The Clinical Presentation of Systemic Lupus Erythematosus

Lahita, Robert G.

doi:10.1016/b978-012433901-9/50019-3

Cited by 35 publications

(54 citation statements)

References 101 publications

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“…Paradoxically, although some symptoms may arise from AAb reactivity to dsDNA, much AAbmediated damage originates from cross-reactivity to other selfantigens (2). Clinical studies indicate that 40-50% of SLE patients carry AAbs that cross-react with dsDNA and NMDA receptors (NMDARs) (8)(9)(10)(11)(12)(13)(14).…”

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confidence: 99%

“…autoimmunity | mitochondrial stress | neuropsychiatric lupus | NMDA receptor S ystemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects ∼0.2% of the world's population, with up to 90% of the cases occurring in women of childbearing age (1,2). The symptoms of SLE include arthritis, immunologic abnormalities, blood disorders, serositis, malar rashes, renal damage, skin rashes, and neurological disorders (3,4).…”

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confidence: 99%

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Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms

Faust

Chang

Kowal

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

191

171

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Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise from direct reactivity to dsDNA, much of the AAb-mediated damage originates from crossreactivity with other antigens. We have studied lupus AAbs that bind dsDNA and cross-react with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In adult mouse models, when the bloodbrain barrier is compromised, these NMDAR-reactive AAbs access the brain and elicit neuronal death with ensuing cognitive dysfunction and emotional disturbance. The cellular mechanisms that underlie these deleterious effects remain incompletely understood. Here, we show that, at low concentration, the NMDAR-reactive AAbs are positive modulators of receptor function that increase the size of NMDAR-mediated excitatory postsynaptic potentials, whereas at high concentration, the AAbs promote excitotoxicity through enhanced mitochondrial permeability transition. Other synaptic receptors are completely unaffected by the AAbs. NMDAR activation is required for producing both the synaptic and the mitochondrial effects. Our study thus reveals the mechanisms by which NMDAR-reactive AAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with SLE. Our study also provides a model in which local AAb concentration determines the exact nature of the cellular response.autoimmunity | mitochondrial stress | neuropsychiatric lupus | NMDA receptor

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mentioning

confidence: 99%

mentioning

confidence: 99%

Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms

Faust

Chang

Kowal

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

191

171

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“…S ystemic lupus erythematosus is an autoimmune disease with immune complex-mediated glomerulonephritis as a major manifestation and determinant of the disease outcome (1). The MRL/lpr mouse carries a mutation in the apoptosis-related Fas gene, resulting in autoreactive lymphocyte proliferation, and is considered as a mouse model that closely mimics the human disease with lymphadenopathy; splenomegaly; hypergammaglobulinemia with anti-dsDNA antibodies that lead to tissue deposition; and injury in various organs, including lung and kidney (2,3).…”

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confidence: 99%

Chemokine Receptor Ccr2 Deficiency Reduces Renal Disease and Prolongs Survival in MRL/lpr Lupus-Prone Mice

Lema

Maier²,

Franz³

et al. 2005

Journal of the American Society of Nephrology

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MRL/MpJ-Faslpr /J (MRL/lpr) mice represent a well-established mouse model of human systemic lupus erythematosus. MRL/lpr mice homozygous for the spontaneous lymphoproliferation mutation (lpr) are characterized by systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, splenomegaly, hypergammaglobulinemia, arthritis, and fatal immune complex-mediated glomerulonephritis. It was reported previously that steady-state mRNA levels for the chemokine (C-C motif) receptor 2 (Ccr2) continuously increase in kidneys of MRL/lpr mice. For examining the role of Ccr2 for development and progression of immune complex-mediated glomerulonephritis, Ccr2-deficient mice were generated and backcrossed onto the MRL/lpr genetic background. Ccr2-deficient MRL/lpr mice developed less lymphadenopathy, had less proteinuria, had reduced lesion scores, and had less infiltration by T cells and macrophages in the glomerular and tubulointerstitial compartment. Ccr2-deficient MRL/lpr mice survived significantly longer than MRL/lpr wild-type mice despite similar levels of circulating immunoglobulins and comparable immune complex depositions in the glomeruli of both groups. Anti-dsDNA antibody levels, however, were reduced in the absence of Ccr2. The frequency of CD8 ؉ T cells in peripheral blood was significantly lower in Ccr2-deficient MRL/lpr mice. Thus Ccr2 deficiency influenced not only monocyte/ macrophage and T cell infiltration in the kidney but also the systemic T cell response in MRL/lpr mice. These data suggest an important role for Ccr2 both in the general development of autoimmunity and in the renal involvement of the lupus-like disease. These results identify Ccr2 as an additional possible target for the treatment of lupus nephritis.

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“…Of particular interest to our group is the diagnosis of two auto-immune disorders, systemic lupus erythematosus (SLE) and Sjogren's Syndrome (SS). In SLE, auto-immune antibodies attack the host's tissue, causing inflammation, damage and pain in joints, kidneys, lungs, heart, blood vessels, the brain, the nervous system and skin [11] . In SS, autoantibodies and immune system cells, called lymphocytes, attack the exocrine glands that produce tears, saliva and sweat, ultimately destroying the glandular tissue [12] .…”

Section: Introductionmentioning

confidence: 99%

Porous silicon biosensor for the detection of autoimmune diseases

Jane

Szili

Reed

et al. 2007

BioMEMS and Nanotechnology III

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Advances in porous silicon (pSi) technology have led to the development of new sensitive biosensors. The unique optical properties of pSi renders the material a perfect candidate for optical transducers exploiting photoluminescence or white light interference effects. The ability of biosensors exploiting these transduction mechanisms to quickly and accurately detect biological target molecules affords an alternative to current bioassays such as enzyme-linked immunosorbent assays (ELISAs). Here, we present a pSi biosensor that was developed to detect antibodies against the autoimmune protein La. This protein is associated with autoimmune diseases including rheumatic disorders, systematic lupus erythematosus (SLE) and Sjogren's syndrome (SS). A fast and sensitive detection platform such as the one described here can be applied to the rapid diagnosis of these debilitating autoimmune diseases. The immobilisation of the La protein onto pSi films gave a protein receptor-decorated sensor matrix. A cascade of immunological reactions was then initiated to detect anti-La antibody on the functionalised pSi surface. In the presence of o-phenylenediamine (OPD), horseradish peroxidase (HRP)/H 2 O 2 catalysed the formation of an oxidised radical species that accelerated pSi corrosion. pSi corrosion was detected as a blue-shift in the generated interference pattern, corresponding to a decrease in the effective optical thickness (EOT) of the pSi film. Compared to an ELISA, the pSi biosensor could detect the anti-La antibody at a similar concentration (500 -125 ng/ml). Furthermore, we found that the experimental process can be significantly shortened resulting in detection of the anti-La antibody in 80 minutes compared to a minimum of 5 hours required for ELISA.

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The Clinical Presentation of Systemic Lupus Erythematosus

Cited by 35 publications

References 101 publications

Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms

Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms

Chemokine Receptor Ccr2 Deficiency Reduces Renal Disease and Prolongs Survival in MRL/lpr Lupus-Prone Mice

Porous silicon biosensor for the detection of autoimmune diseases

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