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PubMed1998

Activation of complement by human IgG1 and human IgG3 antibodies against the human leucocyte antigen CD52.

Activation of the complement cascade by immunoglobulin G (IgG) plays a major role in the host defense against pathogens. Using recombinant human antibodies specific for the leucocyte antigen CD52, different allotypes of human IgG1 subclass were compared for their ability to activate human complement. In addition the roles of the different length hinge regions of IgG1 and IgG3 were investigated. It was found that the naturally occurring allotypes G1m(a,z) and G1m(f), and one artificially created isoallotype, G1m(null), did not significantly differ in their overall ability to cause cell lysis. However, some differences in binding of individual components of the classical activation pathway were detected. More of the complement component C1s seemed to be associated with the allotype G1m(f), although this did not result in an overall improvement in lytic potency. In this system the wild-type IgG3 was found to be less effective in complement lysis than IgG1. By shortening the hinge region of IgG3 to resemble that of an IgG1 antibody, increased complement binding was observed compared with that of wild-type IgG3 and the IgG1 allotypes. The overall lytic potency of the antibody was also improved compared with wild type IgG3 and it was also slightly more effective than the IgG1 allotypes.

Antigens, CD↗
PubMed2002

Apoptosis of thymocytes related to cytokine expression in experimental classical swine fever.

Atrophy of the thymic cortex and loss of thymocytes were studied in 32 pigs inoculated with the virulent strain "Alfort" of classical swine fever (CSF) virus and killed at intervals from 2 to 15 days after infection. Immunohistochemical, ultrastructural, ELISA and TUNEL methods were used. The results suggested that direct action of CSF virus on thymocytes played no more than a minor role. The massive lymphoid depletion observed in the thymus, may, however, have been associated with the numerical increase in monocytes-macrophages in this organ, and their secretory activation, leading to synthesis and release of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1alpha and C1q complement component as main chemical mediators, and IL-1beta and IL-6 as minor mediators. These cytokines (TNF-alpha and IL-1alpha) may have played a role in the apoptosis of thymocytes, demonstrated by TUNEL and ultrastructural methods. The pathogenetic mechanism outlined may contribute to the lymphoid depletion observed in others organs in CSF and may explain the lymphopenia characteristic of the disease.

Animals↗
PubMed2002

The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice.

The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.

Animals↗
PubMed2003

Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB.

Alpha-N-acetylglucosaminidase deficiency (mucopolysaccharidosis IIIB, MPS IIIB) and alpha-l-iduronidase deficiency (MPS I) are heritable lysosomal storage diseases; neurodegeneration is prominent in MPS IIIB and in severe cases of MPS I. We have obtained morphologic and molecular evidence for the involvement of microglia in brain pathology of mouse models of the two diseases. In the cortex, a subset of microglia (sometimes perineuronal) consists of cells that are probably phagocytic; they have large storage vacuoles, react with MOMA-2 (monoclonal antibody against macrophages) and Griffonia simplicifolia isolectin IB(4), and stain intensely for the lysosomal proteins Lamp-1, Lamp-2, and cathepsin D as well as for G(M3) ganglioside. MOMA-2-positive cells appear at 1 and 6 months in MPS IIIB and MPS I mice, respectively, but though their number increases with age, they remain sparse. However, a profusion of cells carrying the macrophage CD68/macrosialin antigen appear in the cortex of both mouse models at 1 month. mRNA encoding CD68/macrosialin also increases at that time, as shown by microarray and Northern blot analyses. Ten other transcripts elevated in both mouse models are associated with macrophage functions, including complement C4, the three subunits of complement C1q, lysozyme M, cathepsins S and Z, cytochrome b558 small subunit, macrophage-specific protein 1, and DAP12. An increase in IFN-gamma and IFN-gamma receptor was observed by immunohistochemistry. These functional increases may represent activation of resident microglia, an influx and activation of blood monocytes, or both. They show an inflammatory component of brain disease in the two MPS, as is known for many neurodegenerative disorders.

Animals↗
PubMed1992

Complement activation by beta-amyloid in Alzheimer disease.

Alzheimer disease (AD) is characterized by excessive deposition of the beta-amyloid peptide (beta-AP) in the central nervous system. Although several lines of evidence suggest that beta-AP is neurotoxic, a mechanism for beta-AP toxicity in AD brain remains unclear. In this paper we provide both direct in vitro evidence that beta-AP can bind and activate the classical complement cytolytic pathway in the absence of antibody and indirect in situ evidence that such actions occur in the AD brain in association with areas of AD pathology.

Alzheimer Disease↗
PubMed2002

beta 1 Integrin-dependent cell adhesion to EMILIN-1 is mediated by the gC1q domain.

EMILIN-1 (Elastin Microfibril Interface Located ProteIN), the prototype of the EMILIN family, consists of a cysteine-rich domain (EMI domain) at the N terminus, an extended region with a high potential coiled-coil structure, a short collagenous stalk, and a self-interacting globular gC1q-l domain. EMILIN-1 is an adhesive extracellular matrix constituent associated with elastic fibers, detected also in the proximity of cell surfaces. To localize the cell attachment site(s), monoclonal antibodies (mAbs) against EMILIN-1 or the gC1q-1 domain were used to inhibit cell attachment to EMILIN-1. Thus, one mAb mapping to the gC1q-1 domain caused complete inhibition of cell attachment. EMILIN-1 and gC1q-1 displayed a comparable dose-dependent ability to promote cell adhesion. Adhesion kinetics was similar to that of fibronectin (FN), reaching the maximum level of attachment at 20 min, but in the absence of cations adhesion was negligible. The relative adhesion strength to detach 50% of the cells was similar for EMILIN-1 and gC1q-1 (250-270 x g) but lower than that for FN (>>500). Cell adhesion to EMILIN-1 or gC1q-1 was completely blocked by a function-blocking beta(1) integrin subunit mAb. In contrast, adhesion to the complement C1q component was totally unaffected. Among the various function-blocking mAbs against the alpha integrin subunits only the anti-alpha(4) fully abrogated cell adhesion to gC1q-1 and up to 70% to EMILIN-1. Furthermore, only K562 cells transfected with the alpha(4) integrin chain, but not wild type K562, were able to adhere to EMILIN-1 and were specifically inhibited by anti-alpha(4) function-blocking mAb. Finally, cells attached to EMILIN-1 or gC1q-1, compared with cells plated on FN or vitronectin, which appeared well spread out on the substrate with prominent stress fibers and focal contacts, were much smaller with wide ruffles and a different organization status of the actin cytoskeleton along the cell periphery. This pattern was in accord with the ability of EMILIN-1 to promote cell movement.

3T3 Cells↗
PubMed1998

Early detection of epidermal dust-like particles in experimentally UV-induced lesions in patients with photosensitivity and lupus erythematosus.

Dust-like particles, producing a specific fine-speckled, epidermo-subepidermal direct immunofluorescence staining pattern, have been associated mainly with subacute cutaneous lupus erythematosus (LE). Under experimental conditions the appearance of immunoglobulins along the basement membrane in ultraviolet (UV) light-induced lesions has been reported as a late phenomenon. In this study, photoprovocations with UVA and UVB light were carried out in 16 photosensitive patients with discoid (n = 13), subacute cutaneous (n = 2) or systemic LE (n = 1) and serial biopsies from UV-induced lesions were processed for direct immunofluorescence. A specific, fine-speckled epidermal staining was detected within 7 to 14 days after UV provocation in 7/16 of the patients; in the majority of those patients associated with anti-SSA antibodies adn discoid LE without systemic manifestations of their disease.

Adult↗
PubMedDate not supplied

Renal tubular basement membrane changes in tubulointerstitial damage in patients with glomerular diseases.

Injury to renal tubules and interstitium occur in various glomerular diseases, leading to functional impairment. Tubular basement membrane (TBM) is an important component in maintaining tubular epithelial cell integrity. Because ultrastructural changes in these structures had not been studied in detail, the authors analyzed 30 patients with various types of glomerular diseases, including minimal change disease (MCD), focal segmental glomerular sclerosis, IgA nephropathy, diffuse proliferative glomerulonephritis, membranous nephropathy, and lupus nephritis, by light, electron, and immunofluorescence microscopy. Ultrastructural changes in the TBM were studied and morphometric measurements were performed. The tubular basement membranes showed membranous structures, lucent or lytic areas, and tubular epithelial detachment. There was significant linear correlation between these tubular basement membrane changes and terminal complement complex neoantigens. The interstitial widening was due to banded collagen fibers, with anchoring fibers in the TBM. The various glomerular diseases lead to tubulointerstitial damage via changes in the TBM, leading to renal dysfunction.

Basement Membrane↗
PubMed2002

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↗
PubMed1986

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↗
PubMed1989

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↗
PubMed1991

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↗
PubMed1995

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↗
PubMed1984

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↗
PubMed1982

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↗