Quantitation of complement factor D in human serum by a solid-phase radioimmunoassay

Barnum, Scott R.; Niemann, Marilyn A.; Kearney, John F.; Volanakis, John E.

doi:10.1016/0022-1759(84)90470-8

Cited by 41 publications

(21 citation statements)

References 10 publications

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“…It is present in a presumably active form in serum, and no inhibitors present in serum have been described (22). The serum concentration is 1-2 ,ug/ml (12,22,25,26). Factor D is probably filtered through the glomerulus and, under normal conditions, nearly completely reabsorbed within the tubules (27).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…The concentration of factor D in blood, 1.8 f 0.4 &ml, (Barnum et al, 1984) is the lowest of any complement protein. These low levels make factor D the limiting enzyme in the activation sequence of the alternative pathway.…”

Section: Proteolytic Activity Of Factor Dmentioning

confidence: 93%

“…This mechanism results in an ecule was structurally similar to pancreatic rather than blood serestimated fractional catabolic rate of about 60% per hour (Pasine proteases and that it lacked an activation peptide ( Fig. 2 Niemann et al, 1984). A search for a proingly high synthetic rate.…”

Section: -mentioning

confidence: 96%

Complement factor D, a novel serine protease

1996

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Factor D is unique among serine proteases in that it requires neither enzymatic cleavage for expression of proteolytic activity nor inactivation by a serpin for its control. Regulation of factor D activity is instead attained by a novel mechanism that depends on reversible conformational changes for expression and control of catalytic activity. These conformational changes are believed to be induced by the single natural substrate, C3bB, and to result in realignment of the catalytic triad, the specificity pocket, and the nonspecific substrate binding site, all of which have atypical conformations. Mutational studies have defined structural determinants responsible for these unique structural features of factor D and for the resultant low reactivity with synthetic esters.Keywords: alternative complement pathway; catalytic triad; complement; enzyme kinetics; mutagenesis; serine proteases Complement is an important effector system of host defense. It consists of multiple, functionally linked proteins that mediate acute inflammatory reactions, clearance of foreign cells and molecules, and killing of susceptible cells. Activation of the complement system is necessary for expression of these activities and proceeds via pathways consisting of successive enzymatic amplification steps (Campbell et al., 1988; Muller-Eberhard, 1988). The key event in complement activation is the cleavage of a single peptide bond on the a-chain of the third component of complement, C3. The reaction is catalyzed by either of two endopeptidases, termed C3-convertases. In the alternative pathway of complement activation, the enzymatic reaction leading to the formation of the C3-convertase is catalyzed by a serine protease, termed factor D. This enzyme exhibits unique functional properties that are ideally suited to its role as the initiating enzyme of an activation cascade. Unlike other mammalian serine proteases in blood, factor D requires neither enzymatic cleavage for expression of proteolytic activity nor inactivation by an inhibitor for its control. Instead, transition of factor D from the catalytically inactive to the active state seems t o be effected by fully reversible conformational changes. A description of the structural correlates of these unusual functional features has begun to emerge from recent crystallographic and mutational studies. In this paper, we will review these studies in the context of " ..

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“…15 The microperfusion protocols were varied in the following fashions to examine the variables of D uptake. To determine the locus of D uptake, nephrons were perfused either from proximal or distal sites at 20 or 10 nl/min, respectively, with perfusate containing 125I-D in a concentration of 3 Mg/ml, which is -1.5 times the normal human serum D concentration of 1-2 jig/ml (14,15). This concentration was chosen to ensure adequate "I activity in the urine during perfusion at the lowest flow rate.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, selective removal of D activity totally impairs alternative pathway function; pathway activity is restored in a dose-dependent fashion by supplementation of the depleted sera with D (3). In the usual physiologic concentration of 1-2 ,ug/ml (14,15), D is the rate-limiting enzyme in the alternative pathway; it becomes nonlimiting at nine times its normal level (3). Thus …”

Section: Methodsmentioning

confidence: 99%