Factor D is essential in catalyzing the cleavage of factor B to Bb, allowing Bb to associate with hydrolyzed C3 or C3b. Factor D deficiency is extremely rare. The most well studied family cluster of factor D deficiency in the Netherlands, with 21 heterozygotes available for study, describes low normal factor D levels and no clinical disease in heterozygotes, supporting autosomal recessive inheritance. Clinical disease from factor D deficiency occurs from a lack of alternative pathway hemolytic activity and greatly reduced opsonization of encapsulated bacteria. Invasive meningococcal infections have been seen in multiple individuals with factor D deficiency. Risk of infection with E. coli and Streptococcus pneumoniae is also increased. Factor D deficiency has not been associated with autoimmunity.
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 hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified factor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D. The gene encoding factor D was found to contain a point mutation that changed the TCG codon for serine 42 into a TAG stop codon. This mutation was found in both alleles of the five completely factor D-deficient family members and in one allele of 21 other members of the same family who had decreased or low-normal factor D levels in their serum. The gene sequence of the signal peptide of human factor D was also identified. Our report is the first, to our knowledge, to document a Factor D gene mutation. The mode of inheritance of factor D deficiency is autosomal recessive, in accordance with the localization of the Factor D gene on chromosome 19. Increased susceptibility for infections in individuals with a partial factor D deficiency is unlikely.
1. Pettigrew H D, et al. (2009). Clinical significance of complement deficiencies. Annals of the New York Academy of Sciences, 1173(1), 108-123.
2. Biesma D H, et al. (2001). A family with complement factor D deficiency. The Journal of clinical investigation, 108(2), 233-240.
3. Morgan B P, et al. (1991). Complement deficiency and disease. Immunology today, 12(9), 301-306.
4. Botto M. (1999). C1q knock-out mice for the study of complement deficiency in autoimmune disease. Experimental and clinical immunogenetics, 15(4), 231-234.
5. Sjöholm A G, et al. (2006). Complement deficiency and disease: an update. Molecular immunology, 43(1), 78-85.