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Studies on hereditary C2 deficiency: Frequent occurrence of severe infections, atherosclerosis and rheumatological manifestations

Jönsson, Göran LU (2007) In 2007:149
Abstract
The complement system is a part of the innate immunity and is essential in the defence against microorganisms. Hereditary C2 deficiency (C2D) is one of the most common complement deficiency states with an estimated prevalence of 1:20,000 in persons of Western descent. In the present investigation, the identification of more than 40 C2D persons at a single centre combined with long observation periods provided a unique basis for assessment of C2D-associated manifestations and diseases. The predominant clinical manifestation was severe bacterial infections. The infections were mainly caused by Streptococcus pneumoniae. Repeated infections occurred primarily during infancy and childhood. On the other hand, about 25-30 % of the C2D persons... (More)
The complement system is a part of the innate immunity and is essential in the defence against microorganisms. Hereditary C2 deficiency (C2D) is one of the most common complement deficiency states with an estimated prevalence of 1:20,000 in persons of Western descent. In the present investigation, the identification of more than 40 C2D persons at a single centre combined with long observation periods provided a unique basis for assessment of C2D-associated manifestations and diseases. The predominant clinical manifestation was severe bacterial infections. The infections were mainly caused by Streptococcus pneumoniae. Repeated infections occurred primarily during infancy and childhood. On the other hand, about 25-30 % of the C2D persons remained healthy during the observation period. Immunological factors as IgG subclass levels, GM allotypes, complement proteins, and Fc receptors were assessed to explain this difference. Homozygosity for the G2M*n allele was strongly associated with protection against severe infections (p<0.001). This indicated that an efficient antibody response to polysaccharide antigens is of great importance in C2D. Mannan-binding lectin deficiency also contributed to the susceptibility to infection. The association between C2D and systemic lupus erythematosus (SLE) was confirmed, but notably the severity of SLE in patients with C2D was similar to that of other SLE patients. Another novel finding was a high occurrence of anti-cardiolipin antibodies (aCL) and antibodies to the collagen-like region of C1q. Both autoantibodies have a pro-atherosclerotic effect that might explain the high occurrence of cardiovascular disease found in the cohort. Interestingly, anti-phospholipid syndrome was not observed despite the high occurrence of aCL. Vaccination in 25 C2D persons resulted in antibody responses which show that C2D persons benefit from vaccination against infections caused by encapsulated bacteria such as pneumococci. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Komplementsystemet utgör en del av den medfödda immuniteten och är viktigt i försvaret mot angripande mikroorganismer. Ärftlig C2-brist (C2D) är en av de vanligaste bristerna inom komplementsystemet och förekommer i en frekvens av 1: 20 000 hos personer med västerländsk härstamning. I de aktuella undersökningarna har mer än 40 personer med C2D identifierats och observerats under lång tid vilket har gett en unik möjlighet att beskriva associerade manifestationer och sjukdomar till C2D. Det mest framträdande kliniska fyndet bland C2-bristarna var svåra bakteriella infektioner. Infektionerna orsakades till stor del av Streptococcus pneumoniae. Återkommande svåra infektioner sågs främst under... (More)
Popular Abstract in Swedish

Komplementsystemet utgör en del av den medfödda immuniteten och är viktigt i försvaret mot angripande mikroorganismer. Ärftlig C2-brist (C2D) är en av de vanligaste bristerna inom komplementsystemet och förekommer i en frekvens av 1: 20 000 hos personer med västerländsk härstamning. I de aktuella undersökningarna har mer än 40 personer med C2D identifierats och observerats under lång tid vilket har gett en unik möjlighet att beskriva associerade manifestationer och sjukdomar till C2D. Det mest framträdande kliniska fyndet bland C2-bristarna var svåra bakteriella infektioner. Infektionerna orsakades till stor del av Streptococcus pneumoniae. Återkommande svåra infektioner sågs främst under spädbarnsåren och i barndomen. Emellertid förblev ungefär 25-30% av C2-bristarna helt befriade från svåra infektioner under observationstiden. Andra immunologiska faktorer såsom IgG subklasser, GM allotyper, komplementproteiner och Fc receptorer undersöktes för att om möjligt finna en förklaring till denna skillnad. Homozygoti (dubbla anlag) för GM*2 allotypen visade sig var starkt förknippat med en skyddande effekt mot svåra infektioner (p<0,001). Detta indikerade att ett kraftfullt antikroppssvar mot polysackaridantigen är mycket viktigt vid C2-brist. Brist på mannanbindande lektin (MBL) bidrog också till en ökad infektionskänslighet. Sambandet mellan risken för att drabbas av systemisk lupus erythematosus (SLE) och C2-brist kunde konfirmeras men intressant nog visade sig SLE vid C2-brist vara lika svår som vid genuin SLE. Andra nya fynd var en hög förekomst av antikardiolipinantikroppar (aCL) och antikroppar mot den kollagenlika dela av C1q. Båda dessa autoantikroppar har en aterosklerotisk (åderförkalkning) effekt vilket skulle kunna förklara den höga förekomsten av hjärt-kärlsjukdom hos C2-bristarna. Märkligt nog återfanns inga C2-bristare med antifosfolipidsyndrom trots den hög förekomst av aCL. I vaccinationsstudien uppvisade C2-bristarna bra svar mot infektioner orsakade av kapslade bakterier såsom pneumokocker. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Wurzner, Reinhard, Dept of Hygiene, Microbiology and Social Medicine, Innsbruck Medical University, Innsbruck, Austria
organization
publishing date
type
Thesis
publication status
published
subject
keywords
transplantation, serology, Immunology, mykologi, bakteriologi, virologi, Mikrobiologi, mycology, Complement, Complement C2 deficiency, Infectious diseases, Atherosclerosis, SLE, Autoantibodies, GM allotypes, Immunodeficiency state, Medicine (human and vertebrates), Medicin (människa och djur), Microbiology, virology, bacteriology, Immunologi, serologi, Infections, Infektioner
in
2007:149
pages
181 pages
publisher
Department of Medical Microbiology, Lund University
defense location
Rune Grubbsalen, Sölvegatan 23, Lund
defense date
2007-11-22 09:00:00
ISSN
1652-8220
ISBN
978-91-85897-27-8
language
English
LU publication?
yes
additional info
Göran Jönsson, Lennart Truedsson, Gunnar Sturfelt, Vivi-Anne Oxelius, Jean-Henrik Braconier and Anders G Sjöholm. 2005. Hereditary C2 deficiency in Sweden: frequent occurrence of invasive infection, atherosclerosis, and rheumatic disease. Medicine (Baltimore), vol 84 pp 23-34.
Göran Jönsson, Vivi-Anne Oxelius, Lennart Truedsson, Jean-Henrik Braconier, Gunnar Sturfelt and Anders G Sjöholm. 2006. Homozygosity for the IgG2 subclass allotype G2M(n) protects against severe infection in hereditary C2 deficiency. The Journal of Immunology, vol 177 pp 722-8.
Göran Jönsson, Anders G Sjöholm, Lennart Truedsson, Anders A Bengtsson, Jean-Henrik Braconier and Gunnar Sturfelt. 2007. Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency. Rheumatology (Oxford), vol 46 pp 1133-9.
Göran Jönsson, Eva Holmström, Barbro Selander, Vivi-Anne Oxelius, Jean-Henrik Braconier, Gunnar Sturfelt and Lennart Truedsson. . Vaccination against infections with encapsulated bacteria in hereditary C2 deficiency: great variation in antibody response. (manuscript)
id
7f2be2dc-b4d6-4770-ba71-17d437c053f2 (old id 599216)
date added to LUP
2016-04-01 16:55:40
date last changed
2019-05-21 08:46:34
@phdthesis{7f2be2dc-b4d6-4770-ba71-17d437c053f2,
  abstract     = {{The complement system is a part of the innate immunity and is essential in the defence against microorganisms. Hereditary C2 deficiency (C2D) is one of the most common complement deficiency states with an estimated prevalence of 1:20,000 in persons of Western descent. In the present investigation, the identification of more than 40 C2D persons at a single centre combined with long observation periods provided a unique basis for assessment of C2D-associated manifestations and diseases. The predominant clinical manifestation was severe bacterial infections. The infections were mainly caused by Streptococcus pneumoniae. Repeated infections occurred primarily during infancy and childhood. On the other hand, about 25-30 % of the C2D persons remained healthy during the observation period. Immunological factors as IgG subclass levels, GM allotypes, complement proteins, and Fc receptors were assessed to explain this difference. Homozygosity for the G2M*n allele was strongly associated with protection against severe infections (p&lt;0.001). This indicated that an efficient antibody response to polysaccharide antigens is of great importance in C2D. Mannan-binding lectin deficiency also contributed to the susceptibility to infection. The association between C2D and systemic lupus erythematosus (SLE) was confirmed, but notably the severity of SLE in patients with C2D was similar to that of other SLE patients. Another novel finding was a high occurrence of anti-cardiolipin antibodies (aCL) and antibodies to the collagen-like region of C1q. Both autoantibodies have a pro-atherosclerotic effect that might explain the high occurrence of cardiovascular disease found in the cohort. Interestingly, anti-phospholipid syndrome was not observed despite the high occurrence of aCL. Vaccination in 25 C2D persons resulted in antibody responses which show that C2D persons benefit from vaccination against infections caused by encapsulated bacteria such as pneumococci.}},
  author       = {{Jönsson, Göran}},
  isbn         = {{978-91-85897-27-8}},
  issn         = {{1652-8220}},
  keywords     = {{transplantation; serology; Immunology; mykologi; bakteriologi; virologi; Mikrobiologi; mycology; Complement; Complement C2 deficiency; Infectious diseases; Atherosclerosis; SLE; Autoantibodies; GM allotypes; Immunodeficiency state; Medicine (human and vertebrates); Medicin (människa och djur); Microbiology; virology; bacteriology; Immunologi; serologi; Infections; Infektioner}},
  language     = {{eng}},
  publisher    = {{Department of Medical Microbiology, Lund University}},
  school       = {{Lund University}},
  series       = {{2007:149}},
  title        = {{Studies on hereditary C2 deficiency: Frequent occurrence of severe infections, atherosclerosis and rheumatological manifestations}},
  url          = {{https://lup.lub.lu.se/search/files/4821069/631332.pdf}},
  year         = {{2007}},
}