C1q Deficiency

The human A, B, and C genes of C1Q are closely linked on chromosome 1p34 through 1p36. Hereditary C1q deficiency is caused either by a failure to synthesize C1q (∼60% of cases) or by the synthesis of a nonfunctional low-molecular-weight (LMW) C1q (∼40%). Coding mutations have been identified that lead to the formation of a premature termination codon at amino acid residues 6 or 41, or frame-shift mutations from codon 43 together with a stop codon at residue 108 of the C-chain, a stop codon at residue 150 of the B-chain, and a stop codon at residue 186 of the A-chain.^9–11

The vast majority of known human subjects with homozygous C1q deficiency (39 of 42, 93%) have developed a clinical syndrome related to SLE (Fig. 19.1) with skin rash (36 subjects, 86%), glomerulonephritis (GN; 16 subjects, 38%), and central nervous system (CNS) involvement (7 subjects, 17%). The disease is present equally in males and females and is typically of early onset, with a median age of 6 years (range: 6 months to 42 years). The prevalence of autoantibodies is slightly lower than that of regular SLE patients: ANA 24/34 (70.6%), ENA (extractable nuclear antigens Sm, RNP, Ro and/or La) 15/24 (62.5%), and anti-dsDNA 5/24 (20.8%). At least one-third of the C1q-deficient patients also suffered from recurrent bacterial infections, including otitis media, meningitides, and pneumonia. Four C1q-deficient patients died with septicemia in early childhood. Some patients developed diffuse monilia and aphtous lesions in the mouth and toenail deformity secondary to moniliasis⁹ (panel A, Fig. 19.1).

Fig. 19.1 Cutaneous lesions and pathology associated with complement-deficient SLE. LE-like syndrome and cutaneous infection in a male child with homozygous C1q deficiency (A, upper) and lesions of discoid LE with scarring lesions on the face in the same patient at the age of 22 years after 6 years of treatment with thalidomide 11 (A, lower). LE syndrome and osteomyelitis in a child with total C4 deficiency (B, upper) and butterfly rash and cheilitis at the age of 3 years and osteomyelitis of the femur at the age of 10 years (B, lower). The patient died at the age of 12 years from pulmonary infection and cardiovascular failure. (C) Anti-Ro/SS-A⁺ acute cutaneous LE in a young women with homozygous type I C2D (upper, typical butterfly rash; lower, photosensitive lesions on sun-exposed area).

Low Levels of C1q Proteins

In addition to coding mutations reported in patients with complete deficiency of C1q, a silent single-nucleotide polymorphism at codon 70 (GGG—>GGA) of the C1QA gene was found to be associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus (SCLE).¹⁰ The cause for such a reduced level of C1q is not known.

Hereditary C1q deficiencies should be distinguished from acquired C1q hypocomplementemia in SLE patients or other autoimmune conditions, including hypocomplementary urticarial vasculitis syndrome (HUVS), cryoglobulinemia, and severe combined immunodeficiency syndromes. These are due to an increased protein consumption, especially under conditions related to the presence of autoantibodies against C1q. C1q autoantibodies are present in approximately one-third of SLE patients, who often have renal disease and higher clinical disease activities. ^9,12,13

C1r and C1s Deficiencies

The genes for C1r and C1s are in close linkage on chromosome 12p13. Typically, those individuals who have no C1r protein may also have reduced levels of C1s (∼20 to 40% of normal level).⁷ Deficiencies of C1r and C1s have been reported in 14 cases so far. Among them, 12 developed a lupus-like disease with skin rash, discoid lupus, or SLE. A majority of patients presented also had severe bacterial or viral infections. The female-to-male ratio was 1.7:1. Relatively lower prevalence of ANA (62.5%) was found. Molecular defects leading to C1s deficiency had been studied in three patients. Among them were two nonsense mutations in exon 12 at codon 534¹⁴ or codon 608¹⁵ and a 4-bp deletion in exon 10 that created frameshift mutations and formation of a premature stop codon.^15,16 The molecular basis of C1r deficiency has not been determined.

Total Deficiencies of C4A and C4B

A remarkable feature of human complement C4 genetics is the variation in the gene copy number and gene size. One to five copies of long (21 kb) or short (14.6 kb) C4 genes can be present at the central region of the MHC on chromosome 6p21.3.¹⁷ To date, 2 to 7 copies of C4 genes in a diploid genome have been demonstrated to be frequently present among different healthy subjects. Each of those C4 genes may code for an acidic C4A protein or a basic C4B protein. The high copy number of C4 genes probably evolved to increase the diversity and reduce the possibility of a total deficiency of C4A and C4B proteins in an individual.

To date, 28 individuals from 19 families with a complete deficiency of both C4A and C4B proteins have been firmly established.^4,18,19 Among these C4D subjects, 17 were diagnosed with SLE according to the ACR criteria. Of the remaining 11 subjects, 5 had lupus-like disorders such as photosensitive skin lesions and/or discoid lupus and 6 had kidney disease such as mesangioproliferative glomerulonephritis, recurrent hematuria, membranous nephropathy, and Henoch-Schöenlein purpura with end-stage kidney failure. Repeated and invasive (and sometimes fatal) infections were reported in at least 7 individuals (bacterial meningitidis, osteomyelitis, otitis media, respiratory tract infections, and septicemia). Only one subject, age 21 at the time of report, remained relatively healthy. The age of SLE disease onset/diagnosis among C4D subjects varied from 2 to 41 years. The female-to-male ratio of affected patients was close to 1:1 (13 female/14 male). Four C4D patients died between 2 and 25 years of age.

Common clinical manifestations of C4D are photosensitivity, severe skin lesions (sometimes with scarring atrophic lesions on the face and extremities), Raynaud’s phenomenon, infections, and renal disease (panel B, Fig. 19.1). Serologically, antinuclear antibodies are generally present at low titers or absent. Of special interests is the frequent presence of anti-Ro/SSA but the absence of anti-La/SSB antibodies. Anti-dsDNA antibody tests were negative in 9 of 11 patients studied.^4,7,19

The molecular basis of total C4 deficiencies was elucidated in 12 Caucasian subjects with six different HLA haplotypes. The common cause of total C4 deficiency is due to the absence of a C4B gene and the presence of a single long C4A mutant gene in an MHC haplotype that has a mini-insertion or deletion (indel). There are also MHC haplotypes with two nonfunctional C4 genes in tandem. The most prevalent molecular defect leading to nonexpression of a C4 protein is a 2-bp insertion at codon 1213 in exon 29.²⁰ Other deleterious mutations include G—A mutation at the donor site of intron 28 (of C4B), a 1-bp deletion at codon 497 (of C4B) or a 2-bp deletion at codon 522 (of C4A) in exon 13, and a 1-bp deletion at codon 811 of exon 20 (of C4A).¹⁸

C4A and C4B Isotype Deficiencies

Gene copy number and gene size variations are the two major factors contributing to the quantitative diversity of complement C4 plasma protein levels among different individuals.²¹ They create a wide range of plasma protein levels for each isotype, including a homozygous lack of C4A or C4B. The initial observations in the early 1980s of an association between homozygous deficiency and partial deficiency of C4A (i.e., substantially lower expression level of C4A than C4B in a subject) and SLE²² have since been replicated and extended. Cumulative results from more than 35 different studies revealed that homozygous C4A deficiency is increased from less than 1% in the healthy populations to 3.5 to 5% in SLE patient cohorts, whereas partial or heterozygous deficiency of C4A increased from 21.7 to 24% in the healthy controls to 40.2 to 42.9% in SLE patient populations. Those study populations included Northern and Central Europeans, Anglo-Saxons, Caucasians in the United States, and East Asians. French SLE patients and controls showed relatively lower frequencies of C4AQ0, but the differences between the patient and control groups were statistically significant.¹⁸

Although C4AQ0 is significantly associated with SLE in many racial or ethnic groups, a difference in the C4BQ0 allelic frequencies between SLE patients and healthy controls is not observed in Northern and Central Europeans, African Americans, and most Orientals. However, the reverse situation was seen for Spanish, Mexican, and Australian Aborigine SLE patients, among whom a significant increase in frequency of C4BQ0 but not C4AQ0 has been demonstrated. Homozygous deficiency of C4B is associated with increased risk of IgA nephropathy and other autoimmune conditions such as insulin-dependent diabetes. Absence of at least one C4B gene that leads to low levels of plasma C4 protein has been associated with dermatological diseases, specifically DLE, angioedema, and urticaria. Such phenomena would suggest a delicate balance in the physiologic roles of C4A and C4B among different ethnic or genetic backgrounds, or differences in the influence of specific environmental factors on the requirement of C4A and C4B proteins.

The clinical manifestations associated with homozygous C4A deficiency have been reported in several studies. In a cohort of 80 Swedish SLE patients, there were 13 homozygous C4A-deficient subjects, who had an increased incidence of photosensitivity but other clinical features were similar to non C4A-deficient individuals. No differences were seen in the percentage of anti-dsDNA, Sm, RNP, Ro/SS-A, La/SS-B, rheumatoid factors, or anticardiolipin antibodies for these patients. In North American studies of Caucasian SLE, homozygous C4A-deficient patients were found to have a higher incidence of cutaneous disease but in general a milder disease course with lower incidence of renal involvement and proteinuria, lower incidence of seizures, and less common anti-dsDNA, anti-SM, anti-Ro, and anticardiolipin antibodies.^23–25 On the contrary, East Asian SLE patients with homozygous C4A deficiency were associated with more severe disease activities (including higher incidence of renal disease and serositis and higher titers of anti-dsDNA) when compared with SLE patients without a homozygous C4A deficiency.