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PubMed1999

Monomeric complement-activating IgG paraproteins.

Three patients presented a unique syndrome of recurrent panniculitis with an IgGkappa paraprotein and depletion of the early components of the classical pathway of complement. The IgGkappa paraproteins were monomers with a normal structure, and with no evidence for aggregation, as assessed by electron microscopy and ultracentrifugation. Both heavy and light chains were of normal molecular size (SDS-PAGE), and the paraproteins were not heavily glycosylated. However, the paraproteins from all three patients had unusual features that included abnormal behavior on gel filtration chromatography and a heavy chain of high pI. When analyzed by fast protein liquid chromatography (Superdex 200), elution of the paraproteins was retarded, particularly when the ionic strength was increased. This retardation was partially reversed in 20% alcohol, and fully reversed in 6 M guanidine-HCl. Neither anti-C1 inhibitor nor anti-C1q autoantibodies were found in any of the patients' sera. However, the paraproteins bound to the globular heads of C1q at normal ionic strength. They activated C4 in normal human serum, but not in C1q-deficient serum. Activation led to the formation of C1s-C1 inhibitor complexes. Taken together, the data suggest that the unusual paraproteins have the capacity to bind C1q, which then leads to activation of C1. The ability of these paraproteins to activate C1, in spite of their being soluble monomers, is likely to be related to their unique physicochemical features.

Chromatography, Gel↗
PubMed2000

The complement component C1s is the protease that accounts for cleavage of insulin-like growth factor-binding protein-5 in fibroblast medium.

Cultured fibroblasts secrete an 88-kDa serine protease that cleaves insulin-like growth factor binding protein-5 (IGFBP-5). Because IGFBP-5 has been shown to regulate IGF-I actions, understanding the chemical identity and regulation of this protease is important for understanding how IGF-I stimulates anabolic functions. The protease was purified from human fibroblast-conditioned medium by hydrophobic interaction, lectin affinity, and heparin Sepharose affinity chromatography followed by SDS-polyacrylamide gel electrophoresis. An 88-kDa band was excised and digested with lysyl-endopeptidase. Sequencing of the high pressure liquid chromatography-purified peptides yielded the complement components C1r and C1s. To confirm that C1r/C1s accounted for the proteolytic activity in the medium, immunoaffinity chromatography was performed. Most of the protease activity adhered to the column, and the eluant was fully active in cleaving IGFBP-5. SDS-polyacrylamide gel electrophoresis with silver staining showed two bands, and IGFBP-5 zymography showed a single 88-kDa band. Amino acid sequencing confirmed that the 88-kDa band contained only C1r and C1s. C1r in the fibroblast medium underwent autoactivation, and the activated form cleaved C1s. C1s purified from the conditioned medium cleaved C(4), a naturally occurring substrate. The purified protease cleaved IGFBP-5 but had no activity against IGFBP-1 through -4. C1 inhibitor, a protein known to inhibit activated C1s, was shown to inhibit the cleavage of IGFBP-5 by the protease in the conditioned medium. In summary, human fibroblasts secrete C1r and C1s that actively cleave IGFBP-5. The findings define a mechanism for cleaving IGFBP-5 in the culture medium, thus allowing release of IGF-I to cell surface receptors.

Amino Acid Sequence↗
PubMed1986

Inherited deficiencies of complement and complement-related proteins.

The complement cascade and cell-surface proteins related to the complement system are critically important to host defense, immune complex catabolism, and possibly immunoregulation. Genetically determined deficiency states have been described for many complement proteins as well as for fluid phase and cell-borne inhibitors of the complement cascade and cellular complement receptors. Autoimmune diseases and enhanced susceptibility to infection are the dominant clinical manifestation of these deficiencies. Classical pathway deficiencies and low numeric expression of erythrocyte C3b receptors (CR1) are typically associated with autoimmune disorders, while alternative pathway, terminal component, and leukocyte iC3b receptor (CR3) defects predispose to pyogenic bacterial disease. This distinction is not absolute, however, and both classes of disease may appear in most of the reported deficiency states. Specific pharmacologic therapy exists for C1-inhibitor deficiency (hereditary angioedema). Management of other complement deficiencies currently involves sustained diagnostic suspicion and meticulous management of complicating diseases.

Anaphylatoxins↗
PubMed2006

[Complement component deficiencies in human disease].

The complement system, composed of several plasma and membrane proteins, is an integral part of the innate immune system and plays a role in inflammatory response, destruction of infectious agents, elimination of immune complexes, and control of the specific (adaptive) immune response. Hereditary deficiencies of complement components are relatively rare and associated with susceptibility to a wide variety of clinical diseases. Complement components may be target of antibodies (anti-C1q, factor H, C3 alternative convertase, or C3NeF autoantibodies or anti-C1 inhibitor antibodies) that lead to acquired deficiencies. Testing the complement system is especially necessary in patients with autoimmune diseases, some kidney diseases, recurrent infections (especially meningococcal), and angioedema. Precise clinical descriptions of the phenotypes associated with these deficiencies and their molecular diagnosis are necessary to improve our understanding of the role that the complement system plays in the physiopathological mechanisms of these diseases and to propose the most specific treatment for them.

Autoimmune Diseases↗
PubMed2003

C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide.

C1 inhibitor (C1INH) is beneficial in animal models of endotoxemia and sepsis. However, the mechanism(s) of C1INH protection remain(s) ill-defined. In this study, we demonstrated that both active C1INH and reactive center-cleaved, inactive C1INH protected mice from lethal Gram-negative endotoxemia. Both forms of C1INH blocked the LPS-binding protein-dependent binding of Salmonella typhimurium LPS to the murine macrophage cell line, RAW 264.7, and suppressed LPS-induced TNF-alpha mRNA expression. Inhibition of LPS binding to RAW 264.7 cells was reversed with anti-C1INH Ab and was more efficient when C1INH was incubated first with LPS rather than with the cells. C1INH also suppressed LPS-induced up-regulation of TNF-alpha mRNA in whole human blood. The interaction of C1INH with LPS was directly demonstrated both by ELISA and by nondenaturing PAGE, but deletion of the amino-terminal 97-aa residues abrogated this binding. Therefore, C1INH, in addition to its function as a serine protease inhibitor, has a novel anti-inflammatory function mediated via its heavily glycosylated amino-terminal non-serpin domain.

Animals↗
PubMedDate not supplied

Prospective analysis of C1 dissociation and complement activation in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the results of complement analysis for assessment of disease activity and severity, and prediction of flares in systemic lupus erythematosus (SLE). METHODS: Patients with mild extra-renal flares, severe extra-renal flares or flares of lupus glomerulonephritis were followed for eight months, with investigations being performed every second month. Findings in initial samples four months before the flares were compared with findings in a control group with stable disease. C-reactive protein, and circulating C1q, C4 and C3 were determined together with two types of complexes containing C1 inhibitor (C1 INH), C1 INH-C1r-C1s and C1 INH-C1r-C1s-C1 INH, and the C3 breakdown product C3d. RESULTS: Enhanced formation of C1 INH-C1r-C1s appeared to be a marker of low specificity and was mainly seen in patients with extra-renal disease. Concentrations of C1 INH-C1r-C1s-C1 INH, C3d, C1q and C3 clearly varied according to disease activity in patients with severe disease. Interestingly, high C1 INH-C1r-C1s-C1 INH values were found four months before the flares in all but one patient with lupus glomerulonephritis. Assessment of the relative predictivity for a subsequent flare indicated low C1q to be the most reliable marker, the predictivity of the complexes being: low C1q > high C1 INH-C1r-C1s-C1 INH > low C3 > high C3d > low C4. CONCLUSION: The importance of C1q and C1-related events in SLE may be underestimated. In addition, our results demonstrate the relevance of serial complement analysis for the assessment of disease activity and severity.

Adolescent↗
PubMed1987

Hereditary angioneurotic oedema: a neglected diagnosis.

A case of hereditary angioneurotic oedema, which was only diagnosed after presentation to several hospital departments, is reported. It was then discovered that the mother of the patient had the same condition but that, unusually, it appeared to have been in remission for more than 20 years. This disease, due to C1 esterase inhibitor deficiency, is potentially fatal but easily treatable. The diagnosis is often missed.

Adult↗
PubMed1992

A single base deletion from the C1-inhibitor gene causes type I hereditary angio-oedema.

RFLP analysis, the polymerase chain reaction and nucleotide sequencing have been used to characterise a C1-inhibitor gene mutation responsible for type I hereditary angio-oedema (HAE). A single base deletion (C-16698) from the eighth exon of the C1-inhibitor gene alters the reading frame of the exon and generates a premature translation termination codon. This represents the first report of this form of C1-inhibitor gene mutation in type I HAE.

Amino Acid Sequence↗
PubMed1975

Complement inhibitor(s) released by leukocytes. III. Evidence for a "new" C1 inhibitor in the supernatants of short-term cultures of mouse spleen and thymus cells.

Mouse spleen or thymus cells in short-term culture release a factor, designated S, that binds to sheep erythrocytes (E). Supernatant-treated sheep erythrocytes (SE) are capable of fixing and transferring the activated first component of guinea pig complement. SEC1, however is not capable of initiating hemolysis by the rest of the complement components. SE is capable of binding but not activating native C1; native C1 bound to SE seems irreversibly inhibited. Evidence is presented that S may be the same factor as the previously described inhibitor released by mouse spleen or thymus cells that inhibits the utilization of C2 by EAC14.

Animals↗
PubMed1977

[Study by means of enzymatic and immunochemical determination of Cl esterase inhibitor in 59 patients with hereditary angioneurotic edema].

Serum C1 esterase inhibitor was determined in 138 members of 18 italian families with hereditary angioedema by immunochemical and enzymatic assays. On the basis of quantitative and functional findings, the type A of hereditary angioedema was diagnosed in 44 subjects, and the type B in 15. Some technical devices concerning serum sample handling were identified. The influence of heparin, EDTA, and citrate on C1 esterase inhibitor activity of normal plasma was also investigated.

Adult↗
PubMed1992

A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444-->Leu).

A P1 mutation (Arg-444-->Leu) was identified in a dysfunctional C1 inhibitor from a patient with type 2 hereditary angioneurotic edema. The mutation was defined at the level of the protein (by sequence analysis of the Pseudomonas aeruginosa elastase-derived reactive center peptide), and the mRNA (CGC-->CTC) (by sequence analysis of PCR-amplified DNA).

Amino Acid Sequence↗
PubMed1971

C1 inhibitor: evidence for decreased hepatic synthesis in hereditary angioneurotic edema.

Although the Cl inhibitor was detected in 5 to 10 percent of normal hepatic parenchymal cells by means of the immunofluorescent technique, none was seen in liver biopsies from two individuals with hereditary angioneurotic edema having low concentrations of Cl inhibitor in the serum. In contrast, the percentages of cells which reacted with fluorescent antiserums to C4 and transferrin were normal. These data suggest that in most subjects with hereditary angioneurotic edema, there is decreased synthesis of the C1 inhibitor but normal synthesis of C4, and that the disease results from this biosynthetic error.

Adult↗
PubMed1989

Pancreatic pseudocyst fluid--a mixture of plasma proteins and pancreatic juice possessing a high proteolytic activity.

Pancreatic pseudocyst fluid from eight patients was examined biochemically. The fluid was found to be a mixture of plasma proteins and pancreatic juice, possessing a high proteolytic activity against high- as well as low-molecular-weight proteins. The proteolytic activity was found to be trypsin-, kallikrein- and plasmin-like. Gel filtration studies showed proteolytic activity to be present corresponding to alpha-2-macroglobulin-bound proteases and also to free proteases. Quantitative immunochemical levels were about 30-100% of normal plasma levels for alpha-2-macroglobulin, C1 inhibitor, antithrombin III and alpha-2-antiplasmin. However, there was practically no functional inhibitory capacity left in the pseudocyst fluid, except for alpha-1-protease inhibitor, which retained its inhibitory capacity. Neither native kininogen nor complement factor C3 was found: this was probably a result of the proteolytic activity. It is concluded, that a continuing proteolytic activity within the pseudocyst, although decreasing with aging of the cyst, could explain symptoms and complications caused by the pseudocyst.

Adult↗
PubMed1992

Characterization of carbohydrate chains of C1-inhibitor and of desialylated C1-inhibitor.

Carbohydrate chains of C1-inhibitor were identified with a binding assay using different lectins. Lectins from Sambucus nigra (SNA) and Maackia amurensis (MAA) that are specific for sialic acids bound to C1-inhibitor. Lectin from Datura stramonium (DSA) reacted also with the inhibitor indicating complex and hybrid sugar structures. C1-inhibitor was enzymatically desialylated and reexamined for lectin binding. SNA and MAA did not react anymore, but in addition to DSA, peanut agglutinin, which can bind to carbohydrate chains after sialic acids are removed, bound to desialylated C1-inhibitor. C1-inhibitor contains about 30 sialic acid residues per molecule. SDS-polyacrylamide gel electrophoresis showed that desialylated C1-inhibitor had a faster mobility than native C1-inhibitor. The N-terminal sequence of desialylated C1-inhibitor was the same as of native C1-inhibitor and no change in the inhibition of human plasma kallikrein was observed.

Blotting, Western↗
PubMedDate not supplied

Hereditary angioedema with recurrent abdominal pain.

Hereditary angioedema is a rare disorder characterized by quantitative or qualitative deficiency of complement C1 esterase inhibitor. We report a family whose members presented with recurrent angioedema and abdominal pain; the diagnosis was confirmed by quantitative assay of C1 inhibitor. The index patient was treated with danazol and was relieved.

Abdominal Pain↗