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Recognition molecules of the complement system: C1q and mannan-binding lectin in autoimmunity and immune defence

Mårtensson, Ulla LU (2006)
Abstract
The C1 subcomponent C1q and the mannan-binding lectin (MBL) are recognition proteins of the complement system, and have similar structure. C1q binds to IgG and IgM and activates the classical pathway. MBL binds to carbohydrate structures and activates the lectin pathway. Autoantibodies to C1q are frequently found in severe systemic lupus erythematosus (SLE) and are present in virtually all patients with the hypocomplementemic urticarial vasculitis syndrome (HUVS). In order to investigate possible heterogeneity with regard to epitope specificity, anti-C1q antibodies in the sera of 12 patients with SLE, HUVS or SLE/HUVS overlap syndromes were subjected to Western blot analysis. The SLE sera were negative by Western blot analysis. By... (More)
The C1 subcomponent C1q and the mannan-binding lectin (MBL) are recognition proteins of the complement system, and have similar structure. C1q binds to IgG and IgM and activates the classical pathway. MBL binds to carbohydrate structures and activates the lectin pathway. Autoantibodies to C1q are frequently found in severe systemic lupus erythematosus (SLE) and are present in virtually all patients with the hypocomplementemic urticarial vasculitis syndrome (HUVS). In order to investigate possible heterogeneity with regard to epitope specificity, anti-C1q antibodies in the sera of 12 patients with SLE, HUVS or SLE/HUVS overlap syndromes were subjected to Western blot analysis. The SLE sera were negative by Western blot analysis. By contrast, HUVS sera showed reactivity with the B and C polypeptide chains of C1q. Investigation of 69 consecutive sera with anti-C1q antibodies and low C1q confirmed the findings, but there were also exceptions to the rule. Anti-C1q antibodies are directed against the collagen-like region of C1q, and the question was asked if the antibodies cross-react with the structurally related collectins MBL, lung surfactant protein A, and bovine conglutinin. Anti-C1q autoantibodies did not cross-react with these proteins. Serial analysis of anti-C1q antibodies in SLE patients with mild extrarenal flares, severe extrarenal flares and flares of lupus nephritis showed a very high prevalence of anti-C1q in the nephritis group, usually in conjunction with anti-dsDNA, and correlation to hypocomplementemia (low C1q). Anti-C1q antibodies did not cross-react with collagen type II antibodies and anti-dsDNA. With regard to complement activation by MBL, strong controversy exists concerning C3-activation and the alternative pathway independent of the C3 convertase C4b2a. Using a C3 deposition ELISA and microtiter plate wells coated with a Salmonella serogroup C-specific oligosaccharide, which binds MBL, we have provided strong evidence for MBL-dependent C2 bypass activation of C3 and the alternative pathway. The mechanism does not require MBL associated serine proteases (MASPs), but may be enhanced by MASP-1. Finally, complement requirements for C3 and C4 deposition on apoptotic cells were investigated by flow cytometry. Assay conditions strongly influenced the results. The classical pathway was of predominant importance. Interestingly, C4 deposition was enhanced in C2-deficient sera. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

C1q, en delkomponent av C1 molekylen, och mannan-bindande protein (MBL) är igenkänningsmolekyler i komplementsystemet. De har likartad struktur. C1q binder till IgG och IgM och aktiverar den klassiska vägen. MBL binder till kolhydratstrukturer och aktiverar lektinvägen. Autoantikroppar mot C1q förekommer ofta vid svår systemisk lupus erythematosus (SLE) och förekommer också hos i stort sett alla patienter med hypokomplementemiskt urtikaria-vaskulitsyndrom (HUVS). För att studera möjlig heterogenitet hos anti-C1q antikropparna beträffande epitop-specificitet analyserade vi med Western blot-analys sera från 12 patienter med SLE, HUVS eller blandformer av SLE och HUVS. SLE-sera var negativa enligt... (More)
Popular Abstract in Swedish

C1q, en delkomponent av C1 molekylen, och mannan-bindande protein (MBL) är igenkänningsmolekyler i komplementsystemet. De har likartad struktur. C1q binder till IgG och IgM och aktiverar den klassiska vägen. MBL binder till kolhydratstrukturer och aktiverar lektinvägen. Autoantikroppar mot C1q förekommer ofta vid svår systemisk lupus erythematosus (SLE) och förekommer också hos i stort sett alla patienter med hypokomplementemiskt urtikaria-vaskulitsyndrom (HUVS). För att studera möjlig heterogenitet hos anti-C1q antikropparna beträffande epitop-specificitet analyserade vi med Western blot-analys sera från 12 patienter med SLE, HUVS eller blandformer av SLE och HUVS. SLE-sera var negativa enligt denna analys, medan sera från HUVS-patienter reagerade med C1q-molekylens B-och C-kedjor. Dessa fynd konfirmerades i en större studie av 69 patienter med anti-C1q och med låg C1q nivå. Dock fanns det undantag från regeln. Anti-C1q antikropparna är riktade mot den kollagen-lika delen av C1q. Detta gjorde att man frågade sig om dessa antikroppar korsreagerar med de strukturellt likartade kollektinerna MBL, lung surfactant protein A och bovint konglutinin. Korsreaktivitet med dessa proteiner kunde inte påvisas. Analys av anti-C1q antikroppar i sekventiella prover från SLE patienter med mild sjukdom, svår extrarenal SLE och SLE med njurengagemang visade en hög prevalens av C1q antikroppar vid SLE-nefrit samtidigt med förekomst av anti-dsDNA och hypokomplementemi (låg C1q). Anti-C1q korsreagerade ej med kollagen typ II och dsDNA. Aktivering av den alternativa vägen via MBL men oberoende av den klassiska vägens C3 konvertas, C4b2a, har varit kontroversiell. Genom att analysera C3 deposition i en ELISA med brunnar klädda med oligosackarider från Salmonella serogrupp C, vilka binder MBL, har vi visat starka belägg för att det finns en MBL-beroende aktivering av alternativa vägen som ej behöver C2 eller C4. Denna väg behöver ej heller medverkan av MBL-associerat serin proteas (MASP). Slutligen undersöktes bindning av C3 och C4 till apoptotiska celler genom flödescytometri. Resultaten visar att den klassiska vägen är den dominerande aktiveringsmekanismen. Den alternativa vägen kan dock aktiveras vid höga serum koncentrationer. (Less)
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author
supervisor
opponent
  • Docent Garred, Peter, Department of clinical Immunology, The National University hospital, Copenhagen, Denmark
organization
publishing date
type
Thesis
publication status
published
subject
keywords
transplantation, serologi, Immunologi, Immunology, serology, autoantibodies, collectins, complement, autoimmunity, Infections, Infektioner
pages
124 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Patologens föreläsningssal Sölvegatan 23 Lund
defense date
2006-02-01 09:15:00
ISBN
91-628-6156-5
language
English
LU publication?
yes
additional info
U Mårtensson, A G Sjöholm, G Sturfelt, L Truedsson and A-B Laurell. 1992. Western blot analysis of human IgG reactive with the collagenous portion of C1q: evidence of distinct binding specificities. Scand J Immunol, vol 35 pp 735-44.
U Mårtensson, S Thiel, J C Jensenius and A G Sjöholm. 1996. Human autoantibodies against Clq: lack of cross reactivity with the collectins mannan-binding protein, lung surfactant protein A and bovine conglutinin. Scand J Immunol, vol 43 pp 314-20.
A G Sjöholm, U Mårtensson and G Sturfelt. 1997. Serial analysis of autoantibody responses to the collagen-like region of Clq, collagen type II, and double stranded DNA in patients with systemic lupus erythematosus. J Rheumatol, vol 24 pp 871-8.
B Selander, U Mårtensson, A Weintraub, E Holmström, L Truedsson, M Matsushita, S Thiel, J C Jensenius and A G Sjöholm. . Mannan-binding lectin-dependent C2 bypass activation of C3 and the alternative pathway of complement. (submitted)
U Mårtensson, K Törnqvist, A G Sjöholm and L Truedsson. . Complement activation by apoptotic Jurkat cells in normal and complement-deficient sera: analysis of C3 and C4 deposition by flow cytometry. (manuscript)
id
f02478e4-3877-4a2a-ba2c-fcfb2a668393 (old id 546114)
date added to LUP
2016-04-01 16:01:18
date last changed
2018-11-21 20:38:09
@phdthesis{f02478e4-3877-4a2a-ba2c-fcfb2a668393,
  abstract     = {{The C1 subcomponent C1q and the mannan-binding lectin (MBL) are recognition proteins of the complement system, and have similar structure. C1q binds to IgG and IgM and activates the classical pathway. MBL binds to carbohydrate structures and activates the lectin pathway. Autoantibodies to C1q are frequently found in severe systemic lupus erythematosus (SLE) and are present in virtually all patients with the hypocomplementemic urticarial vasculitis syndrome (HUVS). In order to investigate possible heterogeneity with regard to epitope specificity, anti-C1q antibodies in the sera of 12 patients with SLE, HUVS or SLE/HUVS overlap syndromes were subjected to Western blot analysis. The SLE sera were negative by Western blot analysis. By contrast, HUVS sera showed reactivity with the B and C polypeptide chains of C1q. Investigation of 69 consecutive sera with anti-C1q antibodies and low C1q confirmed the findings, but there were also exceptions to the rule. Anti-C1q antibodies are directed against the collagen-like region of C1q, and the question was asked if the antibodies cross-react with the structurally related collectins MBL, lung surfactant protein A, and bovine conglutinin. Anti-C1q autoantibodies did not cross-react with these proteins. Serial analysis of anti-C1q antibodies in SLE patients with mild extrarenal flares, severe extrarenal flares and flares of lupus nephritis showed a very high prevalence of anti-C1q in the nephritis group, usually in conjunction with anti-dsDNA, and correlation to hypocomplementemia (low C1q). Anti-C1q antibodies did not cross-react with collagen type II antibodies and anti-dsDNA. With regard to complement activation by MBL, strong controversy exists concerning C3-activation and the alternative pathway independent of the C3 convertase C4b2a. Using a C3 deposition ELISA and microtiter plate wells coated with a Salmonella serogroup C-specific oligosaccharide, which binds MBL, we have provided strong evidence for MBL-dependent C2 bypass activation of C3 and the alternative pathway. The mechanism does not require MBL associated serine proteases (MASPs), but may be enhanced by MASP-1. Finally, complement requirements for C3 and C4 deposition on apoptotic cells were investigated by flow cytometry. Assay conditions strongly influenced the results. The classical pathway was of predominant importance. Interestingly, C4 deposition was enhanced in C2-deficient sera.}},
  author       = {{Mårtensson, Ulla}},
  isbn         = {{91-628-6156-5}},
  keywords     = {{transplantation; serologi; Immunologi; Immunology; serology; autoantibodies; collectins; complement; autoimmunity; Infections; Infektioner}},
  language     = {{eng}},
  publisher    = {{Department of Laboratory Medicine, Lund University}},
  school       = {{Lund University}},
  title        = {{Recognition molecules of the complement system: C1q and mannan-binding lectin in autoimmunity and immune defence}},
  year         = {{2006}},
}