Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several trends become evident from the foregoing discussion. As the different ANA antigenic specificities have been identified, they have often been found to be highly conserved polypeptides that subserve very basic cellular functions that are carried out in the nucleus, nucleolus, and ribosomes. The reasons why only 30 or so basic cellular proteins become the targets of an autoimmune response in patients with connective tissue disease at the exclusions of the other 10,000 macromolecules that exist inside cells remain a mystery. However, some insight into this enigma might be provided by the mechanism of molecular mimicry (Table 9). The possibility that highly conserved immunogenic molecules that are expressed by infectious pathogens can trigger an immune response in a genetically predisposed human host that cross-reacts with cellular autoantigens is a well documented phenomenon in disorders such as rheumatic fever. This mechanism is now being mentioned with increasing frequency in discussions pertaining to the pathogenesis of autoimmune connective tissue diseases. Another trend relates to the increasing sensitivity of the newer assays that have been developed to detect ANA. When highly purified or recombinant autoantigens are used in versatile assays such as ELISA, radioimmunoassays, or immunoprecipitation, the frequency with which certain autoantibodies can be detected in patient subgroups can go up significantly. For example, with classical immunodiffusion, anti-Ro/SS-A antibodies can be detected in 25% of unselected patients with SLE, whereas with an ELISA based on affinity purified Ro/SS-A antigen, 50% of patients with SLE are found to have elevated levels of this autoantibody specificity. As is often the case, we pay for increased sensitivity in a laboratory test with decreased specificity. With immunodiffusion, virtually no normal individuals have anti-Ro/SS-A antibodies, but with the ELISA as many as 10% of normals have elevated anti-Ro/SS-A binding levels. Thus, the incremental diagnostic value of this newer anti-Ro/SS-A assay could be questioned. The true clinical value of this new laboratory technology will become more evident when these more sophisticated ANA assays are used together in a panel-like fashion to profile a given patient's autoimmune response at the very onset of his illness. Preliminary work has already begun in this area. This approach, if well standardized, could have significant diagnostic and prognostic value. Another benefit of this newer technology will be the ability to measure antibody binding levels to individual autoepitopes--limited portions of an autoantigen's amino acid sequence that represent single antibody binding sites. It is possible that certain patterns of clinical disease could be linked to autoantibody production against individual autoepitopes rather than whole autoantigenic molecules. This area is only now beginning to be explored.
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PMID:Antinuclear antibodies: clinical correlations and biologic significance. 137 Dec 22

Pancreatitis in SLE remains an enigma and probably results from multiple pathogenetic mechanisms. However, cases of pancreatic thrombus formation remain few and far between, suggesting that APS is not the major cause of pancreatitis. Whether aPL contribute to pancreatic thrombus formation in rare patients needs to be demonstrated by antemortum arteriographic studies showing thrombus or vasculopathy. The postmortem pancreatic examination of patients who have died of the disseminated vasculopathy-coagulopathy syndrome remains problematic, because if thrombi are found, they may simply represent the endstage of multiple mechanisms, including hypotension, hypoxia, DIC, or TTP, rather than an aPL specific mechanism.
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PMID:Pancreatitis in systemic lupus erythematosus: still in search of a mechanism. 151 54

Despite intensive research, autoimmune-disease pathogenesis is still an enigma, but in the past decade Ts-cell defects have assumed a central role in this pathogenesis. Ts-cell dysfunctions have been reported in numerous autoimmune diseases (e.g. SLE, autoimmune thyroid disease, myasthenia gravis) and in animal models of autoimmune diseases. Therefore, it is currently believed that Ts cells are responsible for maintaining self-tolerance and that perturbations in suppressor functions may initiate development of autoimmune diseases. Ts-cell abnormalities can result from LCTA production, intrinsic biochemical alterations, genetic susceptibility, or environmental factors. Since Ts-cells dysfunctions are believed to initiate autoimmunity, it may be possible to treat autoimmune diseases by correcting the suppressor defects, and indeed, preliminary trials in this direction are promising.
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PMID:The significance of T suppressor cells in the development of autoimmunity. 257 8

Both maternal isoimmunization and maternal autoimmune disease are associated with fetal death. For isoimmunization the immunologic nature of fetal death (hydrops fetalis) is beyond question, but many of the details are poorly understood. It would be extremely helpful to know what immunologic factors are responsible for the wide variation in the degree of fetal hemolysis. This information would surely lead to improved management of isoimmunized pregnancies and create new and more successful therapies for fetuses at risk for hemolysis. The immunology of autoimmune-associated fetal death is, for the most part, an enigma. For the fetal deaths associated with SLE and the antiphospholipid antibodies, demise appears to be a consequence of uteroplacental vascular damage. But the observable pathology is nonspecific, and the evidence for a direct immunologic mechanism is sparse. The similarity between the uteroplacental vascular lesions found with these autoimmune conditions and those seen in preeclampsia demands more intensive investigation. For the fetal deaths caused by complete congenital heart block associated with maternal autoantibodies, the evidence for a direct immunologic mechanism is now being established. As with isoimmunization, a more complete understanding of autoimmune-associated fetal death will open new avenues of management and therapy.
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PMID:Immunologic disease and fetal death. 311 69

Students of systemic lupus erythematosus have long been confused by the paradoxical association of atypical clinical features such as recurrent thrombosis and spontaneous abortion with the lupus anticoagulant and biologic false-positive VDRL reaction. The recent development of sensitive, solid-phase immunoassays for quantitating the autoantibody response to phospholipids holds the promise of illuminating the basis for this seeming enigma. It is now apparent that antiphospholipids antibodies such as anticardiolipin might well play a role in mediating the elements of this paradox. In addition, other cutaneous vascular conditions as diverse as livedo reticularis and Degos' disease might also be related to this type of autoimmune response.
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PMID:The anticardiolipin syndrome. A new way to slice an old pie, or a new pie to slice? 355 50

The pathogenesis of the neuropsychiatric manifestations of systemic lupus erythematosus (SLE) remains an enigma. The observation that many of the lymphocytotoxic antibodies in SLE are also brain-reactive has led to the hypothesis that central nervous system (CNS) lupus, like the autoimmune hematologic manifestations of SLE, is due to the direct effects of autoantibodies to cell membrane antigens. Studies of neuron-reactive antibodies in SLE sera and cerebrospinal fluid support that hypothesis and suggest that the diffuse neuropsychiatric manifestations require the co-existence of serum antibodies to nerve cells and an alteration in the blood-brain barrier that allows those antibodies to enter the CNS.
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PMID:Antibodies reactive with central nervous system antigens. 613 71

It is becoming well accepted that innate immunity serves as a natural adjuvant in enhancing and directing the adaptive immune response. In this review, I have discussed how the complement system, a major mediator of innate immunity, links the two systems. The recent availability of knockout mice bearing selective deficiencies in the critical complement proteins and receptors has allowed formal demonstration of the importance of complement in enhancement of humoral immunity. Characterization of the mice has also uncovered mechanisms for maintaining survival of activated B cells within the lymphoid compartment. For example, co-ligation of the CD21/CD19/Tapa-1 receptor with the BCR not only reduces the threshold for B cell follicular survival but provides a unique signal for survival in the germinal centers. In addition complement receptors are critical for localization of antigen and C3d ligand to FDCs for maintenance of long-term B cell memory. A surprise that has come from analysis of the deficient mice is that complement is also important in negative selection of B lymphocytes. This observation provides new insight to a long-standing enigma that the major predisposing factor in lupus is deficiency in complement C1q or C4. The seeming contradiction of dual role for complement in both B cell activation and tolerance is reconciled by the hypothesis that natural IgM provides a mechanism to selectively identify self-antigens that are highly conserved and cross-react with microbial ones such as DNA and nuclear proteins. Thus, the importance of complement in tolerance to self-antigens is restricted to those self-antigens that are evolutionary conserved, and they are identified by natural antibody. The future should hold further surprises as to the intricate interactions between the complement system and acquired immunity.
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PMID:The role of complement in B cell activation and tolerance. 1060 4

The pathogenesis of autoimmune disease is still an enigma. Whereas the diverse clinical manifestations of many autoimmune diseases cannot be explained by the existence of autoantibodies, idiotypic dysregulation may provide an alternative explanation. Experimental models, serum level changes of pathogenic idiotypes during exacerbation and remission, and the increased expression of pathogenic idiotypes following common infections all support this notion. In this article we review experimental models of autoimmune disease induction (systemic lupus erythematosus, antiphospholipid syndrome, Goodpasture's syndrome, autoimmune thyroiditis, and vasculitis) by manipulation of the idiotypic network, and discuss the utilization of idiotypes for the immunotherapy of autoimmune diseases and other conditions that involve the immune system (e.g., atherosclerosis).
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PMID:Idiotypic network dysregulation: a common etiopathogenesis of diverse autoimmune diseases. 1082 56

The etiopathogenesis of systemic lupus erythematosus remains an enigma that will probably not be solved until the genetic basis for susceptibility is defined. Through genomewide searches, we have provided a foundation for this by identifying and characterizing loci predisposing to specific disease traits in four major lupus-susceptible mouse strains. Further ongoing work that includes the study of interval-specific congenic lines and precise mapping of loci should lead to identification of the corresponding genes and elucidation of processes critical for disease pathogenesis. Another important area of investigation is the study of cell-cycle and apoptosis genes in systemic autoimmunity and aging. Based on earlier work, we proposed that the characteristic overexpansion of memory phenotype cells in these conditions may be owing to replicative senescence. Understanding the molecular mechanisms that regulate the generation of these cells may permit selective manipulations to control this process. Other areas of investigation that we are actively engaged in are the role of T cell receptor repertoire in disease and the definition of cellular genes affected by infection with human immunodeficiency virus.
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PMID:Genetic studies in systemic autoimmunity and aging. 1085 8

The etiologic enigma of systemic lupus erythematosus (SLE) has so far precluded a fully integrated approach to understanding and managing the disease. As new findings continue to uncover relationships between the endocrine system and the besieged immune system in lupus patients, however, researchers have an opportunity to rethink the direction of their investigative efforts. A successful approach to development of long-awaited new treatments may well include modulation of specific hormones. The peptide hormone prolactin may be associated with SLE disease activity. The dopamine agonist bromocriptine, which inhibits pituitary secretion of prolactin, has been shown in a variety of small animal and human trials to reduce disease activity in SLE. Continued research may show that it can be an attractive alternative or adjacent therapy in cases where hydroxychloroquine is contraindicated.
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PMID:Modulation of hormones in the treatment of lupus. 1168 Jul 80


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