The effect of complement deficiency is hierarchical in SLE, with 90% of those with deficiency of C1q, 80% with C4 deficiency and 30% with C2 deficiency developing the disease. While those with C1q deficiency develop classical SLE, with a high incidence of lupus nephritis, deficiency of C4 or C2 lead to unusual clinical and immunological phenotypes. Patients with deficiency of either of these two early complement components present with rash, but no nephritis, have low titre ANA, often in a speckled pattern, do not have antibodies to dsDNA, and have a high prevalence- more than 50%- of anti-Ro antibodies.
C4 and C2 are both in linkage disequilibrium with the MHC antigens. They are positioned on the short arm of chromosome 6 between HLA Class B and DR antigens and are part of HLA Class III molecules along with factor B. Homozygosity for the null allele of C2 is present in 1 in 20,000 Caucasions, and as stated above, around 30% of these subjects develop SLE.
The inheritance of C4 is unusual. Most people have not one, but two alleles of C4 on 6p, designated as C4A and C4B. The two C4 alleles are part of a 4-gene cassette called RCCX which is subject to duplication or deletion, leading to Copy Number Variation, such that individuals may have 1-8 C4 alleles across the two chromosomes. Most Caucasians have 2-4 functioning alleles. Thus, total deficiency of C4 is exceedingly uncommon.
Deletion of C4B has not been associated with lupus, but when both copies of C4A are deleted, there is a higher prevalence of lupus compared with those whose C4A copies are intact. Deletion of C4A is seen as part of extended haplotype HLA B8, SC01, DR3. (S stands for S allele of Factor B, C for C-allele of C2, 0 for null-allele of C4A and 1 is an allele of C4B). Thus, subjects who are homozygous for this extended haplotype are at greater risk of SLE.
The extended haplotype HLA B8, SC01, DR3 is one of the commonest extended haplotypes found in Caucasians, with a haplotype frequency of around 9%. Thus the likelihood of heterozygosity in the Caucasian population using the Hardy Weinberg equilibrium is just under 17%, and the likelihood of homozygosity is 0.8%.
In practice, C3 and C4 levels are measured by most Rheumatologists. C4 levels are normally much lower than C3. A low C4 may be inherited or due to active SLE with complement consumption. An isolated low C4 may thus be difficult to interpret. Total haemolytic complement, or CH50, which is an index of all complement components in the classical pathway and is often measured, will therefore also be low, and will not help in such cases. (CH50 is the reciprocal of the dilution of the patient's plasma which, when added to sheep erythrocytes coated with rabbit anti-sheep antibodies, leads to 50% lysis of the sheep RBC. CH100, which is measured in other labs, is self explanatory). However, complement activation products such as C4d will be raised in complement consumption and low in inherited deficiency without SLE. Complement activation products in plasma are heat labile and technically difficult to measure. Cell bound complement activation products hold a lot of promise.
The HLA B8,DR3 extended haplotype is also associated with Type 1 Diabetes, Coeliac Disease and Adrenal insufficiency as part of polyglandular autoimmune syndrome type II.
Interestingly, just as C4A deficiency is part of an extended haplotype, so is deficiency of the product encoded by another member of HLA Class III, 21-beta hydroxylase. CYP21B is often deleted alongwith C4B as part of two other extended haplotypes. Homozygosity for these haplotypes result in Congenital Adrenal Hyperplasia.
C2 deficiency also occurs as part of an extended haplotype- HLA B18, DR2. Around 1% of Caucasians are heterozygotes. C2 is the only complement component in the classical pathway where heterozygosity is associated with reduced C50. With the others, C50 is only low with a homozygous state.
C4 and C2 are both in linkage disequilibrium with the MHC antigens. They are positioned on the short arm of chromosome 6 between HLA Class B and DR antigens and are part of HLA Class III molecules along with factor B. Homozygosity for the null allele of C2 is present in 1 in 20,000 Caucasions, and as stated above, around 30% of these subjects develop SLE.
The inheritance of C4 is unusual. Most people have not one, but two alleles of C4 on 6p, designated as C4A and C4B. The two C4 alleles are part of a 4-gene cassette called RCCX which is subject to duplication or deletion, leading to Copy Number Variation, such that individuals may have 1-8 C4 alleles across the two chromosomes. Most Caucasians have 2-4 functioning alleles. Thus, total deficiency of C4 is exceedingly uncommon.
Deletion of C4B has not been associated with lupus, but when both copies of C4A are deleted, there is a higher prevalence of lupus compared with those whose C4A copies are intact. Deletion of C4A is seen as part of extended haplotype HLA B8, SC01, DR3. (S stands for S allele of Factor B, C for C-allele of C2, 0 for null-allele of C4A and 1 is an allele of C4B). Thus, subjects who are homozygous for this extended haplotype are at greater risk of SLE.
The extended haplotype HLA B8, SC01, DR3 is one of the commonest extended haplotypes found in Caucasians, with a haplotype frequency of around 9%. Thus the likelihood of heterozygosity in the Caucasian population using the Hardy Weinberg equilibrium is just under 17%, and the likelihood of homozygosity is 0.8%.
In practice, C3 and C4 levels are measured by most Rheumatologists. C4 levels are normally much lower than C3. A low C4 may be inherited or due to active SLE with complement consumption. An isolated low C4 may thus be difficult to interpret. Total haemolytic complement, or CH50, which is an index of all complement components in the classical pathway and is often measured, will therefore also be low, and will not help in such cases. (CH50 is the reciprocal of the dilution of the patient's plasma which, when added to sheep erythrocytes coated with rabbit anti-sheep antibodies, leads to 50% lysis of the sheep RBC. CH100, which is measured in other labs, is self explanatory). However, complement activation products such as C4d will be raised in complement consumption and low in inherited deficiency without SLE. Complement activation products in plasma are heat labile and technically difficult to measure. Cell bound complement activation products hold a lot of promise.
The HLA B8,DR3 extended haplotype is also associated with Type 1 Diabetes, Coeliac Disease and Adrenal insufficiency as part of polyglandular autoimmune syndrome type II.
Interestingly, just as C4A deficiency is part of an extended haplotype, so is deficiency of the product encoded by another member of HLA Class III, 21-beta hydroxylase. CYP21B is often deleted alongwith C4B as part of two other extended haplotypes. Homozygosity for these haplotypes result in Congenital Adrenal Hyperplasia.
C2 deficiency also occurs as part of an extended haplotype- HLA B18, DR2. Around 1% of Caucasians are heterozygotes. C2 is the only complement component in the classical pathway where heterozygosity is associated with reduced C50. With the others, C50 is only low with a homozygous state.
