Homozygous hereditary C1q deficiency and systemic lupus erythematosus: A new family and the molecular basis of C1q deficiency in three families

Slingsby, Jason H.; Norsworthy, Peter; Pearce, Glen; Vaishnaw, Akshay; Issler, Helen; Morley, Bernard J; Walport, Mark J.

doi:10.1002/art.1780390419

Cited by 87 publications

(30 citation statements)

References 8 publications

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“…The last question is whether this in vitro phenomenon has any relevance to in vivo situations. Phagocytosis was suggested to be defective in lupus patients due to rare genetic defects such as complement deficiencies (48) or specific alleles such as Fc␥RIIIa (49). Studies of handling of immune complexes showed that both FcR and complement receptors are saturable (50 -53).…”

Section: Discussionmentioning

confidence: 99%

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

Shoshan

Shapira

Toubi

et al. 2001

The Journal of Immunology

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Impaired handling of apoptotic cells has been suggested as an important factor in the development of systemic lupus erythematosus (SLE), and a role for complement in the removal of apoptotic cells was shown recently. We studied the in vitro function of macrophages from 40 patients with SLE and their matched controls in the removal of heterologous apoptotic cells opsonized by iC3b. Interaction index of apoptotic cells opsonized by iC3b was significantly lower in patients with SLE and averaged 71% ± 37 of that of healthy individuals (p < 0.002) and 69% ± 35 of patients with rheumatoid arthritis (p < 0.007). SLE patients had increased apoptosis of both freshly isolated monocytes (p < 0.001) and maturing macrophages (p < 0.04) that led to decreased density of monocyte-derived macrophages. Apoptosis was inhibited by adding soluble Fas receptor indicating Fas-mediated apoptosis. As demonstrated in both healthy controls and patients with SLE, decreased macrophage density by itself caused significant decreased uptake of apoptotic cells by the remaining macrophages. Maintaining normal density in SLE patients either by an increased initial density or by using soluble Fas restored the interaction capacity of the individual macrophages in the majority of patients. We concluded that impaired in vitro interaction of iC3b-opsonized apoptotic cells with macrophages from patients with SLE was mainly associated with Fas-dependent accelerated apoptosis of the monocytes/macrophages. Accelerated apoptosis of phagocytes may represent a novel in vitro mechanism of impairment of interaction with apoptotic cells that, apart from reducing the number of professional phagocytes, alters the function of the remaining macrophages.

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Section: Discussionmentioning

confidence: 99%

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

Shoshan

Shapira

Toubi

et al. 2001

The Journal of Immunology

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“…The molecular basis of C1q deficiency is single base-pair mutations leading to termination codons, frame shift, or amino acid exchange in each one of the three C1q genes (a, b, and c) associated with absence of detectable protein or expression of reduced levels of dysfunctional protein (5,6,11,12). Although these homozygous C1q deficiencies are a strong risk factor in SLE, they are rare in lupus patients overall (7,13,14).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

C1q Regulatory Region Polymorphism Down-Regulating Murine C1q Protein Levels with Linkage to Lupus Nephritis

Miura-Shimura

Nakamura²,

Ohtsuji³

et al. 2002

The Journal of Immunology

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Much of the pathology of systemic lupus erythematosus (SLE) is caused by deposition of immune complexes (ICs) into various tissues, including renal glomeruli. Because clearance of ICs depends largely on early complement component C1q, homozygous C1q deficiency is a strong genetic risk factor in SLE, although it is rare in SLE patients overall. In this work we addressed the issue of whether genetic polymorphisms affecting C1q levels may predispose to SLE, using the (NZB × NZW)F1 model. C1q genes are composed of three genes, C1qa, C1qc, and C1qb, arranged in this order, and each gene consists of two exons separated by one intron. Sequence analysis of the C1q gene in New Zealand Black (NZB), New Zealand White (NZW), and BALB/c mice showed no polymorphisms in exons and introns of three genes. However, Southern blot analysis revealed unique insertion polymorphism of a total of ∼3.5 kb in the C1qa upstream region of NZB mice. C1q levels in sera and culture supernatants of LPS-stimulated peritoneal macrophages and C1q messages in spleen cells were all lower in disease-free young NZB and (NZB × NZW)F1 mice than in age-matched non-autoimmune NZW and BALB/c mice. Quantitative trait loci analysis using (NZB × NZW)F1 × NZW backcrosses showed that NZB microsatellites in the vicinity of the C1q allele on chromosome 4 were significantly linked to low serum C1q levels and the development of nephritis. These data imply that not only C1q deficiency but also regulatory region polymorphisms down-regulating C1q levels may confer the risk for lupus nephritis by reducing IC clearance and thus promoting IC deposition in glomeruli.

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“…Complete deficiency of the early components C1q, C2 and C4 of the classical pathway of complement are associated with a most striking risk to developing SLE [31][32][33][34][35][36][37][38][39][40][41][42][43]. Deficiency of C4A, so called C4Anull, is probably the most commonly inherited complement deficiency, occurring in varying frequency in different populations [44].…”

Section: Studies Of Candidate Genesmentioning

confidence: 99%

The Genetics of Systemic Lupus Erythematosus

Lindqvist

Alarcón‐Riquelme

1999

Scand J Immunol

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Lindqvist AKB, Alarcón-Riquelme ME. The Genetics of Systemic Lupus Erythematosus. Scand J Immunol 1999;50:562-571. There is considerable evidence that the development of systemic lupus erythematosus (SLE) has a strong genetic basis. For more than 20 years, much effort has been made to understand the genetics of SLE. Association studies in humans suggest the existence of genetic effects by the alleles encoded in the HLA, deficiencies in the complement genes and the low-affinity variants of Fc␥-receptors. In mouse models of SLE at least 13 loci have been identified, including the MHC, linked to lupus-related phenotypes such as nephritis and production of autoantibodies. Recently, linkage studies have been performed in human SLE; one investigating a candidate region based on synteny to a murine susceptibility locus and four genome-wide linkage studies in various populations. Linkage was demonstrated to several chromosomal regions, some of which are syntenic to murine lupus susceptibility loci. Interestingly, many of the identified chromosomal regions co-localise with loci implicated in other autoimmune diseases.

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Homozygous hereditary C1q deficiency and systemic lupus erythematosus: A new family and the molecular basis of C1q deficiency in three families

Cited by 87 publications

References 8 publications

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

C1q Regulatory Region Polymorphism Down-Regulating Murine C1q Protein Levels with Linkage to Lupus Nephritis

The Genetics of Systemic Lupus Erythematosus

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