• 한국미생물학회:학술대회논문집
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• 한국미생물학회 2008년도 International Meeting of the Microbiological Society of Korea
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• pp.23-25
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• 2008

Serum complement proteins comprise an important system that is responsible for several innate and adaptive immune defence mechanisms. There were three well described pathways known to lead to the generation of a C3 convertase, which catalyses the proteolysis of complement component C3, and leads to the formation of C3 opsonins (C3b, iC3b and C3d) that fix to bacteria. A pivotal step in the complement pathway is the assembly of a C3 convertase, which digests the C3 complement component to form microbial-binding C3 fragments recognized by leukocytes. The spleen clears microorganisms from the blood. Individuals lacking this organ are more susceptible to Streptococcus pneumoniae. Innate resistance to S. pneumoniae has previously been shown to involve complement components C3 and C4, however this resistance has only a partial requirement for mediators of these three pathways, such as immunoglobulin, factor B and mannose-binding lectin. Therefore it was likely that spleen and complement system provide resistance against blood-borne S. pneumoniae infection through unknown mechanism. To better understand the mechanisms involved, we studied Specific intracellular adhesion molecule-grabbing nonintegrin (SIGN)-R1. SIGN-R1, is a C-type lectin that is expressed at high levels by spleen marginal-zone macrophages and lymph-node macrophages. SIGN-R1 has previously been shown to be the main receptor for bacterial dextrans, as well as for the capsular pneumococcal polysaccharide (CPS) of S. pneumoniae. We examined the specific role of this receptor in the activation of complement. Using a monoclonal antibody that selectively downregulates SIGN-R1 expression in vivo, we show that in response to S. pneumoniae or CPS, SIGN-R1 mediates the immediate proteolysis of C3 and fixation of C3 opsonins to S. pneumoniae or to marginal-zone macrophages that had taken up CPS. These data indicate that SIGN-R1 is largely responsible for the rapid C3 convertase formation induced by S. pneumoniae in the spleen of mice. Also, we found that SIGN-R1 directly binds C1q and that C3 fixation by SIGN-R1 requires C1q and C4 but not factor B or immunoglobulin. Traditionally C3 convertase can be formed by the classical C1q- and immunoglobulin-dependent pathway, the alternative factor-B-dependent pathway and the soluble mannose-binding lectin pathway. Furthermore Conditional SIGN-R1 knockout mice developed deficits in C3 catabolism when given S. pneumoniae or its capsular polysaccharide intravenously. There were marked reductions in proteolysis of serum C3, deposition of C3 on organisms within SIGN-$R1^+$ spleen macrophages, and formation of C3 ligands. The transmembrane lectin SIGN-R1 therefore contributes to innate resistance by an unusual C3 activation pathway. We propose that in the SIGN-R1 mediated complement activation pathway, after binding to polysaccharide, SIGN-R1 captures C1q. SIGN-R1 can then, in association with several other complement proteins including C4, lead to the formation of a C3 convertase and fixation of C3. Therefore, this new pathway for C3 fixation by SIGN-R1, which is unusual as it is a classical C1q-dependent pathway that does not require immuno globulin, contributes to innate immune resistance to certain encapsulated microorganisms.

• The Korean Journal of Pain
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• 제37권2호
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• pp.91-106
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• 2024

The mechanisms of the chronic pain and depression comorbidity have gained significant attention in recent years. The complement system, widely involved in central nervous system diseases and mediating non-specific immune mechanisms in the body, remains incompletely understood in its involvement in the comorbidity mechanisms of chronic pain and depression. This review aims to consolidate the findings from recent studies on the complement system in chronic pain and depression, proposing that it may serve as a promising shared therapeutic target for both conditions. Complement proteins C1q, C3, C5, as well as their cleavage products C3a and C5a, along with the associated receptors C3aR, CR3, and C5aR, are believed to have significant implications in the comorbid mechanism. The primary potential mechanisms encompass the involvement of the complement cascade C1q/C3-CR3 in the activation of microglia and synaptic pruning in the amygdala and hippocampus, the role of complement cascade C3/C3a-C3aR in the interaction between astrocytes and microglia, leading to synaptic pruning, and the C3a-C3aR axis and C5a-C5aR axis to trigger inflammation within the central nervous system. We focus on studies on the role of the complement system in the comorbid mechanisms of chronic pain and depression.

• Macromolecular Research
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• 제12권1호
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• pp.46-52
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• 2004

In a continuation of our previous studies on blood compatibility profiles of anion-substituted poly(vinyl alcohol) (PVA) membranes, in which hydroxyl groups have been replaced with carboxymethyl (C-PVA) and sulfonyl groups (S-PVA), we have studied the activation of complement components and the changes in white cell and platelet count in vitro and compared them with those of unmodified PVA, Cuprophane, and low-density polyethylene. Complement activation of fluid phase components, C3a, Bb, iC3b, and SC5b-9, and of bound phases, C3c, C3d, and SC5b-9, were assessed by enzyme-linked immunosorbent assay (ELISA) and immunoblot, respectively. The changes in the number of white cells and platelets following complement activation were counted using a Coulter counter. C-PVA and S-PVA activated C3 to a lesser extent than did PVA, which we attribute to the diminished level of surface nucleophiles of the samples. In addition, C- and S-PVA exhibit increased inhibition of Bb production, resulting in a decrease in the extent of C5 activation. Consequently, because of the reduced activation of C3 and C5, C- and S-PVA samples cause marked decreases in the SC5b-9 levels in plasma. We also found that the negatively charged sulfonate and carboxylate groups of the samples cause a greater extent of adsorbtion of the positively charged anaphylatoxins, C3a and C5a, because of strong electrostatic attraction, which in turn provides an inhibition of chemotaxis and activation of leukocytes. The ability to inhibit complement production, together with the binding ability of anaphylatoxins of the C- and S-PVA samples, leads to a prominent decrease in lysis of leukocytes as well as activation of platelets.

• Childhood Kidney Diseases
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• 제21권2호
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• pp.160-164
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• 2017

C3 glomerulopathy (C3G) is a recently defined pathological entity characterized by C3 accumulation with absent or scant immunoglobulin deposition, leading to variable glomerular inflammation. The clinical presentation of patients with C3G is highly variable, as they may present with symptoms ranging from microscopic or mild proteinuria to full-blown nephrotic syndrome, with or without renal impairment. However, there is no consensus recommendation for specific treatment in children with C3G. Recently, new therapies have been suggested to target complement pathways, owing to an improvement in the understanding of the pathogenesis of C3G. C3G complement blockade with eculizumab, a monoclonal antibody targeted against complement C5, inhibits activation of the alternative complement pathway. We could not use eculizumab owing to its high price; thus, we administered oral prednisolone and mycophenolate mofetil (MMF). MMF was replaced with cyclosporine because proteinuria persisted, with a consistently low serum C3 level; we tapered off the prednisolone because of a Cushingoid appearance and amenorrhea. Thereafter, proteinuria improved, and the serum C3 level returned to normal. Thus, we report the effectiveness of cyclosporine in a patient with C3G and an inadequate response to prednisolone and MMF, who was detected via school urinary screening.

• Molecules and Cells
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• 제43권12호
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• pp.1023-1034
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• 2020

Complement fragment iC3b serves as a major opsonin for facilitating phagocytosis via its interaction with complement receptors CR3 and CR4, also known by their leukocyte integrin family names, αMβ2 and αXβ2, respectively. Although there is general agreement that iC3b binds to the αM and αX I-domains of the respective β2-integrins, much less is known regarding the regions of iC3b contributing to the αX I-domain binding. In this study, using recombinant αX I-domain, as well as recombinant fragments of iC3b as candidate binding partners, we have identified two distinct binding moieties of iC3b for the αX I-domain. They are the C3 convertase-generated N-terminal segment of the C3b α'-chain (α'NT) and the factor I cleavage-generated N-terminal segment in the CUBf region of α-chain. Additionally, we have found that the CUBf segment is a novel binding moiety of iC3b for the αM I-domain. The CUBf segment shows about a 2-fold higher binding activity than the α'NT for αX I-domain. We also have shown the involvement of crucial acidic residues on the iC3b side of the interface and basic residues on the I-domain side.

• Journal of Chest Surgery
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• 제28권7호
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• pp.649-657
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• 1995

From December 1993 to April 1994, to investigate complement activation and pulmonary leukostasis, thirty adult patients were studied during cardiopulmonary bypass[CPB for cardiac surgery in Department of Cardiovascular & Thoracic Surgery, Pusan Paik Hospital, Inje University. Total patients were divided into group I and II according to the purpose of study ; Group I was 15 patients undergoing CPB with bubble oxygenator, Group II was 15 patients undergoing CPB with membrane oxygenator. The results of study were summarized as follows.1. The decrease of C3 and C4 levels were observed within few minutes of beginning of CPB in all patients[P<0.05 , and this decrease was proved to be due to complement activation, not by the influence of hemodilution.2. In the correlation between the change of C3 and C4, group I showed linear correlation each other suggesting complement activation occurred through the classical pathway, group II showed a correlation at only partial sampling times suggesting complement activation via both classical and alternative pathway, however there was no significant statistical difference at the change of C3 and C4 concentrations in two groups[P>0.05 .3. After switching to partial CPB, a few difference between right atrial and left atrial WBC count was observed, but statistically not significant and median cell count difference between group I and II was not significant, too [P>0.05 . With the above result, we concluded that CPB itself contributes to the activation of complement system, but bubble oxygenator does not activate always complement system more than membrane oxygenator.

• Natural Product Sciences
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• 제14권4호
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• pp.249-253
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• 2008

Two oleanane-type triterpenes (1, 2) and their glycosides (4-6), and one ursane-type triterpene (3) have been isolated from a methanolic extract of Patrinia saniculaefolia Hemsley (Valerianaceae) through repeated silica gel and reversed-phase C-18 column chromatography. Their chemical structures were determined as oleanolic acid (1), oleanonic acid (2), 23-hydroxyursolic acid (3), 3-O-${\alpha}$-L-arabinopyranosyl-oleanolic acid (4), 3-O-${\beta}$-D-glucopyranosyl-oleanolic acid (5), and oleanolic acid 3-O-[${\alpha}$-D-xylopyranosyl-($1{\rightarrow}3$)-${\beta}$-D-glucuronopyranoside-6-O-butyl-ester] (6) on the basis of their MS, $^1H$-, and $^{13}C$-NMR spectral data. All compounds were isolated from the whole plant of the P. saniculaefolia for the first time. These compounds were examined for their anti-complement activity against the classical pathway of the complement system. Among them, compounds 1 - 3 exhibited anti-complement activity with $IC_{50}$ values of 470.1, 212.2, and 121.0 ${\mu}M$, respectively, whereas compounds 4 - 6 were inactive. These results suggest that the carbonyl or hydroxy group at C-3 in the oleananeand/or ursane-triterpenes are important for the anti-complement activity against the classical pathway.

• Childhood Kidney Diseases
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• 제25권1호
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• pp.29-34
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• 2021

C3 glomerulonephritis (C3GN), a rare condition associated with dysregulation of the alternative pathway of the complement system, is histopathologically characterized by isolated or dominant C3 deposition in the renal glomeruli. We report a case of C3GN associated with anti-complement factor H (CFH) autoantibodies and CHF-related protein deficiency in an adolescent male. A 16-year-old adolescent male was admitted to a hospital with a 1-month history of generalized edema prior to presentation. Persistent microscopic hematuria and low serum C3 levels were incidentally detected at 7 and 10 years of age, respectively. Laboratory test results revealed hypoalbuminemia, nephrotic-range proteinuria, microscopic hematuria, and normal serum creatinine levels. The serum C3 and C4 levels were 17 mg/dL (normal 80-150 mg/dL) and 22 mg/mL (17-40 mg/mL), respectively. Renal biopsy showed typical features of C3GN. Further investigations revealed positive results on plasma anti-CFH autoantibody testing and a homozygous deletion of CFHR1 and CFHR3, which encode CFH-related proteins 1 and 3, respectively. Proteinuria persisted despite treatment with intravenous methylprednisolone, mycophenolate mofetil, and angiotensin-receptor blocker; however, his renal function remained stable. In conclusion, anti-CFH autoantibodies serve as important contributors to C3GN. This is the first case report that describes C3GN in an adolescent Korean male with anti-CFH autoantibodies and homozygous CFHR1 and CFHR3 deletion.

• Childhood Kidney Diseases
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• 제17권1호
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• pp.1-5
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• 2013

사구체에 면역글로불린은 음성이면서 C3 만 침착되는 경우, 다른 원인이 없는 경우 C3GN을 의심하여야 한다. 광학현미경으로는 세포의 증식이 있는 경우와 없는 경우가 있지만, 전자현미경으로는 EDD가 내피세포 밑으로 혹은 메산지움 등에 침착함을 확인하여야 한다. 대체보체경로의 조절이상이 원인임으로 혈청 C3 치를 비롯하여 CFH, CFI, CFB 등을 측정하여야 하며, C3 nephritic factor, anti-factor H 자가항체 등을 조사하는 것이 필요하다. 보체 조절이상을 일으키는 유전자 돌연변이를 조사해 보아야 한다. 예후는 안정적이지만, 치료는 대증적이다. 이론적으로 보체의 활성화를 저지하는 약으로 가능할 것으로 생각되며, C5 항체인 eculizumab으로 치유된 보고도 있다.

• Childhood Kidney Diseases
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• 제10권1호
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• pp.45-51
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• 2006

저자들은 C3의 감소와 육안적 혈뇨를 보인 환아에서 현미경적 혈뇨가 지속되면서 8주 후 시행한 검사에서도 C3의 감소가 지속되어 MPGN을 의심하고 신생검 예정이었다. 추적 관찰 중 수막구균 뇌수막염이 동반되었고, C3와 C5의 지속적인 감소와 C7과 C9의 일시적인 감소를 확인하였으며, 신생검에서 1형 MPGN으로 확인되었다. 본 증례의 아쉬운 점은 nephritic factor의 존재나 factor H의 결핍을 입증하여야 하나 아직까지 국내에서는 시행되지 않아 확인은 하지 못하였다. 앞으로 국내에서도 nephritic factor나 다양한 보체계(complement profile)에 대한 검사들이 시행되어야 할 것이다. 이제까지 국내에서는 후기 보체 결핍에 의하여 수막구균 뇌수막의 발생 증례 보고는 2004년 이후 여러 차례 있었지만, MPGN 환자에서 수막구균의 감염은 국내에 보고된 바가 없다. 본 증례를 통해 저보체혈증이 지속되는 일부의 MPGN 환자에서는 수막구균 감염 위험성이 존재하며, nephritic factor 검사와 함께 후기 보체 결핍에 대한 검사가 필요하다고 생각한다. 또한 수막구균성 뇌수막염에 이환된 모든 환자에 대해서 보체 검사를 시행하고 이런 환자에서 주기적인 소변 검사를 통하여 이상이 있을시 MPGN의 가능성을 고려하여 신생검을 고려하여야 할 것이다.