some SLE patients as well. Treatment with prolactin that causes mild to moderate hyperprolactinemia, similar to that present in SLE patients, breaks tolerance and induces a lupus-like illness in non-spontaneously autoimmune mice with a susceptible genetic background. These immuno stimulatory effects of prolactin are mediated by a decrease in negative selection and the maturation of autoreactive B cells to the follicular subset. Consistent with the fact that follicular B cells are T cell dependent, CD4+ T cells are necessary for the prolactin-mediated break down of B cell tolerance. In mice, the effects of prolactin on the immune system are genetically determined, suggesting that only a subset of SLE patients are likely to have a prolactin-responsive disease. The manipulation of serum prolactin or, even more specifically, follicular B cells that are susceptible to the immuno stimulatory effects of prolactin, may provide novel therapeutic options for those SLE patients with a prolactin-modulated disease.

Animals↗
PubMed2004

Cognition and immunity; antibody impairs memory.

Patients with lupus (SLE) experience progressive cognitive loss without evidence of CNS vascular disease or inflammation. SLE patients produce anti-DNA antibodies that crossreact with NMDA receptors and are capable of mediating excitotoxic death. We now show that mice induced by antigen to express these antibodies have no neuronal damage until breakdown of the blood-brain barrier occurs. Following administration of lipopolysaccharide (LPS) to immunized mice, antibodies gain access to the brain. They bind preferentially to hippocampal neurons and cause neuronal death with resulting cognitive dysfunction and altered hippocampal metabolism on magnetic resonance spectroscopy. Memantine, an NMDA receptor antagonist, given prior to LPS administration, prevents neuronal damage. Thus, systemic immune responses can cause cognitive impairment in the absence of an inflammatory cascade, implicating the immune system in yet another arena of human pathobiology. Furthermore, NMDA receptor antagonists prevent antibody-mediated damage and may constitute a new approach to therapy in SLE.

Animals↗
PubMed2004

B-cell biology.

In recent years, our understanding of B-cell biology and the roles of B cells in normal immune responses and autoimmunity has increased dramatically. We no longer think of B cells simply as antibody factories. It is clear that these diverse and exquisitely regulated cells may contribute in a multitude of ways to immune responses. Animal models, clinical trials of biologic agents, and the ever expanding field of molecular biology have made great contributions to our current knowledge. With this improved understanding, we are afforded the opportunity to consider numerous potential therapeutic targets for treating autoimmune disease. As this growing science evolves, we can expect to see the advent of new therapies and new hope for patients who are afflicted with these disorders.

Animals↗
PubMed2004

A second heavy chain permits survival of high affinity autoreactive B cells.

Anti-DNA antibody is the serological hallmark of systemic lupus erythematosus (SLE). While antibodies with this specificity may be generated in many individuals, only patients with SLE fail to regulate them effectively. We have demonstrated previously that in non-autoimmune mice transgenic for the heavy chain of the R4A-gamma2b anti-DNA antibody, the existence of high affinity, IgG2b dsDNA binding B cells is tightly correlated with the co-expression of endogenous IgM heavy chain. These cells are anergic. In contrast, low affinity IgG2b dsDNA binding B cells do not express an endogenous heavy chain and represent a population of immunocompetent autoreactive B cells. In order to determine whether the presence of a second heavy chain permits the high affinity autoreactive B cells to escape deletion, the R4A-gamma2b mouse was mated to a strain with a targeted deletion of the transmembrane portion of the mu heavy chain, muMT mice, to produce R4A-gamma2b/muKO mice. Serum titers of anti-DNA antibodies were negligible in both R4A-gamma2b and R4A-gamma2b/muKO mice. In R4A-gamma2b/muKO mice, however, LPS was able to activate a DNA-reactive population although an LPS inducible DNA-reactive population. Light chain gene usage in transgene expressing B cells from R4A-gamma2b/muKO mice was similar to that of the previously defined low affinity anti-DNA B cells that escape tolerance. These data suggest a requirement for a second heavy chain for the survival of this anergic B cell subset.

Amino Acid Sequence↗
PubMed2003

The naive B cell repertoire predisposes to antigen-induced systemic lupus erythematosus.

It is clear that the development of an autoimmune disease usually depends on both a genetic predisposition and an environmental trigger. In this study, we demonstrate that BALB/c mice develop a lupus-like serology following immunization with a peptide mimetope of DNA, while DBA/2 mice do not. We further demonstrate that the critical difference resides within the B cell compartment and that the naive B cell repertoire of DBA/2 mice has fewer B cells specific for the DNA mimetope. Differences in the strength of B cell receptor signaling exist between these two strains and may be responsible for the difference in disease susceptibility. BALB/c mice possess more autoreactive cells in the native repertoire; they display a weaker response to Ag and exhibit less Ag-induced apoptosis of B cells. DBA/2 mice, in contrast, display a stronger B cell receptor signal and more stringent central tolerance. This correlates with resistance to lupus induction. Thus, the degree to which autoreactive B cells have been eliminated from the naive B cell repertoire is genetically regulated and may determine whether a nonspontaneously autoimmune host will develop autoimmunity following exposure to Ag.

Animals↗
PubMed2003

Identification of an antigen-specific B cell population.

The difficulty in characterizing antigen-specific B cells that arise in the native B cell repertoire has been a formidable obstacle to understanding both protective and pathogenic antibody responses. We have developed a tetramer-based technique for identifying antigen-specific B cells. Biotin-labeled antigen is made tetrameric by interaction with streptavidin. The enhanced avidity of this antigenic compound for the B cell membrane permits the visualization, characterization and isolation of antigen-specific B cells.

Animals↗
PubMed2003

Prolactin modulates the naive B cell repertoire.

Prolactin is a peptide hormone produced by the anterior pituitary gland that is critical in lactation. Prolactin can also be produced by lymphocytes, and both B and T cells express prolactin receptors. These findings have suggested that prolactin has immunomodulatory functions. Studies in spontaneously autoimmune hosts have demonstrated a role for prolactin in augmenting autoreactivity. We chose to analyze prolactin effects on anti-DNA B cells in nonspontaneously autoimmune female BALB/c mice transgenic for the heavy chain of an anti-DNA antibody. Treatment with prolactin for 4 weeks induced a lupus-like phenotype with an increased number of transgene-expressing B cells, elevated serum anti-DNA antibody titers, and glomerular immunoglobulin deposits. Prolactin caused a decrease in the population of transitional B cells and an increase in mature follicular and marginal zone B cells. The DNA-reactive B cells had a follicular cell phenotype. Anti-DNA hybridomas demonstrated that prolactin alters selection of the naive B cell repertoire. The expansion and activation of anti-DNA B cells in prolactin-treated R4A-gamma2b BALB/c mice was dependent on the presence of CD4(+) T cells. Finally, treatment with prolactin was unable to break tolerance in R4A-gamma2b transgenic C57Bl/6 mice, suggesting that responsiveness of the immune system to prolactin is genetically determined.

Animals↗
PubMed2002

Regulating the isotypic and idiotypic profile of an anti-PC antibody response: lessons from peptide mimics.

Protection against microbial invasion depends not only on the host's ability to mount an immune response, but on its ability to mount the correct immune response. Whether an antibody response is protective or not depends on both the fine antigenic specificity, that may be associated with particular idiotypes and epitope binding characteristics, and the isotype, determining antibody effector function. Thus, both the variable and the constant region of the antibodies induced by a peptide mimotope must be considered when assessing the success of any immunization. Phosphorylcholine (PC), an epitope present on the cell-wall C-polysaccharide of all pneumococcal serotypes, is capable of eliciting a protective antibody response to pneumococcal infection in mice and provides an attractive model system for understanding the immune response generated by peptide mimics. In this system, both the idiotype and isotype of protective antibodies have been determined and the characteristics of the in vivo response are well described and highly reproducible. We describe here the immune response generated by two peptide mimics of PC. Mice immunized with the peptides developed antibodies binding PC and C-polysaccharide. The idiotypic profile of the response differed depending on the peptide, but never included canonical T15(+) antibodies. The isotype of the response to peptide mimics differed depending on a combination of peptide and adjuvant, and included both IgG2a and IgG2b antibodies which are not typically seen in the response to PC. Thus, peptide mimotopes may elicit anti-polysaccharide responses, but fail to elicit the idiotypes and isotypes observed in the protective response to the microbial antigen.

Amino Acid Sequence↗
PubMed2002

Persistence of partially functional double-stranded (ds) DNA binding B cells in mice transgenic for the IgM heavy chain of an anti-dsDNA antibody.

One mechanism by which anti-double stranded (ds) DNA B cells are regulated is anergy. Multiple phenotypes have been attributed to anergic B cells in various transgenic models. Differences in the nature of the antigen and in the avidity of antigen-antibody interactions may account for these variations in phenotype. In the present study we describe a population of dsDNA binding B cells that display many of the features of anergic B cells, but have characteristics which suggest they are partially functional as well. These B cells do not spontaneously secrete antibody nor can they be induced to secrete antibody following receptor cross-linking in vitro. Furthermore, they display an immature phenotype and have a shortened lifespan, characteristic of anergic B cells. However, they can be induced to secrete anti-dsDNA antibody following activation with T cell-derived factors as well as with lipopolysaccharide (LPS) and they can be recovered by somatic cell hybridization even in the absence of LPS stimulation prior to fusion. These results suggest that antigen receptor signaling can be uncoupled from signaling induced by T cell-derived factors or LPS and that this may be a mechanism for maintaining tolerance. This may have protective advantages because it may enable B cells to be down-regulated in response to autoantigen yet be available for recruitment in an inflammatory response.

Animals↗