Deficiencies of C4A or C4B in Human SLE

4.1. Low Complement Activity and C4 Protein Concentrations in SLE

It has been known for over half a century that SLE patients manifest reduced complement hemolytic activity (CH50) (Vaughan et al., 1951; Elliot and Mathieson, 1953). Reduced serum or plasma levels of complement C1q, C4, and C3 have been consistently observed in lupus patients, particularly those with lupus nephritis (Lewis et al., 1971; Cameron et al., 1976; Hebert et al., 1991). Serial analysis of serologic factors in SLE revealed that in many patients lower C4 levels occurred before the depression of other complement components. After the induction of remission, C4 had a tendency to return to normal levels more slowly than C3 (Gewurz et al., 1968; Kohler and Ten Bensel, 1969). The persistence of low C4 levels in many lupus nephritis patients before relapses and after remissions suggests the presence of a genetic factor as a cause for low C4 protein levels.

4.2. Homozygous or "Partial" Deficiency of C4A in SLE across

Multiple Ethnic Groups

In the early 1980s, Bachelor's group in London (UK) and Dawkins' group in Perth (Australia) reported the association of C4 null alleles (C4Q0) or partial deficiency of C4A and/or C4B with human SLE (Christiansen et al., 1983; Fielder et al., 1983). Since then the associations of C4AQ0 or C4BQ0 with SLE have been examined extensively in many ethnic groups that are summarized as follows (Figure 7.2).

Historically, an apparently heterozygous or partial C4A deficiency was determined by the presence of lower C4A protein concentrations or band intensities than those of C4B proteins in phenotypic experiments such as C4 allotyping. The interpretation for such a phenomenon is the higher expression levels of C4B than C4A, which are the combined results of higher C4B gene dosages and short C4B genes. A genuine heterozygous C4A deficiency is defined as the presence of only one intact or functional C4A gene in a diploid genome. However, most published literature on C4 genetics in the past 20 years did not distinguish an apparent or partial deficiency from a heterozygous deficiency. (Fielder et al., 1983; Christiansen et al., 1983; Dunckley et al., 1987; Zhao et al., 1989; Hartung et al., 1992; Petri et al., 1993; Fan et al., 1993; for complete references, please see Yang et al., 2004a).

Caucasians: The most intensively studied patient groups are Europeans and American Caucasians. In the healthy controls, the Nordics and Anglo-Saxons have C4AQ0 frequencies of 0.141 and 0.169, respectively. In the SLE populations, the C4AQ0 allelic frequencies are 0.315 for the Nordics and 0.319 for Anglo-Saxons. The frequencies of homozygous C4AQ0 were 7.5-8% in the patient groups, and 0.5-2.93% in the control groups. Partial deficiency of C4A had a frequency of 47% in northern European, British, or Australian SLE patients, and 22.4-32.7% in the control groups. With more than half of SLE patients possessing a homozygous or partial deficiency, C4A deficiency appears to be one of the most common genetic risk factors for SLE in these ethnic groups.

A slightly lower C4AQ0 allelic frequency, but a highly significant difference, was observed in Germans and Swiss, and in Caucasians residing in North America. The C4AQ0 allelic frequencies are between 0.236 and 0.264 for the patient groups, and 0.108 and 0.12 for the control groups. Homozygous and partial C4A deficiencies were present at 3.45-5.01% and 40.2-42.9%, respectively, in the western European SLE patient populations; and 0% and 21.7-24%, respectively, in the control populations (Figure 7.2, panels A and B).

The French probably have the lowest frequencies of C4AQ0 in both patient and control groups. However, the allelic frequency of C4AQ0 in SLE is still significantly different from that in the French healthy controls. It is of interest that the C4AQ0 allelic frequency is only 0.037 in the French control population, and 0.169 in the French SLE patients. The latter is very close to the C4AQ0 allelic frequency in the healthy controls of Anglo-Saxons (0.169) and Nordics (0.141). In other words, 31.8% of the French SLE patients have a homozygous or a partial C4A deficiency. Such phenotype frequency in the French lupus patients is even lower than that of healthy controls in Anglo-Saxons (33.2%). Such phenomenon underscores the importance of applying matched controls with the appropriate ethnic groups for data analyses (Figure 7.2, panel B).

African Americans: The C4AQ0 allelic frequencies in African American SLE patients and controls were slightly higher but still close to those in the French groups. The allelic frequency of C4AQ0 was 0.192 in the Black SLE patients and 0.07 in the matched controls (c2 = 43.8, p = 3.7 x 10-11). About 35% of the African American SLE patients had a homozygous or a partial C4A deficiency, compared with 14.1% in matched controls.

Orientals: For Chinese, Korean, and Japanese, the SLE patients had C4AQ0 allelic frequencies of 0.293, compared with 0.123 in the corresponding control populations. In total, 54.5% of the Oriental SLE patients have partial or homozygous C4A deficiencies, which is >2 times higher than that of the matched controls (24.5%).

4.3. Deficiency of C4B in SLE Patients from Spanish, Mexican, and Australian Aborigines

While C4AQ0 is significantly associated with SLE, a difference in the C4BQ0 allelic frequencies between SLE patients and healthy controls was not observed in northern and western Europeans, African Americans, and most

Orientals. In contrast, the reverse situation is true for Spanish (De Juan et al., 1993; Naves et al., 1998), Mexican (Reveille et al, 1995; Reveille et al., 1998), and Australian Aborigine (Ranford et al., 1987; Christiansen et al., 1991) SLE patients. In these ethnic groups a significant increase in frequencies of C4B, but not C4A, deficiency, was found in the SLE patient populations. Such a phenomenon would suggest a delicate shift of the physiologic roles of C4A and C4B among different ethnic groups or genetic backgrounds, or that a difference in the genetic milieu, such as racial backgrounds, could change the dependence on C4A or C4B in the emergence of autoimmunity.

4.4. Partial Deficiencies versus Polygenic Variations of C4A

and C4B

In the past, higher plasma protein levels of C4B than of C4A was usually interpreted as a partial or apparent heterozygous deficiency of C4A caused by the presence of a "silent allele" for C4A, or by a C4A gene deletion. Such apparent or partial C4A or C4B deficiency actually reflects an unequal expression of C4A and C4B genes, which is mainly caused by polygenic and gene size variations. Unequal C4A and C4B gene number is likely in an individual whenever (a) a monomodular or trimomodular RCCX structure is present, or (b) a bimodular structure has a homoexpression of either C4A or C4B proteins. Higher expression levels are observed for short C4 genes, which more frequently code for C4B proteins. Therefore, it is essential to conduct a concurrent genotypic analysis to determine the number and size of C4A and C4B genes present in the patients, and phenotypic analysis to elucidate the C4A and C4B allotypes and protein levels.

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