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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In face of numerous benefits induced by therapy based on interferon (IFN) associated with ribavirin for the treatment of chronic hepatitis C, there is an increasing concern regarding its tolerance, which can, in some cases, reduce the quality of life as well as compliance of patients. Among the less common side effects, there are the autoimmune ones which can be globally divided into appearance or increase in titres of auto-antibodies and/or manifestation of overt autoimmune pathologies. Whereas the former may concern more than 50% of treated subjects, the latter is reported in only 1-2% of patients under therapy. Thyroid dysfunction represents the well-studied autoimmune disorder. The presence of pre-existing anti-thyroid antibodies and being of female sex, constitute relevant risk factors for the development of a disease involving this gland. Often the treatment of thyropathy must be continuous in spite of IFN discontinuation because the disturbance usually does not abate with stopping antiviral therapy. Some observations have pointed out to the fact that IFN can lead to the development of insulin-dependent diabetes mellitus. Sometimes, during, as well as after IFN treatment, the appearance of anti-islet cell antibodies has been shown, but its interrelationship with the development of disease is uncertain. While being treated with IFN for chronic hepatitis C, the finding of non-organ specific antibodies at baseline can increase the likelihood of the development of autoimmune hepatitis. However, their presence does not constitute an absolute contraindication to the treatment, except in case of high titre. Other disorders, such as a lupus erythematosus-like syndrome, haemolytic anaemia, and immune-mediated thrombocytopenia have been reported. In conclusion, although the presence of auto-antibodies is considered to be an epiphenomenon without pathogenic significance in most patients suffering from chronic hepatitis C, it poses a problem when they need to be treated with IFN. This antiviral drug can induce or exacerbate a multitude of autoimmune-related disorders, however, clinically overt immune-mediated diseases are rare and affect a subset of subjects who have an underlying autoimmune diathesis.
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PMID:Autoimmune manifestations during interferon therapy in patients with chronic hepatitis C: the hepatologist's view. 1575 46

The highly selective nature of organ-specific autoimmune disease is consistent with a critical role for adaptive immune responses against specific autoantigens. In type 1 diabetes mellitus, autoantibodies to insulin are important markers of the disease process in humans and nonobese diabetic (NOD) mice; however, the Ag-specific receptors responsible for these autoantibodies are obscured by the polyclonal repertoire. NOD mice that harbor an anti-insulin transgene (Tg) (V(H)125Tg/NOD) circumvent this problem by generating a tractable population of insulin-binding B cells. The nucleotide structure and genetic origin of the endogenous kappa L chain (Vkappa or IgL) repertoire that pairs with the V(H)125Tg were analyzed. In contrast to oligoclonal expansion observed in systemic autoimmune disease models, insulin-binding B cells from V(H)125Tg/NOD mice use specific Vkappa genes that are clonally independent and germline encoded. When compared with homologous IgL genes from nonautoimmune strains, Vkappa genes from NOD mice are polymorphic. Analysis of the most frequently expressed Vkappa1 and Vkappa9 genes indicates these are shared with lupus-prone New Zealand Black/BINJ mice (e.g., Vkappa1-110*02 and 9-124) and suggests that NOD mice use the infrequent b haplotype. These findings show that a diverse repertoire of anti-insulin B cells is part of the autoimmune process in NOD mice and structural or regulatory elements within the kappa locus may be shared with a systemic autoimmune disease.
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PMID:Multiple germline kappa light chains generate anti-insulin B cells in nonobese diabetic mice. 1600 8

Generalized vitiligo is an autoimmune disorder in which acquired white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. Although usually sporadic, family clustering of vitiligo may occur, in a non-Mendelian pattern typical of multifactorial, polygenic inheritance. Sporadic vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus; these same disorders occur at increased frequency in patients' first-degree relatives. Here, we studied 133 'multiplex' generalized vitiligo families, with multiple affected family members. The age of onset of vitiligo is earlier in these 'multiplex' families than in patients with sporadic vitiligo. Affected members of the multiplex vitiligo families have elevated frequencies of autoimmune thyroid disease, rheumatoid arthritis, psoriasis, adult-onset insulin-dependent diabetes mellitus, pernicious anemia, and Addison's disease. Probands' unaffected siblings have elevated frequencies of most of these same autoimmune diseases, particularly if the proband had non-vitiligo autoimmune disease. Familial generalized vitiligo is thus characterized by earlier disease onset and a broader repertoire of associated autoimmune diseases than sporadic vitiligo. This mostly likely reflects a greater inherited genetic component of autoimmune susceptibility in these families. These findings have important implications for autoimmune disease surveillance in families in which multiple members are affected with vitiligo.
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PMID:Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. 1602 22

Mice deficient in programmed cell death 1 (PD-1, Pdcd1), an immunoinhibitory receptor belonging to the CD28/cytotoxic T lymphocyte-associated antigen-4 family, spontaneously develop lupus-like autoimmune disease and autoimmune dilated cardiomyopathy on C57BL/6 and BALB/c backgrounds, respectively. However, how PD-1 deficiency induces different forms of autoimmune diseases on these two strains was unknown. Here, we report that PD-1 deficiency specifically accelerates the onset and frequency of type I diabetes in NOD (nonobese diabetic) mice, with strong T helper 1 polarization of T cells infiltrating into islets. These results suggest that PD-1 deficiency accelerates autoimmune predisposition of the background strain, leading to the induction of different forms of autoimmune diseases depending on the genetic background of the strain. Using NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes, we screened diabetes-susceptible loci by genetic linkage analysis. The diabetic incidence of NOD-Pdcd1-/- mice was controlled by five genetic loci, including three known recessive loci [Idd (insulin-dependent diabetes) 1, Idd17, and Idd20] and two previously unidentified dominant loci [Iddp (Idd under PD-1 deficiency) 1 and Iddp2].
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PMID:Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. 1608 65

Premature coronary heart disease (CHD) has emerged as a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Overall SLE patients have a 5-6-fold increased risk of CHD and this excess risk is especially pronounced in younger women where the excess risk may be >50-fold. Studies from our group and others have also demonstrated that SLE patients have a higher prevalence of subclinical atherosclerosis compared with controls, with approximately 30% having evidence of subclinical involvement. It is important to consider what factors may underlie this excess risk. We have found that certain 'classic' risk factors, i.e. hypertension and diabetes mellitus, are more prevalent in SLE and that persistent hypercholesterolaemia independently predicts patients who will develop CHD. These risk factors alone do not completely explain the excess risk observed, and after adjusting for classic risk factors SLE remains independently associated with both clinical and subclinical outcomes. Certain other metabolic changes also occur more frequently in SLE, namely premature menopause, renal impairment, high triglycerides and higher plasma homocysteine. In addition, insulin resistance is more pronounced in patients with SLE, and approximately 18% have the metabolic syndrome. It is also increasingly accepted that atherosclerosis is a chronic inflammatory condition, and in SLE systemic complement activation as well as immune complex formation can result in changes that promote the development of atheroma. Similarly, autoantibody production, especially antibodies directed against lipoprotein subtypes and those in the antiphospholipid (APLA) family, are gaining increasing attention. The role of the latter are particularly controversial as different subtypes have been shown to both promote and protect against atherogenesis. In a study looking at carotid plaque in SLE, we found that APLA was independently associated with the presence of plaque; this study also found that patients with plaque had higher white cell counts, suggesting ongoing chronic inflammation. We have also noted a negative correlation between activation of transforming growth factor beta-1 and carotid intima-medial thickness. This cytokine, which is known to be a potent anti-inflammatory molecule, has also been shown to be protective against atherogenesis. With regard to therapy, steroids may be a true double-edged sword, with low doses exerting a beneficial anti-inflammatory role whereas higher doses may be detrimental through exacerbation of metabolic risk factors. In contrast, we have found that antimalarials have a beneficial effect on lipids especially when co-prescribed with steroids, and this, along with anti-inflammatory and proposed antiplatelet effects, may confer protection against CHD in lupus. The risk of premature CHD in SLE is therefore mediated by a number of factors that involve not only classic risk factors but also a range of factors associated with SLE itself. Preventative strategies will therefore need to address all potential risk factors of relevance. A more through understanding of the interplay between autoimmunity and atherogenesis should be possible by the study of SLE, and this may not only benefit lupus patients but also may have implications for our understanding of atherosclerosis in general.
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PMID:'Not only...but also': factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. 1623 77

Both epidemiological and experimental studies have shown that impaired growth in utero due to maternal malnutrition, resulting in low birth weight, is associated with a high incidence of glucose intolerance, insulin resistance, and type 2 diabetes in adult life. Maternal malnutrition is a worldwide problem and unavoidable; therefore, prevention of type 2 diabetes in low birth weight infants who reach adulthood is difficult to achieve. Administration of human umbilical cord blood (HUCB) mononuclear cells into type 1 and type 2 diabetic mice has been shown to improve both their blood glucose levels and survival. It has also been shown that the progenitor cells derived from HUCB improve not only glycemia but also other disease conditions, including systemic lupus erythematosis, amyotrophic lateral sclerosis, Alzheimer's disease, stroke, brain damage in animals and certain malignancies in humans. Transfusion of unrelated HUCB, although abundantly available, is underutilized as a therapeutic agent. Therefore, we propose the hypothesis that transfusion of HUCB to low birth weight infants be considered a therapeutic modality to prevent the development of type 2 diabetes in their adulthood.
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PMID:Administration of human umbilical cord blood to low birth weight infants may prevent the subsequent development of type 2 diabetes. 1648 Nov 20

Estrogens influence many physiological processes in mammals, including but not limited to reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen is also implicated in the development or progression of numerous diseases, which include but are not limited to various types of cancer (breast, ovarian, colorectal, prostate, endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. In many of these diseases, estrogen mediates its effects through the estrogen receptor (ER), which serves as the basis for many therapeutic interventions. This Review will describe diseases in which estrogen, through the ER, plays a role in the development or severity of disease.
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PMID:Estrogen receptors and human disease. 1651 88

We previously reported that systemic lupus erythematosus (SLE) patients have a higher risk of insulin resistance and abnormal insulin secretion. Recent studies demonstrated that interleukin (IL)-18, a novel pro-inflammatory cytokine, may be involved in triggering the inflammatory processes in SLE and the concentrations of circulating IL-18 in SLE patients were significantly higher than those in healthy subjects. IL-12 has a synergistic effect with IL-18, and both cytokines are inducers of interferon (IFN)-gamma. The objective of this study was to identify the effect of fasting insulin levels on circulating concentrations of IL-18, IL-12 and IFN-gamma in patients with SLE. Plasma levels of proinflammatory Th-1 cytokines were determined by enzyme-linked immunosorbent assay in a total of 70 female SLE patients and 34 age-matched healthy females. Insulin resistance (IR) and secretion were evaluated by homeostasis model assessment (HOMA). All patients were further classified into subgroups based on the quartiles of fasting insulin levels. SLE patients with fasting insulin levels in the top quartile compared with other quartiles had significantly higher plasma levels of IL-18. The presence of insulin auto-antibodies (IAA) in SLE patients had no influence on plasma levels of IL-18. In addition, fasting insulin levels and HOMA IR were positively correlated with IL-18 in all SLE patients, respectively. In conclusion, elevated circulating IL-18 concentrations corresponded with increases in fasting insulin levels and the status of insulin resistance in patients with SLE.
Lupus 2006
PMID:Elevation of plasma interleukin-18 concentration is associated with insulin levels in patients with systemic lupus erythematosus. 1668 59

The chronic graft-versus-host (cGvH) reaction is a model of induced lupus caused by alloreactive CD4(+) T cells from a Bm-12 mouse in a C57BL/6 recipient. We used this cGvH reaction in C57BL/6 anti-DNA H chain transgenic mice, 56R/B6, to understand the structure, specificity, and origin of the induced autoantibodies (auto-Abs). We found anti-DNA Abs that reacted to several different antigens, such as phosphatidylserine, myelin basic protein, thyroglobulin, histone, insulin, cytochrome C, and beta-galactosidase. This polyreactivity was found for Abs from B cells that expressed the 56R H chain transgene with "editor" L chains that did not completely veto autoreactivity. We suggest that such incomplete editing results in polyreactivity and that incompletely edited polyreactive B cells influence the subsequent expression of pathogenic auto-Abs in disease. We also found B cells that coexpress kappa and lambda L chain. These B cells contributed to the autoimmune response and are possibly in the marginal zone of the spleen.
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PMID:Light chain editing generates polyreactive antibodies in chronic graft-versus-host reaction. 1680 98

CD4+CD25+ regulatory T cells (Treg) constitute an important mechanism of peripheral immune tolerance. Organ-specific autoimmune conditions, such as thyroiditis and insulin-dependent diabetes mellitus have been attributed to a breakdown of this tolerance mechanism. However, this T-cell subset has not been well studied in patients and mice with systemic lupus erythematosus (SLE; lupus). The information that has been gathered so far using new tools that discriminate Treg from activated T cells indicates that reduced numbers of Treg may exist in patients with lupus. In addition, potential defects in SLE Treg function have been documented in humans and mice. Our group has demonstrated equivalent proportions of thymic Treg in lupus prone and normal mice. We therefore propose that Treg function in SLE is the more important factor to address in future studies of murine lupus. Recent studies have shown that Toll-like receptor (TLR) ligation can result in an abrogation of Treg-mediated suppression; specifically ligation of TLR-2, -4, -8 and -9. We address this new information about TLRs and Treg and propose a model for Treg tolerance breakdown to nucleic acid-binding SLE autoantigens.
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PMID:Regulatory T cells and systemic lupus erythematosus. 1691 89


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