A0002154 a2154 No.ofPages:6 SEETHARAMAK Complement:Deficiency Disease of normal)and amo erate reduction of Cls(20 50 app oe。Cls with the abse of Clr i system and the kinin system. patients is unknown.although it may relate to their close Asymptomatic ent 500/ Some patients with Most CIr/Cls-deficient patients ha nted with SLE,although isolated glomerulonephritis has also been developed a serious infection or a rheumatic disorder scribed.In addition,some patients have been ascer- ned as a iefeauene.oi ing fam lves have b y mem because of clinical problems. C4 deficiency There Specific Disorders are two loci (C4A and C4B)within the ajor x that encode for C4.Alth Most of the geneticay the products of the two loci share some functional, etermined deficiencies of the characteristics that identify them eptions:deficiency of ropnoret CI inhibitor has an autosomal dominant mode of identification.Patients with total C4 deficiency are omozygous defcient at both loc and have severel Clq deficiency serm levels of both and ncona C3 and C5-C9 and can mediated via activa The first componer nt of complement is composed of three alternative pathway,such as opsc onic.chemotactic and w ither function he of ar degree or as quickly as in norma In the other form,immunochemical Clq is present,but it The predomn nifestation of lacks function IS deficiency has been an sle-like illness.characterized by unctiona ulin G ive skin rashes,renal disease and occasionally tes Clr and C The most common clinical presentation ofeither form of SLE-like illness is also present Clq deficiency has beenalupus-likesy The clinica Although complete C4 deficiency is rare.individuals mar in patients with Cl deficiency are omozygous nt for either A or C4B are sufficient individuals although theas of on at is s popu what earlier and the disease can be very severe with is deficient in C4B.As mentioned.C4A and C4B difter somewhat in function;C4A binds more efficiently to Patient nave 4B DI ore efficiently in rbohydrate C4A are mis ng h sotype t due to their inability to generate opsonically active C3b via ot be able to clear protein-co ntaining immune complexes activation of the classical pathway normally and be more susceptible to immune complex SLE.In the prevale of h mo CIr/Cls deficiency ygous 10 The genes encoding Clr and Cls map to the short arm of opulation.Individuals who are deficient in C4B lack the chromosome 12,are separated by only 9.5kb and are isotype that is more efficient in interacting with poly re might not be able to ass I pathway ENCYCLOPEDIA OF LIFE SCIENCES/e 2001 Nature Publishing Group /www.els.net the development of angio-oedema in C1 INH deficiency is not fully understood, but appears to relate to the inability of C1 INH to inhibit the activation of both the complement system and the kinin system. Asymptomatic Some patients with genetically determined complement deficiencies are relatively asymptomatic, never having developed a serious infection or a rheumatic disorder. These asymptomatic patients are usually ascertained as a consequence of screening family members of complement￾deficient patients who themselves have been ascertained because of clinical problems. Specific Disorders Most of the genetically determined deficiencies of the complement system are inherited as autosomal recessive traits. There are only two known exceptions: deficiency of C1 inhibitor has an autosomal dominant mode of inheritance, while properdin deficiency is inherited as an X-linked recessive disorder. Clq deficiency The first component of complement is composed of three distinct subunits, Clq, Clr and Cls. There appear to be two distinct forms of Clq deficiency. In one form, Clq cannot be detected by either functional or immunochemical analysis. In the other form, immunochemical Clq is present, but it lacks functional activity, i.e. it is dysfunctional. The dysfunctional C1q is antigenically deficient, and it does not interact with either immunoglobulin G (IgG) or its substrates, Clr and Cls. The most common clinical presentation of either form of Clq deficiency has been a lupus-like syndrome. The clinical manifestations of SLE in patients with Clq deficiency are not markedly different from those seen in complement￾sufficient individuals, although the age of onset is some￾what earlier and the disease can be very severe with significant central nervous system (CNS) and renal disease. Patients with Clq deficiency also have an increased susceptibility to bloodborne infections with pyogenic organisms, such as sepsis and/or meningitis, presumably due to their inability to generate opsonically active C3b via activation of the classical pathway. Clr/Cls deficiency The genes encoding Clr and Cls map to the short arm of chromosome 12, are separated by only 9.5 kb and are highly homologous. Genetically determined deficiency of Clr is characterized by a marked reduction of Clr (less than 1% of normal) and a moderate reduction of Cls (20–50% of normal). The basis for the association of the moderately reduced levels of Cls with the absence of Clr in these patients is unknown, although it may relate to their close structural and functional similarity. Interestingly, one patient has been described in which Cls is markedly reduced while Clr levels are 50% of normal. Most Clr/Cls-deficient patients have presented with SLE, although isolated glomerulonephritis has also been described. In addition, some patients have been ascer￾tained as part of family studies and have been clinically well. C4 deficiency There are two loci (C4A and C4B) within the major histocompatibility complex that encode for C4. Although the products of the two loci share some functional, structural and antigenic characteristics that identify them as C4, they differ sufficiently with respect to electrophoretic mobility, molecular weight of the a chain, specific epitopes and functional haemolytic activity to allow their separate identification. Patients with total C4 deficiency are homozygous deficient at both loci and have severely depressed serum levels of both antigenic and functional C4 (less than 1%). Those serum activities that depend on C3 and C5–C9 and can be mediated via activation of the alternative pathway, such as opsonic, chemotactic and bactericidal activities, are present but are not generated to the same degree or as quickly as in normal sera because of a lack of an intact classical pathway. The predominant clinical manifestation of complete C4 deficiency has been an SLE-like illness, characterized by photosensitive skin rashes, renal disease and occasionally arthritis. Although some patients have an increased susceptibility to infection, these are patients in whom the SLE-like illness is also present. Although complete C4 deficiency is rare, individuals who are homozygous deficient for either C4A or C4B are relatively common. Approximately 1% of the population is homozygous deficient in C4A and 3% of the population is deficient in C4B. As mentioned, C4A and C4B differ somewhat in function; C4A binds more efficiently to proteins and C4B binds more efficiently in carbohydrates. Individuals who lack C4A are missing the isotype that interacts most efficiently with proteins, and therefore might not be able to clear protein-containing immune complexes normally and be more susceptible to immune complex diseases such as SLE. In fact, the prevalence of homo￾zygous C4A deficiency in SLE is between 10% and 15%, a prevalence at least 10 times higher than that in the general population. Individuals who are deficient in C4B lack the isotype that is more efficient in interacting with poly￾saccharides and therefore might not be able to assemble the classical pathway C3-cleaving enzyme on bacterial poly￾a2154 No. of Pages: 6 SEETHARAMAK Complement: Deficiency Diseases A0002154 2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net