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PubMed2005

Novel collectin/C1q receptor mediates mast cell activation and innate immunity.

Mast cells play a critical role in innate immunity, allergy, and autoimmune diseases. The receptor/ligand interactions that mediate mast cell activation are poorly defined. The alpha2beta1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1 (MMP-1), endorepellin, and several viruses, has been implicated in normal developmental, inflammatory, and oncogenic processes. We recently reported that alpha2 integrin subunit-deficient mice exhibited markedly diminished neutrophil and IL-6 responses during Listeria monocytogenes- and zymosan-induced peritonitis. Peritoneal mast cells require alpha2beta1 integrin expression for activation in response to pathogens, yet the ligand and molecular mechanisms by which the alpha2beta1 integrin induces activation and cytokine secretion remain unknown. We now report that the alpha2beta1 integrin is a novel receptor for multiple collectins and the C1q complement protein. We demonstrate that the alpha2beta1 integrin provides a costimulatory function required for mast cell activation and cytokine secretion. This finding suggests that the alpha2beta1 integrin is not only important for innate immunity but may serve as a critical target for the regulation of autoimmune/allergic disorders.

Animals↗
PubMed1984

Reduction of phagocyte adherence by nephritic sera: relation to complement activation.

Phagocytes isolated from either normal donors or from patients with poststreptococcal (P-SGN), lupus erythematosus (SLE-GN), or membranoproliferative (MPGN) glomerulonephritis showed normal adherence to glass (PAg) after incubation in normal human serum (NHS), but was reduced after incubation in patient serum. Low PAg was the consequence of incubation of normal phagocytes with the earliest available sera from all 22 P-SGN patients, 28 of 37 SLE-GN patients, 19 of 25 patients with MPGN type I, all 10 with types II and III, and all 5 with nephritis associated with chronic bacteremia. Low C3 and decreased PAg were related by regression analysis in sera from patients with P-SGN (P less than 0.001), SLE-GN (P less than 0.005), and MPGN (P less than 0.001) type I. In patients with P-SGN and one patient with nephritis associated with chronic bacteremia, complement levels and PAg returned to normal in parallel with clinical improvement. In vitro, PAg was reduced by NHS treated with either zymosan or bovine serum albumin (BSA)-anti-BSA complexes but neither BSA-anti-BSA complexes or zymosan, previously incubated in NHS, reduced PAg. PAg was normal in serum deficient in C4 or C5 unless treated with zymosan.

Adult↗
PubMed1982

Circulating immune complexes in multiple sclerosis: relation with disease activity.

Two hundred fifty-four MS patients were studied for circulating immune complexes (CIC) by three different assays: Raji-RIA, Clq-PEG, and Conglutinin-BA. Thirty-five percent of the sera were positive by one or more of these tests; Raji-RIA had the highest sensitivity (29.4%). Incidence of CIC in acute relapse, progressive, remission, and stable state of MS was 33.3%, 30.2%, 26.1%, and 23.1%, respectively, by Raji-RIA, compared with 7.75% and 8.82% among normal and neurologic controls. The incidence of CIC in neurologic controls differed significantly from both acute relapse and progressive disease, and almost significantly from patients in remission. There was no significant difference between patients with stable MS and neurologic controls, and there was no association of CIC with HLA-B7.

Adolescent↗
PubMed2005

Lymphocyte apoptosis and thrombocytopenia in spleen during classical swine fever: role of macrophages and cytokines.

Thirty-two Large White x Landrace pigs, 4 months old, were inoculated with the classical swine fever (CSF) or hog cholera virus strain "Alfort" in order to identify the mechanism responsible for the lymphopenia and thrombocytopenia observed in the spleen during the experimental induction of disease, by immunohistochemical and ultrastructural techniques. Results showed a progressive depletion of splenic lymphoid structures and evidence of platelet aggregation processes. Lymphoid depletion was due to lymphocyte apoptosis, which could not be ascribed to the direct action of the virus on these cells; direct virus action could play only a secondary role in the death of these cells. Absence of severe tissue and endothelial damage, together with moderate procoagulant cytokine levels in the serum, suggest that these pathologies can be ruled out as the cause of platelet aggregation and thrombocytopenia in CSF. Monocyte/macrophages were the main target cells for the CSF virus, and they exhibited phagocytic and secretory activation leading to the synthesis and release of tumor necrosis factor alpha, which proved to be the chief mediator, followed by IL-6, IL-1alpha, and C1q complement component. In view of their characteristics, TNF-alpha and, to a lesser extent, IL-1alpha and IL-6 appear to be the major cytokines involved in the pathogenesis of lymphocytopenia and thrombocytopenia; a clear spatial and temporal relationship was observed between these two phenomena.

Animals↗
PubMed1981

Wegener's granulomatosis. Electron microscopic and immunofluorescent studies.

We report a case of classic Wegener's granulomatosis. Direct immunofluorescent study showed finely granular deposits of IgG and IgM in some of the alveolar walls, and of IgM in the maxillary sinus arteries. Electron-microscopic study of the lung and maxillary sinus showed intravascular fibrin, but failed to demonstrate electron-dense deposits in the blood vessel walls. Our patient also had circulating cryoglobulins, consisting of IgG, IgM, Clq, and C3, and evidence of circulating immune complexes as demonstrated by the Clq-binding test. These findings suggest that circulating immune complexes may play an important role in the pathogenesis of the respiratory lesions of Wegener's granulomatosis.

Complement Activating Enzymes↗
PubMed1993

Immune complex glomerulonephritis in a pregnant woman with congenital C9 deficiency.

A 27-year-old woman developed proteinuria, hypertension, and peripheral edema during the ninth month of her first pregnancy. The clinical and serological features were compatible with a diagnosis of toxemia of pregnancy, except for the presence of hypocomplementemia. The patient had glomerulonephritis characterized by large electron-dense deposits, predominantly in the mesangium. Immunofluorescence studies revealed striking accumulations of Clq and C3, and the presence of small amounts of IgG and IgM in the mesangium. Serum and plasma levels of complement components were normal, except for the C9 component. Family studies demonstrated that the C9 deficiency was inherited.

Adult↗
PubMedDate not supplied

Complete Clq deficiency associated with IgG multiple myeloma.

We report a case of IgG multiple myeloma with selective complete Clq deficiency. The patient was a 75-year-old Japanese woman who exhibited urticaria on the arm and an absence of serum hemolytic complement activity (CH50). Further studies revealed no vasculitis in the urticarial lesion but showed selective complete deficiency of Clq without low molecular weight Clq precipitin. Addition of highly purified Clq restored the CH50 level of the patient's serum to normal. It is suggested that this abnormality was a primary Clq deficiency. We discussed a relationship between the Clq deficiency and myeloma and reviewed the literature.

Aged↗
PubMed1982

Application of cultured human myeloid cells (K562) for detection of immune complexes in human sera.

Cultured human myeloid cells (K562) are known to bear Fc receptors that bind with aggregated human IgG (AHG). These cells were used to develop a radiometric assay for detection and quantitation of immune complexes (IC) in human sera. The binding of AHG or in vitro-formed IC between keyhole lympet hemocyanin (KLH) and human anti-KLH to the K562 cells did not require complement. When the K562 radiometric assay was compared to the complement-consumption assay, the K562 radiometric assay could detect IC over a wider range of antibody:antigen ratios. The incidence and mean IC values detected by the K562 radiometric assay in sera from cancer patients and patients with connective tissue diseases (498 +/- 445 and 436 +/- 209 micrograms AHG equ/ml, respectively) were significantly higher than in sera from healthy volunteers (107 +/- 62 micrograms AHG equ/ml). The IC level among sera from cancer patients ranged from 1-3200 micrograms AHG equ/ml. Studies with a limited number of sera from melanoma and sarcoma patients revealed that the mean IC values were significantly higher in patients who had clinically detectable disease than in those with no evidence of disease. Since the K562 cells do not require complement to interact with AHG, the K562 radiometric assay may be potentially useful for detecting IC in pathologic sera which may or may not contain in vivo-bound complement components.

Antigen-Antibody Complex↗
PubMed1983

Perfusion of canine serum over Staphylococcus aureus Cowan 1: Evidence for release of protein A and changes in specific antibody activity.

Sera from three normal dogs were assessed for levels of Clq binding IgG and complement consumption after perfusion over Staphylococcus aureus Cowan I (SAC). Increased levels of Clq binding IgG were detected after perfusion of sera over SAC and were associated with complement consumption. Canine antiserum to human erythrocytes were also perfused over SAC and assessed for Clq binding IgG and hemolytic activity. Increased levels of Clq binding IgG in post-perfusion samples were detected which were associated with a decrease in hemolytic activity. IgG was determined to be present in molecular weight fractions greater than 200,000 M.W. in post-perfusion chromatographically fractionated sera. Moreover, 5% polyethylene glycol (PEG) precipitated IgG from post-perfusion sera was functional in antibody dependent cellular cytotoxicity assays. Putative staphylococcal protein A isolated from post-perfusion sera produced a precipitin band in double diffusion agarose gel studies when reacted with normal human and canine sera. A polypeptide co-migrating with purified protein A could be detected by polyacrylamide gel electrophoresis (PAGE) analysis of the post-perfusion isolated protein A. Addition of purified protein A to canine antiserum resulted in decreased hemolytic activity of the serum which was associated with increased levels of Clq binding IgG.

Animals↗
PubMed1991

C1-INH defect as an example of deficiency disease.

Primary defect of C1-inhibitor (C1-INH), the regulatory protein of the initial classical pathway of complement, is the cause of hereditary angioedema. Clinical symptoms involve potentially fatal obstruction of the upper respiratory tract, abdominal pains, and subcutaneous edemas. Since the description of functional tests for C1-INH two types of hereditary defect have been known: type I and type II. Sixteen patients with the type I of hereditary angioedema were diagnosed and treated in our hospital. The onset of the disease occurred between 1.5-12 y. of age. Clinical symptoms were observed in skin, gastrointestinal and respiratory tracts. Mean concentration of C1-INH in sera of 16 patients was 3.25 mg/dl, below 8.75 mg/dl that is the critical for well-functioning C1-INH. Inhibitory activity of C1-INH for C1 esterase in plasma was zero in most of the patients, while it was 0.94 +/- 0.20 U/ml in plasma samples of 91 healthy blood donors. Three modalities of treatment are available: substitution with C1-INH concentrate in acute attacks and antifibrinolytic and/or anabolic drugs for prophylaxis. We have obtained good therapeutic results with epsilon-aminocaproic acid (antifibrinolytic), 2g daily during 3 months, with 6 months intervals.

Adolescent↗
PubMed2000

Cutting edge: complement-activating complex of ficolin and mannose-binding lectin-associated serine protease.

Both ficolins and mannose-binding lectin (MBL) are lectins characterized by the presence of collagen-like and carbohydrate-binding domains in a subunit, although their carbohydrate-binding moieties are quite different. A fibrinogen-like domain is in ficolins, and a carbohydrate recognition domain is in MBL. On binding to pathogens, human MBL activates the complement system via the lectin pathway in association with two types of MBL-associated serine proteases (MASP), MASP-1 and MASP-2 and its truncated form, small MBL-associated protein (sMAP, also called MAp19). We report here that ficolin/P35, a human serum ficolin, was found to copurify with MASPs and sMAP. MASPs that were complexed with ficolin/P35 exhibited proteolytic activities against complement components C4, C2, and C3. The ficolin/P35-MASPs-sMAP complex that was bound to Salmonella typhimurium activated complement. These findings indicate that ficolin/P35 is a second collagenous lectin capable of activating the lectin pathway and thus plays a role in innate immunity.

Biopolymers↗
PubMed2004

Generation of a complement-independent bactericidal IgM against a relapsing fever Borrelia.

The spirochetemia of relapsing fever in mice is cleared by a complement-independent, polyclonal IgM response with reactivity to two prominent Ags of 20 and 35 kDa. In this study, we have dissected the polyclonal IgM Ab response against a relapsing fever spirochete to determine the specificity of its complement-independent bactericidal properties. Our experimental approach selectively generated an IgM murine mAb from the early specific immune response to a variable outer membrane protein. This IgM is bactericidal in the absence of complement and is part of the polyclonal Ab response that mediates the clearance of this bacterium from the blood. Purified monoclonal IgM caused direct structural damage to the outer membrane of the spirochete, in the absence of complement, and protected both B cell- and C5-deficient mice from challenge when administered passively. The direct, complement-independent, bactericidal activity of Abs is a critical mechanism of host defense against infection.

Animals↗
PubMed2005

Additive inhibition of complement deposition by pneumolysin and PspA facilitates Streptococcus pneumoniae septicemia.

Streptococcus pneumoniae is a common cause of septicemia in the immunocompetent host. To establish infection, S. pneumoniae has to overcome host innate immune responses, one component of which is the complement system. Using isogenic bacterial mutant strains and complement-deficient immune naive mice, we show that the S. pneumoniae virulence factor pneumolysin prevents complement deposition on S. pneumoniae, mainly through effects on the classical pathway. In addition, using a double pspA-/ply- mutant strain we demonstrate that pneumolysin and the S. pneumoniae surface protein PspA act in concert to affect both classical and alternative complement pathway activity. As a result, the virulence of the pspA-/ply- strain in models of both systemic and pulmonary infection is greatly attenuated in wild-type mice but not complement deficient mice. The sensitivity of the pspA-/ply- strain to complement was exploited to demonstrate that although early innate immunity to S. pneumoniae during pulmonary infection is partially complement-dependent, the main effect of complement is to prevent spread of S. pneumoniae from the lungs to the blood. These data suggest that inhibition of complement deposition on S. pneumoniae by pneumolysin and PspA is essential for S. pneumoniae to successfully cause septicemia. Targeting mechanisms of complement inhibition could be an effective therapeutic strategy for patients with septicemia due to S. pneumoniae or other bacterial pathogens.

Animals↗
PubMed2000

Cbln3, a novel member of the precerebellin family that binds specifically to Cbln1.

Precerebellin (Cbln1) is the precursor of the brain-specific hexadecapeptide cerebellin. Although cerebellin has properties of a conventional neuropeptide, its function is controversial because Cbln1 has structural features characteristic of circulating atypical collagens. Cbln1 is related to the three subunits of the complement C1q complex. Therefore, we hypothesized that Cbln1 participated in analogous heteromeric complexes with precerebellin-related proteins. Using LexA-Cbln1 as bait in a yeast two-hybrid screen, we isolated a cDNA encoding a novel Cbln1-related protein, designated Cbln3. The gene encoding cbln3 had the same intron-exon structure as cbln1 but mapped to a different mouse chromosome (14). The deduced amino acid sequence of Cbln3 was 55% identical to Cbln1 and also contained a C1q signature domain and signal sequence for secretion. In addition to binding avidly to Cbln3, Cbln1 also formed homomeric complexes. In contrast, Cbln3 homomeric association was weak. These interactions exhibited specificity because C1qB bound to neither Cbln1 nor Cbln3. Like cbln1, cbln3 was expressed in the cerebellum and dorsal cochlear nucleus in which it was detected in granule neurons. Because Cbln1 and Cbln3 are coexpressed in the brain and interact avidly, they may function as a secreted heteromeric complex in vivo.

Aging↗
PubMed2002

[Evaluation of C3c, C4 and C1-esterase inhibitor (C1-INH) during unstable angina].

BACKGROUND: The complement system plays an important role in the physiopathology of acute myocardial infarction (AMI) taking part in myocardial damage and reperfusion injury. The aim of this study is to investigate the plasmatic levels of some complement components (C3c, C4 and C1-INH) during unstable angina (C1-INH) and their different concentrations in relation to the different myocardial areas affected by ischemia. METHODS: The plasmatic levels of C1-INH, C3c and c4 in 30 patients affected by unstable angina, and those of 22 clinically healthy subjects (control group) were evaluated (Nefelometer Behering). The patients were divided into four groups according to the different myocardial area affected by ischemia (anterior, antero-lateral, lateral or inferior ischemia), RESULTS: No statistically significant differences were found in plasmatic levels of C3c, C4 and C1-INH between the group of patients and the control group. There is a statistically significant difference between the C1-INH levels of the patients with inferior ischemia and the plasmatic concentrations of the whole patients' group (p<0,01), the control group (p<0,01) and the group of patients with lateral ischemia (p<0,02). CONCLUSIONS: There seems to be a different activation of the complement system during unstable angina, in relation to the different myocardial area affected by ischemia.

Aged↗
PubMedDate not supplied

[Complex studies of virology, microbiology, biochemistry and epidemiology in the adults of a semi-closed community vaccinated against influenza with the inactivated NIVGRIP vaccine intranasally].

A study was conducted on the specific and non specific immunomodulator effects of the inactivated vaccine NIVGRIP. The results revealed the seroconversion of HAI antibodies against influenza and mumps viruses and the reduction of viral and microbial flora of the pharynx. The kinetics of some proteins specific to the acute stage (siderophiline antitrypsin, microglobulin, complement C1q and C2 factors, C reactive protein and fibronectin) was also investigated and significant quantitative modifications were noticed in vaccinated subjects. The mean illness duration (acute respiratory disease) was three times as short in vaccinated subjects as in controls.

Acute-Phase Proteins↗