A0002154 a2154 No.ofPages:6 SEETHARAMAK Complement:Deficiency Diseases A second typeofC7 defic roir2 study of C9 deficie meningococcal sepsis and meningtis. ove) Factor I deficiency terminal components,systemic neisserial infections have occurred in most C7 deficiency. Factor I controls the assembly and expression of the reported cases of Individual patien have also pres nted with lupus. renosum.Finally.there have been a few patients with C7 ency factor I.there is no controlimposed on the formation and deficiency who have been clinically well therefore,have C8 deficiency Native C8 is composed of three chains(B and )The C3 is not in its native form.but rather in the form of its covalently joined to form one subunit inactive cleavage product,C3b.Those serum activities that id (C8B) oded covalen cy or ind cy depend o the avilability f )a re rec patients lack the Cy subunit.while in the The most common clinical ext ssion of factor I other form,the C8B subunit is deficier deficiency is an incre ased susceptibility to infection.As more common in whit while with primary 3 ces, Th producing a premature stop codon.suggesting a founder responsible for these infections have been encapsulated effect. pyogenic bacteria,such as the streptococcus,pneumococ- d In fi e of the six nu which organism ate ts have premature s op codon.in either c&ory deficienc or C8B evels of circulating immune complexes.There have as yet there s eer factor I deficienc ma n 1 as has been the case has bee and chort components.Meningococcaemia,meningococcal menin ized by fever.rash.arthralgia.haematuria and proteinuria gitis and disseminated gonococcal infections have pre. dominated.but SLE has also rarely been seen Properdin deficiency C9 deficiency Properdin deficiency is the only complement deficiency that is inherited as an X-linked recessive trait.Properdin Only a few patien alternative pathway enzymes th the mos The seruble lence of 0.036-0.095%.The lysis of bacteria can h alternative pathway.There are a number of forms of mediated by a membrane attack complex composed of properdin deficiency.In one form,affected males have Csb-and is ot,therefore.strictly.As rkedly reduced levels of properdin (<1%of normal) icidera e of killing m,prop en ut in redu the ird c deficieney has peen described in which present The first few individuals with C9 deficiency were in normal concentrations but is dysfunctional that C9 any c an ENCYCLOPEDIA OF LIFE SCIENCES/e 2001 Nature Publishing Group /www.els.net A second type of C7 deficiency has been described in which the quantity of C7 is diminished but not absent. The C7 that is present exhibits an altered isoelectric point. Interestingly, this form of C7 deficiency, termed subtotal C7 deficiency (C7SD), has been seen primarily in associa￾tion with C6SD (see above). A number of clinical presentations have been associated with C7 deficiency. As with the other deficiencies of terminal components, systemic neisserial infections have occurred in most reported cases of C7 deficiency. Individual patients have also presented with lupus, rheumatoid arthritis, scleroderma and pyoderma gang￾renosum. Finally, there have been a few patients with C7 deficiency who have been clinically well. C8 deficiency Native C8 is composed of three chains (a, b and g). The a and g chains are covalently joined to form one subunit (C8ag), which is joined to the other subunit composed of the b chain (C8b) by noncovalent bonds. Each of the C8 polypeptides is encoded by separate genes. In one form of C8 deficiency, patients lack the C8ag subunit, while in the other form, the C8b subunit is deficient. Deficiency of C8b is more common in white populations while C8ag deficiency is more common in Africans. Eighty-six percent of C8b null alleles are due to a C-T transition in exon 9 producing a premature stop codon, suggesting a founder effect. The molecular basis of C8ag deficiency has been identified in three patients. In five of the six null alleles, an intronic mutation alters the splicing of exons 6 and 7 of C8A and creates a 10-bp insertion that generates a premature stop codon. In either C8ag deficiency or C8b deficiency, C8 activity is markedly reduced and there is a marked reduction in bactericidal activity. The clinical presentation of C8 deficiency has been similar to the other deficiencies in terminal complement components. Meningococcaemia, meningococcal menin￾gitis and disseminated gonococcal infections have pre￾dominated, but SLE has also rarely been seen. C9 deficiency Only a few patients with C9 deficiency have been identified in Western populations but it appears to be the most common complement deficiency in Japan with a preva￾lence of 0.036–0.095%. The lysis of bacteria can be mediated by a membrane attack complex composed of C5b-8 and is not, therefore, strictly dependent on C9. As a result, the sera of patients with C9 deficiency possess some bactericidal activity, although the rate of killing is significantly reduced. The first few individuals with C9 deficiency were asymptomatic, suggesting initially that C9 deficiency was not associated with any clinical problems. However, most subsequent patients with C9 deficiency presented with systemic meningococcal infections. In addition, an epide￾miological study of C9 deficiency in Japan provided strong evidence for a relationship between C9 deficiency and meningococcal sepsis and meningitis. Factor I deficiency Factor I controls the assembly and expression of the alternative pathway enzyme that activates C3. Factor I deficiency is characterized by uncontrolled activation of C3 via the alternative pathway because, in the absence of factor I, there is no control imposed on the formation and expression of the alternative pathway that activates C3. Patients with factor I deficiency, therefore, have a secondary consumption of C3 resulting in markedly reduced levels of native C3 in their serum. Most of the C3 is not in its native form, but rather in the form of its inactive cleavage product, C3b. Those serum activities that directly or indirectly depend on the availability of native C3 (opsonic activity, chemotactic activity and bactericidal activity) are reduced in patients with factor I deficiency. The most common clinical expression of factor I deficiency is an increased susceptibility to infection. As with primary C3 deficiency (see above), infections have included both localized infections on mucosal surfaces, as well as systemic infections. The organisms most commonly responsible for these infections have been encapsulated pyogenic bacteria, such as the streptococcus, pneumococ￾cus, meningococcus and H. influenzae organisms, for which C3 is an important opsonic ligand. In addition to problems with infection, some patients have had elevated levels of circulating immune complexes. There have as yet been no reports of patients with factor I deficiency developing chronic renal disease as has been the case with C3 deficiency. However, there has been one report of a transient illness resembling serum sickness and character￾ized by fever, rash, arthralgia, haematuria and proteinuria. Properdin deficiency Properdin deficiency is the only complement deficiency that is inherited as an X-linked recessive trait. Properdin acts to stabilize the alternative pathway enzymes that activate C3 and C5. The serum of patients with properdin deficiency is therefore unable to activate C3 via the alternative pathway. There are a number of forms of properdin deficiency. In one form, affected males have markedly reduced levels of properdin (51% of normal), while in another form, properdin is present but in reduced amounts (10% of normal). A third form of properdin deficiency has been described in which properdin is present in normal concentrations but is dysfunctional. The most common clinical manifestation of properdin deficiency has been fulminant meningococcaemia and a2154 No. of Pages: 6 SEETHARAMAK Complement: Deficiency Diseases A0002154 4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net