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J M Ahearn - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis and autoimmunity: Complement Deficiency and systemic lupus erythematosus revisited
Current Rheumatology Reports, 2000Co-Authors: J S Navratil, J M AhearnAbstract:Apoptosis may have a dual role in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. First, this process may be integral in the clonal deletion of self-reactive lymphocytes and maintenance of peripheral tolerance. Second, apoptosis generates altered self-antigens with the potential for breaking self-tolerance. This review will discuss these two aspects of apoptosis and autoimmunity, and explore the potential role of the classical Complement pathway in this context.
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Systemic lupus erythematosus and Complement Deficiency: clues to a novel role for the classical Complement pathway in the maintenance of immune tolerance.
Immunopharmacology, 1999Co-Authors: J S Navratil, L C Korb, J M AhearnAbstract:Complete Deficiency of C1q, the first component of the classical pathway of Complement activation, is almost invariably associated with the development of systemic lupus erythematosus. Understanding why Complement Deficiency results in the specific autoimmune phenotype of SLE may provide valuable clues to the role of Complement in the maintenance of immune tolerance. The following review will focus on the characteristics of Complement-deficient SLE and the experimental evidence in support of our hypothesis that C1q may critically influence the immune response to self-antigen contained within surface blebs generated by apoptotic cells.
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c1q binds directly and specifically to surface blebs of apoptotic human keratinocytes Complement Deficiency and systemic lupus erythematosus revisited
Journal of Immunology, 1997Co-Authors: L C Korb, J M AhearnAbstract:Complete Deficiency of C1q is almost invariably associated with the development of systemic lupus erythematosus. It has been suggested that this association may result from a generalized failure to clear Ag-Ab complexes. However, it has not been demonstrated how such a broad impairment results in this specific and consistent autoimmune phenotype, in which photosensitive skin disease is the most prominent manifestation. We believe there is another role for the classical pathway in maintaining immune tolerance. Surface blebs of apoptotic keratinocytes are concentrated sources of autoantigens, and these packages may define a novel immune context and challenge self-tolerance if not properly cleared and processed. We demonstrate here that when human keratinocytes are rendered apoptotic, they also develop the capacity to specifically and directly bind to C1q in the absence of Ab. C1q may mediate Ab-independent clearance of apoptotic keratinocytes, and prevent immunization with autoantigens of cutaneous origin.
Dan Lipsker - One of the best experts on this subject based on the ideXlab platform.
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Cutaneous manifestations of Complement deficiencies.
Lupus, 2010Co-Authors: Dan Lipsker, Georges HauptmannAbstract:In this review we address the main cutaneous manifestations and diseases associated with deficiencies in components of the Complement system. The first part is devoted to hereditary angioedema, in which acute, sometimes life-threatening recurrent attacks of acute swelling, usually associated with gastrointestinal symptoms, occur. It is related to a structural or functional Deficiency of C1 esterase inhibitor. Patients usually have lowered C4 levels, and diagnosis relies on determination of antigenic and/or functional C1 inhibitor level. The second part focuses on lupus erythematosus, as deficiencies in early components of the Complement system, such as C1q, C1r, C1s, C2 or C4, are the strongest known disease susceptibility genes for the development of human systemic lupus erythematosus. Severe infections early in life and marked photosensitivity in a patient with lupus erythematosus are clues to an underlying Complement Deficiency. The genetic background and the clinical associations of the different comp...
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Which Complement assays and typings are necessary for the diagnosis of Complement Deficiency in patients with lupus erythematosus? A study of 25 patients.
Clinical immunology (Orlando Fla.), 2006Co-Authors: P. Boeckler, Alice Meyer, Béatrice Uring-lambert, Georges Hauptmann, Bernard Cribier, Joëlle Goetz, Dan LipskerAbstract:Abstract Introduction: Deficiencies in components of the classical pathway of Complement activation are strong risk factors for lupus erythematosus (LE).Yet, it has not been addressed whether the conventional measurements of the serum hemolytic CH50 activity and antigenic concentrations of C3 and C4 are sufficient to asses a Deficiency in C4A, C4B or C2 components, the most common deficiencies associated with LE. Patients and methods: In a retrospective series, we performed Complement analyses in 35 patients with LE who were systematically screened for a Complement Deficiency. The majority of patients had cutaneous LE with mild systemic involvement and no Complement consumption. Of 25 patients (72%) with Complement Deficiency we found 13 with a partial C4A Deficiency, 2 with a complete C4A Deficiency, 6 with a partial C4B Deficiency, 2 with a complete C4B Deficiency and 2 with a combined partial C2 and C4A Deficiency. Results: The total Complement activity (CH50) was decreased in only one out of two patients with complete C4B Deficiency. CH50 level was found to be low–normal (35–38 U/ml− 1) in one patient with partial C4B Deficiency, one patient with complete C4B Deficiency and both patients with combined partial C4A and C2 Deficiency. Total C4 levels were normal in 9 out of 13 the patients with a partial C4A Deficiency and in 2 out of 6 patients with a complete C4B Deficiency. The antigenic concentration of C3 was low in only 1 patients with a complete C4B Deficiency and within the normal range in all the others patients. Overall, 50% of the patients had normal or elevated C3, C4, and CH50 levels. Discussion: This study emphasizes that the usual measurements of CH50, C3 and C4 levels are not adequate to detect a C4 and/or C2 Deficiency in patients with LE. In epidemiologic or investigative studies addressing the prevalence of Complement Deficiency, more elaborated diagnostic tests, such as C4 protein allotyping, C2 level measurement and genetic screening for type I C2 Deficiency should also be performed.
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The combination of Complement Deficiency and cigarette smoking as risk factor for cutaneous lupus erythematosus in men; a focus on combined C2/C4 Deficiency
The British journal of dermatology, 2005Co-Authors: P. Boeckler, M Milea, Alice Meyer, Béatrice Uring-lambert, Ernest Heid, Georges Hauptmann, Bernard Cribier, Dan LipskerAbstract:Summary Background Although deficiencies in the early components of the Complement system were among the first identified genetic risk factors for systemic lupus erythematosus (SLE), only a few studies addressed their significance in patients with cutaneous LE (CLE). Among environmental factors, it was postulated that cigarette smoking might intervene in the pathogenesis of LE. Objectives To describe the clinical and biological features of patients with CLE and a Complement Deficiency. A secondary objective was to assess cigarette smoking in patients with CLE. Patients and methods A retrospective study including all patients diagnosed as having LE between 1995 and 2003 in the Dermatology Department of Strasbourg University Hospital. Patient charts were reviewed and those patients in whom a C4 and/or C2 Deficiency was diagnosed were included. Two patients with a combined C2/C4 Deficiency were analysed in detail. Results There were 48 females and 37 males (F/M ratio = 1·3), with a mean age of 41 years at diagnosis; 73% of the patients had chronic LE and 27% subacute CLE. Among 32 screened patients, 24 patients with a mean age of 36 years had a Complement Deficiency; 17 had a C4A Deficiency, five a C4B Deficiency and two a combined C4A/C2 Deficiency. A high proportion (58%) of these patients was male; 82% of the patients were smokers. This was especially true in males: 94% were smokers compared with 69% of females. Conclusions Partial Deficiency of C4, C2 or C4 and C2 is a common finding in patients with CLE. Most male patients with CLE are smokers. It is thus suggested that the combination of cigarette smoking and Complement Deficiency could be a risk factor for LE in men.
Lennart Truedsson - One of the best experts on this subject based on the ideXlab platform.
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eLS - Complement: Deficiency Diseases
eLS, 2015Co-Authors: Lillemor Skattum, Lennart TruedssonAbstract:The Complement system is crucial for defence against pathogens, removal of unwanted materials such as dying cells or immune complexes as well as for development of adaptive immune responses. Genetically determined deficiencies of components of the Complement system are usually relatively rare, but they result in many severe diseases such as an increased susceptibility to recurrent, severe bacterial infections, autoimmune disorders (systemic lupus erythematosus), glomerulonephritis including dense deposit disease and C3 glomerulonephritis, paroxysmal nocturnal haemoglobinuria or angioedema. In addition, mutations and polymorphisms in Complement proteins, particularly Complement inhibitors, have been associated with atypical haemolytic uremic syndrome and age-related macular degeneration. The elucidation of the pathophysiological basis for the different clinical presentations of Complement-deficient individuals has contributed to a better understanding of the physiological role of Complement in normal individuals as well as to the development of emerging therapies. Key Concepts The majority of Complement deficiencies are rare but cause severe diseases. Deficiencies of the components of the classical pathway (C1q/r/s, C4 and C2) predispose to bacterial infections and systemic lupus erythematosus. The majority of Complement deficiencies predispose to infections either with Neisseria species (Deficiency of factor D, factor B, properdin, C5, C6, C7, C8 and C9) or with other encapsulated bacteria (C1q/r/s, mannose-binding lectin, C2, C4, C3 and factor I). Mutations in C1q/r/s, C2, C4, C3, factor I and factor H can cause glomerulonephritis. Paroxysmal nocturnal haemoglobinuria is caused by Deficiency of Complement inhibitors CD55 and CD59. Hereditary angioedema is found in patients with low C1-inhibitor level or dysfunctional C1-inhibitor. Atypical haemolytic uremic syndrome is mainly associated with mutations and polymorphisms in Complement inhibitors. Age-related macular degeneration is associated with polymorphisms in Complement inhibitor factor H. Keywords: age-related macular degeneration; angioedema; bacterial infection; Complement Deficiency; haemolytic uremic syndrome; paroxysmal nocturnal haemoglobinuria; systemic lupus erythematosus
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European Union funded project on the development of a whole Complement Deficiency screening ELISA-A story of success and an exceptional manager: Mohamed R. Daha.
Molecular immunology, 2015Co-Authors: Reinhard Würzner, Lennart Truedsson, Francesco Tedesco, Peter Garred, Tom Eirik Mollnes, Malcolm W. Turner, Yngve Sommarin, Jörgen Wieslander, Robert B. SimAbstract:A whole Complement ELISA-based assay kit, primarily designed to screen for deficiencies in components of the Complement system was developed during a European Union grant involving more than a dozen European scientists and a small-medium enterprise company (Wieslab, which later merged into Eurodiagnostica). The consortium was led by Prof. Mohamed R. Daha who had already guided a preceding European grant which prepared the ground for this endeavor to create a novel and sophisticated Complement measurement tool. The final result of the grant was a scientific publication (Seelen et al., 2005, J. Immunol. Methods 296, 187-198) and a commercially available Complement Deficiency screening kit, WIESLAB(®) Complement system Screen. Thereafter, the group decided to carry on with a grant, located at Innsbruck Medical University, and supported by royalties and unrestricted educational grants from Eurodiagnostica, Malmo, entitled "Search for Applications for WIESLAB(®) Complement system Screen (SAW)" with the aim to look for further applications of this assay. During the latter project the group organized several scientific meetings aimed at evaluating the use of the assay as well as developing further branches of its platform. A look back over almost two decades reveals a great story of excellent research which was also commercially successful, fulfilling the aims of European Union grants. It is also a story of ageless friendship, only possible due to the vision and guidance of an exceptional manager: Moh Daha.
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Complement Deficiency states and associated infections
Molecular immunology, 2011Co-Authors: Lillemor Skattum, Marcel Van Deuren, Tom Van Der Poll, Lennart TruedssonAbstract:A major function of the immune system is to protect the host from microbial infections. The Complement system plays important roles in both the innate and the adaptive immune defense and also acts as a bridge between these arms of immunity. This is obvious from Complement deficiencies which in varying degree, depending on which factor is missing, are associated with increased infection susceptibility and also increased risk for other, mainly autoimmune diseases. Genetically determined deficiencies are described for almost all Complement proteins but the consequences show a wide variation. Here the genetic defects and molecular abnormalities in Complement deficient persons, related clinically relevant infections and the options for prevention and therapy are reviewed. The roles of Complement in host defense against common infections are also discussed.
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Molecular characterization of two novel cases of complete Complement inhibitor Factor I Deficiency.
Molecular immunology, 2011Co-Authors: Izabela Nita, Lennart Truedsson, Ferah Genel, Sara C. Nilsson, Joanne Smart, Sharon Choo, Anna M. BlomAbstract:Factor I (FI) is the major Complement inhibitor that degrades activated Complement components C3b and C4b in the presence of specific cofactors. Complete FI Deficiency results in secondary Complement Deficiency due to uncontrolled spontaneous alternative pathway activation. In this study we describe two unrelated patients with complete FI Deficiency and undetectable alternative Complement pathway activity. Both patients had experienced recurrent infections and arthralgia/arthritis. In one patient, analysis of genomic DNA revealed deletion of two adenine nucleotides in exon 2 of the CFI gene (c.133-134delAA), causing a frame shift and premature STOP codon/termination in the FIMAC (FI-membrane attack complex) domain (p.K45SfsX11). The other patient carried an A>T substitution in exon 6 (c.866A>T) encoding the LDLr2 (low density lipoprotein receptor) domain (p.D289V), resulting in an aspartic acid to valine change. Both patients were homozygous for the mutations while their healthy parents were heterozygous carriers. The mutations were introduced into recombinant FI, causing lack of FI expression and secretion upon transient transfection. Mutation p.K45SfsX11 theoretically allows expression of a 55 amino acid fragment of FI that lacks the serine protease domain, preventing proteolytic activity. In contrast, aspartic acid D289 is crucial for folding of FI. This report describes the molecular and functional consequences of two novel mutations of FI, providing a unique insight into the pathogenesis of complete FI Deficiency in these patients.
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Genetic, molecular and functional analyses of Complement factor I Deficiency.
European journal of immunology, 2008Co-Authors: Sara C. Nilsson, Ferah Genel, A G Sjoholm, Leendert A. Trouw, Nicolas Renault, Maria A. Miteva, Marta Zelazko, Hanne Vibeke Marquart, Klaus Müller, Lennart TruedssonAbstract:Complete Deficiency of Complement inhibitor factor I (FI) results in secondary Complement Deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI Deficiency and three patients with no detectable serum FI and also close family members revealed homozygous or compound heterozygous mutations in several domains of FI. These mutations were introduced into recombinant FI and the resulting proteins were purified for functional studies, while transient transfection was used to analyze expression and secretion. The G170V mutation resulted in a protein that was not expressed, whereas the mutations Q232K, C237Y, S250L, I339M and H400L affected secretion. Furthermore, the C237Y and the S250L mutants did not degrade C4b and C3b as efficiently as the WT. The truncated Q336x mutant could be expressed, in vitro, but was not functional because it lacks the serine protease domain. Furthermore, this truncated FI was not detected in serum of the patient. Structural investigations using molecular modeling were performed to predict the potential impact the mutations have on FI structure. This is the first study that investigates, at the functional level, the consequences of molecular defects identified in patients with full FI Deficiency.
Maryam Mahmoudi - One of the best experts on this subject based on the ideXlab platform.
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Two related cases of primary Complement Deficiency.
Immunological investigations, 2003Co-Authors: Abolhassan Farhoudi, Nasrin Bazargan, Zahra Pourpak, Maryam MahmoudiAbstract:Primary Complement deficiencies are rare and two related patients are reported here. The first patient is a 41‐year‐old man with eighteen episodes of pneumococcal meningitis and other purulent infections. The serum C3 level was checked at three separate times, showing that this was a primary C3 deficient case; other immunological tests were normal. This patient now takes prophylactic antibiotics and the meningitis had not recurred, but he does have glomerulonephritis. The second case is a 40‐year‐old woman with repeated episodes of orofacial and laryngeal edema and dyspnea. The serum C1INH levels were 4.3 to 7 which is very low compared with normal healthy subjects (C1INH was 40–50 mg/dl) and C4 was lower than normal but other immunological tests were normal. Other causes of angioedema such as lymphoproliferative disorders were excluded. She had hereditary angioedema without a family background. The condition may be due to genetic mutation. The angioedema was controlled with Danazol and Stanasol. As our p...
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TWO RELATED CASES OF PRIMARY Complement Deficiency
Iranian journal of allergy asthma and immunology, 2003Co-Authors: Abolhassan Farhoudi, Nasrin Bazargan, Zahra Pourpak, Maryam MahmoudiAbstract:Primary Complement deficiencies are rare and two related patients are reported here. The first patient is a 41- year- old man with eighteen episodes of pneumo¬coccal meningitis and other purulent infections. The serum C3 level was checked at three separate times, showing that this was a primary C3 deficient case; other immunological tests were however normal. This patient now takes prophylactic antibiotics and the meningitis has not recurred, but he does have glomerulone¬phritis. The second case is a 40 - year-old woman with repeated episodes of orofacial and laryngeal edema and dyspnea. The serum C1INH levels were 4.3 to 7 mg/dL which were very low compared with normal healthy subjects (C,INH was 40-50 mg/dL in ten normal controls) and C4 was lower than normal but other immunological tests were normal. Other causes of angioedema such as lymphoproliferative disorders were excluded. She had hereditary angioedema with¬out a family background. The condition may be due to genetic mutation. The angioedema was controlled with Danazol and Stanasol. As our patients are re¬lated, this may suggest a genetic relationship between these two disorders.
Sondes Makni - One of the best experts on this subject based on the ideXlab platform.
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Complement Deficiency and systemic lupus erythematosus: consensus and dilemma.
Expert review of clinical immunology, 2008Co-Authors: Maryam Kallel-sellami, Lilia Laadhar, Yousr Zerzeri, Sondes MakniAbstract:The involvement of the Complement system in the pathogenesis of autoimmune diseases is a matter of debate. However, the link between Complement abnormalities and systemic lupus erythematosus (SLE) is well established and widely described. Homozygous and/or heterozygous Complement-component deficiencies of the classical pathway (C1q, C1r, C1s, C4A, C4B and C2) are causally associated with susceptibility to the development of SLE. Although the severity of the disease and the strength of the association are heterogeneous for deficiencies of these proteins, they commonly cause peculiar SLE syndromes with an early age of onset, a susceptibility to bacterial infections and negative anti-dsDNA antibodies. In this review, we highlight the available data on Complement Deficiency and SLE with a focus on deficiencies in classical Complement pathway components. We also discuss the paradox of the link between Complement Deficiency and lupus. The Complement system acts as a ‘friend’ through the clearance of immune comp...
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Hereditary Complement Deficiency and lupus: report of four Tunisian cases.
Annals of the New York Academy of Sciences, 2007Co-Authors: Maryam Kallel-sellami, Lilia Laadhar, Yousr Zerzeri, Lilia Baili‐klila, Jacques Blouin, R. Abdelmalek, Véronique Frémeaux-bacchi, Mondher Zitouni, Sondes MakniAbstract:: The aim of the study was to assess the clinical and immunological profile of lupus erythematosus (LE) patients with inherited Complement Deficiency (ICD). A laboratory-based study was conducted in which all LE patients with hypoComplementemia were included. ICD was assessed by hemolytic and antigenic assays. Type I C2 Deficiency was assessed by polymerase chain reaction (PCR). ICD was diagnosed in four cases. In three systemic LE patients, ICD were: homozygous C2 Deficiency in the first case, heterozygous C2 Deficiency in the second, and homozygous C1q Deficiency in the third case. In a discoid LE patient, a combined homozygous C2 and C6 Deficiency was diagnosed. Almost all of our patients presented the classical clinical and immunological features of LE associated with ICD. Severe lupus with renal involvement and recurrent infections was present in half of the patients suggesting that these patients are prone to a serious management.