Dysfunctional Properdin in a Dutch Family with Meningococcal Disease

Sjöholm, Anders G.; Kuijper, Ed J.; Tijssen, Cees; Jansz, A; Bol, P.; Spanjaard, Lodewijk; Zanen, H. C.

doi:10.1056/nejm198807073190106

Cited by 75 publications

(47 citation statements)

References 18 publications

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“…A previous report ( 11) described a twin with a partial (8% of normal levels) deficiency of factor D. Apparently the defect in the present case is inherited, since the mother shows half-normal levels of factor D. The factor D levels in the father, the sister and parents of the mother of the patient were within the normal range. This can be explained by an X-linked mode of inheritance, as has been described for properdin deficiency (10,28), in which the putative new mutation has occurred in the mother. Further studies are clearly required to support this suggestion.…”

Section: Discussionmentioning

confidence: 88%

Complete and partial deficiencies of complement factor D in a Dutch family.

Hiemstra¹,

Langeler²,

Compier³

et al. 1989

J. Clin. Invest.

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A young man suffering from recurrent Neisseria infections was shown to lack detectable serum complement factor D hemolytic activity. Addition to the patient's serum of purified factor D to a final concentration of 1 ;g/ml resulted in full restoration of the activity of the alternative pathway. Using an enzymelinked immunosorbent assay, it was shown that the patient's serum did not contain measurable amounts of factor D antigen either. The sister, the father, as well as the parents of the mother had factor D levels within the normal range, and the factor D level of the mother was decreased. The capacity of the patient's serum, at concentrations up to 5%, to promote phagocytosis of Escherichia coli by normal human granulocytes was low when compared to normal serum. Substitution of the patient's serum with purified factor D resulted in a full restoration of opsonic activity. This study describes the first complete deficiency of factor D, and demonstrates its possible relation to recurrent Neisseria infections.

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Section: Discussionmentioning

confidence: 88%

Complete and partial deficiencies of complement factor D in a Dutch family.

Hiemstra¹,

Langeler²,

Compier³

et al. 1989

J. Clin. Invest.

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“…We have shown that properdin can identify apoptotic T cells and facilitate their clearance. Although no published studies have examined clearance of apoptotic cells in these properdin-deficient individuals, and only isolated reports have suggested a possible relationship between properdin deficiency and autoimmune disease (32,33), other pathways can also promote the clearance of apoptotic cells (6) and so in some cases the lack of properdin may not preclude the safe clearance of apoptotic cells. We have also observed that properdin binds malignant T cell lines.…”

Section: Discussionmentioning

confidence: 99%

The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis

Kemper

Mitchell

Zhang

et al. 2008

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

139

170

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Apoptotic cells must be rapidly eliminated to avoid harmful inflammatory and autoimmune reactions. Innate immunity is designed/poised to identify dying cells by their unique surfaceassociated molecular patterns. Here we demonstrate for the first time, to our knowledge, that the human complement protein properdin binds to early apoptotic T cells and initiates complement activation, leading to C3b opsonization and ingestion by phagocytic cells. Properdin binding was facilitated by the glycosaminoglycan chains of surface proteoglycans. Properdin released by activated neutrophils was particularly effective at recognition of apoptotic T cells, whereas the binding activity of properdin in the serum appeared to be inhibited. ''Properdin tagging'' of apoptotic T cells also induced their uptake by phagocytes independent of complement activation or other complement proteins. Although our findings were made primarily with apoptotic T cells, they suggest that properdin could play a similar role during apoptosis of other cell types.apoptosis ͉ glycosaminoglycan

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“…Properdin deficiency in humans is associated with increased susceptibility to Neisserial infections. [8][9][10] Based on our current understanding of the pathogenesis of C3 glomerulopathy, 1,2 enhancing properdin activity (e.g., through gain of function mutations) would, through increased AP activation, be predicted to exacerbate C3 glomerulopathy. Conversely, reducing properdin activity (e.g., through genetic or therapeutic manipulation) would, through reduced AP activation, be predicted to ameliorate C3 glomerulopathy.…”

mentioning

confidence: 99%

Loss of Properdin Exacerbates C3 Glomerulopathy Resulting from Factor H Deficiency

Ruseva

Vernon

Lesher

et al. 2013

Journal of the American Society of Nephrology

103

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Complement factor H (CFH) is a negative regulator of the alternative pathway of complement, and properdin is the sole positive regulator. CFH-deficient mice (CFH 2/2 ) develop uncontrolled C3 activation and spontaneous renal disease characterized by accumulation of C3 along the glomerular basement membrane, but the role of properdin in the pathophysiology is unknown. Here, we studied mice deficient in both CFH and properdin (CFH 2/2 .P 2/2 ). Although CFH 2/2 mice had plasma depleted of both C3 and C5, CFH 2/2 .P 2/2 animals exhibited depletion of C3 predominantly, recapitulating the plasma complement profile observed in humans with properdin-independent C3 nephritic factors. Glomerular inflammation, thickening of the capillary wall, and glomerular C3 staining were significantly increased in CFH 2/2 .P 2/2 compared with CFH 2/2 mice. We previously reported that exogenous CFH ameliorates C3 staining of the glomerular basement membrane and triggers the appearance of mesangial C3 deposits in CFH 2/2 mice; here, we show that these effects require properdin. In summary, during uncontrolled activation of C3 driven by complete CFH deficiency, properdin influences the intraglomerular localization of C3, suggesting that therapeutic inhibition of properdin would be detrimental in this setting.

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Dysfunctional Properdin in a Dutch Family with Meningococcal Disease

Cited by 75 publications

References 18 publications

Complete and partial deficiencies of complement factor D in a Dutch family.

Complete and partial deficiencies of complement factor D in a Dutch family.

The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis

Loss of Properdin Exacerbates C3 Glomerulopathy Resulting from Factor H Deficiency

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