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

Systemic lupus erythematosus (SLE) is a disease characterised by diverse clinical manifestations and the presence of multiple autoantibodies. There are multiple aetiological factors involved in its pathogenesis. Genetic factors do play an important role and the major histocompatibility complex has been studied extensively and many human leukocyte antigen (HLA) associations have been reported. Twin and familial lupus studies confirm the importance of genetic factors in the development of SLE. Reported HLA associations range from that of HLA-DR3 in Caucasians to HLA-DR2 in Chinese, Japanese and American Blacks. These associations however may only represent linkage disequilibrium and not the actual susceptibility genes. Other non-major histocompatibility complex genes have also been reported to play important roles in the pathogenesis of lupus. The advent of molecular biological techniques has advanced the understanding of susceptibility genes in many diseases. The use of microsatellite genome scanning to study multiplex lupus families has yielded a wealth of information on clusters of susceptibility genes. The identification of these genes will be an important advance in the understanding of this complex disease.
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PMID:The genetics of systemic lupus erythematosus. 958 74

Considerable evidence suggests that the development of systemic lupus erythematosus (SLE) has a strong genetic basis. Recent studies have emphasized that this disease, like other autoimmune diseases, is a complex genetic trait with contributions from major histocompatibility complex (MHC) genes and multiple non-MHC genes. Etiologic genes in these disorders determine susceptibility, and no particular gene is necessary or sufficient for disease expression. Studies of murine models of lupus have provided important insight into the immunopathogenesis of IgG autoantibody production and lupus nephritis, and genetic analyses of these mice overcome certain obstacles encountered when studying patients. Genome-wide linkage studies of different crosses have mapped the position of at least 12 non-MHC disease-susceptibility loci in the New Zealand hybrid model of lupus. Although the identity of the actual genes is currently unknown, recent studies have begun to characterize how these genetic contributions may function in the autoimmune process, especially in terms of their role in autoantibody production. Studies of MHC gene contributions in New Zealand mice have shown that heterozygosity for particular haplotypes greatly increases pathogenic autoantibody production and the incidence of severe nephritis. The mechanism for this effect appears to be genetically complex. Studies in human SLE have mostly focused on the association of disease with alleles of immunologically relevant genes, especially in the MHC. Associations with various complement component deficiencies and an allele of a particular Fc gamma receptor gene (FCGR2A) also have been described. In a diversion from previous association studies, a recent directed linkage analysis of sibpairs with SLE was based on mapping studies in murine lupus and may be an important step toward identifying a new disease-susceptibility gene in patients. Since the genes that predispose to autoimmunity are probably related to key events in pathogenesis, their identification in patients and murine models will almost certainly provide important insight into the breakdown of immunological self-tolerance and the cause of autoimmune disease.
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PMID:Genetic susceptibility to systemic lupus erythematosus. 959 31

Human autoimmune diseases are thought to develop through a complex combination of genetic and environmental factors. Genome-wide linkage searches of autoimmune and inflammatory/immune disorders have identified a large number of non-major histocompatibility complex loci that collectively contribute to disease susceptibility. A comparison was made of the linkage results from 23 published autoimmune or immune-mediated disease genome-wide scans. Human diseases included multiple sclerosis, Crohn's disease, familial psoriasis, asthma, and type-I diabetes (IDDM). Experimental animal disease studies included murine experimental autoimmune encephalomyelitis, rat inflammatory arthritis, rat and murine IDDM, histamine sensitization, immunity to exogenous antigens, and murine lupus (systemic lupus erythematosus; SLE). A majority (approximately 65%) of the human positive linkages map nonrandomly into 18 distinct clusters. Overlapping of susceptibility loci occurs between different human immune diseases and by comparing conserved regions with experimental autoimmune/immune disease models. This nonrandom clustering supports a hypothesis that, in some cases, clinically distinct autoimmune diseases may be controlled by a common set of susceptibility genes.
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PMID:Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. 970 86

Genome-scale analysis in type 1 diabetes has resulted in a number of non-major histocompatibility complex loci of varying levels of statistical significance. In no case has a specific gene been proven to be the source of genetic linkage at any candidate locus. Comparative analysis of the position of loci for type 1 diabetes with candidate loci from other autoimmune/inflammatory diseases shows considerable overlap. This supports a hypothesis that the underlying genetic susceptibility to type 1 diabetes may be shared with other clinically distinct autoimmune diseases such as systemic lupus erythemastosus, multiple sclerosis, and Crohn's Disease.
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PMID:Comparative genetics of type 1 diabetes and autoimmune disease: common loci, common pathways? 1038 38

Studies in both humans and in animal models of specific disorders suggest that polymorphisms of multiple genes are involved in conferring either a predisposition to or protection from autoimmune diseases. Genes encoding polymorphic proteins that regulate immune responses or the rates and extent of metabolism of certain chemical structures have been the focus of much of the research regarding genetic susceptibility. We examine the type and strength of evidence concerning genetic factors and disease etiology, drawing examples from a number of autoimmune diseases. Twin studies of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type I diabetes, and multiple sclerosis (MS) indicate that disease concordance in monozygotic twins is 4 or more times higher than in dizygotic twins. Strong familial associations (odds ratio ranging from 5-10) are seen in studies of MS, type I diabetes, Graves disease, discoid lupus, and SLE. Familial association studies have also reported an increased risk of several systemic autoimmune diseases among relatives of patients with a systemic autoimmune disease. This association may reflect a common etiologic pathway with shared genetic or environmental influences among these diseases. Recent genomewide searches in RA, SLE, and MS provide evidence for multiple susceptibility genes involving major histocompatibility complex (MHC) and non-MHC loci; there is also evidence that many autoimmune diseases share a common set of susceptibility genes. The multifactorial nature of the genetic risk factors and the low penetrance of disease underscore the potential influence of environmental factors and gene-environment interactions on the etiology of autoimmune diseases.
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PMID:The role of genetic factors in autoimmune disease: implications for environmental research. 1050 33

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL/lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl(2)-induced exacerbation of autoimmunity. Such genetic predisposition may have to be considered when assessing the immunotoxicity of xenobiotics. Additional comparative studies using autoimmune-prone and nonautoimmune mice strains with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations susceptible to autoimmune diseases.
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PMID:Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity. 1050 38

With donor and recipient matched at the major histocompatibility complex (MHC) locus, peripheral lymphoid tissue transplantation can be carried out without producing a graft-versus-host reaction or graft-versus-host disease (GVHD), thus correcting profound T cell immunodeficiencies of neonatally thymectomized mice. This analysis set the stage for clinical application of bone marrow transplantation (BMT) to provide for the first time cure of a human disease. With successful BMT, we cured immunologic deficiencies of a patient with XL severe combined immunodeficiency; thereafter we were the first to employ BMT to cure aplastic anemia. BMT regularly corrects immune and hematologic deficiencies caused by fatal irradiation without producing GVHD if the bone marrow (BM) used for the transplants has been purged of postthymic T cells. Over two decades in conjunction with Ikehara et al., we have shown that lethal total body irradiation (TBI) plus allogeneic BMT prevents or cures many organ-specific and systemic experimental autoimmune diseases. Animal models successfully treated by BMT include type I diabetes in nonobese diabetes (NOD) mice, type II diabetes in insulin-insensitive, glucose intolerant, diabetes mellitus (KK/Ay) mice, and autoimmune lupus erythematosus (LE) and glomerulonephritis in New Zealand Black x New Zealand White first generation hybrid (NZB x NZW)F1 females. El-Badri extended Ildstad's original research showing a high frequency of survival with a normal functioning immune system after stable mixed chimerism is produced by mixed BMT in C57BL/6 (normal long-lived black strain) mice transplanted with T cell-depleted marrow (TCDM) from BALB/c ("normal" long-lived strain) allogeneic donors and C57BL/6 syngeneic donors. We showed that osteoblasts act as facilitator cells for allogeneic BMT and promote engraftment of allogeneic hematopoietic stem cells. Wang et al. then showed that the autoimmunities and fulminating renal disease of BXSB (C57BL x SB cross and selective lupus-like systemic autoimmunity) male mice was prevented and could be cured by transplantation using TCDM from both BALB/c (resistant) and BXSB (susceptible) strains given to BXSB recipients after lethal TBI. This treatment produced mixed BMT and a stable mixed chimerism, increased longevity, corrected all manifestations of autoimmunity, and cured fulminant glomerulonephritis in these recipients. These studies generated a new perspective on the potential usefulness of BM and stem cell transplants to cure major diseases that can possibly be treated by BMT. Mixed BMT from TCD BALB/c and BXSB mice cured autoimmunities and fulminant glomerulonephritis in BXSB mice. LE disease plus coronary vascular disease that occurs in (NZW x BXSB)F1 mice, along with idiopathic thrombocytopenic purpura, is also cured in lethally irradiated (NZW x BXSB)F1 mice by BMT from C57BL/6 donors. Furthermore, hemolytic anemia, autoimmune phenomena, and hyalinizing glomerular renal disease of New Zealand Black (NZB) mice were prevented or cured by stem cell transplants using purified stem cells from MHC-matched DBA/2 donors or NZB donors. Consequently, we reasoned that autoimmunities reside in stem cells. More recently, we found that transplants of both BM cells and bones can completely and permanently prevent otherwise highly resistant autoimmune diseases of MRL/lpr lpr mice and an autoimmune polyarthritis of NZB/Kn mice. Ildstad concluded that lethal preparative measures would not be acceptable for preparations to treat autoimmune diseases, so we now employ a gentle method for producing stable mixed chimerism described by Sharabi and Sachs to achieve mixed marrow transplantation and mixed hematopoietic chimerism. Other diseases we are approaching using this gentle manipulation include two forms of diabetes: insulin-dependent diabetes mellitus (IDDM) type I in NOD mice and non-insulin-dependent diabetes mellitus (NIDDM) type II in KK/Ay mice, atherosclerosis of apolipoprotein-E + kno
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PMID:Progress toward production of immunologic tolerance with no or minimal toxic immunosuppression for prevention of immunodeficiency and autoimmune diseases. 1083 46

The drug-metabolizing capacity of the liver is well known but cannot account for most idiosyncratic adverse drug reactions. Of the extrahepatic sources of reactive drug metabolites, the neutrophil has received the most attention because of its vast numbers and robust oxidizing machinery. Many drugs associated with autoimmunity are susceptible to oxidative transformation by the enzymatic action of myeloperoxidase, a protein released into the extracellular environment when neutrophils are activated. Production of the resulting drug metabolites within lymphoid organs maximizes their immune-perturbing effects. Mechanisms proposed for the initiation of drug-induced blood dyscrasias, hypersensitivity reactions, or lupus-like symptoms center around three views: (1) presentation of the implicated compound in the major histocompatibility complex of antigen-presenting cells via direct binding or after processing as a hapten bound to self-macromolecules, (2) direct cytotoxicity, or (3) interference in the development of T-cell tolerance in the thymus. How participation of reactive drug metabolites in these processes might lead to symptomatic disease is discussed.
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PMID:Phagocyte-mediated oxidation in idiosyncratic adverse drug reactions. 1113 24

The New Zealand white (NZW) H2(z) locus is strongly associated with the development of autoimmune disease in (NZB x NZW)F(1) mice, a model of systemic lupus erythematosus. To better understand the role of H2(z) in autoimmunity, we generated CD4(+) T cell hybridomas from the spleen and lymph nodes of unimmunized (NZB x NZW)F(1) mice and characterized their specificity. We found that over 50% of the hybridomas responded to syngeneic (H2(d/z)) spleen cells in the absence of exogenous antigen. Many of these autoreactive hybridomas responded to spleen cells expressing H2(z) and used H2(z) class II (I-A(z) or I-E(z)) molecules for presentation. Interestingly, nearly one third of the H2(z)-reactive hybridomas could not respond to spleen cells expressing only H2(z) class II molecules. These studies characterize a frequent population of autoreactive CD4(+) T cells in lupus mice and indicate that major histocompatibility complex molecules in addition to class II may be important for this self-recognition.
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PMID:Characterization of CD4(+) T cell autoreactivity to self-MHC in New Zealand hybrid mice. 1114 31

Recent evidence suggests that polymorphic light eruption (PLE) is an inherited photosensitivity disorder which may predispose to cutaneous lupus erythematosus (LE). In this study we examine the relative risk (RR) attributable to the presence of PLE, together with the effect of the major histocompatibility complex (MHC) in the development of cutaneous LE. Eighty-five Caucasian patients with annular subacute cutaneous LE (SCLE) and discoid LE (DLE) were recruited, together with 102 first degree relatives and 200 healthy local Caucasian controls. Symptoms suggestive of PLE were elicited in patients and relatives, and human leukocyte antigen (HLA) typing determined by PCR-SSP. Standard association analysis and family transmission disequilibrium testing (TDT) were then used to compare the HLA frequencies between groups. We found a significant (P < 0.05) association of the HL4 A*01, B*08, DRB1*0301 extended haplotype with both SCLE and DLE and also significant association of DLE with the HLA A*03, B*07, DRB1*15 haplotype, with a possible protective effect in SCLE for HLA B*44 and DRB1*04 (P=0.002 and 0.001 respectively). Association was observed between PLE and cutaneous LE (P < 0.001), but not between PLE and any HLA allele. From these figures we estimate, for the general population, that the RR of developing SCLE given the presence of (a) PLE, (b) DRB1*0301 and (c) both PLE and DRB1*0301 is 3.37, 5.45 and 12.03, respectively. For DLE, equivalent RRs are 3.11, 2.15 and 6.94. In conclusion, these data imply the involvement of both PLE and HLA DRB1*0301 in the development of SCLE and DLE. They form a basis for examining the genetic architecture of photosensitivity, some aspects of which may be common to both cutaneous LE and PLE.
Lupus 2001
PMID:Polymorphic light eruption and the HLA DRB1*0301 extended haplotype are independent risk factors for cutaneous lupus erythematosus. 1148 Aug 44


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