Biomedical subjects

Elena Peeva

Publications and source records attributed to Elena Peeva.

10 recordsLinked to original sources

PubMed2006

Cutting edge: lupus susceptibility interval Sle3/5 confers responsiveness to prolactin in C57BL/6 mice.

Prolactin is of interest in the pathogenesis of systemic lupus erythematosus (SLE) because almost 25% of SLE patients display hyperprolactinemia, and serum prolactin correlates with disease activity in some patients. Furthermore, hyperprolactinemia causes early mortality in lupus-prone mice and induces a lupus-like phenotype in nonspontaneously autoimmune mice. We show here that the immunomodulatory effects of prolactin are genetically determined; hyperprolactinemia breaks B cell tolerance and causes a lupus-like serology in BALB/c mice expressing a transgene encoding the H chain of an anti-DNA Ab but not in C57BL/6 transgenic mice. In C57BL/6 mice that express both the H chain transgene and the lupus susceptibility interval Sle3/5, prolactin induces increased serum titers of anti-DNA Ab and glomerular Ig depositions. The increase in costimulation due to prolactin-mediated up-regulation of both CD40 on B cells and CD40L on T cells would appear to play a central role in lupus induction in this model.

Administration, Cutaneous↗

PubMed2006

Cutting Edge: Hormonal milieu, not antigenic specificity, determines the mature phenotype of autoreactive B cells.

Although both marginal zone and follicular B cells produce anti-DNA Abs in murine models of systemic lupus erythematosus, it has been unclear whether these distinct B cell subsets make identical or different Abs. Single-cell analysis demonstrates that the same DNA-reactive B cells can mature to either subset, depending on the hormonal environment. Anti-DNA B cells in estradiol-treated mice become marginal zone cells while identical cells from prolactin-treated mice become follicular cells. The B cell receptor signaling pathway is influenced by hormonal milieu. Thus, hormonal milieu and perhaps B cell receptor signaling, but not antigenic specificity, correlates with the differentiation pathway. These observations have implications for the pathogenesis and treatment of autoimmune disease.

Animals↗

PubMed2006

Prolactinoma and systemic lupus erythematosus: do serum prolactin levels matter?

The lactogenic hormone prolactin is produced in part by cells of the immune system and serves as an upregulator of immune function. Hyperprolactinemia is common in patients with systemic lupus erythematosus (SLE), raising the possibility that the hormone contributes to the excessive immune response in the disease. The highest levels of circulating prolactin occur in association with prolactin-secreting tumors, but prolactinomas have only rarely been encountered in patients with SLE. We present here three patients with SLE and prolactinomas. As with the previously reported six patients, there was no consistency in the presence of findings related to prolactin excess or in the coincidence of hyperprolactinemia with flares of SLE disease activity. We speculate that this may be due to genetic differences in the response to prolactin and/or to the presence of variant prolactin isoforms detected in the clinical immunoassay that have reduced or absent biologic activity.

Adult↗

PubMed2005

Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes.

Pathogenic autoimmunity requires a combination of inherited and acquired factors. In as much as hormones influence the sexual dimorphism of the immune system, it is possible that they can initiate or accelerate an autoimmune process, and contribute to gender-biased autoimmune disorders. Not only natural hormones, but also endocrine disruptors, such as environmental estrogens, may act in conjunction with other factors to override immune tolerance to self-antigens. In lupus, murine and human studies demonstrate that female sex hormones are implicated in disease pathogenesis. In the B cell compartment, both prolactin and estrogen are immunomodulators that affect maturation, selection and antibody secretion. Their impact may be based on their capacity to allow autoreactive B cells to escape the normal mechanisms of tolerance and to accumulate in sufficient numbers to cause clinically apparent disease. Both hormones lead to the survival and activation of autoreactive B cells, but they skew B cell maturation towards different directions, with prolactin inducing T cell-dependent autoreactive follicular B cells and estrogen eliciting T cell-independent autoreactive marginal zone B cells. Differential modulation of the cytokine milieu by hormones may also affect the development and activation of specific mature B cell subsets. This novel insight suggests that targeted manipulation of these pathways may represent a promising avenue in the treatment of lupus and other gender-biased autoimmune diseases.

Animals↗

PubMed2005

Tamoxifen blocks estrogen-induced B cell maturation but not survival.

Estrogen treatment has been shown not only to exacerbate disease activity and accelerate death in spontaneous murine models of lupus but also to induce a lupus-like phenotype in non-spontaneously autoimmune mice. In mice transgenic for the H chain of an anti-DNA Ab, estrogen rescues naive autoreactive B cells that normally are deleted and causes them to mature to a marginal zone phenotype. Estrogen further leads to the activation of this population causing an elevation of serum anti-DNA Ab titers and renal disease. This study was designed to evaluate the therapeutic potential of tamoxifen, a selective estrogen receptor modulator, on estrogen-induced lupus. Mice treated with both estradiol and tamoxifen showed no elevation in anti-DNA Ab titers and consequently no glomerular IgG. The DNA-reactive B cell population that is rescued by estrogen was present in an anergic state in mice treated with both estradiol and tamoxifen. Estradiol enhances transitional B cell resistance to apoptosis and expands the population of marginal zone B cells; tamoxifen did not impede the enhanced resistance to apoptosis, but prevented the development of autoreactive cells as marginal zone B cells. Thus, estrogen-induced autoimmunity proceeds through two distinct molecular pathways, one affecting survival and the other maturation. Activation, but not survival, of autoreactive B cells can be abrogated by tamoxifen. Drugs that modulate even some of the effects of estrogen may be beneficial in patients with lupus. Eventually, understanding the pathways involved in survival and activation of autoreactive B cells will permit the development of therapeutics that target all relevant pathways.

Animals↗

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↗

PubMed2004

Relapsing arterial aneurysms in juvenile Behçet's disease.

Vascular involvement in Behçet's disease has a wide range of clinical manifestations, the most common being thrombophlebitis and arterial aneurysms. Every major vessel may be involved, but aneurysms of the carotid artery are relatively rare in adults and even rarer in children. We describe here a case of a 13-year-old boy with Behçet's disease with a recurrent carotid artery aneurysm treated with arterial ligation and immunosuppressive therapy who later developed an abdominal aortic aneurysm in the absence of other indications of disease activity. This case underscores the need for continuous monitoring of patients with vascular manifestations of Behçet's disease.

Adolescent↗

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

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↗

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↗