Ultrastructural Localization of the Membrane Attack Complex of Complement in Human Renal Tissues

Falk, Ronald J.; Sisson, Susan; Dalmasso, Agustin P.; Kim, Youngki; Michael, Alfred F.; Vernier, Robert L.

doi:10.1016/s0272-6386(87)80089-6

Cited by 72 publications

(110 citation statements)

References 23 publications

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“…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.…”

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confidence: 58%

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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: Resultssupporting

confidence: 58%

supporting

confidence: 58%

Glycation Inactivation of the Complement Regulatory Protein CD59

et al. 2004

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“…This is no surprising result, since a strong interaction of Vn and collagen type-4 in vitro is well known (Gebb et al, 1986). Furthermore, a colocalisation of both proteins is known in the bm of the kidney tubulus and of vascular bm's (Falk et al, 1987;Sawa et al, 1993). The presence of Vn within the bm and the expression of uPAR in MEs of both DCIS and normal breast glands suggests an important cell -matrix interaction, which regulates the cell adhesion and detachment.…”

Section: Discussionmentioning

confidence: 99%

Protein and mRNA expression of uPAR and PAI-1 in myoepithelial cells of early breast cancer lesions and normal breast tissue

Hildenbrand

Arens

2004

Br J Cancer

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Myoepithelial cells (MEs), which surround ducts and acini of the breast glands, exhibit an anti-invasive phenotype and form a natural border separating proliferating tumour cells of ductal carcinoma in situ (DCIS) from basement membrane (bm) and underlying stroma. Invasion requires penetration of these host cellular and extracellular matrix barriers. This destruction is caused by proteolytic activity of tumour cells and host bystander cells. There is substantial evidence that high concentrations of the urokinase plasminogenactivating system are conducive to tumour cell spread and metastasis. Prompted by the conspicuous absence of studies examining the role of the ME in breast cancer progression, we studied the expression of the urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor type-1 (PAI-1) in MEs of 60 DCIS samples. Our results show that nearly all MEs of DCIS and normal breast glands exhibit the uPAR antigen, whereas the PAI-1 antigen was mainly expressed in MEs of high-grade DCIS. In one intermediate DCIS numerous ducts showed an incomplete myoepithelial layer expressing uPAR and PAI-1. We conclude that uPAR in MEs may be necessary to attach them to the bm by uPAR/vitronectin (Vn) interaction. The strong expression of PAI-1, which is known to resolve the uPAR/Vn binding, may be involved in the detachment of MEs of DCIS. Although the role of PAI-1 acting as cell detachment factor could not be demonstrated in our study, we speculate that the loss of the anti-invasive ME layer in DCIS may be triggered by PAI-1 and could be an early sign of subsequent tumour cell infiltration.

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“…clusierin und S-protein) (all P<OOOOI), although MAC was often detected in ihe absence of inhibitors (McNemar /-P<00001), These relations were further investigated after separating the biopsies into two groups, those with or wit hoy I immunogiobulin deposits. Tbe concordance between immunoglobulin and MAC deposits was poor (Ar<0-04) since in many cases C9 was found in the absence of immunoglobulin deposits, as described by others [3][4][5]. By contrast the concordance of immunoglobulin versus clusterin and S-protciii deposits was fair to good (A^=0-50 and Ar=05I, respectively).…”

Section: Resultsmentioning

confidence: 77%

Clusterin in renal tissue: preferential localization with the terminal complement complex and immunoglobulin deposits in glomeruli

French

Tschopp

Schifferli

1992

Clinical and Experimental Immunology

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SUMMARYThe membrane attack complex (MAC) of complement is aclivatcd by imtiiune and non-immune mechanisms in the kidney. MAC has been found associaled wilh glomerular immune deposits, hut also lo cell remnants, particularly along tubu!es and in vessel walls. Clusicrin and S-prolein (vitronectin) bind to MAC. rendering it cytolylically inactive. Both have been found associated with MAC in renal tissue. Here we analysed the deposition of clusterin and S-protein in 118 renal biopsies relative to the localization of the MAC using MoAbs. Statistical analysis was performed comparing no or little versus evident or strong staining by immuofluorescence (IF), in gtomeruli. out of the 92 biopsies where both MAC and immunoglobulins were evaluated, deposits of MAC were found in the presence {32 out of 41) but also in the absence of immunoglobulins (20/51). Clusterin and S-protein deposits were seen, respectively, in 25 out of 61 and 36 out of 61 biopsies containing glomerular MAC and almost never in its absence (one out of 50 for both). The association of (he two inhibitors with MAC was observed mainly in glomeruli containing immunoglobulin deposits (respectively. 21 out of32 and 25 out of 32), but not when immunoglobulins were absent (three out of 20 and seven out of 20) (coefficient of concordance. A' = 0-47 and 0-43). The localization of MAC along tubules and in vessels was easily identified in most biopsies (93 out of 118) and was accompaied by S-protein in most cases (tubules, 86 out of 93; vessels. 82 out of 93) (A'=0 58 and 057 respectively) but not by clusterin (28 out of 93 and 24 out of 93). These results suggest that clusterin does not co-localize with MAC whenever there is formation and fixation ofthe MAC. It seems that clusterin has a particular affinity for MAC which is associated with immunoglobulin. This observation should help to distinguish between the different forms of MAC. and might indicate that MAC associated with immunoglobulin is essentially in its cytolylically inactive form.

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Ultrastructural Localization of the Membrane Attack Complex of Complement in Human Renal Tissues

Cited by 72 publications

References 23 publications

Glycation Inactivation of the Complement Regulatory Protein CD59

Glycation Inactivation of the Complement Regulatory Protein CD59

Protein and mRNA expression of uPAR and PAI-1 in myoepithelial cells of early breast cancer lesions and normal breast tissue

Clusterin in renal tissue: preferential localization with the terminal complement complex and immunoglobulin deposits in glomeruli

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