Rheumatology Advance Access originally published online on August 4, 2008
Rheumatology 2008 47(10):1588-1589; doi:10.1093/rheumatology/ken289
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Complement C1q and C8β deficiency in an individual with recurrent bacterial meningitis and adult-onset systemic lupus erythematosus-like illness
1Molecular Genetics and Rheumatology Section, Imperial College, London, UK, 2Department of Physiology and Pathology, University of Trieste, Trieste, Italy and 3Institute of Medical Microbiology and Hygiene, Johannes Gutenberg-University, Mainz, Germany
Correspondence to: M. C. Pickering, Molecular Genetics and Rheumatology Section, Imperial College, London, UK. E-mail: matthew.pickering{at}imperial.ac.uk
SIR, A 49-yr-old nulliparous Caucasoid lady presented with a several week history of florid oral ulceration, malaise, weight loss and fever. There was no rash, photosensitivity, arthralgia, alopoecia, RP, headache, ocular disturbance or recent foreign travel. Past medical history included hypothyroidism associated with anti-thyroid microsomal antibodies for which she was taking thyroxine, bacterial meningitis at the age of 21 and 27 yrs and group A meningococcal septicaemia at the age of 44 yrs. There was a family history of consanguinity. She was dehydrated with low-grade pyrexia of 37.6°C and had multiple oral aphthous ulcers. ESR was >100 mm/h, CRP 11 mg/l (0–10), Hb 9.4 g/l, mean cell volume 92.1 fl, white cell count 5 x 109/l, lymphocytes 1 x 109/l, platelet count 248 x 109/l. Renal function, creatinine phosphokinase and immunoglobulin levels were normal. Liver function tests were abnormal: aspartate transaminase 219 IU/l (0–31), alanine transaminase 117 IU/l (0–31), 
GT 331 IU/l (2–30), alkaline phosphatase 177 IU/l (30–130), bilirubin 6 µmol/l (0–17) and albumin 27 g/l (33–47). Hepatitis B surface antigen, hepatitis C antibody, HIV serology were negative and viral studies for CMV, Epstein–Barr virus, Herpes simplex virus and parvovirus did not indicate acute infection. ANAs (1 : 320), anti-Ro antibodies (>100 u/ml, normal range 0–20) and anti-thyroid microsomal antibodies were positive. Anti-double-stranded DNA, aCLs, ANCAs, anti-mitochondrial and anti-liver/kidney microsomal antibodies were negative. Percutaneous liver core biopsy showed mild mononuclear cell infiltrate in the portal tracts, moderate interface hepatitis and focal necrosis and hepatocyte apoptosis within parenchymal areas, features consistent with autoimmune hepatitis.
Whilst C3 and C4 levels were normal, total complement haemolytic activity (CH50) was repeatedly absent indicating possible complement deficiency state. Reconstitution assays were performed in which sera with selective defects of complement components or subunits were mixed with the patient sera and the haemolytic activity of the resultant mixture measured (Table 1). Serum deficient in either the C8β subunit of the C8 protein or the classical pathway component C1q did not restore haemolytic activity to the patient's sera. Normal CH50 was only restored following the addition of both C8 and C1q to the patient's sera. Antigenic assays confirmed complete absence of both C8β and C1q in our patient (Table 1). The genetic basis of the C8β deficiency was a homozygous null mutation within exon 9 of the C8B gene (R427Term, Table 1), a mutation previously identified as the commonest cause of C8β deficiency in Caucasoid individuals [1]. The C1q deficiency was due to a homozygous point mutation (G34R) in the first coding exon of the C1qC gene, a mutation previously identified as a cause of C1q deficiency in German, Indian and Saudi Arabian families [2]. The G34R mutation is associated with the presence of an abnormal, non-functional C1q protein in circulation (low molecular weight C1q) [3] which was detected in our patient (Table 1). Parental DNA was not available and no C1q or C8B mutations were present in a healthy sibling.
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A diagnosis of SLE-like illness associated with homozygous C1q deficiency was established together with homozygous C8β deficiency associated with recurrent bacterial meningitis. Immunosuppressive therapy with prednisolone and AZA resulted in complete resolution of her transaminitis. AZA therapy was poorly tolerated, hence maintenance treatment with mycophenolate mofetil was started. Three years later she remains in remission and has not suffered any infective complications.
Homozygous C1q deficiency is a strong susceptibility factor for the development of an SLE-like illness: 
93% of C1q-deficient individuals developed an SLE-like illness, typically beginning in childhood and frequently associated with cutaneous vasculitis, glomerulonephritis and cerebritis [4]. Homozygous deficiency of complement C8 presents with selective deficiency of either C8β or C8
- subunits [5] and is associated with an increased risk of recurrent neisserial infections, a feature common to all terminal pathway component deficiencies [6]. To our knowledge, this individual represents the first reported case of combined C1q and C8β deficiency. It was particularly striking that the onset of the SLE-like illness was considerably later than that reported in individuals lacking C1q alone (median onset 6 yrs) [4]. Moreover, her SLE-like illness appeared to be less severe: vasculitis, glomerulonephritis or cerebritis have been described in C1q-deficient individuals with the G34R mutation [3, 7, 8]. Thus, we speculated that the inability to develop terminal pathway-mediated tissue injury (by virtue of the C8β deficiency) could have limited the extent of SLE-induced organ damage in this individual. The scarcity of reports of SLE in individuals with terminal pathway deficiency precluded any attempt to determine if the illness severity in such cases differed from that seen in complement-sufficient SLE patients. However, this unique case supports an important role for the membrane attack complex in the development of tissue injury in SLE.
Disclosure statement: The authors have declared no conflicts of interest.
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References |
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 Top References |
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- Kaufmann T, Hansch G, Rittner C, et al. Genetic basis of human complement C8 beta deficiency. J Immunol (1993) 150:4943–7.[Abstract]
- Petry F. Molecular basis of hereditary C1q deficiency. Immunobiology (1998) 199:286–94.[Web of Science][Medline]
- Kirschfink M, Petry F, Khirwadkar K, et al. Complete functional C1q deficiency associated with systemic lupus erythematosus (SLE). Clin Exp Immunol (1993) 94:267–72.[Web of Science][Medline]
- Pickering MC, Botto M, Taylor PR, et al. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol (2000) 76:227–324.[Web of Science][Medline]
- Tedesco F, Densen P, Villa MA, et al. Two types of dysfunctional eighth component of complement (C8) molecules in C8 deficiency in man. Reconstitution of normal C8 from the mixture of two abnormal C8 molecules. J Clin Invest (1983) 71:183–91.[CrossRef][Web of Science][Medline]
- Morgan BP, Walport MJ. Complement deficiency and disease. Immunol Today (1991) 12:301–06.[CrossRef][Web of Science][Medline]
- Slingsby JH, Norsworthy P, Pearce G, et al. Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum (1996) 39:663–70.[Web of Science][Medline]
- Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus. Immunobiology (1998) 199:265–85.[Web of Science][Medline]
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