Leiner's disease (erythroderma desquamativum): A review and approach to therapy.

Leiner's disease (LD) is a rare and serious syndrome of infantile erythroderma of severe and progressive generalized seborrheic-like dermatitis, recalcitrant diarrhea, malabsorption and wasting, and recurrent local and systemic infections. The purpose of this study is to provide an updated review on management with a summarized review of available peer-reviewed articles on LD. The mechanisms underlying this disease process remain unclear. The diagnosis includes demonstration of deficient opsonic activity along with the clinical tetrad of erythroderma, persistent gastrointestinal disturbance, superimposed bacterial or candidal infection, and marked wasting. An important correlation between LD and defective yeast and Staphylococcus aureus opsonization has been established. For the familial form of LD, an association of either complement three deficiency or complement five dysfunction has been made. LD should be distinguished from other types of infantile erythroderma, including Omenn syndrome. Treatment includes fluid and nutrition replacement, antibiotics to control infection, and fresh-frozen plasma therapy. The prognosis is unclear; it depends on treatment. LD is a life-threatening condition that requires prompt identification and hospitalization. Affected infants who receive vigorous treatment not only have the prospect of surviving, but also generally lead a normal life after infancy.

Progress towards the Development of a NEAT Vaccine for Anthrax II: Immunogen Specificity and Alum Effectiveness in an Inhalational Model.

Bacillus anthracis is the causative agent of anthrax disease, presents with high mortality, and has been at the center of bioweapon efforts. The only currently U.S. FDA-approved vaccine to prevent anthrax in humans is anthrax vaccine adsorbed (AVA), which is protective in several animal models and induces neutralizing antibodies against protective antigen (PA), the cell-binding component of anthrax toxin. However, AVA requires a five-course regimen to induce immunity, along with an annual booster, and is composed of undefined culture supernatants from a PA-secreting strain. In addition, it appears to be ineffective against strains that lack anthrax toxin. Here, we investigated a vaccine formulation consisting of recombinant proteins from a surface-localized heme transport system containing near-iron transporter (NEAT) domains and its efficacy as a vaccine for anthrax disease. The cocktail of five NEAT domains was protective against a lethal challenge of inhaled bacillus spores at 3 and 28 weeks after vaccination. The reduction of the formulation to three NEATs (IsdX1, IsdX2, and Bslk) was as effective as a five-NEAT domain cocktail. The adjuvant alum, approved for use in humans, was as protective as Freund's Adjuvant, and protective vaccination correlated with increased anti-NEAT antibody reactivity and reduced bacterial levels in organs. Finally, the passive transfer of anti-NEAT antisera reduced mortality and disease severity, suggesting the protective component is comprised of antibodies. Collectively, these results provide evidence that a vaccine based upon recombinant NEAT proteins should be considered in the development of a next-generation anthrax vaccine.

Impaired insulin signaling in the B10.D2-Hc0 H2d H2-T18c/oSnJ mouse model of complement factor 5 deficiency.

Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5-deficient (C5def, B10.D2-Hc0 H2d H2-T18c/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5def mice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5def mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5def mice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the C5 gene, whole genome sequencing revealed an intronic 31-bp deletion in the Insr gene in the B10.D2-Hc0 H2d H2-T18c/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5cont and C5def mice, indicating an insulin-sensitizing function of C5.

Effects of immune suppression in murine models of disseminated Candida glabrata and Candida tropicalis infection and utility of a synthetic peptide vaccine.

Candida species are the second most frequent cause of fungal infections worldwide. Current knowledge of immunity to Candida has been gleaned almost exclusively from studies on Candida albicans, the most common disease-causing species. Knowledge of immunity to non-albicans Candida (NAC) species is still at an early stage due to the lack of tractable animal models with which to study these important pathogens. This is partly because many NAC species are not usually pathogenic in mouse models of candidiasis. In this study, we established an immunosuppressed mouse model of disseminated candidiasis by the two clinically important NAC species, C. glabrata and C. tropicalis. The inbred mouse strains, A/J and BALB/c, show distinct susceptibilities to disseminated Candida infection. A/J mice, deficient for complement C5, are more susceptible to disseminated infection with both C. glabrata and C. tropicalis compared to BALB/c mice, the latter having functional C5. Here we show that peptide-pulsed dendritic cell (DC) vaccination with a peptide derived from a C. tropicalis cell surface protein, significantly improved survival and reduced the fungal burdens of disseminated candidiasis in these immunocompromised mice. Importantly, this study is the first report of protective efficacy conferred by a peptide vaccine against medically important NAC species in immunosuppressed hosts. Establishing this experimental mouse model provides an important tool to further understand pathogenesis and host resistance in Candida infection. Significantly, our findings also demonstrate how this model can be used to evaluate new control strategies against candidiasis, such as vaccines.

Complement factor 5 (C5) p.A252T mutation is prevalent in, but not restricted to, sub-Saharan Africa: implications for the susceptibility to meningococcal disease.

Complement C5 deficiency (C5D) is a rare primary immunodeficiency associated with recurrent infections, particularly meningitis, by Neisseria species. To date, studies to elucidate the molecular basis of hereditary C5D have included fewer than 40 families, and most C5 mutations (13 of 17) have been found in single families. However, the recently described C5 p.A252T mutation is reported to be associated with approximately 7% of meningococcal disease cases in South Africa. This finding raises the question of whether the mutation may be prevalent in other parts of Africa or other continental regions. The aim of this study was to investigate the prevalence of C5 p.A252T in Africa and other regions and discuss the implications for prophylaxis against meningococcal disease. In total, 2710 samples from healthy donors within various populations worldwide were analysed by quantitative polymerase chain reaction (qPCR) assay to detect the C5 p.A252T mutation. Eleven samples were found to be heterozygous for p.A252T, and nine of these samples were from sub-Saharan African populations (allele frequency 0·94%). Interestingly, two other heterozygous samples were from individuals in populations outside Africa (Israel and Pakistan). These findings, together with data from genomic variation databases, indicate a 0·5-2% prevalence of the C5 p.A252T mutation in heterozygosity in sub-Saharan Africa. Therefore, this mutation may have a relevant role in meningococcal disease susceptibility in this geographical area.

Novel Mutations Causing C5 Deficiency in Three North-African Families.

The complement system plays a central role in defense to encapsulated bacteria through opsonization and membrane attack complex (MAC) dependent lysis. The three activation pathways (classical, lectin, and alternative) converge in the cleavage of C5, which initiates MAC formation and target lysis. C5 deficiency is associated to recurrent infections by Neisseria spp. In the present study, complement deficiency was suspected in three families of North-African origin after one episode of invasive meningitis due to a non-groupable and two uncommon Meningococcal serotypes (E29, Y). Activity of alternative and classical pathways of complement were markedly reduced and the measurement of terminal complement components revealed total C5 absence. C5 gene analysis revealed two novel mutations as causative of the deficiency: Family A propositus carried a homozygous deletion of two adenines in the exon 21 of C5 gene, resulting in a frameshift and a truncated protein (c.2607_2608del/p.Ser870ProfsX3 mutation). Families B and C probands carried the same homozygous deletion of three consecutive nucleotides (CAA) in exon 9 of the C5 gene, leading to the deletion of asparagine 320 (c.960_962del/p.Asn320del mutation). Family studies confirmed an autosomal recessive inheritance pattern. Although sharing the same geographical origin, families B and C were unrelated. This prompted us to investigate this mutation prevalence in a cohort of 768 North-African healthy individuals. We identified one heterozygous carrier of the p.Asn320del mutation (allelic frequency = 0.065 %), indicating that this mutation is present at low frequency in North-African population.

Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis.

BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of chronic pancreatitis. We investigated the roles of complement component 5 (C5) in pancreatic fibrogenesis in mice and patients. METHODS: Chronic pancreatitis was induced by ligation of the midpancreatic duct, followed by a single supramaximal intraperitoneal injection of cerulein, in C57Bl6 (control) and C5-deficient mice. Some mice were given injections of 2 different antagonists of the receptor for C5a over 21 days. In a separate model, mice were given injections of cerulein for 10 weeks to induce chronic pancreatitis. Direct effects of C5 were studied in cultured primary cells. We performed genotype analysis for the single-nucleotide polymorphisms rs 17611 and rs 2300929 in C5 in patients with pancreatitis and healthy individuals (controls). Blood cells from 976 subjects were analyzed by transcriptional profiling. RESULTS: During the initial phase of pancreatitis, levels of pancreatic damage were similar between C5-deficient and control mice. During later stages of pancreatitis, C5-deficient mice and mice given injections of C5a-receptor antagonists developed significantly less pancreatic fibrosis than control mice. Primary pancreatic stellate cells were activated in vitro by C5a. There were no differences in the rs 2300929 SNP between subjects with or without pancreatitis, but the minor allele rs17611 was associated with a significant increase in levels of C5 in whole blood. CONCLUSIONS: In mice, loss of C5 or injection of a C5a-receptor antagonist significantly reduced the level of fibrosis of chronic pancreatitis, but this was not a consequence of milder disease in early stages of pancreatitis. C5 might be a therapeutic target for chronic pancreatitis.

Complement C5-deficient mice are protected from seizures in experimental cerebral malaria.

Studies have demonstrated that the membrane attack complex (MAC) of complement can evoke seizures when injected directly into rodent brain. In the course of studies that examine the role of complement in the development of experimental cerebral malaria (ECM), we observed fewer seizures in mice deficient in C5, a component required for MAC formation. To determine if the MAC contributed to the tonic-clonic seizures characteristic of ECM, we performed long-term video-electroencephalography (EEG) on C5(-/-) mice with Plasmodium berghei ANKA-induced cerebral malaria and observed significantly reduced spike and seizure frequency compared to wild-type mice. Our data suggest a role for the MAC in malaria-induced seizures and that inhibition of the terminal complement pathway may reduce seizures and seizure-related neurocognitive deficits.

C5 complement deficiency in a Saudi family, molecular characterization of mutation and literature review.

INTRODUCTION: Complement deficiencies are rare primary immunodeficiency disorders, the diagnosis of which is often underestimated. Only a small number of molecular studies have been carried out for the characterization of the underlying genetic defects in these cases. PURPOSE: Reporting the first family from the Arabian Gulf region with multiple members affected by meningococcemia and abscent serum complement 5 (C5). We tried to correlate clinical, biochemical and molecular genetics features of this family. METHODS: Determination of the serum level of all complement proteins including the terminal cascade (C5-9), followed by mutation analysis on DNA extracted from fresh blood samples of each alive family member. RESULTS: Molecular studies showed a homozygous nonsense mutation in exon 1, with the change of cytosine to thymine at position 55 (55C > T) leading to change of the glutamine amino acid at position 19 to a stop codon (Q19X), and serologically absence of C5 in the serum. A similar but compound heterozygous mutation has been reported in one African-American family. previously. CONCLUSION: Characterization of the underlying mutations in C5 deficient families is important, to understand this uncommon complement deficiency, and try to elucidate structure-function relationships in the C5 gene. This report also highlights the importance of complement screening in cases of sporadic meningococcal Infections, especially in communities with high prevalence of consanguineous marriages, which will ensure timely and adequate clinical interventions.

Deficiency of complement component 5 ameliorates glaucoma in DBA/2J mice.

BACKGROUND: Glaucoma is an age-related neurodegenerative disorder involving the loss of retinal ganglion cells (RGCs), which results in blindness. Studies in animal models have shown that activation of inflammatory processes occurs early in the disease. In particular, the complement cascade is activated very early in DBA/2J mice, a widely used mouse model of glaucoma. A comprehensive analysis of the role of the complement cascade in DBA/2J glaucoma has not been possible because DBA/2J mice are naturally deficient in complement component 5 (C5, also known as hemolytic complement, Hc), a key mediator of the downstream processes of the complement cascade, including the formation of the membrane attack complex. METHODS: To assess the role of C5 in DBA/2J glaucoma, we backcrossed a functional C5 gene from strain C57BL/6J to strain DBA/2J for at least 10 generations. The prevalence and severity of glaucoma was evaluated using ocular examinations, IOP measurements, and assessments of optic nerve damage and RGC degeneration. To understand how C5 affects glaucoma, C5 expression was assessed in the retinas and optic nerves of C5-sufficient DBA/2J mice, using immunofluorescence. RESULTS: C5-sufficient DBA/2J mice developed a more severe glaucoma at an earlier age than standard DBA/2J mice, which are therefore protected by C5 deficiency. Components of the membrane attack complex were found to be deposited at sites of axonal injury in the optic nerve head and associated with RGC soma in the retina. CONCLUSION: C5 plays an important role in glaucoma, with its deficiency lessening disease severity. These results highlight the importance of fully understanding the role of the complement cascade in neurodegenerative diseases. Inhibiting C5 may be beneficial as a therapy for human glaucoma.

Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis.

Antibodies against acetylcholine receptors (AChRs) cause pathogenicity in myasthenia gravis (MG) patients through complement pathway-mediated destruction of postsynaptic membranes at neuromuscular junctions (NMJs). However, antibodies against muscle-specific kinase (MuSK), which constitute a major subclass of antibodies found in MG patients, do not activate the complement pathway. To investigate the pathophysiology of MuSK-MG and establish an experimental autoimmune MG (EAMG) model, we injected MuSK protein into mice deficient in complement component five (C5). MuSK-injected mice simultaneously developed severe muscle weakness, accompanied by an electromyographic pattern such as is typically observed in MG patients. In addition, we observed morphological and functional defects in the NMJs of EAMG mice, demonstrating that complement activation is not necessary for the onset of MuSK-MG. Furthermore, MuSK-injected mice exhibited acetylcholinesterase (AChE) inhibitor-evoked cholinergic hypersensitivity, as is observed in MuSK-MG patients, and a decrease in both AChE and the AChE-anchoring protein collagen Q at postsynaptic membranes. These findings suggest that MuSK is indispensable for the maintenance of NMJ structure and function, and that disruption of MuSK activity by autoantibodies causes MG. This mouse model of EAMG could be used to develop appropriate medications for the treatment of MuSK-MG in humans.

Complement factor C5 deficiency significantly delays the progression of biliary fibrosis in bile duct-ligated mice.

Fibrogenesis represents the universal response of the liver to chronic liver injury. Complement factor C5 has been linked to fibrosis in murine toxic liver injury and human chronic hepatitis C. C5 may also play a central role in chronic cholestatic disorders, since the BA receptor FXR has been characterized as an activator of the C3 gene. We aimed to investigate, whether C5 deficiency is able to prevent biliary fibrosis in the mouse bile-duct-ligation model. BDL for 1-4 weeks was performed in either Hc(0)/Hc(0) mice (deficient for C5) or WT controls. BA levels were measured by RIA. Histological examination included H&E, sirius-red and immunohistochemistry. mRNA expression was quantified by RT-PCR. Protein expression levels were determined by Western blotting or ELISA. Enzymatic MMP-activity was analysed by zymography. One week BDL leads to fibrosis in WT (F2.0 ± 0), while it is almost absent in Hc(0)/Hc(0) mice (F0.5 ± 0.5). No differences in fibrosis can be detected at week-4. Together with delayed fibrogenesis at week-1, fibrotic markers are decreased in Hc(0)/Hc(0) mice. Expression of the inflammatory cytokine TNF-α is decreased in Hc(0)/Hc(0) mice. In parallel C5 deficiency leads to an attenuated peribiliary infiltration of CD45(+) cells in fibrotic areas together with decreased MMP-9 expression and gelatinase activity. The present study proves a functional role of C5 during biliary fibrogenesis. C5 deficiency leads to attenuated inflammation and normalized MMP-9 activity concomitantly with a significant reduction of fibrosis. C5 appears to be an attractive target for future therapeutic intervention in chronic cholestatic liver disease.

A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement.

The clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is chronic intravascular hemolysis that is a consequence of unregulated activation of the alternative pathway of complement (APC). Intravascular hemolysis can be inhibited in patients by treatment with eculizumab, a monoclonal antibody that binds complement C5 thereby preventing formation of the cytolytic membrane attack complex of complement. However, in essentially all patients treated with eculizumab, persistent anemia, reticulocytosis, and biochemical evidence of hemolysis are observed; and in a significant proportion, their PNH erythrocytes become opsonized with complement C3. These observations suggest that PNH patients treated with eculizumab are left with clinically significant immune-mediated hemolytic anemia because the antibody does not block APC activation. With a goal of improving PNH therapy, we characterized the activity of anti-C3b/iC3b monoclonal antibody 3E7 in an in vitro model of APC-mediated hemolysis. We show that 3E7 and its chimeric-deimmunized derivative H17 block both hemolysis and C3 deposition on PNH erythrocytes. The antibody is specific for the APC C3/C5 convertase because classical pathway-mediated hemolysis is unaffected by 3E7/H17. These findings suggest an approach to PNH treatment in which both intravascular and extravascular hemolysis can be inhibited while preserving important immune functions of the classical pathway of complement.

Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature.

Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1beta and IL-8 were more dependent on complement than IFN-gamma and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-gamma inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to gram-negative bacteria.

The development of atypical hemolytic uremic syndrome depends on complement C5.

Gene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS.

Critical roles of complement and antibodies in host defense mechanisms against Neisseria meningitidis as revealed by human complement genetic deficiencies.

Certain complement defects are associated with an increased propensity to contract Neisseria meningitidis infections. We performed detailed analyses of complement-mediated defense mechanisms against N. meningitidis 44/76 with whole blood and serum from two adult patients who were completely C2 or C5 deficient. The C5-deficient patient and the matched control were also deficient in mannose-binding lectin (MBL). The proliferation of meningococci incubated in freshly drawn whole blood was estimated by CFU and quantitative DNA real-time PCR. The serum bactericidal activity and opsonophagocytic activity by granulocytes were investigated, including heat-inactivated postvaccination sera, to examine the influence of antimeningococcal antibodies. The meningococci proliferated equally in C2- and C5-deficient blood, with a 2 log(10) increase of CFU and 4- to 5-log(10) increase in DNA copies. Proliferation was modestly decreased in reconstituted C2-deficient and control blood. After reconstitution of C5-deficient blood, all meningococci were killed, which is consistent with high antibody titers being present. The opsonophagocytic activity was strictly C2 dependent, appeared with normal serum, and increased with postvaccination serum. Serum bactericidal activity was strictly dependent on C2, C5, and high antibody titers. MBL did not influence any of the parameters observed. Complement-mediated defense against meningococci was thus dependent on the classical pathway. Some opsonophagocytic activity occurred despite low levels of antimeningococcal antibodies but was more efficient with immune sera. Serum bactericidal activity was dependent on C2, C5, and immune sera. MBL did not influence any of the parameters observed.

The fifth component of complement (C5) in the mouse. Analysis of the molecular basis for deficiency.

C5-deficient mice differed from C5-sufficient mice both quantitatively and qualitatively in C5 protein, C5 mRNA, and the C5 gene. C5-deficient protein was present as decreased amounts of an unprocessed, single-chain precursor. C5-deficient mRNA was decreased in amount and present in two forms, the smaller of which was the same as the single form in normal cells. Nuclei from both normal and deficient cells contained the larger form of C5 mRNA, and C5-deficient DNA demonstrated differences from the normal pattern on Southern analysis for two restriction enzymes. These data suggest that the primary transcript of the C5-deficient gene is abnormal, retarding the processing of the C5 mRNA, and that the C5-deficient mRNA codes for an abnormal protein.

Tumor necrosis factor/cachectin. Induction of hemorrhagic necrosis in normal tissue requires the fifth component of complement (C5).

TNF induces hemorrhagic necrosis (HN) when injected into skin exposed to bacterial agents but not when injected into normal skin. In this paper, we present several lines of evidence suggesting that TNF requires the fifth component of complement (C5) to induce HN in skin exposed to bacteria. First, mouse strains that do not have C5 did not develop HN after injection of TNF and bacteria into skin. Second, plasma from C5-sufficient mice could correct the defect in these C5-deficient mice. Third, heating at 56 degrees C for 30 min inactivated the capacity of plasma to reconstitute C5-deficient mice. Fourth, CVF, which is known to inactivate complement, abrogated the capability of C5-sufficient mice to respond. Fifth, depleting plasma of hemolytic activity while generating C5a did not affect the capacity of the activated plasma to reconstitute C5-deficient mice. Finally, only the plasma fraction containing molecules of the size range of C5a reconstituted C5-deficient mice. These findings indicate that C5a and not the membrane attack complex is required for HN. Although we do not know through which mechanism C5a participates in the development of HN, we propose that the described HN response is related to a local defense mechanism in which TNF and C5a lead to the disruption of capillaries in the direct vicinity of bacteria. By this mechanism the rapid spread of bacteria or their products into the circulation is prevented. Such a tissue response is consistent with the known higher susceptibility of C5-deficient mice to bacterial infections and provides a model with which to search for the multiple steps involved in this important local defense mechanism.

[Hereditary complement C5 deficiency: study of 3 Tunisian adult cases and literature review]. / Deficit héréditaire en protéine C5 du complément: etude de 3 cas tunisiens de l'adulte et revue de la littérature.

BACKGROUND: The complement system is one of the main effectors of both innate and adaptive immunity. Hereditary complement deficiency, mainly those of the terminal pathway (C5-C9), is at increased risk for septic meningitides particularly meningococcal ones. AIM: to assess clinical and biochemical features of 3 Tunisian adults with C5 hereditary complement deficiency (C5D), with a familial study performed for two of them. METHODS: Functional activity of the classical and the alternative pathway of complement (CH50 and AP50 respectively) were measured according to standards haemolytic procedures. Serum concentration of complement components were determined by nephelemetry and ELISA. C5D was diagnosed when CH50, AP50 and C5 antigenic level were highly decreased. RESULTS: Our patients were 2 men and one woman. All these patients presented clinical symptoms of septic meningitides. Meningococcal orign was confirmed in one case. C5 level varies between 0 and 0.4%. Levels of other complement components: Clq, C3, C4, properdine, C6, C8 and C9 were normal. Antigenic C7 level was 50% in the female patient. Familial study revealed no similar hereditary complement deficiency in relatives. CONCLUSION: Only 27 cases with C5D were reported in the literature. The description of 3 cases in our series demonstrates that: * C5D is not rare in Tunisia, ** C5D is clinically commonly complicated by meningitides with unconstant severity, *** C5D is biologically caracterised by a variable level of the plasmatic C5 component.