Local activation of the complement system in endoneurial microvessels of diabetic neuropathy

Rosoklija, Gorazd; Dwork, Andrew J.; Younger, David S.; Karlikaya, G.; Latov, Norman; Hays, Arthur P.

doi:10.1007/pl00007406

Cited by 47 publications

(36 citation statements)

References 38 publications

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“…5). Together, the results of this work indicate that glycation inactivates hCD59 in diabetic subjects and provide a probable molecular explanation for the reported findings of increased MAC deposition in diabetic kidneys (22), nerves (23), and retinas (24). These findings support the hypothesis that the increased complement deposition in diabetic tissues as a result of the glycation inactivation of hCD59 plays a role in the high sensitivity of humans to develop diabetic vascular complications.…”

Section: Discussionsupporting

confidence: 81%

“…If glycation of hCD59 as a consequence of hyperglycemia in diabetes were to limit similarly its function in vivo, then one would expect increased MAC deposition in diabetic tissues. This prediction has been confirmed by several studies that demonstrated MAC deposition in kidneys (22), nerves (23), and retinas (24) of diabetic patients with minimal or no MAC deposits in the same tissues from nondiabetic individuals. However, the mechanism underlying this reported MAC deposition in diabetic tissues is still poorly understood.…”

Section: Resultssupporting

confidence: 58%

“…On the basis of these findings, we proposed that glycation inactivation of hCD59 in diabetes could increase MAC deposition in diabetic tissues and link the complement system to the pathogenesis of diabetic vascular complications. The previously reported findings of increased MAC deposition in diabetic kidneys (22), nerves (23), and retinas (24) are consistent with this hypothesis, but the mechanism that induces MAC deposition in diabetic tissues has not been investigated in humans. Here, we report an immunocytochemistry study in human diabetic and nondiabetic kidney and nerve biopsy samples showing the presence of glycated hCD59 colocalized with MAC in diabetic but not in nondiabetic tissues.…”

supporting

confidence: 59%

“…Table 1 summarizes the renal function and pathological records of 12 of the 13 patients with diabetic nephropathy. Nerve biopsies, provided by Dr. A. Hayes (Columbia-Presbyterian, New York, NY), were the same samples reported previously (23). All samples were obtained with approval by the institutional review boards of the respective institutions.…”

Section: Methodsmentioning

confidence: 99%

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Glycation Inactivation of the Complement Regulatory Protein CD59

et al. 2004

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Micro-and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes. Diabetes 53: [2653][2654][2655][2656][2657][2658][2659][2660][2661] 2004

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Section: Discussionsupporting

confidence: 81%

Section: Resultssupporting

confidence: 58%

supporting

confidence: 59%

Section: Methodsmentioning

confidence: 99%

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Glycation Inactivation of the Complement Regulatory Protein CD59

et al. 2004

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“…Clinical observations of endoneurial mononuclear infiltrates in peripheral nerves of diabetic neuropathic patients (Said et al 1994) and clinical improvement of diabetic neuropathy with immune-modulating therapies (Krendel et al 1995) have raised the possibility of an immune component to this disorder. As additional evidence from in vitro studies emerges (Milicevic et al 1997;Shigeta et al 1997;Rosoklija et al 2000), an antibody-mediated mechanism of nerve injury in diabetes mellitus merits further evaluation.…”

Section: Discussionmentioning

confidence: 99%

Antibodies to L‐periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits

Lawlor¹,

Richards

Vries

et al. 2002

Journal of Neurochemistry

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L-Periaxin is a PDZ-domain protein localized to the plasma membrane of myelinating Schwann cells and plays a key role in the stabilization of mature myelin in peripheral nerves. Mutations in L-periaxin have recently been described in some patients with demyelinating peripheral neuropathy, suggesting that disruption of L-periaxin function may result in nerve injury. In this study, we report the presence of autoantibodies to L-periaxin in sera from two of 12 patients with diabetes mellitus (type 2)-associated neuropathy and three of 17 patients with IgG monoclonal gammopathy of undetermined significance (MGUS) neuropathy, an autoimmune peripheral nerve disorder. By comparison, anti-L-periaxin antibodies were not present in sera from nine patients with IgM MGUS neuropathy or in sera from 10 healthy control subjects. The effect of anti-L-periaxin serum antibody on peripheral nerve function was tested in vivo by intraneural injection. Sera containing anti-L-periaxin antibody, but not sera from age-matched control subjects, injected into the endoneurium of rat sciatic nerve significantly (p < 0.005, n ¼ 3) attenuated sensory-evoked compound muscle action potential (CMAP) amplitudes in the absence of temporal dispersion. In contrast, motor-evoked CMAP amplitudes and latencies were not affected by intraneural injection of sera containing anti-L-periaxin antibody. Light and electron microscopy of anti-L-periaxin serum-injected nerves showed morphologic evidence of demyelination and axon enlargement. Depleting sera of anti-L-periaxin antibodies neutralized the serum-mediated effects on nerve function and nerve morphology. Together, these data support anti-L-periaxin antibody as the pathologic agent in these serum samples. We suggest that anti-L-periaxin antibodies, when present in sera of patients with IgG MGUS-or diabetesassociated peripheral neuropathy, may elicit sensory nerve conduction deficits. Keywords: antibody, diabetes, MGUS, neuropathy, periaxin. Peripheral neuropathies are a heterogeneous group of nerve disorders often characterized by a mixture of sensory and motor disturbances (Adams et al. 1997). Although the etiology of the peripheral neuropathy is often obscure, some patients exhibit strong familial histories consistent with an autosomal dominance, autosomal recessive, or X-linked pattern of inheritance. In other patients, the peripheral neuropathy is acquired such as in monoclonal gammopathy of undetermined significance (MGUS) neuropathy (Kyle 1992) or is secondary to a metabolic disturbance such as diabetes mellitus.Serum autoantibodies have been implicated as potential pathogenic agents in several autoimmune-mediated peripheral nerve disorders (Ho et al. 1998;Quarles and Weiss 1999). In addition, a role of autoimmunity in peripheral nerve disorders associated with metabolic disturbances, such as diabetic neuropathy, has been entertained (Said et al. 1994;Krendel et al. 1995). However, the antigenic specificities Abbreviations used: CMAP, compound muscle action potential; D/P, distal (ankle) to...

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A specific and sensitive assay for blood levels of glycated CD59: A novel biomarker for diabetes

et al. 2013

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Increasing evidence links the complement system with complications of human diabetes. The complement regulatory protein CD59, an inhibitor of formation of membrane attack complex (MAC), is inhibited by hyperglycemia-induced glycation fostering increased deposition of MAC, a major effector of complement-mediated tissue damage. CD59, an ubiquitous GPI-anchored membrane protein, is shed from cell membranes by phospholipases generating a soluble form present in blood and urine. Methods We established an ELISA to measure serum/plasma glycated hCD59 (GCD59) and evaluated its potential as a diabetes biomarker. We used a synthetic peptide strategy to generate a) a mouse monoclonal antibody to capture hCD59, b) a rabbit monoclonal antibody to detect GCD59, and c) a GCD59 surrogate for assay standardization. ELISA conditions were optimized for precision, reproducibility and clinical sensitivity. The clinical utility of the assay was initially evaluated in 24 subjects with or without diabetes and further validated in a study that included 100 subjects with and 90 subjects without a diagnosis of diabetes. Results GCD59 a) was significantly higher in individuals with than in individual without diabetes, b) was independently associated with HbA1c, and) identified individuals with diabetes with high specificity and sensitivity. Conclusions We report the development and standardization of a novel, sensitive, and specific ELISA for measuring GCD59 in blood. The assay distinguished individuals with diabetes from those without, and showed strong correlation between GCD59 and HbA1c. Because GCD59 likely contributes to the pathogenesis of diabetes complications, measurement of blood levels of GCD59 may be useful in the diagnosis and management of diabetes.

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Local activation of the complement system in endoneurial microvessels of diabetic neuropathy

Cited by 47 publications

References 38 publications

Glycation Inactivation of the Complement Regulatory Protein CD59

Glycation Inactivation of the Complement Regulatory Protein CD59

Antibodies to L‐periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits

A specific and sensitive assay for blood levels of glycated CD59: A novel biomarker for diabetes

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