IntroductionThe complement system consists of more than 20 plasma proteins and plays an important role in the defense against microorganisms (1). Activation of the classical or the alternative pathway results in the cleavage of C3, the central component of the system. In the alternative pathway, the spontaneous hydrolysis product iC3 (i.e., C3 with intact peptide chains but with a hydrolyzed thioester) complexes with factor B in the presence of magnesium ions, which allows factor D to cleave factor B bound to iC3, thus producing the fluid-phase, alternative C3 convertase iC3Bb. This iC3Bb convertase generates C3b from native C3 and accounts for the spontaneous "tick-over" of C3 in plasma. The C3b generated in this way may bind to a bacterial surface, where it is protected from degradation by factors I and H and can bind factor B to give the C3bB complex. Upon cleavage of factor B in this complex by factor D, another C3 convertase is generated, which cleaves additional C3. This convertase C3bBb can become stabilized by binding properdin. C3bBbP bound to bacteria generates many C3b molecules, which in their turn can bind to the nearby bacterial surface and be protected from degradation as a result. Bound C3b molecules can either remain as such and act as opsonins for enhanced phagocytosis of the bacteria by phagocytic cells, they can bind new molecules of factor B to generate new C3 convertase complexes in the amplification loop of C3 activation, or they can combine with factor B and another molecule of C3b to generate the C5 convertase C3bBb3b. This last enzyme binds and cleaves C5, with the subsequent generation of C5a and C5b. Interaction of C5b with the terminal components of the complement system C6, C7, C8, and C9 results in the formation of the "membrane attack complex."Factor D fulfills an essential role in the initiation and propagation of the alternative pathway of complement activation and in the amplification loop of C3 activation. Factor D is a serine protease of about 24 kDa that circulates in the blood as a constitutively active enzyme. It is synthesized by fat cells and macrophages (2). Deficiencies have been described for almost all components of the complement system, including factor D (3). Increased susceptibility to (recurrent) Neisseria infections has been observed in patients with deficiencies in terminal or alternative pathway components (4). We describe a patient suffering from meningococcemia caused by N. A complement factor D deficiency was found in a young woman who had experienced a serious Neisseria meningitidis infection, in a deceased family member with a history of meningitis, and in three relatives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils. The alternative pathway-dependent hemol...

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