Serum C1q Research Articles

Autoantibodies against complement C1q in acute post-streptococcal glomerulonephritis

Autoantibodies against complement C1q (anti-C1q) strongly correlate with the occurrence of severe lupus nephritis. Recent data suggest that anti-C1q might also correlate with more severe forms of acute post-streptococcal glomerulonephritis (APSGN). Therefore, we prospectively investigated the role of anti-C1q in 50 children with newly diagnosed APSGN. Associations between anti-C1q and disease manifestations as well as serum complement concentrations were analyzed. Nineteen of the 50 children (38%) with APSGN were positive for anti-C1q compared to 0 / 40 healthy controls. Levels of anti-C1q correlated negatively with serum C1q and C3 concentrations. Anti-C1q positive patients had significantly higher proteinuria and serum creatinine as well as more often oliguria, hypertension and delayed resolution of the disease than patients without anti-C1q. The data point to a potential pathogenic role of anti-C1q in APSGN. Determination of anti-C1q might help to identify patients at risk for prolonged courses of the disease.

Classical Complement Pathway in Experimental Autoimmune Myasthenia Gravis Pathogenesis

Mice deficient for complement factors C3, C4, or C5 are resistant to experimental autoimmune myasthenia gravis (EAMG). Acetylcholine receptor (AChR) immune lymph node cells (LNC) of C3 deficient mice produce less interleukin 6 (IL-6), and EAMG-resistant IL-6 deficient mice have less serum C3. Increased serum C1q-circulating immune complex (CIC) levels correlated with EAMG disease severity in RIIIS/J mice. The CIC promotes EAMG severity by stimulating the production of LNC IL-6, serum C1q, and C3 via FCgammaR interaction. Therefore, EAMG/MG could be treated by blocking the activation of classical complement pathway (CCP) and/or IL-6. Anti-C1q antibody administration before and following AChR immunization suppressed EAMG by reducing LNC IL-6 production and neuromuscular junction deposits of IgG, C3, and C5b-C9 complexes. Treatment with low dose (10 microg) of anti-C1q antibody twice a week for 4 weeks in mice with ongoing clinical EAMG reduced the clinical severity of disease and LNC IL-6 production. Therefore, inhibitors of CCP factors C1q, C2, or C4 could treat MG and would preserve the alternate complement pathway activation. Our goal is to tailor MG therapy using anti-C2/C4 reagents in combination, with or without anti-cytokine (e.g., anti-IL-6) reagents.

Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity

Background:Several findings link systemic lupus erythematosus (SLE) with C1q, the first molecule of the classical complement pathway. Polymorphisms of the C1qA gene are associated with low serum C1q levels in...

Oral 9, Hypocomplementaemic urticarial vasculitis: a rare but important cause of urticaria and angio-oedema

A 12-year-old girl presented initially with arthritis, back and abdominal pain, weight loss and lethargy. Preliminary blood tests showed a positive antinuclear factor, and low C3 and C4. Serum creatinine was normal but repeat urinalysis demonstrated a persistent proteinuria. A diagnosis of systemic lupus erythematosus was made and immunosuppressive treatment was commenced with hydroxychloroquine and prednisolone orally and methotrexate by intramuscular injection. Initially her joint symptoms slightly improved but after 3 months she was still complaining of lethargy with abdominal pains. She also complained of facial swelling and was noted to have urticaria on her face and limbs. Because of the urticaria and angio-oedema, low complement levels and abdominal pain, a diagnosis of hypocomplementaemic urticarial vasculitis (HUVS) was considered and serum C1q and C1q antibody titres were determined showing the presence of C1q antibodies and a low C1q titre. A diagnosis of HUVS was made and the immunosuppressive treatment was increased with pulsed methylprednisolone, with improvement of her symptoms. HUVS is a rare condition. Diagnosis depends on the presentation of hypocomplementaemia, urticaria and at least two of the following: vasculitis from dermal biopsies, arthralgia and arthritis, glomerulonephritis, uveitis or episcleritis, recurrent abdominal pain and the presence of C1q precipitating factor in the plasma.1,2 This disorder can present in isolation or in association with other diseases.2 Treatment of HUVS is notoriously difficult and affected individuals are at particular risk of end-stage renal disease. References 1 Schwartz HR, McDuffie FC, Black LF et al. Hypocomplementemic urticarial vasculitis: association with chronic pulmonary disease. Mayo Clinic Proc 1982; 57:231–8. 2 Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus. Immunobiology 1998; 199:265–85.

Soluble Human MDA-7/IL-24: Characterization of the Molecular Form(s) Inhibiting Tumor Growth and Stimulating Monocytes

Interleukin-24 (IL-24), also known as melanoma differentiation-associated gene-7 (mda-7), is a member of the IL-10 family that exhibits both tumor suppressor and proinflammatory properties. We describe the purification of this novel dual-function tumor suppressor/cytokine from the supernatant of IL-24 gene-transfected HEK 293 cells and define the biochemical and functional properties of the soluble human IL-24 protein. Size exclusion chromatography demonstrates that an IL-24 macromolecular complex fractionates in a broad peak with a median of 110 kDa and comprises several IL-24 isoforms, identified by immunoblotting with anti-IL-24 polyclonal antibody after reducing SDS-PAGE analysis. IL-24 was found to associate with two serum components, albumin and C1q. Cation exchange purification results in the isolation of at least two N-linked glycosylated IL-24 dimers covalently associated via intermolecular disulfide bonds. These molecularly defined N-glycosylated IL-24 dimers elicited dose-dependent secretion of tumor necrosis factor-alpha (TNF-alpha) and IL-6 from human monocytes, as well as cytotoxicity to human melanoma cell lines. Thus, we demonstrated that the secreted, glycosylated, dimeric, human IL-24 is immunomodulatory to monocytes and exhibits tumor cell growth inhibition.

A C1q-binding 40 kDa porin from Aeromonas salmonicida: Cloning, sequencing, role in serum susceptibility and fish immunoprotection

A 40 kDa C1q-binding outer membrane protein from Aeromonas salmonicida was identified by direct-binding assay with biotinylated C1q, a subcomponent of the complement classical pathway component C1. The 40 kDa porin structural gene from the A450 A. salmonicida typical strain (A +:O +) was cloned in Escherichia coli and sequenced. The amino acid sequence of the 40 kDa A. salmonicida porin, its ability to bind C1q in an antibody independent process, and its immunological cross-reaction with the A. hydrophila AH-3 porin II, allow us to determine the role of this protein in serum susceptibility. Furthermore, we obtained defined A. salmonicida 40 kDa porin insertion mutants in serum sensitive or resistant strains, and we complemented these mutants with a plasmid harboring only the 40 kDa porin gene from A. salmonicida A450 in order to define its role as an important surface molecule involved in serum susceptibility and C1q binding. Similar complementation was obtained using the A. hydrophila AH-3 porin II gene. The 40 kDa porin gene and/or protein was present in all the A. salmonicida typical or atypical strains tested. Furthermore, the A. hydrophila AH-3 porin II seems to be an important molecule for fish immunoprotection against either A. salmonicida or A. hydrophila strains.

The roles of complement 1q and anti-C1q autoantibodies in pathogenesis of lupus nephritis

To analyze the correlation of serum levels of complement 1q (C1q) and anti-C1q autoantibodies (C1qAb) with renal pathology in lupus nephritis (LN) and to explore the probable mechanism of C1q and C1qAb in the development of systemic lupus erythematosus (SLE), especially LN. The serum samples of 80 SLE patients, 40 LN patients and 40 non-LN patients, were collected to detect the level of C1q with single radial immunodiffusion and the level of C1qAb with enzyme-linked immunosorbent assay. Renal biopsy was conducted in 25 of the 32 LN patients so as to observe the deposition of apoptotic cells and apoptotic bodies in the glomeruli with TdT-mediated dUTP nick end labeling. The serum level of C1q was (130 +/- 50) mg/L in the LN patients, significantly lower than that in the non-LN patients [(170 +/- 70) mg/L, P = 0.004]. The serum level of C1qAb (P/N value) was 7 +/- 4 in the LN patients, significantly higher than that in the non-LN patients (4 +/- 3, P < 0.001). The correlation coefficient between C1qAb and C1q in the LN patients was -0.567 (P < 0.01), showing a significant negative correlation. The correlation coefficient between C1qAb and C1q in the non-LN patients was -0.509 (P = 0.001), showing a significant negative correlation. The serum C1q level of the type IV LN patients was significantly lower than that in the type I LN patients, and the serum C1qAb level of the type IV LN patients was significantly higher than that in the type I LN patients (P < 0.05). The serum C1q was significantly lower in the LN patients with renal C1q deposition (++) than in the LN patients with renal C1q deposition (+), however, the serum C1qAb was significantly higher in the LN patients with renal C1q deposition (++) than in the LN patients with renal C1q deposition (+) (both P < 0.05). The serum C1q level was significantly lower in the LN patients with positive IgG deposition than in the LN patients with negative IgG deposition and the serum C1qAb level was significantly higher in the LN patients with positive IgG deposition than in the LN patients with IgG negative deposition (both P < 0.05). The serum C1q level in the LN patients with positive C3 deposition was significantly lower than that in the LN patients with negative C3 deposition (P < 0.05). The serum C1q level in the LN patients with marked apoptotic cells and deposition of apoptotic bodies was significantly lower than that in the LN patients without marked apoptotic cells and deposition of apoptotic bodies, and the serum C1qAb level in the LN patients with obvious apoptotic cells and deposition of apoptotic bodies was significantly higher than that in the LN patients without obvious apoptotic cells and deposition of apoptotic bodies (both P < 0.05). The decrease of serum C1q level and increase of serum C1qAb were significantly positively correlated with the deposition of C1q, IgG, and C3 in the kidney, and with the appearance of apoptotic cells and deposition of apoptotic bodies in the kidney. C1q and C1qAb may be involved in the pathogenesis of SLE, especially LN. The probable mechanism may be that they promote renal deposition of circulating immune complexes combined with C1q or promote the renal deposition of apoptotic cells and apoptotic bodies.

1012. Ad Interactions with the Complement Systems of Humans and Mice

Advanced generation Ad vectors can allow for long term persistence by avoiding activation of the adaptive arm of the immune response. Unfortunately, significant acute toxicities can be incurred after i.v. injection of Ads. Precious little is known about Ad interactions with the acellular defense systems present in the blood, including the complement system. The complement system has evolved to rapidly sequester invading pathogens, while rapidly initiating multiple downstream immune functions. However, inappropriate or excessive complement activation is also known to be associated with a number of serious clinical consequences. Intriguingly, many of these are known to also occur after high dose Ad injections, suggesting that Ads may be directly activating the complement cascade. We therefore set out to test this hypothesis. The exposure of Ad5 capsids to Ad-seropositive or sero-negative human serum resulted in activation of the complement cascade, suggesting that the presence of anti-Ad antibodies was not required for Ad induced complement activation. We found that complement consumption occurred despite specific blockade of the classical complement pathway (using the AP50 assay) implicating the alternative complement pathway as being directly activated by Ads. Ads also activated the alternative pathway when C1q depleted human serum (C1q is typically required for classical complement pathway activation) was utilized in the AP50 assay. Supporting these observations, we did not detect consumption of human C4 activity in either of these experiments. In vitro analyses confirmed that the human C3 protein could bind to immobilized Ad5 particles in the presence of EGTA (blocks classical pathway) but not EDTA (blocks both the classical and alternative complement pathways). This result was also achieved when Ad5 particles were incubated with C1q depleted serum. Again, the human C4 protein was not found to bind Ad particles under any of these assay conditions. We also found that 125-I labeled C3 bound to immobilized Ad particles, and this binding was significantly enhanced in the presence of purified Factor B and Factor D (members of the alternative pathway). Our results demonstrate that high titer Ads directly interact with proteins of the alternative complement pathway, leading to C3 binding of the virus particles. Most recently, we have found that human Ads activate the murine complement system, and blockade of the murine complement system prevented a typical Ad induced toxicity, namely thrombocytopenia.

Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus.

We report an association between a non-familial form of photosensitive Lupus-specific skin disease, subacute cutaneous lupus erythematosus (SCLE), and a new single nucleotide polymorphism (SNP) in the C1QA gene. We also describe an association between this SNP and lower levels of serum C1q. This SNP consists of adenine replacing the third guanine in the codon for aminoacid residue Gly70 (position excludes the 22 amino acid leading peptide) that is located in the second exon of the C1QA gene. We have designated this SNP C1qA-Gly70GGA (the GenBank sequence at this location is C1qA-Gly70GGG). A survey of 19 SCLE patients showed that 11 (58%) were homozygous for C1qA-Gly70GGA SNP, seven (37%) were heterozygous, and only one patient (5%) was homozygous for the GenBank sequence. In contrast, only 13 of 62 (21%) normal controls were homozygous for the C1qA-Gly70GGA SNP, 41 (66%) controls were heterozygous and eight (13%) controls were homozygous for the GenBank sequence. Thus, the C1qA-Gly70GGA SNP is strongly associated with SCLE (P-value = 0.005 by chi-square analysis with Yates correction). This SNP would traditionally be classified as clinically silent as it does not encode a different amino acid. However, our studies have suggested that this SNP appears to be associated with a functional abnormality of C1q expression since its presence correlates inversely with serum levels of C1q antigenic protein in both SCLE patients and normal controls. The mechanism by which this phenotypic change is associated with the translationally silent (synonymous) ClqA-Gly70GGA genetic variation is currently unknown.

C1q regulatory region polymorphism down-regulating murine c1q protein levels with linkage to lupus nephritis.

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 x NZW)F(1) 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 approximately 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 x NZW)F(1) mice than in age-matched non-autoimmune NZW and BALB/c mice. Quantitative trait loci analysis using (NZB x NZW)F(1) x 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.

Reconstitution of the complement function in C1q-deficient (C1qa-/-) mice with wild-type bone marrow cells.

Besides Ab-independent and Ab-dependent activation of the complement classical pathway in host defense, C1q plays a key role in the processing of immune complexes and in the clearance of apoptotic cells. In humans, C1q deficiency leads to systemic lupus erythematosus-like symptoms in over 90% of the cases, thus making this defect a strong disease susceptibility factor. Similarly, C1q-deficient mice (C1qa-/-) develop systemic lupus erythematosus-like symptoms, such as autoantibodies and glomerulonephritis. We have previously provided evidence that C1q is produced by cells of the monocyte-macrophage lineage. In this study, we have tested whether transplantation of bone marrow cells would be sufficient to reconstitute C1q levels in C1qa-/- mice. C1qa-/- mice received a single graft of 10(7) bone marrow cells from wild-type (wt) donors after irradiation doses of 6, 7, 8, or 9 Gy. Engraftment was monitored by a Y chromosome-specific PCR and a PCR that differentiated wt from C1qa-/- genotype. Serum levels of C1q Ag and C1 function increased rapidly in the recipient mice, and titers reached normal levels within 6 wk after bone marrow transplantation. In wt mice that received C1qa-/- bone marrow, serum levels of C1q decreased constantly over time and became C1q deficient within 55 wk. These data clearly demonstrate that bone marrow-derived cells are the source of serum C1q and are competent to reconstitute normal C1q serum levels in C1q-deficient mice. Therefore, stem cell transplantation could be a therapy for patients with hereditary C1q deficiency.

Cloning, sequencing, and role in serum susceptibility of porin II from mesophilic Aeromonas hydrophila.

We cloned and sequenced the structural gene for Aeromonas hydrophila porin II from strain AH-3 (serogroup O:34). The genetic position of this gene, like that of ompF in Escherichia coli, is adjacent to aspC and transcribed in the same direction. However, upstream of the porin II gene no similarities with E. coli were found. We obtained defined insertion mutants in porin II gene either in A. hydrophila (O:34) or A. veronii sobria (serogroup O:11) serum-resistant or -sensitive strains. Furthermore, we complemented these mutants with a plasmid harboring only the porin II gene, which allowed us to define the role of porin II as an important surface molecule involved in serum susceptibility and C1q binding in these strains.

DNA Levels in Circulating Immune Complexes Decrease at Severe SLE Flares—Correlation with Complement Component C1q

The objective of this study was to investigate the relationship of DNA content in circulating immune complexes with disease course and activity in SLE. The DNA content in circulating immune complexes containing anti-DNA antibodies of IgG class was determined in serial samples from 28 patients with SLE by a quantitative immunochemical assay. The patients presented various active disease manifestations over 5–55 months. Disease activity (SLEDAI-score), drug treatment and ACR-criteria were recorded. Levels of anti-dsDNA, CRP, leukocytes, complement components C3, C4 and C1q were measured. Patients with severe flares and high SLEDAI scores had low Clq levels at onset of active disease manifestations. The patients with low C1q serum levels during flare (n=13) had significantly lower amounts of DNA in immune complexes than patients with normal Clq (P=0.001). Levels of DNA in immune complexes correlated with Clq at flares (r=0.62,P <0.0001) and correlated inversely with SLEDAI scores (r=−0.47, P=0.012). In conclusion, the low levels of DNA in circulating immune complexes found in severely ill SLE patients with concomitantly low serum concentrations of Clq prior to flares might be related to tissue deposition of immune complexes.

A one-step solid phase immunoassay for simultaneous detection of serum IgG and IgM antibodies to Borrelia burgdorferi

A one-step immunoassay for simultaneous detection of serum IgG and IgM antibodies to Borrelia burgdorferi has been developed. The assay is based on C1q, which binds to immune complexes containing IgG and/or IgM antibodies. Micro-beads pre-coated with antibodies to human C1q are mixed with human serum samples and fluorochrome-labelled B. burgdorferi flagellum antigen. In the presence of serum IgG and/or IgM antibodies to B. burgdorferi, fluorochrome-labelled antigen/antibody complexes are formed. These are then bound by serum C1q and are subsequently captured on the anti-C1q-coated beads. The sample is analysed on a flow cytometer and the presence of fluorescent beads is, thus, indicative of a positive test result. In the present study the sensitivity and specificity of the assay are compared to those of the indirect IDEIA™ B. burgdorferi IgG and the μ-chain capture IDEIA™ B. burgdorferi IgM ELISAs for separate determination of IgG and IgM. Detection using a flow cytometer can be performed without separation of the beads from the reaction mixture, which means that in practice, the method is carried out as a one-step assay and it is, thus, very suitable for automation. Other advantages of this kind of assay includes an antibody/antigen reaction which occurs in solution and the potential of using the method for the detection of antibodies against several antigens from the same or different infectious agents (multi-parameter screening).

The C1q-Binding Cell Membrane Proteins cC1q-R and gC1q-R Are Released from Activated Cells: Subcellular Distribution and Immunochemical Characterization

Two types of widely coexpressed cell surface C1q-binding proteins (C1q-R): a 60-kDa calreticulin-homolog which binds to the collagen-like “stalk” of C1q and a 33-kDa protein with affinity for the globular “heads” of the molecule, have been described. In this report, we show that the two molecules are also secreted by Raji cells and peripheral blood lymphocytes and can be isolated in soluble form from serum-free culture supernatant by HPLC purification using a Mono-Q column. The two purified soluble proteins had immunochemical and physical characteristics similar to their membrane counterparts in that both bound to intact C1q and to their respective C1q ligands, cC1q and gC1q. In addition, N-terminal amino acid sequence analyses of the soluble cC1q-R and gC1q-R were found to be identical to the reported sequences of the respective membrane-isolated proteins. Ligand blot analyses using biotinylated membrane or soluble cC1q-R and gC1q-R showed that both bind to the denatured and nondenatured A-chain and moderately to the C-chain of C1q. Moreover, like their membrane counterparts, the soluble proteins were found to inhibit serum C1q hemolytic activity. Although cC1q-R was released when both peripheral blood lymphocytes and Raji cells were incubated in phosphate-buffered saline for 1 hr under tissue culture conditions, gC1q-R was releasable only from Raji cells, suggesting that perhaps activation or transformation leading to immortalization is required for gC1q-R release. Subcellular fractionation of Raji cells and analyses by enzyme-linked immunosorbent assay and Western blotting showed that the two molecules are present in the cytosolic fractions as well as on the membrane. The data suggest that soluble forms of both C1q-binding molecules are released from cells and that these molecules may play important rolesin vivoas regulators of complement activation.

Discordant renal histopathologic findings and complement profiles in membranoproliferative glomerulonephritis type III

Patients with membranoproliferative glomerulonephritis (MPGN) type III and a low serum C3 concentration tend to have evidence for a nephritic factor of the terminal complement pathway (Nft). Complement profiles were studied in three patients with MPGN type III and low serum C3 concentrations. Serum C3 concentrations were 52, 21, and 14 mg/dL (normal range, 83 to 177 mg/dL). Serum C1q, C2, C4, properdin, and C5 concentrations were normal in all patients, whereas two had a slight decrease of C7 or C8. This pattern of complement activation resembles that seen with MPGN type II in which a nephritic factor activates the amplification loop (NFa). We conclude that in patients with MPGN type III the previously reported profile/presence of Nft is not always found, at least in the chronic stage of the disease, despite a low C3 value.

Effects of transfer of hybridomas producing various isotypes of immunoglobulins on the C1q metabolism in mice.

In order to elucidate possible effects of immunoglobulin on C1q metabolism at the anabolic steps, serum C1q levels and C1q mRNA of peritoneal exudate cells (PEC) and spleen cells were measured in female BALB/c mice implanted intraperitoneally with complement-(C)-fixing IgG2b- or non-C-fixing class IgG3-producing hybridomas and/or with immunoglobulin-non-productive myeloma cells (p3x63-Ag.8.653)(myeloma 653)(2 x 10(6)/0.2 ml) or without any treatment as controls. In the IgG2b-hybridoma-treated mice, the serum C1q levels and C1q mRNA in PEC increased conspicuously as compared with those in the controls, but C1q mRNA in spleen cells was almost equal to that in the control mice. On the other hand, in the IgG3-hybridoma-treated mice, the serum C1q levels decreased significantly, but the extent of such decrease and the level of C1q mRNA in their PEC were almost equivalent to those in the myeloma 653-implanted mice. The serum C1q levels and C1q mRNA in PEC fluctuated similarly in mice injected intraperitoneally with highly purified IgG2b and/or IgG3 preparations. These results suggest some anabolic interaction, as well as catabolic interaction, between the C-fixing class of immunoglobulin and C1q.

Autoreactivity to mouse C1q in a murine model of SLE.

A large proportion of systemic lupus erythematosus (SLE) patients develop glomerulonephritis, coincident with the appearance of autoantibodies to C1q, the Fc-recognizing collagen-like subcomponent of the first component of complement, C1. The MRL/lpr/lpr mouse is an established model for SLE, developing both antinuclear and anti-type II collagen autoantibodies, and rheumatoid factors(s), exhibiting reduced complement levels and later on developing glomerulonephritis and often arthritis. We report here an age-dependent decrease in serum C1q levels coincident with the development of IgG2b autoantibodies reactive with mouse C1q in MRL/lpr/lpr mice. Unlike IgG2b, although high levels of IgM, IgG1 and IgG2a are present in these mice, few, if any, antibodies of these subclasses reactive with mouse C1q were observed in this study. This is the first report of autoantibodies against autologous C1q in an animal model, and the results should facilitate in clarification of the roles of C1q and autoantibodies reactive with C1q in SLE, as well as their potential connection with glomerulonephritis.

Hypocomplementemic Urticarial Vasculitis Syndrome: Clinical and Serologic Findings in 18 Patients

We identify and describe clinical findings in hypocomplementemic urticarial vasculitis syndrome (HUVS), an uncommon to rare illness related to systemic lupus erythematosus (SLE). A patient with recurrent, idiopathic urticaria-like lesions was diagnosed as having HUVS if a lesional biopsy showed leukocytoclastic vasculitis, the serum C1q was markedly decreased, and antibody to C1q was detected in the patient's serum. The clinical characteristics, serologic findings, and outcome of patients who met these criteria were determined from prospective and retrospective data, including hospital and office records, patient interviews, previously banked serum samples, and freshly drawn sera. Eighteen patients with HUVS were identified, and high incidences of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease were found. Renal and lung biopsies showed mesangial or membranoproliferative glomerulonephritis and severe pulmonary emphysema without vasculitis. Pulmonary function was measured in 17 patients, 11 of whom had dyspnea. All dyspneic patients had moderate to severe airflow obstruction, which progressed in all 11 and subsequently improved in only 1. Six of these 11 patients died of respiratory failure, 1 underwent lung transplantation, and 3 of the remaining 4 have moderately severe to life-threatening respiratory insufficiency. Treatment did not appear to alter the progression of obstructive lung disease. In contrast, renal insufficiency improved with treatment in 2 of 2 patients. Angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis appear to be common in HUVS, and lung disease causes substantial morbidity and mortality. The pathogenesis of HUVS may involve humoral autoimmunity, although it is not clear how autoimmunity would participate in development of obstructive lung disease. Cigarette smoking appears to be a risk factor for fatal lung disease in HUVS. All patients with HUVS should be made aware of this possibility and should be advised, encouraged, and helped to avoid tobacco smoke.

C1q, the collagen‐like subcomponent of the first component of complement C1, is a membrane protein of guinea pig macrophages

C1q, a subcomponent of C1--the first component of complement, is synthesized by macrophages (M phi). Immunofluorescence and immunoperoxidase studies first indicated the presence of C1q on the surface of guinea pig (gp) and human peritoneal M phi (Loos, M., Storz, R., Müller, W. and Lemmel, E. M., Immunobiology 1981. 158: 213). In our study different methods for labeling of gp serum and gp M phi C1q were employed. The presence of C1q protein on the surface of gp peritoneal M phi is shown by cell surface labeling with the biotin derivative sulfosuccinimdyl-6-(biotinamido)-hexanoate and subsequent immunoprecipitation. The mechanism by which C1q is attached to the cell membrane was also investigated. Intact cells were treated with acid stripping-buffers or phosphatidylinositol-specific phospholipase C and separated membranes were extracted with a buffer containing 1 M KCl and 3 M urea. Regardless of which method was used, C1q remained attached to the membrane. When surface-labeled cells were cultured, they were found to release the C1q from their surface membrane into the culture medium. Lysates of biosynthetically labeled cells were used to show that, like secreted or serum C1q, cellular M phi C1q binds to immobilized homologous IgG. This implies that the globular regions of the cellular C1q are functionally active. The results reveal that (i) cellular M phi C1q is firmly located in the membrane throughout the biosynthetic pathway, such that it is comparable with an integral membrane protein, (ii) cellular M phi C1q is not reversibly bound to the cell surface via a receptor. We suggest that C1q, as a membrane protein of M phi, serves as an Fc binding factor that also is secreted into the environment.