Purification of subcomponents Clq, Cl(-)r and Cl(-)s of the first component of complement from Cohn Fraction I by affinity chromatography.
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Chromatography, Affinity↗
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I-PLA(2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation.
Deficiency of serum immunoglobulin (Ig)M is associated with the development of a lupus-like disease in mice. Recent studies suggest that classical complement components facilitate the clearance of apoptotic cells and that failure to do so predisposes mice to lupus. Since IgM is a potent activator of the classical complement pathway, we examined IgM binding to dying cells. IgM, but not IgG, bound to apoptotic T cells through the Fab' portion of the antibody. Exposure of apoptotic cell membranes to phospholipase (PL) A2 increased, whereas PLD reduced, IgM binding and complement activation. Absorption studies combined with direct plate binding assays, revealed that IgM antibodies failed to bind to phosphatidyl lipids, but did recognize lysophosphatidylcholine and the phosphorylcholine head group. Both iPLA(2) and cPLA(2) are activated during apoptosis. Since inhibition of iPLA2, but not cPLA2, attenuated IgM binding to apoptotic cells, these results strongly suggest that the endogenous calcium independent PLA(2), iPLA(2), is involved in the hydrolysis of plasma membrane phospholipids and exposure of the epitope(s) recognized by IgM. We propose that recognition of dying cells by natural IgM antibodies is, in part, responsible for complement activation on dying cells leading to their safe clearance.
Animals↗
Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes.
To explore the biological significance of gene expression in the pathogenesis of inflammatory myopathies, we performed microarray experiments followed by real-time PCR and immunohistochemistry on muscle biopsies obtained before and after therapy from patients with dermatomyositis (DM) who improved and patients with inclusion body myositis (sIBM) who did not improve after controlled trials with three monthly intravenous immunoglobulin (IVIg) infusions. The pretreatment biopsies showed high expression of immunoglobulin, adhesion molecules, chemokines and cytokine genes in both sIBM and DM (sIBM > DM). In the repeated biopsies of DM patients who clinically improved, 2206 genes were downregulated more than 1.5-fold; in contrast, 1700 of the same genes remained unchanged in sIBM patients who did not improve. Genes markedly downregulated in DM, but not sIBM, were interleukin 22, Kallmann syndrome 1 (KAL-1), an adhesion molecule shown for the first time in muscle, ICAM-1, complement C1q, and several structural protein genes. Because mRNA for KAL-1 was selectively upregulated in vitro by transforming growth factor (TGF) beta1, a fibrogenic cytokine immunolocalized in the endomysial connective tissue of pretreatment DM muscles, the downregulation of both TGF-beta and KAL-1 after IVIg only in DM suggests that these molecules have a functional role in connective tissue proliferation and fibrosis. The improved muscles of DM, but not sIBM, showed upregulation of chemokines CXCL9 (Mig) and CXCL11, and several immunoglobulin-related genes, suggesting an effect on muscle remodelling and regeneration. The results suggest that IVIg modulates several immunoregulatory or structural muscle genes, but only a subset of them associated with inflammatory mediators, fibrosis and muscle remodelling are connected with the clinical response. Gene arrays, when combined with clinical assessments, may provide important information in the pathogenesis of inflammatory myopathies.
Adult↗
No lupus nephritis in the absence of antiC1q autoantibodies?
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Autoantibodies↗
Fibronectin binding with immunoglobulin aggregates and its association with rheumatic disorders.
Fibronectin was shown to bind heat-aggregated, but not monomeric, human IgG, suggesting that fibronectin may bind directly to IgG immune complexes. The presence of material both binding and already containing fibronectin was demonstrated in polyethylene glycol precipitates of sera and synovial fluids from patients with rheumatoid arthritis (RA) and gout, but not normal sera. By contrast, complement-fixing complexes contained fibronectin in RA synovial fluids and sera, but not in sera and synovial fluids from other rheumatic disorders. It is considered that fibronectin binds to immune complexes in RA synovial fluids and sera but that some other, as yet unidentified material, is effective in binding fibronectin in sera and synovial fluids from patients with osteoarthritis and crystal synovitis.
Antigen-Antibody Complex↗
A4 protein in Alzheimer's disease: primary and secondary cellular events in extracellular amyloid deposition.
This study was designed to investigate the role of serum proteins, microglia, glial fibrillary acidic protein (GFAP) positive cells and dystrophic neurites in the genesis of cerebral amyloid. Using A4 protein antisera, we found an amorphous non-congophilic, form of plaque, which was not seen in Bielschowsky silver staining or Bodian impregnations. GFAP-positive glial cells, cells immunolabelled for some macrophage markers and dystrophic neurites were detected in congophilic plaques with crystalline amyloid, but not in the amorphous, non-congophilic plaques. The presence of alpha l-antichymotrypsin, complement factors and P component, but not of common serum proteins in both the amorphous and congophilic plaques, indicates that these three proteins may have a pathogenetic role in amyloid formation. Amorphous plaques may be the earlier forms of plaque and consequently, the presence of reactive cells and dystrophic neurites may be secondary phenomena.
Alzheimer Disease↗
Circulating immune complexes in allogeneic marrow graft recipients.
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Adolescent↗
Recurrent nephrotic syndrome following renal transplantation in patients with focal glomerulosclerosis. A one-center study of plasma exchange effects.
Forty seven renal allografts performed over a period of 12 years in 43 recipients with chronic renal failure due to biopsy-proved focal glomerulosclerosis (FGS, 5.34% from 888 cadaveric renal transplantations) were reviewed. Recurrence of the disease was suspected in 14 grafts (29.8%) on the basis of immediate proteinuria, but recurrence of FGS lesions was demonstrated in only 7 patients. The remaining 7 patients had minimal-change nephropathy or mesangial hyperplasia. The duration of renal disease before transplantation was a clear predictive risk factor of FGS recurrence, and mesangial hyperplasia in the native kidneys was associated with 50% risk of FGS recurrence. Some reports have suggested that plasma exchange may be beneficial in the treatment of FGS recurrence. Our experience, in 9 patients, indicates that plasma exchange initiated early in the course of recurrent proteinuria leads to transient but significant disappearance (2 cases) or decrease (5 cases) of proteinuria, with a return to pre-plasma exchange levels within 2 weeks after the end of treatment. In 2 cases, there was no beneficial effect on proteinuria. Plasma exchange efficacy was correlated with proteinuria levels relative to disease severity. Although plasma exchange does not seem to improve the outcome of FGS recurrence, it demonstrates the possible presence of circulating factor(s) and argues for the characterization of humoral mediator(s).
Complement C1q↗
Multimerin.
Multimerin is a massive, disulfide-linked protein with a unique complementary DNA sequence. It is stored in platelets and the endothelium of blood vessels and is comprised of subunits linked by interchain disulfide bonds to form large, variably sized homomultimers. The multimerin subunits are derived from a common precursor protein, promultimerin, which undergoes proteolysis and extensive N-glycosylation during biosynthesis. The complementary DNA sequence of multimerin indicates that multimerin is a novel protein, with Arg-Gly-Asp-Ser, coiled-coil, and epidermal growth factor-like domains. The C-terminal region of multimerin resembles the globular head domain of complement C1q and collagens type VIII and X. Multimerin is expressed by megakaryocytes and endothelial cells and stored within platelet alpha granules and endothelial cell Weibel-Palade bodies. Following cellular activation, multimerin is released and binds to these cells and the extracellular matrix. The function of this novel protein in hemostasis is under investigation. Recent studies have identified multimerin as a specific Factor V/Va binding protein that is complexed with Factor V within platelet alpha granules.
Blood Platelets↗
Complement fixation by pemphigus antibody. I. In vitro fixation to organ and tissue culture skin.
Although complement is often detected in the intercellular substance of pemphigus skin lesions, the ability of pemphigus antibodies to fix complement in vitro is controversial. The purpose of this study was to test in vitro complement fixation abilities of pemphigus antibodies further using organ and tissue culture methods. Epidermal cell monolayers from mouse tail were incubated with the purified IgG fraction of pemphigus serum followed by purified Clq. Binding of Clq, as well as IgG was demonstrated by immunofluorescence methods. When purified Clq was replaced with normal human serum as a complement source, positive C3 and C4 staining were also evident. When purified IgG of normal human serum was used in place of pemphigus IgG, similar immunofluorescence staining was not observed. Further evidence for complement fixation in vitro by pemphigus antibodies was obtained using organ cultures. Organ culture of normal human skin and monkey esophageal mucosa cultured in purified pemphigus IgG showed intercellular substance binding of IgG. No binding was observed when normal IgG was substituted for pemphigus IgG. Additional organ culture sections were then treated with complement (fresh normal human serum) and tested by in vitro complement staining. Fixation of Clq, C4, and C3 was noted in intercellular substance areas of organ cultured skin and mucosa incubated with pemphigus IgG but not those incubated with normal IgG. Prior treatment of pemphigus IgG organ cultured skin sections with unlabeled anti-C3, blocked positive C3 staining. These results suggest that some pemphigus antibodies are capable of activating complement in vitro.
Animals↗
Antibody-independent binding of Clq and activation of serum complement by human skin in vitro.
By exposing frozen sections of human skin to fresh normal human serum, binding and activation of complement was observed. Attached complement components Clq, C4, and C3 were detected by immunofluorescence microscopy using anticomplement conjugates. Isolated Clq bound to the same structures as serum Clq, C4, and C3 and binding of C4 and C3 was dependent on binding of Clq. The complement components bound to capillary endothelial cells and to fibrillar structures in the dermis and reacted with the epidermis. Complement binding dermal fibrillar structures in adult skin were scant but abundant in fetal skin. They had similar distribution as "microfibrils" demonstrable by human autoantibodies. Antibody independence of the Clq binding was shown using isolated Clq and by the observed constant and reproducible binding of complement of normal sera lacking antibodies to the described target structures. The observations suggest that antibody independent binding of complement should be considered as a possible mechanism leading to dermal complement deposition in vivo.
Adult↗
Circulating IgA immune complexes in patients with psoriasis.
The sera of 21 patients with psoriasis were examined for the presence of IgA-containing circulating immune complexes (CIC) using the Raji IgA radioimmunoassay. In addition, the Raji IgG radioimmunoassay and 125I-Clq binding assay were used to detect IgG- and IgM-containing CIC. Twenty-five patients with other hyperkeratotic skin disorders were studied as controls. Patients were studied before institution of systemic therapy with etretinate (20 patients) or 13-cis-retinoic acid (1 patient). In addition, sera of 15 of the patients treated with etretinate were studied before, during, and after therapy. The extent of pretreatment disease involvement as well as response to therapy were evaluated in a blinded fashion. Fourteen of 21 (67%) patients with psoriasis had evidence of IgA-containing CIC at some time during the course of their disease, as compared to only 1 of 25 patients with other hyperkeratotic skin disorders. In contrast, only 2 of 19 (11%) had evidence of IgG-containing CIC using the Raji IgG assay, and only 1 of 19 (5%) had evidence of IgG- or IgM-containing CIC using the 125I-Clq binding assay. A positive correlation was found between the extent of pretreatment disease involvement and the level of IgA-containing CIC by linear regression analysis (p = 0.01). There was, however, no correlation between clinical improvement and the presence or level of IgA-containing CIC in 15 patients followed during therapy. Sucrose density gradient analysis of the IgA-containing CIC found in 2 of these patients demonstrated IgA-containing CIC in the 9S to 13S region. The finding of IgA-containing CIC in a significant number of patients with psoriasis and the relative absence of IgG- or IgM-containing CIC suggest that IgA-containing CIC may play a role in psoriasis. The lack of correlation with clinical improvement, however, suggests these IgA-containing CIC are not directly related to the cutaneous manifestations of psoriasis, but may be important in the modification of immune or inflammatory responses in these patients.
Adult↗
Immunofluorescence study of drug-induced lichen planus-like lesions.
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Adult↗
New complement fixation test with peroxidase-labeled complement Clq for direct and quantitative determination of antibodies to herpes simplex virus.
An enzyme-labeled complement fixation (ELISA-CF) test for the direct and quantitative determination of complement fixing (CF) antibodies has been developed. This paper described the introduction of the ELISA-CF test that used peroxidase-labeled Clq component of complement to detect CF antibodies which had reacted with herpes simplex virus (HSV), as a virus model. Equal volumes of heat-inactivated serum and the peroxidase-labeled Clq (P*-Clq) were simultaneously added to wells of microplates which had been coated with HSV CF antigen or with cell control antigen. The enzymatic activities of P*-Clq bound to the immune complex were determined photometrically. The ELISA-CF test allows processing of serum specimens in a 3-hr operation, with procedural simplicity and increased specificity and sensitivity compared with the conventional CF test.
Antibodies, Viral↗
Bullous pemphigoid: a correlative study of autoantibodies, circulating immune complexes and dermo-epidermal deposits.
Twenty bullous pemphigoid (BP) patients were studied to establish any correlation between free anti-basement membrane zone (BMZ) antibodies, circulating immune complexes (CIC) and dermo-epidermal junction deposits. CIC levels were evaluated by 2% polyethylene glycol (PEG) precipitation. The twenty patients were found to have IgG and/or C3 deposited in the BMZ. Eight of the twelve patients who had no free anti-BMZ antibodies displayed a positive in vivo C4 and/or CIq staining and high levels of CIC. Moreover, CIC were detected in only one patient with positive circulating free anti-BMZ antibodies. The presence of free anti-BMZ antibodies was generally found to correlate with the absence of cutaneous deposits of CIq and /or C4 and with negative CIC; on the other hand, the absence of free anti-BMZ antibodies was generally found to correlate with high levels of CIC and with deposits of C3 and CIq and/or C4. The absence of circulating free anti-BMZ antibodies in BP patients, could be explained by the formation of CIC. It is possible that BMZ antigens released from damaged tissue could combine with free antibodies and form complexes in the blood. The release could involve locally formed immune complexes. Elevated CIC levels were generally found to correlate with the presence of active disease.
Aged↗
Complement in chronic cutaneous lupus erythematosus.
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Complement Activating Enzymes↗
The lupus band test in oral mucosa, conjunctiva and skin.
The prevalence and clinical significance of subepithelial immunoglobulin and complement deposition (the lupus band) were examined in the uninvolved sun-protected skin of the forearm, the uninvolved sun-protected lip mucosa and sun-protected bulbar conjunctival mucosa in systemic lupus erythematosus (SLE) and chronic cutaneous lupus erythematosus (CCLE). In SLE, linear deposition of an immunoreactant at the BMZ was detected in 32% (6/19) of skin biopsies; 21% (4/19) of lip mucosal biopsies and 42% (5/12) of conjunctival biopsies. There was no significant difference in the sensitivity of the test at different sites in SLE and no correlation between a positive test in skin, lip or conjunctiva and clinical mucosal involvement. In CCLE, linear deposition of an immunoreactant at the BMZ was found in 3% (1/32) of skin biopsies; 3% (1/29) of lip mucosal biopsies and 50% (10/20) of conjunctiva and clinical mucosal involvement. In the conjunctiva, IgG was present in all but one of the biopsies and was the only immunoreactant in 90% (9/10) of positive CCLE biopsies and 60% (3/5) of positive SLE biopsies. In lupus erythematosus immunoreactants may be deposited in the basement membrane zone beneath non-keratinizing mucosal surfaces of the lip and the eye as well as the skin. In CCLE, the test may be positive in conjunctiva when skin and lip are negative.
Adolescent↗
Characterization of anti-endothelial cell antibodies in systemic lupus erythematosus (SLE).
IgG anti-endothelial antibodies (AEA), as measured by ELISA or immunoblotting technique could be detected in serum samples of 56 out of 64 patients with SLE (88%) and mainly occurred in monomeric form. AEA were not cell specific, because the binding reactivity was absorbed partially by both fibroblasts and peripheral blood mononuclear cells. No correlation was found between the presence of AEA and anti-nuclear antibodies. Immunoblotting revealed reactivity of AEA against endothelial antigens ranging in size from 15 to 200 kD. AEA titres were significantly higher in patients with joint or skin abnormalities, compared with patients without these abnormalities. A significant correlation was found between nephritis in SLE and the presence of AEA reactivity against endothelial membrane antigens of 38, 41 and 150 kD. These data show that the pattern of AEA reactivity in serum of SLE patients is heterogeneous, and suggest that AEA against a limited number of antigens may be involved in the pathogenesis of nephritis in SLE.
Antibodies, Anti-Idiotypic↗