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PubMed1989

Renal injury in DOCA-salt hypertensive C5-sufficient and C5-deficient mice.

We induced hypertension by uninephrectomy and treatment with desoxycorticosterone (DOCA) and 1% NaCl in the drinking water in congenic mice that differ in the single gene locus responsible for the presence or absence of the complement component C5 and compared them to uninephrectomized normotensive (no DOCA-NaCl) mice. In contrast to C5-sufficient (C5S) mice. C5-deficient (C5D) mice can neither generate C5a nor assemble C5b-9. After four weeks of treatment, DOCA-C5S and -C5D mice developed similar degrees of hypertension; mice receiving no DOCA remained normotensive. Only hypertensive mice developed glomerular injury. Hypertensive DOCA-C5D mice developed more glomerular capillary loop dilatation and larger glomerular capillary tuft volumes than DOCA-C5S mice (1.0 +/- 0.1 vs. 0.7 +/- 0.03 X 10(6) microns 3, respectively, P less than 0.05). However, DOCA-C5S mice, compared to DOCA-C5D mice, had significantly more glomerular cell proliferation (64.5 +/- 2 vs. 42 +/- 3 nuclei/glomerulus), cell necrosis (injury score 22 +/- 1 vs. 17 +/- 1), extracapillary proliferation (26 +/- 4 vs. 2.5 +/- 2% of glomeruli) and proteinuria (5.9 +/- 0.8 vs. 3.7 +/- 0.5 mg/24 hr; all P less than 0.05). By immunofluorescence microscopy both DOCA-C5S and -C5D had mesangial C3 deposits but only DOCA-C5S mice had C9 deposits. After 16 weeks of DOCA-NaCl C5S mice, in comparison to C5D mice, had more severe glomerulosclerosis (injury score 50 +/- 6 vs. 12 +/- 4), proteinuria (16.6 +/- 0.1 vs. 9 +/- 0.1 mg/24 hr), and renal insufficiency (serum creatinine 0.25 vs. 0.15 mg/dl), all P less than 0.05. These changes occurred despite levels of hypertension that were similar in DOCA-NaCl C5S and C5D throughout the whole study period. We conclude that C5a and/or C5b-9 may play an important role in hypertensive glomerular injury. Moreover, these studies demonstrate that differences in host responses may determine target organ susceptibility to similar injurious mechanisms.

Animals↗
PubMed1987

Inhibition of antibody-dependent lymphocyte cytotoxicity by homologous restriction factor incorporated into target cell membranes.

The 65 kD homologous restriction factor (HRF) was isolated from normal human erythrocytes (E) by immunoadsorption using rabbit anti-human HRF. The protein was radiolabeled and incorporated into the membrane of sheep erythrocytes (Es). Es bearing HRF exhibited a markedly reduced susceptibility to reactive lysis by C5b-9. Es-HRF with 1,000-3,000 HRF molecules per cell and sensitized with rabbit IgG anti-Es also were less susceptible to lysis by human large granular lymphocytes (LGL) than untreated Es sensitized with IgG antibody. Similarly, human E of a patient with paroxysmal nocturnal hemoglobinuria (PNH), lacking HRF and sensitized with IgG antibody underwent lysis by human LGL. Lysis was abrogated by incorporation of isolated human HRF. Incorporation of human decay-accelerating factor (DAF) into sensitized Es had no effect on antibody-dependent, cell-mediated cytotoxicity. Furthermore, lysis of Es by the isolated cytolytic C9-related protein (C9RP) of human cytotoxic lymphocytes could be inhibited by cell bound human HRF. These results suggest that HRF inhibits channel formation not only by C5b-9, but also by cytotoxic lymphocytes.

Animals↗
PubMed1998

Antibodies specific to surface antigens are not effective in complement-mediated killing of Haemophilus ducreyi.

The bactericidal activity of serum is an important primary host defence against gram-negative bacteria. Little is known regarding such antibodies that are specific to outer membrane (OM) antigens as pili and lipooligosaccharides (LOS) in the bactericidal killing of Haemophilus ducreyi. Presence of serum antibodies with specificity to a 430 kDa protein (polymer of the 24 kDa protein, named fine-tangled pili) and LOS in serum from chancroid patients and healthy individuals were investigated by ELISA. Using a bactericidal assay, we investigated the role of human and rabbit antibodies with the aforementioned specificity. Accessibility of LOS and of OM antigens, as well as the deposition of components of the complement (C) system on the surface of the bacteria, was further investigated by whole-cell ELISA and immunoelectron microscopy. Immunoglobulin G (IgG) antibodies specific to the 430 kDa polymer and to LOS were demonstrated in the majority of sera from chancroid patients and healthy individuals. However, sera from chancroid patients did not significantly enhance the C-mediated killing of H. ducreyi compared with normal human serum (NHS). Similar results were demonstrated using rabbit sera to whole bacteria, specific to the 430 kDa protein and LOS of H. ducreyi. However, using the same assay noncapsulatedH. influenzae was totally killed, as were H. influenzae type b in presence of specific antibodies. This suggests a limited effectiveness of antibodies specific to surface antigens in C-mediated killing of H. ducreyi. LOS was detectable on the surface of H. ducreyi with a specific monoclonal antibody in white-cell ELISA. However, a significant enhancement of LOS detection was demonstrated on washed bacteria. OM antigens of 26, 40, 45 kDa and the major outer membrane protein (MOMP) of 43 kDa were not detectable on the surface of nonwashed and washed bacteria by specific monoclonal antibodies, indicating a lack of accessibility of these antigens on the bacterial surface. However, the C6 to C9 components of C were detected on the bacterial surface, suggesting capacity of forming the membrane attack complex. Altogether, these findings imply that antibodies specific to surface antigens, such as the 430 kDa protein and LOS, are not capable of enhancing killing of bacteria. The demonstrated relative resistance is probably due not to a lack of deposition of the membrane attack complex components, but rather to a blocking of LOS accessibility and OM proteins as potential targets of bactericidal antibodies and C action.

Animals↗
PubMed1997

C5b-7 and C5b-8 precursors of the membrane attack complex (C5b-9) are effective killers of E. coli J5 during serum incubation.

The finding that C9-deficient sera (C9D) can kill serum sensitive strains of Gram-negative bacteria by us and other investigators, questions the role of C9 in the membrane attack complex as necessary for cell death. In these studies we have demonstrated that C5b-8 complexes generated on E. coli J5 during incubation in C9-depleted and C9-neutralized sera are effective in killing Gram-negative bacteria. In the same study, we extended our investigations to show that the deposition of C5b-7 complexes (from C8-deficient [C8D], C8 depleted and C8-neutralized sera) is also effective in killing Gram-negative bacteria. In all cases, these studies demonstrated that when E. coli J5 was incubated with C8D, C9D and pooled normal human serum [PNHS], deposited C5b-9 complexes from PNHS produced more killing than C5b-7 or C5b-8 complexes alone. These experiments clearly demonstrated that C5b-7 and C5b-8 complexes are bactericidal and that multimeric C9 within C5b-9 is not an absolute requirement for inner membrane damage and cell death of Gram-negative bacteria.

Blood Bactericidal Activity↗
PubMed1973

C2 deficiency. Development of lupus erythematosus.

The study of serum from a patient with C2 deficiency is described. The patient had an episode of pneumococcal meningitis at 5 mo of age with seizures and transient hemiparesis and apparent purpuric skin lesions. He was first admitted to the University of Minnesota Hospitals at 10 yr of age following the discovery of proteinuria accidentally by his mother. Since then he has been admitted repeatedly to this hospital with numerous clinical findings including arthralgia, recurrent abdominal pain, proteinuria, membranous nephropathy, malar butterfly rash, seizures, personality aberrations, and recurrent fever. In June 1971, the patient developed positive DNA and DNP antibodies and positive LE cells. When the C profile was studied before and after recognition of lupus, C1q, C1s, and C4 dropped. C3 levels were elevated as were C5, C6, and C7, C3 proactivator had been reduced in the patient even before he developed lupus. Also because of a traumatic renal biopsy leading to a perirenal hematoma, he required surgery and a blood transfusion. 1 h after blood transfusion, a C2 titer of 23 hemolytic units was detected. Almost immediately levels of C3, C5, C6, and C7 dropped, C8 and C9 remained elevated. The addition of C2 from normal blood permitted dramatic activation of C3. These findings support the view that the rare deficiency in production of C2 predisposes to serious susceptibility to infection, vascular and mesenchymal disease as well as to renal disease and a lupus syndrome.

Antibodies↗
PubMed1989

Isolation of homologous restriction factor from human urine. Immunochemical properties and biologic activity.

A soluble form of homologous restriction factor (HRF-U) was isolated from normal human urine. With respect to m.w. (65,000) and immunoblotting characteristics, it resembled membrane HRF (HRF-M) that had been isolated from human E membranes. The protein exhibited limited cross-reactivity with the channel-forming proteins of C and cytotoxic lymphocytes. It inhibited reactive lysis of E by human C5b-9. Inhibition occurred at the attachment stage of C5b-7 to target cells, rather than at the C8 or C9 stage of membrane attack complex assembly which is inhibited by HRF-M. In this respect, HRF-U acts analogously to S protein of serum, but no immunochemical relationship between these two proteins was detected. HRF-U might be derived from the soluble HRF detected in cytoplasmic granules of killer lymphocytes.

Animals↗
PubMed1977

Activation of the alternative complement pathway with rabbit erythrocytes by circumvention of the regulatory action of endogenous control proteins.

Cleavage of C3 by the alternative complement pathway occurs in at least two distinct phases: continuous low grade generation of C3b by the interaction of native C3, B, D, and P, and subsequent amplified cleavage of C3 by the interaction of C3b, B, D, and P which forms the amplification convertase, P,C3b,Bb. Transition to C3b-dependent amplification is necessary to achieve substantial C3 cleavage and is normally limited by the combined action of C3b inactivator (C3bINA) and betalH. An activator of the alternative pathway, such as rabbit erythrocytes (E(r)), provides sites that protect bound C3b and P,C3b,Bb from the action of these regulatory proteins and permits C3b deposited by the low grade fluid phase reaction to assemble a membrane-associated amplification convertase which can deposit additional protected C3b. Under conditions in which the control proteins, C3bINA and beta1H, almost completely inactivated C3b bound to sheep erythrocytes (E(s)), which does not activate the alternative pathway, the function of C3b bound to E(r) was diminished by less than one-fifth. Further, the P- stabilized amplification convertase on E(r) was 10-fold less sensitive to beta1H-mediated decay-dissociation than the convertase on E(s). The addition of E(r) to a regulated mixture of purified C3, B, D, P, C3bINA, and beta1H resulted in amplified inactivation of C3 and B by formation of the amplification convertase on E(r) as indicated by its lysis with subsequent exposure to C3-C9. In contrast, E(s) did not advance the low grade fluid phase inactivation of C3 and B to amplified inactivation and the cell was not converted to an intermediate susceptible to lysis by C3- C9. Since E(r) and E(s) did not differ in their inefficient fixation of C3b generated during an unregulated fluid phase reaction, the activating capacity of E(r) must reside in its protection of bound C3b and P, C3b,Bb from the regulatory proteins rather than in enhanced capacity to bind C3b from the fluid phase. When the reaction is limited to low grade fluid phase turnover, introduction of E(r) but not E(s) results in a 100-fold increase in the deposition of C3b, indicating that surface-dependent activation of the alternative pathway is characterized by efficient deposition of C3b on the initiating surface. Thus, the activating surfaces advance the interaction of the alternative pathway proteins to the amplification phase because of the selective inability of the regulatory proteins to deal with their substrates when deposited on these surfaces and results in a specificity that is not necessarily dependent on adaptive immunity.

Animals↗
PubMed1984

The effect of ethylenedinitrilotetraacetic acid (EDTA) on the reaction between the guinea-pig C5 convertase and guinea-pig C5.

Guinea-pig C5 was reacted with EAC1423 in the washed-cell intermediate assay in the presence of glucose gelatin veronal buffer (GGVB), Zn2+-GGVB (0.025 mM), GGVB2+ containing Ca2+ and/or Mg2+ or EDTA (0.013 M)-GGVB. The EDTA inhibited the formation of competent SAC14235, while Ca2+ and/or Mg2+ had a slight enhancing effect compared to GGVB alone and Zn2+ gave a four-fold increase. Similar results were obtained by using human C5 with guinea-pig C5 convertase and functionally pure guinea-pig C6, C7, C8 and C9. When guinea-pig C6 was incorporated into these various reaction mixtures with guinea-pig C5, its addition markedly reduced the inhibition by EDTA, while Zn2+ still showed an enhancing effect. These results demonstrate that EDTA inhibited formation of competent SAC14235 by preventing activation of C5. The association of C6 with C5 can partially overcome the inhibition of C5 conversion by EDTA and may account for C5 activity in reaction mixtures containing C-EDTA.

Animals↗
PubMed1975

Studies on the inhibition of C56-initiated lysis (reactive lysis). III. Characterization of the inhibitory activity C567-INH and its mode of action.

An activity in serum which inhibits reactive lysis has recently been shown to do so by preventing the attachment of C567 complexes to cells, and hence has been designated C567-INH. This report describes certain physiochemical characteristics of the inhibitory activity. It behaves as a heat-stable pseudoglobulin, soluble in 20 per cent Na2SO4, and having alpha1 mobility on Pevikon block electrophoresis. It is excluded from CM cellulose at pH 6-0, RSC Equals 0.007 M, is retained by an XM-100 membrane and is heterogenous on Sephadex G-200, eluting in at least two peaks. The combined active materials from the Sephadex column elute from DE-52 in at least four peaks. The mechanism of action of material from each of these four peaks is shown to involve prevention of attachment of C567 complexes to membranes, and this is shown to involve an effect on C567 complexes in solution rather than an effect on the membrane. A less dramatic effect on the lysis of EC567 by limited quanities of C8 and C9 can be demonstrated. Haemolytic studies using cell-bound C567 suggest that the interaction of C567-INH with C567 involves a loose reversible association. It is therefore postulated that C567-INH inhibits reactive lysis primarily by reversibly associating with the nascent C567 complex in solution, increasing its bulk and decreasing its diffusion capacity so that it is unable to reach a cell membrane before its haemolytic potential decays.

Animals↗
PubMed1992

Acute serum sickness in normal and C6 deficient rabbits: role of membrane attack complex.

Acute serum sickness was induced in New Zealand White (NZW) and in C6 deficient (C6D) rabbits, to compare the histology, immunofluorescence, especially distribution of poly C9 (MAC), and electron microscopic characteristics of the disease in each strain. Glomerulonephritis and albuminuria of comparable extent occurred in 13/17 NZW and 4/8 C6D rabbits. In NZW rabbits with albuminuria an early intense glomerular infiltration by mononuclear cells was associated with focal small fine granular glomerular basement membrane (GBM) deposits of IgG and BSA and more diffuse and larger deposits of C3 and MAC. After the disappearance of monocytes and decrease in mesangial cell proliferation, development of large subepithelial GBM deposits rich in all immune reactants was observed in NZB rabbits. In C6D rabbits with albuminuria a similar monocytic infiltrate occurred, but no association with IgG and C3 GBM immune deposits was noted. No deposits of MAC and no large subepithelial GBM 'humps' were observed in C6D rabbits. We conclude that the exudative (monocytic) phase of glomerular injury and albuminuria in acute serum sickness nephritis are not dependent upon terminal complement components, but the subsequent formation of large subepithelial GBM deposits does not occur in this model in the absence of MAC.

Albuminuria↗
PubMed1979

Studies on the terminal stages of immune hemolysis. IV. Effect of metal salts.

The inhibitory effect of metal salts on the formation and transformation of E to ghosts was studied. Ferrous and ferric salts inhibited the binding of C9 to EAC1-8 cells but had no other inhibitory role in the reaction. Uranly, copper, and zinc salts inhibited the transformation of the EAC1-9inserted intermediate to E ghosts. This inhibition occurred at a stage prior to detectable damage as measured by 86Rb or hemoglobin release and at a step prior to that inhibitable by high molarity EDTA. Consequently a further step in the reaction sequence of E to ghosts was identified. The reaction sequence leading from EAC1-9 to ghosts can be summarized as follows: formula: (see text).

Animals↗
PubMed1991

Quantitative analysis of adenine nucleotides during the prelytic phase of cell death mediated by C5b-9.

The nucleated cell death mediated by C5b-9 depends on the extent of C fixation and parameters that affect the ability of the cell to eliminate C5b-9. When C5b-9 formation exceeds elimination, cell death can be initiated. High Ca2+ in the medium accelerates Ehrlich ascites cell death induced by a large number of C5b-9, whereas osmotic prevention of cell swelling has little effect in protecting Ehrlich cells from killing by C5b-9. In the present study, we investigated the interrelationship between intracellular Ca2+, intra- and extracellular adenine nucleotides, and mitochondrial membrane potential, to understand the mechanism of acute cell death induced by C5b-9. When Ehrlich cells carrying C5b-8 were exposed to C9, rapid and profound ATP depletion in the cell was observed before cell death. Leakage of the adenine nucleotides ATP, ADP, and AMP also began during the prelytic phase. Studies using digital imaging fluorescence microscopy showed that loss of mitochondrial membrane potential was noted immediately after C9 addition but before nuclear staining with propidium iodide. These findings suggest that an increase in intracellular Ca2+ through C5b-9 channels and loss of mitochondrial membrane potential may initiate rapid cell death. The prelytic leakage of ATP precursors may also contribute to cell death by decreasing nucleotide pools, because recovery of ATP production was observed after a similar degree of ATP loss in cells exposed to sublethal doses of KCN, in which ADP and AMP leakage was not present.

Adenine Nucleotides↗
PubMed1999

Characterization of a surface membrane molecule expressed by natural killer cells in most inbred mouse strains: monoclonal antibody C9.1 identifies an allelic form of the 2B4 antigen.

A newly generated monoclonal antibody (mAb C9.1) described in this study identifies a surface membrane molecule that is involved in the lytic programme of activated natural killer (NK) cells. This conclusion is based on the facts that, first, this antigen was expressed on the vast majority of surface immunoglobulin (sIg)- CD3- CD4- CD8- spleen lymphocytes, albeit it was also present on minor subsets of sIg+ B (approximately 7%) and CD3+ T (approximately 2%) lymphocytes; second, that all splenic NK activity was contained within the C9.1+ cell population, and was almost totally abolished by treatment of spleen cells with mAb C9.1 and complement; third, that mAb C9.1 was capable of increasing interleukin-2-cultured and in vivo polyinosinic:polycytidylic acid-activated, NK cell-mediated, antibody-redirected lysis, but not freshly isolated NK cell-mediated killing. Furthermore, the strain distribution of the C9.1 antigen was shown to be antithetical to that of the 2B4 antigen already described as a molecule associated with major histocompatibility complex-unrestricted killing mediated by activated NK cells. The gene encoding C9.1 antigen was linked to the Akp1 isozyme locus on chromosome 1 close to the 2B4 gene. Although C9.1 and 2B4 were monomeric glycoproteins of 78 000 MW and 66 000 MW, respectively, removal of N-linked sugars from both antigens by endoglycosidase F yielded identical protein backbones of 38 000 MW. Thus, all of these results suggest that mAb C9.1 recognizes an allelic form of the 2B4 antigen. However, the detection of mAb C9.1-reactive antigen on a minor subset of B cells may suggest a possible reactivity of mAb C9. 1 with some product of other members of the 2B4 family genes.

Animals↗
PubMed2001

Tears contain the complement regulator CD59 as well as decay-accelerating factor (DAF).

Previous studies have shown that DAF (or CD55), a cell surface inhibitor of autologous C3 activation, is present in tears and that > 90% of the C3 convertase regulatory activity in tear fluid resides in this protein (Lass JH et al., Invest Ophth Vis Sci 1990; 31:1136-48). This study investigated whether (i) the membrane cofactor protein (MCP or CD46), an additional factor that regulates C3 activation, and (ii) the membrane inhibitor of reactive lysis (MIRL or CD59), a cell surface regulator that acts to prevent formation of the membrane attack complex, are also present in tears, and if so, are functional. Two-site immunoradiometric assays showed that MCP is present in tears at low levels (42 + 8 ng/ml, n = 8) while CD59 is present at levels (222 + 78 ng/ml, n = 14) comparable to those of DAF (325 + 289 ng/ml, n = 12). The concentrations of CD59 (i) were increased two-fold or more in closed eye tears, and (ii) were decreased in reflex tears. Western blotting showed that CD59 protein in tears migrates with an apparent mol. wt similar to membrane CD59 protein. Phenyl-Sepharose adsorption and Triton X-114 partitioning of tear CD59 as well as of tear DAF however, showed that both proteins are devoid of GPI anchors. Assays using cobra venom factor-activated human serum and guinea pig erythrocytes showed that CD59 is functionally active in inhibiting autologous C5b-9-mediated lysis and, under constitutive conditions, accounts for > 85% of the C9 inhibitory activity in tear fluid.

CD55 Antigens↗
PubMed1987

Generation of an activated form of human C5 (C5b-like C5) by oxygen radicals.

Treatment of purified human C5 with hydrogen peroxide leads to a reduction of functional activity in the classical immune haemolysis assay. The effect of H2O2 is enhanced by traces of iron-EDTA, and becomes even stronger when ascorbic acid is present in addition. The enhancement by iron and protective effects of various radical scavengers indicate that the conversion of C5 is brought about by hydroxyl radicals mainly, generated from H2O2 during its decomposition. By the conversion C5 acquires a new functional property: it becomes capable of binding C6, and the resulting complex C56 lyses non-sensitized red cells in cooperation with the late components C7, C8, and C9 (reactive lysis). In this respect, H2O2-treated C5 resembles the activation fragment of C5, C5b. However, unlike C5b, C5(H2O2) is not fragmented but comprises the whole molecule, according to polyacrylamide gel electrophoresis. In accordance with the lack of cleavage, no chemotactic activity indicating formation of C5a, became apparent after H2O2 treatment of C5. In whole human serum, however, the H2O2 system induces additional processes leading to the generation of C5a activity and indicating C5 cleavage. The pathways to this reaction are as yet not clear. The effect of oxygen radicals on C5 may be the basis of the enhancing effect of stimulated leukocytes on C5 activation in body fluids. Activated leukocytes are known to produce H2O2 and oxygen radicals.

Complement Activation↗
PubMed1994

Occurrence of C3 nephritic factor and C4 nephritic factor in membranoproliferative glomerulonephritis (MPGN).

One hundred patients diagnosed with hypocomplementaemic MPGN (C3 < 40%) were studied to determine the presence of C3 nephritic factor (C3NeF) and/or C4 nephritic factor (C4NeF). Of those studied, 12 were C3NeF-positive, nine were C4NeF-positive and 10 were positive for both C3NeF and C4NeF. In the 10 patients both C3NeF- and C4NeF-positive, a marked decrease in C3 and C5 levels and a decrease in levels of late components from C6 to C9 were observed. This observation was in contrast to that seen in patients who were either C3NeF- or C4NeF-positive. Patients positive for both C3NeF and C4NeF continued to exhibit hypocomplementaemia after therapy. Immunofluorescent findings revealed heavy C3 immunoglobulin deposits in the 10 patients who were both C3NeF- and C4NeF-positive, whereas no such deposits were found in those patients who were either C3NeF- or C4NeF-positive only. When those patients who were both C3NeF- and C4NeF-positive were compared with those who were either C3NeF- or C4NeF-positive, nephritic syndrome and a poor prognosis were observed more frequently. This study demonstrates a correlation between clinical outcome and hypocomplementaemic MPGN. Further investigations of MPGN as an autoimmune disease are necessary.

Adolescent↗
PubMed2002

Apolipoprotein J/clusterin prevents a progressive glomerulopathy of aging.

Apoliprotein J (apoJ)/clusterin has attracted considerable interest based on its inducibility in multiple injury processes and accumulation at sites of remodeling, regression, and degeneration. We therefore sought to investigate apoJ/clusterin's role in kidney aging, as this may reveal the accumulated effects of diminished protection. Aging mice deficient in apoJ/clusterin developed a progressive glomerulopathy characterized by the deposition of immune complexes in the mesangium. Up to 75% of glomeruli in apoJ/clusterin-deficient mice exhibited moderate to severe mesangial lesions by 21 months of age. Wild-type and hemizygous mice exhibited little or no glomerular pathology. In the apoJ/clusterin-deficient mice, immune complexes of immunoglobulin G (IgG), IgM, IgA, and in some cases C1q, C3, and C9 were detectable as early as 4 weeks of age. Electron microscopy revealed the accumulation of electron-dense material in the mesangial matrix and age-dependent formation of intramesangial tubulo-fibrillary structures. Even the most extensively damaged glomeruli showed no evidence of inflammation or necrosis. In young apoJ/clusterin-deficient animals, the development of immune complex lesions was accelerated by unilateral nephrectomy-induced hyperfiltration. Injected immune complexes localized to the mesangium of apoJ/clusterin-deficient but not wild-type mice. These results establish a protective role of apoJ/clusterin against chronic glomerular kidney disease and support the hypothesis that apoJ/clusterin modifies immune complex metabolism and disposal.

Aging↗
PubMed1982

Structural and functional studies in C1q deficiency.

The sera of two brothers were found totally lacking hemolytic C activity. One of them, a 16-yr-old male, presented a severe lupus-like syndrome, whereas the other was apparently healthy. Immunochemical quantitation of C components in both sera showed depressed levels of C1q, whereas the levels of C1r, C1s, and C1 inhibitor were elevated. C4, C3, C5, factor B, and beta 1H levels were in the normal range. Hemolytic C1 activity was totally lacking. C4 titers were elevated (150% of normal). C2 hemolytic activity was about one-third of normal, and the titers of the terminal components C3-C9 were also reduced in the two siblings. Double immunodiffusion against anti-C1q antiserum showed a partial loss of C1q antigenic determinants in the two siblings. Furthermore, the C1q of both siblings was unable to interact with immunoglobulins or to associate with C1r and C1s. Addition of purified human C1q to the sera restored their total C and C1 hemolytic activity. The dose response to the C1q addition was linear, indicating that the functional deficiency was not due to the presence of a serum inhibitor. Although antigenically deficient in comparison with normal C1q, the abnormal C1q appeared to have a larger m.w., as determined by gel chromatography. Investigation of other members of this family suggests a genetically linked disorder, because four out of six siblings had the same dysfunctional C1q in their serum.

Adolescent↗