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PubMed2005

Role of anti-C1q autoantibodies in the pathogenesis of lupus nephritis.

Anti-C1q autoantibodies can be found in the sera of patients with several autoimmune diseases, but also in healthy individuals. Although these anti-C1q autoantibodies were already identified several decades ago, they still puzzle both immunologists and nephrologists. The main reason for this puzzling effect are observations that seemed to indicate quite clearly that anti-C1q should be pathogenic to the kidney and the observation on the other hand that anti-C1q autoantibodies can be found in several disease conditions, as well as in healthy individuals, and are then unrelated to overt renal inflammation. This puzzle is the focus of the current review, which will provide an overview of the historical data, define the clinical interests and, importantly, will try to put several aspects in perspective based on recent observations in patients and in murine models. In addition, the paper will discuss therapeutic intervention possibilities regarding anti-C1q-mediated damage in systemic lupus erythematosus, as well as the therapeutic potential of anti-C1q antibodies in other conditions.

Animals↗
PubMed1984

Location of the binding site in subcomponent C1q for plasma fibronectin.

Previous studies on the interaction of fibronectin with C1q have yielded apparently conflicting results since both the globular head regions (produced by collagenase digestion) and the collagen-like domains (produced by limited pepsin digestion) have been reported to bind to fibronectin. In this study, the binding of 125I-labelled fibronectin to either intact C1q, or the collagenase or pepsin digestion products, immobilised on plastic microtitre plates was examined. Inhibition of the C1q-fibronectin interaction by the C1q digestion products was also examined. The results confirmed that both globular 'head' region preparations and collagen-like region preparations, can interact with fibronectin. Since the fragments used in these studies share a section of common amino acid sequence from the C1q molecule it can be concluded that the binding site, on C1q for fibronectin, is located in a region formed from the residues 81-97 of each of the three chains of the C1q molecule.

Amino Acid Sequence↗
PubMed1984

Influence of serum complement and rheumatoid factor on detection of immune complexes by the C1q and monoclonal rheumatoid factor solid-phase assay.

Soluble purified monoclonal and polyclonal rheumatoid factor, total serum complement, and soluble C1q all inhibit the detection of model tetanus toxoid/anti-toxoid immune complexes in the solid-phase C1q assay. The binding of these immune complexes to solid-phase monoclonal rheumatoid factor is less inhibited by soluble C1q and by total serum complement, but clearly decreased by soluble monoclonal or polyclonal rheumatoid factor. Serum complement does not reduce the size of these model complexes. We recommend the use of low ionic strength EDTA (10 mM) to partly neutralize the complement-mediated inhibition. This procedure is shown to be superior to currently used higher EDTA concentrations and to the use of IgG-Sepharose.

Antibodies, Monoclonal↗
PubMed1999

Alzheimer's beta-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner.

beta-Amyloid (beta-A) accumulates in the brain of patients with Alzheimer's disease (AD) and is presumably involved in the pathogenesis of this disease, on account of its neurotoxicity and complement-activating ability. Although assembly of beta-A in particular aggregates seems to be crucial, soluble non-fibrillar beta-A may also be involved. Non-fibrillar beta-A does not bind C1q, so we investigated alternative mechanisms of beta-A-dependent complement activation in vitro. On incubation with normal human plasma, non-fibrillar beta-A 1-42, and truncated peptide 1-28, induced dose-dependent activation of C1s and C4, sparing C3, as assessed by densitometric analysis of immunostained membrane after SDS-PAGE and Western blotting. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar beta-A can still activate C1s and C4 in plasma genetically deficient in C1q (C1qd). In Factor XII-deficient plasma (F.XIId) the amount of cleaved C4 was about 5-10% less that in C1qd and in normal EDTA plasma; the reconstitution of F.XIId plasma with physiologic concentrations of F.XII resulted in an increased (8-15%) beta-A-dependent cleavage of C4. Thus our results indicate that the C1q-independent activation of C1 and C4 can be partially mediated by the activation products of contact system. Since the activation of contact system and of C4 leads to generation of several humoral inflammatory peptides, non-fibrillar beta-A might play a role in initiating the early inflammatory reactions leading to a multistep cascade contributing to neuronal and clinical dysfunction of AD brain.

Alzheimer Disease↗
PubMed1987

Human blood platelets possess specific binding sites for C1q.

Although platelet interactions with C1q are implied by the inhibitory effect of C1q on collagen-induced platelet aggregation, specific receptors have not as yet been identified. To address the question of platelet receptors for free C1q, direct radioligand binding studies were performed by using human blood platelets and purified, 125I-labeled C1q, and a monoclonal antibody (II1/D1) (IgM, lambda) directed against C1q receptors on peripheral blood leukocytes. Washed platelets bound both purified 125I-labeled C1q and II1/D1 in a specific and saturable manner under physiologic ionic strength conditions. At equilibrium, approximately 4000 molecules of C1q bound per platelet with an apparent dissociation constant of 3.5 X 10(-7) M. Maximum C1q binding was achieved in 5 min and correlated well with inhibition of collagen-induced platelet aggregation. Equilibrium binding of 125I-labeled II1/D1 to washed platelets required an incubation period of 15 to 30 min and II1/D1 concentrations approaching 50 micrograms/ml. Approximately 2000 molecules of II1/D1 bound per platelet, with an apparent dissociation constant of 2.8 X 10(-8) M. II1/D1 binding could be inhibited by the collagenous tail of C1q (c-C1q), suggesting that platelet receptors for these ligands are either the same or in close proximity. The data demonstrate that human blood platelets possess specific and saturable binding sites for free C1q that may function as collagen receptors, and may antigenically resemble C1q receptors on peripheral blood leukocytes.

Antibodies, Monoclonal↗
PubMed1984

The C1q receptor site on human immunoglobulin G.

Of the many functional properties of the immunoglobulin G (IgG) molecule, only antigen binding and the interaction with the C1q component of complement have been shown to be uniquely associated with the individual compact domains which make up this immunoglobulin. The chemical and biological evidence for the exclusive association of the C1q-binding site with the CH2 domain is reviewed, affirming that the site probably is centered on the residues 279-295 which are located on the outside of the molecule and contain, in particular, three positively charged residues which are thought to be vital to the interaction. An alternative site (residues 316-338), having similar exposure and charge characteristics, is discussed and arguments are presented indicating why the former is currently favoured.

Amino Acid Sequence↗
PubMed1995

Evidence for activation of the terminal pathway of complement and upregulation of sulfated glycoprotein (SGP)-2 in the hypoglossal nucleus following peripheral nerve injury.

In a previous study, we found immunoreactivity for complement factors C3, C3d, and C4d, as well as endogenous IgG in the hypoglossal nucleus following hypoglossal nerve transection, suggesting that activation of the complement cascade had taken place in the vicinity of the axotomized motorneurons. In the present study, we found increased immunoreactivity for complement factor C1 and C1q in reactive microglia, indicating an increased potential for initiation of the classical pathway by binding of IgG to C1q. Furthermore, we found immunoreactivity for C9, which contributes to the formation of C5b-9, the final lytic product of the complement cascade close to the axotomized neurons and perineuronal glia. In addition, immunoreactivity and mRNA labeling of sulfated glycoprotein (SGP-2), a putative complement inhibitor, was increased in a subpopulation of the axotomized motorneurons. SGP-2 immunoreactivity was also increased in astroglial cells ipsilateral to the nerve injury. The results lend further support to the hypothesis that the complement cascade is activated in the vicinity of axotomized neurons, which in turn may be protected by complement inhibitors. The balance between activation of complement and complement inhibitors might have an impact on the degenerative components of the axon reaction and, in particular, the events leading to nerve cell death.

Animals↗
PubMed1985

Isolation and purification of a Clq-anti Clq precipitin ring enhancing protein from sera of patients with rheumatoid arthritis.

We have isolated and purified to apparent homogeneity a serum protein which appears to be a biological marker for active rheumatoid arthritis. The protein has been found in the sera in all 44 active rheumatoid arthritis patients thus far studied and is absent from, or present in undetected amounts, in sera from normal subjects or from patients with other arthritides. The protein has a molecular weight of 135,000 daltons, an isoelectric pH of 5.1-5.3, and it enhances the size of the C1q-anti C1q ring.

Antibodies↗
PubMed1991

Reactions of the immune system in chronic degenerative neurological diseases.

Elements consistent with a cell mediated immune response were identified immunohistochemically in amyotrophic lateral sclerosis (ALS) spinal cord and Alzheimer disease (AD) hippocampus. T helper/inducer and cytotoxic/suppressor lymphocytes were detected in affected tissues in both diseases. In addition, abundant reactive microglia were found expressing the major histocompatibility glycoproteins HLA-A,B,C and HLA-DR, as well as receptors for the Fc chain (Fc gamma R1), for complement 3 and 4, and for vitronectin. In AD, the complement proteins C1q, C4d, C3d and C5b-9 were found on dystrophic neurites, neuropile threads and some neurofibrillary tangles. In ALS, the only complement proteins identified were C4d and C3d. The integrin ligands vitronectin and ICAM-1 were also identified in affected tissues in both diseases.

Alzheimer Disease↗
PubMed1986

Antibody-independent interactions of fibronectin, C1q, and human neutrophils with Treponema pallidum.

Although recent evidence suggests that fibronectin may be involved in the attachment of treponemes to mammalian cells, its possible role in promoting phagocytosis of Treponema pallidum has not been investigated. In the present study, we examined the antibody-independent interactions of fibronectin, C1q, and human polymorphonuclear leukocytes with T. pallidum. Binding of [125I]fibronectin was specific and saturable with an affinity constant of approximately 2 X 10(7) M-1. The number of binding sites per treponeme at 37 degrees C, irrespective of the mammalian source of fibronectin, was between 2,500 and 7,500, with a mean of approximately 4,700. Binding of [125I]C1q to T. pallidum, in the absence of antibodies to the organism, also was saturable and specific. Pretreatment of treponemes with C1q enhanced binding of soluble [125I]fibronectin two- to threefold and also increased attachment of 125I-surface-labeled treponemes to fibronectin-coated surfaces. Treatment of 125I-labeled T. pallidum with fibronectin alone, or together with C1q, however, did not enhance surface phagocytosis by neutrophils.

Bacterial Proteins↗
PubMed1989

Biological functions of C1q expressed by conformational changes.

Of all the serum proteins C1q is one of the most positively charged. Two dimensional-isoelectric focussing studies revealed an isoelectric point of 9.3. Due to its unique character C1q is able to interact directly with highly negatively charged molecules (e.g. mucopolysaccharides, MPS.) This interaction is ionic in nature as demonstrated by electro-immunoassay. Binding of C1q to immune complexes induces conformational changes. The inhibitory effect of MPS on C1q, as measured by hemolytic assay, provides positive evidence for such conformational changes. The detection of neoantigens further supports this observation. These in vitro studies suggest that the observed autoantibodies against the collagenous portion of C1q in certain SLE patients are induced by long-acting conformational changes within the C1q-immune complex.

Antibodies, Monoclonal↗