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PubMed2003

Complement C3 F and BF S allotypes are risk factors for Chagas disease cardiomyopathy.

The heterogeneity in the clinical expression of Chagas disease gives strong evidences for the involvement of genetic factors on its pathogenesis. Several studies have indicated different markers of genetic susceptibility to Chagas cardiomyopathy. In the present study, we present evidence of association between complement C3 and BF allotypes, and the susceptibility to Chagas disease and the development of cardiomyopathy. C3, BF, C4A, C4B and C2 polymorphism were determined in 100 seropositive Chagasic patients [cardiomyopathic (CARD), n = 57; asymptomatic indetermined (IND), n = 43] and in 100 non-related seronegative healthy controls. Patients and controls were matched according to their ethnic and geographical origin. A significantly increased frequency of C3F was observed in patients with the CARD form (8/57 14.03%), when compared with those presenting the IND form (0/43, 0%; RR 7.0) and with the healthy controls (5/100, 5%; RR 3.1). A negative association of the BF S allotype was observed in the CARD patients (19/57 33.33%) and in the Chagas total (38/100 38.0%), when compared with the controls (55/100, 55.0%; RR 0.4). All other C3, BF, C4A, C4B and C2 alleles showed no significant differences. These results suggest the allele C3F as a susceptible marker for the progression of the CARD form. On the other hand, BF S may represent a protective role against severe CARD disease. These results corroborate the importance of the alternative pathway in Trypanosoma cruzi infection and indicate possible genetic markers of Chagas cardiomyopathy.

Adult↗
PubMed2005

Protein and lipid motifs regulate phosphatidylserine traffic in yeast.

Phosphatidylserine (PtdSer) is synthesized in the endoplasmic reticulum and its subdomains associated with the mitochondria [MAM (mitochondria-associated membrane)] and subsequently transported to the loci of the PtdSer decarboxylases, Pds1p (phosphatidylserine decarboxylase 1 encoded by the PSD1 gene that complements psd1 mutations) in the mitochondria, and Psd2p (PtdSer decarboxylase 2 encoded by the PSD2 gene that complements psd2 mutations) in the Golgi. Decarboxylation of PtdSer to PtdEtn (phosphatidylethanolamine) can be used as a biochemical indicator of transport to these organelles, which is regulated by specific lipid and protein motifs. PtdSer transport to mitochondria is controlled by ubiquitination via the action of the ubiquitin ligase subunit Met30p (a ubiquitin ligase subunit encoded by the MET30 gene that complements the met30 mutation affecting methionine biosynthesis). Mutant strains with lesions in the MET30 gene are defective in PtdSer transport and show altered ubiquitination of specific target proteins, such as the transcription factor Met4p (a transcription factor encoded by the MET4 gene that complements the met4 mutation affecting methionine biosynthesis). Mutations to MET30 cause defects in both the MAM as a donor of PtdSer, and the mitochondria as an acceptor of PtdSer in the transport reaction. PtdSer transport to the locus of Psd2p is controlled by specific protein and lipid motifs. The C2 (Ca2+ and phospholipid-binding sequence) domain of Psd2p, and the lipid-binding protein PstB2p (PtdSer transport B pathway protein encoded by the PSTB2 gene that complements the pstB2 mutation affecting PtdSer transport), must be present on acceptor membranes for PtdSer transport to occur. In addition, the action of the PtdIns 4-kinase, Stt4p (PtdIns 4-kinase encoded by the STT4 gene that complements the stt4 mutation causing staurosporine and temperature-sensitive growth) is also required for PtdSer transport to the locus of Psd2p. Reconstitution of PtdSer transport to Psd2p using liposomes demonstrates that PtdSer-rich domains present in vesicles are preferred substrates for transport. In addition, the incorporation of phosphatidic acid into donor membranes enhances the rate of PtdSer transport. Collectively, these data support a model for PtdSer transport in which specific proteins and lipids are required on donor and acceptor membranes.

Animals↗
PubMed1976

Serum factors activating the alternative complement pathway in autoimmune disease: description of two different factors from patients with systemic lupus erythematosus.

Serum factors which activated the alternative pathway of complement were detected in 10 of 26 patients with systemic lupus erythematosus (SLE), three of 18 patients with mixed connective tissue disease, one patient with scleroderma, and one with Sjögren's syndrome. This activation was detected by conversion of factor B and C3 into split products and by lysis of glutathione-sensitized human erythrocytes under conditions where classical pathway activation was blocked. The serum factors capable of activating the alternative pathway could be seperated into 7S and 19S-type molecules by sucrose density gradient ultracentrifugation. In two patients with SLE, serum factors were isolated by ion-exchange chromatography, preparative electrophoresis, and molecular sieve chromatography. The serum 7S factor was immunochemically identical to the C3 nephritic factor (C3NeF) of hypocomplementemic chronic glomerulonephritis. Antisera to other complement components failed to react with this purified material. The 7S factor was able to activate the alternative pathway in C2 deficient serum, and in normal human serum under conditions where classical pathway was blocked, but was unable to do so in sera depleted of factor B, factor D, and C3. The activity could be removed by antiserum to C3NeF. In contrast, the serum 19S activator of the alternative pathway was not reactive with antiserum to C3NeF. It had a fast gamma mobility on electrophoresis and the activity could be removed by absorption with anti-IgG and anti-IgM. It was suggested that the 19S factors could consist, in part, of immune complexes.

Absorption↗
PubMed1987

A complement-resistant HeLa cell line (T638) is blocked at the step of C3 deposition.

A complement-resistant line of HeLa cells (T638) was derived by serial passage of complement-susceptible HeLa cells in anti-beta 2-microglobulin (b2m) antiserum and complement. The T638 line maintained stable complement resistance when passed for an additional 1500 generations in the absence of antiserum and complement. T638 cells expressed equivalent levels of cell-associated b2m as did the parent HeLa cell line. Furthermore, T638 cells were resistant to killing by complement and anti-HeLa antiserum with specificity for molecules other than b2m. These results indicate that the resistance of T638 cells does not simply reflect loss of anti-b2m binding antigens. We next investigated the mechanism of resistance of T638 cells to complement-mediated killing. Antibody-sensitized HeLa and T638 cells both consumed CH50 activity completely from normal human serum; cytotoxicity was not mediated via the alternative complement pathway. HeLa and T638 cells caused equivalent utilization of C4 from normal human serum in the presence of antibody. Consumption of C2, greater with T638 than with HeLa cells during incubation in serum, was complete when cells bearing purified C1 and limited C4 were incubated with C2. T638 cells bound more 3H-C4 than HeLa cells during incubation in serum, but binding of 3H-C3 by T638 cells was fourfold to fivefold less than by HeLa cells. Finally, we investigated the rate of decay in the capacity of C142 on HeLa and T638 to cleave and deposit 3H-C3. The T1/2 for decay of C142-mediated binding of 3H-C3 on HeLa was 3.9 min, whereas minimal C3 deposition was detected on T638 cells at all time points. These results show that T638 cells evade complement-mediated lysis despite activating early components of the classical complement pathway. The mechanism of resistance is a failure to form an effective C3 convertase.

Antibodies↗
PubMed1981

The role of immunoglobulins in alternative complement pathway activation by zymosan. I. Human IgG with specificity for Zymosan enhances alternative pathway activation by zymosan.

Prior absorption of normal human serum (NHS) or C2-deficient human serum (C2D) with zymosan at 0 degrees C results in diminished consumption of C3 and factor B during subsequent incubation of the sera in Mg-EGTA buffer with zymosan at 37 degrees C for 30 min. An acid eluate from the zymosan restores the defect of absorbed NHS and C2D, and also enhances C3 and factor B utilization in hypogammaglobulinemic serum (H gamma S) in a dose-dependent fashion. The activity is specific in that the eluate from zymosan fails to enhance C3 and B depletion in H gamma S or absorbed NHS by lipopolysaccharide or Sepharose. The active component of th zymosan eluate emerges from both Sepharose 4B and Sephacryl S-200 in the region of molecules with m.w. of 150,000. Absorption with protein A-Sepharose removes the activity, demonstrating that it is IgG. Digestion of the IgG with pepsin fails to diminish activity, indicating that the Fc region is not required for activity; reduction to monovalent Fab' fragments, however, abrogates activity. When IgG antibody is bound to Protein A-Sepharose, it fails to enhance C3 depletion in H gamma S by Sepharose, indicating that binding of IgG antibody by the Fab region is necessary for enhancement of alternative pathway activity in human serum.

Antibody Specificity↗
PubMed1983

Analysis of active and inactive complement C4 complotypes associated with subtypes of HLA-B17 in different racial groups.

HLA-A, B, and C antigens and the HLA-linked markers BF, C2, and C4 were determined in 1,799 unrelated Caucasians, 140 North American blacks, 140 Chinese, and 66 Japanese. One allele of the C4A locus (Rodgers), C4A*6, was found to code for a functionally inactive product in HLA-B17 (Bw57)-positive individuals, but for a functionally active product in HLA-B37- or HLA-B27-positive individuals. Further studies revealed that the functionally inactive C4A*6 gene product was found only in one subtype of HLA-B17, namely, 17.1 (Bw57, long). In addition, it was found that the frequency of the other subtype of HLA-B17, namely, 17.2(Bw58, short) varies greatly in different populations and that HLA-Bw58 is associated with either C4A*3,B*1 or C4A*3,B*Q0.

Alleles↗
PubMed1975

C1-bypass complement-activation pathway in patients with chronic urticaria and angio-oedema.

During the routine screening of 152 patients with urticaria or angio-oedema for hypocomplementaemia, 4 patients were found to have low serum levels of the third component of complement (C). These patients were noteworthy and differed from previous reports of patients with urticaria-like skin lesions and hypocomplementaemia because of the absence of immune-complex disease. In addition to the low C3, 2 of these patients were unique on the basis of low serum levels of haemolytic C1, C1q, C1s, and properdin factor B, but normal concentrations of C4 and C2. These C abnormalities may reflect a new clinical entity, and these cases form the first description in man of the C1-bypass complement-activation pathway.

Adult↗
PubMed1979

Cryptic peptidoglycan and the antiphagocytic effect of the Staphylococcus aureus capsule: model for the antiphagocytic effect of bacterial cell surface polymers.

The antiphagocytic effect of the Staphylococcus aureus capsule is known to be related to its ability to interfere with opsonization by normal human serum. In this study, evidence is presented with isolated cell surface components which indicates that the capsule hinders opsonization by masking cell wall peptidoglycan. In contrast to intact, encapsulated S. aureus M cells, peptidoglycan particles isolated from the organism were efficiently opsonized by normal human serum and phagocytized by human polymorphonuclear leukocytes. Cell wall particles retaining capsular material were opsonized less efficiently than peptidoglycan. Studies comparing the opsonic capacities of normal, C2-deficient, and heat-inactivated sera led to the conclusion that both the classical and the alternative complement pathways contribute to the opsonization of peptidoglycan in normal human serum. It appears that the capsule interferes with opsonization via both of these complement pathways. Serum from rabbits immunized with S. aureus M had significant heat-stable opsonic activity for the intact organism and cell walls retaining capsular material, but not for peptidoglycan. A general model is proposed to explain how antiphagocytic cell surface polymers may inhibit bacterial opsonization and thereby impede natural immunity.

Cell Wall↗
PubMed1986

A new BF variant (F025).

A rare variant of Factor B exhibiting a mobility intermediate between BF F and BF S was described. After comparison with the mobilities of BF F and F075, this variant was designated BF F025. The allele was transmitted together with C2*C, C4A*3, and C4B*1.

Alleles↗
PubMed1976

[Polymorphism of factor B of the properdin system (C3PA, GBG, and Bf) and histocompatibility-complement linkage].

Several recent studies have shown that the genetic polymorphism of factor B of the Properdin system (GBG or Bf) is closely linked to the major histocompatibility complex (MHC). The genetic polymorphism of Bf, a component of the alternate pathway of complement activation, is revealed by "immunofixation" technique after prolonged high voltage agarose electrophoresis. In this report, we describe technique for the Bf grouping and give the results in two families showing the linkage between HL-A and Bf loci. The study of a family with a recombinant between the second HL-A locus (SD-2) and the major MLC locus (LD-1) provides evidence that the Bf locus is not located outside the MLC's because the Bf allele remains linked to the SD-2 allele. In this family, a crossover occurs between Bf and LD-1, and since crossovers between Bf and SD-2 have already been discovered, it is now possible to locate the Bf locus between SD-2 and LD-1. The Bf phenotypes were determined in the serum of 247 normal unrelated caucasian individuals from the area of Strasbourg. The calculated allele frequencies in this population are: BfS=0.757, BfF=0.219, BfS1=0.014, BfF1=0.010. These allele frequencies are intermediary between those found by ALPER and RITTNER. The linkage between MHC and the complement system is now even more evident after the discovery that genes involved in the synthesis of the second and fourth complement components also belong to the MHC on the chromosome 6. These linkages were demonstrated by the study of several families with hereditary C2 deficiency in the U.S.A., and one family with C4 deficiency discovered in Strasbourg. C2 deficiency was found to be associated with three kinds of HL-A haplotypes (HL-A 10, W18; HL-A 2, W18 and HL-A2, 4A2) and the LD-7a specificity. In the family with C4 deficiency, the C4 deficient gene is associated with the HL-A haplotype 2, T3, W10 and a new hitherto unknown MLC type "Re". The linkage between C4 and MHC has been demonstrated recently also in the mouse (the Ss protein in the complement C4 fraction in the mouse) and in the guinea pig. The significance of the genetic linkage between some important components of the complement system and MHC is still unknown. It appears necessary to study all the genetic markers located within or in the vicinity of the MHC region on the chromosome 6 in investigations of the relationship between "pathologic states and HL-A antigens".

Alleles↗
PubMed1984

Effect of reduction and alkylation on structure and function of rabbit IgG antibody--II. Effects on classical pathway C3 convertase formation.

Anaerobic reduction of purified rabbit IgG antibody (Ab) with 1.5 moles of dithiothreitol per mole of Ab at pH 8.0, followed by alkylation, cleaves 39% of the inter-heavy-chain (H-H) disulfide (SS) bonds. This treatment has the following effects on the ability of the Ab to activate the classical pathway of complement. Compared to control Ab, reduced and alkylated (RA) Ab retained 4-5.6% of overall hemolytic activity and 55% of complement-fixing activity at 0 degrees C. Complexes of RA Ab and equivalent amounts of soluble Ag consumed C4, C2 and C3 at 37, 51 and 44%, respectively, of the rate at which these components were consumed by equal concns of complexes containing control Ab. Complexes made with RA Ab bound 18% as much C-1 as those made with native Ab. These data indicate that the principal, if not the only, effect of RA is on C-1 binding. Measurements of the ability of complexes of Ab with cell-bound Ag to bind C-1 showed at most a 20% loss of C-1 binding sites and a ca two-fold decrease in affinity for C-1. Similar results were obtained with purified (activated) C-1 and with native C1 in serum. No significant difference could be detected in the rate of activation of bound C1. Normal rabbit IgG which was reduced and alkylated under the same conditions retained 52% of its H-H SS bonds and 30% of its ability to bind C-1. This finding suggests that the impairment in C-1 binding results from an effect on the C1 binding site itself, rather than from an effect on the ability of the RA Ab to transmit a putative conformational "signal" from the Ag-binding site to the C1 binding site. Finally, our data show that the observed functional effect of reduction and alkylation depends strongly on the assay used to evaluate that effect.

Alkylation↗
PubMed1981

Complement receptor is an inhibitor of the complement cascade.

A glycoprotein from the membrane of human erythrocytes has been identified as a receptor for C3b (CR1). It promotes the dissociation of the alternative pathway C3 convertase C3b,Bb and the cleavage of C3b by C3b/C4b inactivator. We find that CR1 also inactivates the C3 and C5 convertases of the classical pathway. CR1 inhibits the consumption of C3 by C3 convertase EAC142 and enhances the decay of C4b,2a sites. On a weight basis, CR1 is approximately 5-10 times more active than C4 binding protein, a serum inhibitor of C4b,2a. The binding of 125I-CR1 to EAC14 cells is inhibited by C2. Therefore, it is likely that CR1 and C2 compete for a site on C4b. CR1 inhibited C5 convertase even more effectively, but had no effect on the assembly of the late complement components. At high concentrations, CR1 alone has no irreversible effects on cell-bound C4b. In the fluid phase, CR1 can function as a cofactor for the cleavage of the alpha' chain of C4b by C3b/C4b inactivator. A well-known function of CR1 is to promote adherence of microbes or immune complexes bearing C3b and C4b to cells. This interaction could result in a microenvironment damaging to the plasma membrane of the responding cell because the extrinsic C3b and C4b fragments can serve as additional sites of assembly of enzymes of the cascade. We therefore wish to propose that CR1 on the surface of cells supplies an increased local concentration of a strong inhibitor of the amplifying enzymes of the complement system and provides cells with a mechanism for circumventing damage when they bind C3b- and C4b-bearing substrates.

Complement C3-C5 Convertases↗
PubMedDate not supplied

Complement and opsonins in alveolar secretions and serum of rats with pneumonia due to Streptococcus pneumoniae.

Complement appears to have an important role in the early defense against Streptococcus pneumoniae, but the role of complement as a defense mechanism within the lung is not well defined. Complement and heat-labile opsonins in pneumococcal pneumonia were studied by analysis of bronchoalveolar lavage fluid (BALF) of rats inoculated intratracheally with type 3 S. pneumoniae. BALF and serum were obtained at 0, 6, and 24 hr after infection. Leukocyte counts in BALF and histologic studies revealed an acute inflammatory response in the lung at 6 hr; this inflammation progressed for 24 hr. Levels of C1, C2, C3, and alternative pathway activity in pooled, concentrated (20X) BALF of normal and infected rats varied according to the stage of infection and the complement parameter studied, but in all cases the levels were only a small fraction of the levels in serum. Concentrated BALF had measurable levels of pneumococcal heat-labile opsonins, but these were also low as compared with serum levels. A small amount of C3 was detected by immunofluorescence on pneumococci recovered from BALF of infected animals, but these same organisms could be coated much more fully with C3 by brief incubation in serum. The milieu in the lung during bacterial infection is very different from that in serum and may be marginally suitable for effective opsonization of successful pulmonary pathogens such as type 3 S. pneumoniae.

Animals↗
PubMed1986

An inherited deficiency of the third component of complement, C3, in guinea pigs.

Hereditary deficiency of the third component of complement, C3, is found very seldom in the human. C3 deficiency is associated with severe bacterial infections revealing the central role of C3 in complement activation via the classical or alternative pathway. We describe a new hereditary C3 deficiency in strain 2 guinea pigs. Serum from these animals had a markedly reduced lytic activity in a standard assay for complement-dependent, antibody-mediated cytotoxicity. In functional assays of individual components, the hemolytic activity of the components C4, C2, C5 and of factors B, D and H was in the normal range. The functional C3 titer, and similarly C3 antigenic activity in the serum of these C3-deficient animals (C3D) was on average only 5.7% of normal activity. Typing the animals with alloantisera or monoclonal antibodies to guinea pig Ia-antigens revealed that the C3D animals had the major histocompatibility complex-haplotype of inbred strain 2 guinea pigs (B.1, Ia.2,4). The C3 defect is not linked to the major histocompatibility complex and, in addition, is not linked to a C3a receptor deficiency. Macrophages and hepatocytes of the C3D animals have an unimpaired capacity for synthesis and secretion of C3 as measured by enzyme-linked immunosorbent assay. There was no indication for hypercatabolism of normal C3 by the animals as shown by plasma clearance of 125I-radiolabeled C3. Thrombocytes of the C3D animals responded normally to stimulation with purified C3a in an ATP-release assay without an indication for a desensitization in vivo. Possibly the fault resides in an enhanced susceptibility of their own C3 to proteolysis. However, C3 partially purified from the plasma of the C3D animals or secreted by hepatocytes exhibited no obvious structural differences to purified normal C3 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis or in immunoblotting. The C3D serum had a reduced bactericidal activity compared to normal or to C4-deficient serum. Nevertheless, the animals are apparently healthy without an indication for increased frequency of bacterial infections. These guinea pigs provide an unique model for analysis of the biological functions of C3 in vivo and in vitro without the need for artificial C3-depletion procedures with all their known and unknown side-effects.

Animals↗
PubMed2006

Small mannose-binding lectin-associated protein plays a regulatory role in the lectin complement pathway.

Mannose-binding lectin (MBL) and ficolins are pattern recognition proteins acting in innate immunity, and they trigger the activation of the lectin complement pathway through MBL-associated serine proteases (MASPs). Upon activation of the lectin pathway, MASP-2 cleaves C4 and C2. A truncated form of MASP-2, named small MBL-associated protein (sMAP), is also associated with MBL/ficolin-MASP complexes. To clarify the role of sMAP, we have generated sMAP-deficient (sMAP(-/-)) mice by targeted disruption of the sMAP-specific exon. Because of the gene disruption, the expression level of MASP-2 was also decreased in sMAP(-/-) mice. When recombinant sMAP (rsMAP) and recombinant MASP-2 (rMASP-2) reconstituted the MBL-MASP-sMAP complex in deficient serum, the binding of these recombinant proteins to MBL was competitive, and the C4 cleavage activity of the MBL-MASP-sMAP complex was restored by the addition of rMASP-2, whereas the addition of rsMAP attenuated the activity. Therefore, MASP-2 is essential for the activation of C4 and sMAP plays a regulatory role in the activation of the lectin pathway.

Animals↗
PubMed1999

Up-regulated production and activation of the complement system in Alzheimer's disease brain.

We used reverse transcriptase-polymerase chain reaction and Western blotting techniques to measure the levels of complement mRNAs and their protein products in Alzheimer's disease (AD) brain compared with non-AD brain. mRNAs for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 were detected in the 11 regions of brain that were investigated. The mRNA levels were markedly up-regulated in affected areas of AD brain. In the entorhinal cortex, hippocampus, and midtemporal gyrus, which had dense accumulations of plaques and tangles, C1q mRNA was increased 11- to 80-fold over control levels, and C9 mRNA 10- to 27-fold. These levels were substantially higher than in the livers of the same cases. Western blot analysis of AD hippocampus established the presence of all of the native complement proteins as well as their activation products C4d, C3d, and the membrane attack complex. These data indicate that high levels of complement are being produced in affected areas of AD brain, that full activation of the classical complement pathway is continuously taking place, and that this activation may be contributing significantly to AD pathology.

Adult↗
PubMed1989

[Complement-inhibiting acidic factors from the venom of Central Asian cobra Naja naja oxiana].

Two anticomplementic factors isolated from the venom of the Central Asian cobra Naja naja oxiana by chromatography on DEAE-Sepharose CL-6B and subsequent gel filtration on Sephacryl S-200 were studied. Of these, five factors (CFA-Ia, CFA-Ib, CFA-Ic, CFA-IIa and CFA-IIb), CFA-Ib had been characterized earlier, while CFA-Ia was assigned to a previously identified H-CoF factor. It was shown that CFA-Ic has a molecular mass of 3900 Da; its content in the venom amounts to 2.6 mg/g of dry venom. This factor inhibits the classical pathway of C3 convertase formation abrogating the C2 component activation by subcomponent C1s [Ki = (2.5 +/- 0.8).10(-7) M]. CFA-IIa and CFA-IIb are present in the venom in very low amounts (2 mg/g) and have Mr of 5700 and 3200 Da, respectively. The complement-inhibiting action was studied for a more active CFA-IIa. Factor CFA-IIa was shown to inactivate the native component of C2 with a rate constant, k, of (2.7 +/- 0.2).10(3) s-1M-1 (37 degrees C, pH 7.4). CFA-IIa had no effect on C2 and C2a within their complexes with C4b.

Chromatography, DEAE-Cellulose↗
PubMed1983

Activation of the alternative pathway of complement by monosodium urate crystals.

Monosodium urate crystals (MSU) have been shown to activate the alternative pathway of complement in a dose- and time-dependent fashion at 37 degrees C. Activation was maximal upon addition of 10-20 mg/ml monosodium urate crystals to C2-deficient human serum (C2D) or normal human serum containing 5 mM MgEGTA. Immunoelectrophoretic analysis of such treated sera demonstrated cleavage of C3 and factor B. Incubation of highly purified C3 and factor B with 10 mg/ml MSU did not, however, affect their immunoelectrophoretic pattern, suggesting that cleavage of either factor B or C3 in serum requires an intact alternative complement pathway. The fluid-phase control proteins, Factor H and Factor I, were not found to be diminished upon incubation of C2D serum or NHS containing MgEGTA with MSU. Thus activation appeared to be surface dependent and not a consequence of control protein depletion. It was also found, in agreement with earlier observations, that the classical complement pathway is activated, with concomitant depletion of C1 and C4. We conclude that MSU crystals activate both the classical and alternative pathways, and that such activation may participate in the pathogenesis of gouty arthritis.

Complement Activation↗