[Recurrent meningitis and inherited complement deficiency]. / Recidivující meningitidy a vrozený deficit komplementového systému.

Complement deficiency represents 5% of primary immunodeficiencies worldwide. A total of seven patients with deficiencies of the classical complement pathway were reported in the Czech Republic by the end of 2015. Typical manifestations of complement deficiency are recurrent meningitis, other bacterial infections, autoimmunity and kidney disease.Two case reports are presented of patients with molecularly confirmed C7 (compound heterozygote, c.663_644del in exon 6 and c.2350+2T:>C in intron 16) and C8 (homozygous c.1282C>T in exon 9) deficiency. The first patient had four attacks of meningococcal meningitis and an episode of pneumonia of unknown aetiology in childhood. The second had six attacks of meningitis. He also suffered from recurrent infections (otitis media, tonsillitis, chronic mucopurulent rhinitis and subsequent pansinusitis complicated by nasal polyposis) since childhood. No autoimmune disease was documented in either patient. They both received meningococcal and pneumococcal vaccines. Antibiotic prophylaxis was used only in the second patient, leading to a decline in the number of ENT infections.Complement deficiency should be suspected in patients with recurrent meningococcal infections, especially if combined with other infections caused by encapsulated bacteria or autoimmunity diseases. Prophylaxis with conjugate polysaccharide vaccines is recommended and antibiotic prophylaxis should be considered in individual cases.

Complement factor C7 contributes to lung immunopathology caused by Mycobacterium tuberculosis.

Mycobacterium tuberculosis (MTB) remains a significant global health burden despite the availability of antimicrobial chemotherapy. Increasing evidence indicates a critical role of the complement system in the development of host protection against the bacillus, but few studies have specifically explored the function of the terminal complement factors. Mice deficient in complement C7 and wild-type C57BL/6 mice were aerosol challenged with MTB Erdman and assessed for bacterial burden, histopathology, and lung cytokine responses at days 30 and 60 post-infection. Macrophages isolated from C7 -/- and wild-type mice were evaluated for MTB proliferation and cytokine production. C7 -/- mice had significantly less liver colony forming units (CFUs) at day 30; no differences were noted in lung CFUs. The C7 deficient mice had markedly reduced lung occlusion with significantly increased total lymphocytes, decreased macrophages, and increased numbers of CD4+ cells 60 days post-infection. Expression of lung IFN-γ and TNF-α was increased at day 60 compared to wild-type mice. There were no differences in MTB-proliferation in macrophages isolated from wild-type and knock-out mice. These results indicate a role for complement C7 in the development of MTB induced immunopathology which warrants further investigation.

Disseminated gonococcal infection in a Japanese man with complement 7 deficiency with compound heterozygous variants: A case report.

RATIONALE: Complement deficiency are known to be predisposed to disseminated gonococcal infection (DGI). We herein present a case of DGI involving a Japanese man who latently had a complement 7 deficiency with compound heterozygous variants. PATIENT CONCERNS: A previously healthy 51-year-old Japanese man complained of sudden-onset high fever. Physical examination revealed various skin lesions including red papules on his trunk and extremities, an impetigo-like pustule on left forearm, and tendinitis of his right forefinger. DIAGNOSIS: Blood culture testing detected gram-negative cocci, which was confirmed to be Neisseria gonorrhoeae based on mass spectrometry and a pathogen-specific PCR test. INTERVENTIONS: Screening tests for underlying immunocompromised factors uncovered that complement activities (CH50) was undetectable. With a suspicion of a congenital complement deficiency, genetic analysis revealed rare single nucleotide variants in complement 7 (C7), including c.281-1G>T and a novel variant c.1454C>T (p.A485V). CH50 was normally recovered by adding purified human C7 to the patient's serum, supporting that the patient has C7 deficiency with compound heterozygous variants. OUTCOMES: Under a diagnosis of DGI, the patient underwent an antibiotic treatment with cefotaxime for a week and was discharged without any sequela. LESSONS: DGI is a rare sexually-transmitted infection that potentially induces systemic complications. Complement immunity usually defeats N. gonorrhoeae and prevents the organism from causing DGI. This case highlighted the importance of suspecting a complement deficiency when a person develops DGI.

C7 deficiency and meningococcal infection susceptibility in two spanish families.

In this work, we report the genetic basis of C7 deficiency in two different Spanish families. In family 1, by using exon-specific polymerase chain reaction and sequencing, a recently described mutation was found in homozygosity in the patient; a single base change in exon 15 (C2107T) leading to a stop codon that causes truncation of the C-terminal portion of C7 (Q681X). Patient's father, mother and sister were heterozygous for this mutation. Interestingly, patient's parents were not related. In family 2, a new single base mutation in exon 2 (G90A), leading to a stop codon that causes the premature truncation of C7 (W8X), was found in the patient, mother and sister 1. Additionally, patient 2, her father and sisters, displayed a missense mutation in exon 9 (G1135C) resulting in a change of aminoacid (G357R). Although sister 1 bore the same mutations in the C7 gene that patient 2, she remains asymptomatic. Because both mutations were found in the patient and her sister, we analyse other defence mechanisms such as FcgammaR polymorphisms as well as mannose-binding lectin alleles (MBL2 gene) and MBL levels. Results showed that both siblings bore identical combinations of FcgammaR allotypes and different MBL2 alleles, exhibiting patient 2 a MBL-insufficient genotype. Normal MBL levels were found in patient 1 and in two previously studied C7-deficient siblings, suggesting the involvement of other mechanisms of immunity distinct of FcgammaR variants and the MBL pathway, for the absence of meningococcal recurrent infections in certain C7-deficient individuals.

Inherited deficiency of the seventh component of complement associated with nephritis. Propensity to formation of C56 and related C7-consuming activity.

A 46-yr-old female with chronic pyelonephritis was found to lack complement (C) activity by the use of hemolytic screen assays in agarose gels. These assays also revealed a propensity of patient serum to form an activated complex of the fifth and sixth components of C, C56. Each of the C component hemolytic activities was present in normal or elevated amounts with the exception of C7, which was undetectable; addition of purified C7 led to the restoration of hemolytic activity. C-dependent phagocytosis, immune adherence, and neutrophil chemotaxis were normal. Family studies demonstrated that the defect was transmitted as an autosomal codominant apparently not linked with alleles at the HLA-A or HLA-B loci. Persisting C56 was readily formed in this as compared to normal serum upon incubation with multiple C activators including zymosan, inulin, immune complexes, heat-aggregated human gamma globulin, endotoxin, and agarose. A heat-stable (56 degrees C, 30 min) activity which consumed C7 with time-and temperature-dependent kinetics was detected in plasma and serum, and seemed to be similar to a "C7 inactivator" previously described in another C7-deficient individual. However, this activity was found to have properties identical to those of C56 during low ionic strength precipitation and chromatography on Sephadex G-200, to be specifically removed upon passage through an anti-C5 immunoadsorbent column, and to be associated with a small amount of C56, suggesting that it represents an expression of small amounts of C56 rather than a new C-inhibitory activity. Thus, an individual with chronic nephritis lacking C7 is reported; the utility of a hemolytic screen assay in agarose plates for the detection of such patients is emphasized; persisting C56 is shown readily to be formed in this serum; and the presence of C7-consuming activity which is associated with and in all likelihood attributable to C56 is shown.

Hereditary C7 deficiency. Diagnosis and HLA studies in a French-Canadian family.

The serum of a 44-yr-old woman of French-Canadian descent having a B-27 positive ankylosing spondylitis was deficient in the seventh component of complement (C7) as determined by hemolytic and immunochemical methods. No inhibitor against C7 was detected, and the levels of all other complement components were normal. No deficiency in the opsonic activity of the serum was found, and the results of basic coagulation studies of the plasma were normal. On investigation of the patient's family, two sisters were found to have the same deficiency but were otherwise in good health. The seven other siblings were heterozygous for C7 deficiency, while the paternal aunt had a normal C7 level. In the third generation, six children of the three homozygous sisters and five children of heterozygotes were available for testing. Studies of the HLA antigens in all the 22 subjects and in three spouses indicated no close linkage between the CM deficienty and the HLA system. In addition, the simultaneous occurrence of two hereditary complement deficiencies (C2 and C7) was discovered in one family of this remarkable kindred.

Hereditary deficiency of the seventh component of complement.

Deficiency of the seventh component of complement has been found in the serum of a 42-yr-old Caucasian woman who has Raynaud's phenomenon, sclerodactyly, and telangiectasia. Partial deficiency was found in the serum of the patient's parents and children, indicating a pattern of inheritance of autosomal codominance. Transfusion experiments indicated that exogenous C7 had a 91-h halk-life in the patient. There was no evidence for C7 synthesis after transfusion. No C7 inhibitors were detected in the patient's serum. The patient's serum was found to support the activation of complement by both the classical and properdin pathways to the C7 stage. The addition of C7 to the patient's serum permitted it to support hemolytic reactions initiated by either pathway. No defects could be detected in plasma or whole blood coagulation. The patient's serum was deficient in opsonizing unsensitized yeast particles in serum and in the generation of chemotactic factor by antigen-antibody complexes and endotoxin. Both deficiencies were corrected by the addition of C7. These observations suggest a key role for C7 for in vitro yeast phagocytosis and chemotaxis generation. However, the patient's lack of infections indicates a relatively minor role for C7 in human resistance to infection.

Deficiency of the seventh component of complement in a Taiwanese boy.

Inherited complement deficiencies are rare, particularly those associated with late components of the complement cascade. We report a 5-year-4-month-old Taiwanese boy with systemic meningococcal infection who had undetectable CH50 level of < 6 U/mL (normal, 32.6-39.8 U/mL). Levels of C3, C4, C5, C6 and C8 were normal, but C7 was undetectable (< 5.8 mg/dL; reference, 55-85 mg/dL). The patient's sister was also C7-deficient (CH50 < 6 U/mL, C7 < 5.8 mg/dL). His father's CH50 was 25.9 U/mL and C7 was 27.8 mg/dL. His mother's CH50 was 31.2 U/mL and C7 was 22.7 mg/dL. His parents thus both had a partial complement deficiency, indicating an autosomal codominant inheritance pattern. Awareness of the possibility of late complement deficiency is important as they comprise a small percentage of patients who present with disseminated meningococcal disease or other serious infections caused by encapsulated organisms.

[Combined-heterozygous deficiency of complement C7 in a patient with recurrent meningitis]. / Kombiniert-heterozygote Defizienz von Komplementfaktor C7 bei einer Patientin mit rezidivierender Meningitis.

BACKGROUND: The association between complement deficiencies and the increased risk for meningococcal infections and bacterial meningitis is well described and most striking in patients with deficiencies of one of the late complement components, i.e., C5-C9. CASE REPORT: In the presented study the first case of a patient with combined-heterozygous deficiency of complement C7 is described. The defect led to a strongly reduced but still measurable production of C7. However, the low concentration of C7 was not protective against recurrent bacterial meningitis. CONCLUSION: The reported case illustrates once again the necessity of complement analysis in patients with meningitis. Not only patients with undetectable complement activity but also those with strongly reduced but still measurable complement function should be analyzed for a possible complement deficiency.

[Complement protein hereditary deficits during purulent meningitis: study of 61 adult Tunisian patients]. / Déficits héréditaires en protéines du complément au cours des méningites purulentes: étude de 61 patients adultes tunisiens et revue de la littérature.

Sixty one Tunisian adult patients with bacterial meningitis were screened for complement deficiency. Functional activity of the classical and the alternative pathways of complement (CH50 and AP50 respectively) were measured according to standard haemolytic procedures. Serum concentrations of C3 and C4 were determined by nephelometry. Late complement component (C5-C9) and properdin concentrations were assessed by double-ligand EISA. Complement deficiency was found in eight patients (13%): Seven had late complement component deficiency (three C7 deficiency, two C5 deficiency, one C6 deficiency and one C8 deficiency) and one had partial properdin deficiency. Patients with late complement component deficiency had a mean age of 24 years (range 17-32 years). All deficient patients had meningococcal meningitis. Recurrent meningitis was reported in half of the patients. Our findings demonstrated a high prevalence of complement deficiency in Tunisia suggesting that screening for hereditary complement deficiency should be performed in case of bacterial meningitides and meningococcal disease patients.

FcgammaRIIIb and complement component C7 codeficiency in a patient with recurrence of fulminant meningococcal septic shock.

Individuals with deficiencies of the late components of complement exhibit a susceptibility to the recurrence of meningococcal disease with a usually mild clinical presentation. We report the recurrence of fulminant meningococcal disease in a complement component C7-deficient patient. We found a total deficiency of FcgammaRIIIb on neutrophils, which could partially explain the unusually severe clinical presentation.

Familial late complement component (C6, C7) deficiency with chronic meningococcemia.

Two patients with chronic meningococcemia were found to lack hemolytic complement, one because of C6 deficiency, the other because of C7 deficiency. In both cases family studies were consistent with inheritance of the deficiencies as non-HLA-linked, autosomal co-dominant traits. Functional studies showed the deficient sera to support monocyte chemotaxis but not phagocytosis or lysis of meningococci. Both patients have remained well following antibiotic treatment.

Meningococcal disease in patients with late complement component deficiency: studies in the U.S.S.R.

The purpose of this study was to examine the occurrence of late complement component deficiency (LCCD) states in the USSR. Thirty deficient individuals were detected: 27 with C8 beta and 3 with C7 deficiency. Among individuals with a first episode of meningococcal infection, about 1% had LCCD, whereas among patients with recurrent bacterial meningitis the prevalence of LCCD rose to approximately 50%. This corresponds to a prevalence for LCCD of approximately 12 per 100,000 in the general population. The individuals with LCCD identified in this study experienced about 77 episodes of meningococcal disease and acute bacterial meningitis. Mathematical analysis of the morbidity from meningococcal disease in individuals with LCCD demonstrated that the probability of disease did not change with the age of the patient and was not affected by prior episodes of infection. This finding suggest that in contrast to the situation in the general population, prior infection fails to protect the deficient individual from recurrent disease. In comparison to complement-sufficient persons, the course of disease in individuals with LCCD is less severe, as shown by a reduction in the number of episodes of endotoxic shock and mortality as well as their more rapid recovery. These findings suggest that exuberant complement activation and concomitant formation of membrane attack complexes during meningococcal infection in complement-sufficient patients plays an important role in the activation and injury of peripheral blood cells and endothelial cells during endotoxic shock.

Use of C6- and C7-deficient human sera in quantitative hemolytic assays for C6 and C7.

Quantitative hemolytic assays for C6 and C7 using as R reagents sera from patients deficient in these components are described. The assays gave linear results. Normal range for serum C6 was found to be 21,400--41,700 C6 hemolytic units/ml; for serum C7 the normal range was 5540--9860 C7 hemolytic units/ml.

Genetic detection of the silent allele (*Q0) in hereditary deficiencies of the human complement C6, C7, and C9 components.

DNA polymorphisms (RFLPs) of the human complement component C6, C7, and C9 genes were studied in three C7-deficient (C7D) families, one C6-deficient (C6D) family, and one C9-deficient (C9D) family. The 3 loci are closely linked on human chromosome 5. The haplotypes carrying the "silent" allele (C7*Q0, C6*Q0, and C9*Q0) were defined in each family, allowing for the detection of carriers among asymptomatic relatives. This paper describes familial studies on a type of hereditary trait, characterized by recurrent Neisseria infections in individuals homozygous for "silent" alleles at the C6, C7, or C9 loci.

High prevalence of complement C7 deficiency among healthy blood donors of Moroccan Jewish ancestry.

The incidence of the specific component deficiencies in various ethnic groups is not known, although there appears to be an ethnic predilection for C6 and C8alpha-gamma deficiencies in blacks, whereas C7 and C8beta deficiencies are predominantly noted in Caucasians. Infectious diseases, particularly recurrent meningococcal infections, are observed more commonly with late component deficiencies. In the current study, we have simplified the PCR technique by using site-directed mutagenesis and designer primers in a cohort of Israeli Moroccan Jewish blood donors to ascertain allele frequency in this ethnic group, which, based on earlier studies, was considered to be at risk for C7 deficiency. The total mutant allele frequency in this ethnic cohort was 1.1% of a total of 365 healthy Israeli Moroccan Jews, including one homozygote. The identification of mutant alleles was efficient and inexpensive, and hence a large cohort was studied. The finding of complement deficiency identifies individuals at risk for Neisserial infections, which are known to be potentially life-threatening. Conversely, when a patient of Moroccan ancestry is diagnosed with a Neisserial infection, it is important to determine the complement status.

C7 complement deficiency in an Israeli Arab village.

Deficiencies of terminal complement components, particularly the latter ones, are often detected because of increased susceptibility to Neisserial infections. Herein we document the first report of C7 deficiency among a highly inbred Arab population living in the lower Galilee region of Israel. Both biochemical and molecular analysis were performed on samples from infected survivors and parents of children who succumbed to Neisserial infections in a 4-year period. Only the index case who suffered recurrent infections and a sibling who had not suffered an infection during the outbreak were found to be C7-deficient. The mutation was found to be the one previously described to be prevalent among Israeli Jews of Moroccan ancestry (mutation G1135C). The implications of this finding are discussed in the context of family pedigree, the protective effect of complement deficiency, and the clinical outcome.

Deafness, complement deficiencies and immunoglobulin status in patients with meningococcal diseases due to uncommon serogroups.

The prevalence of deafness and complement deficiencies in association with meningococcal disease caused by uncommon serogroups of meningococci was studied in 30 patients (Group A) and 30 controls with Serogroup B disease (Group B). In Group A 8 patients (26.6%) had hearing impairment in contrast to only 1 patient (3.3%) in Group B (P < 0.01). Complement deficiency was detected in 8 patients (26.6%) of Group A whereas none of the Group B patients showed a defect in the complement system (P < 0.01). Association between complement deficiencies and meningococcal disease was detected for Serogroups Y (n = 5; 16.6%) and W135 (n = 3; 10.0%). Localization of the defects revealed only complement deficiencies of the classical pathway (C8-beta or C7 defects). The levels of Ig and IgG subclasses were found to be within the normal range for all patients. Our results suggest that meningococcal diseases caused by uncommon serogroups are more often associated with deafness and late complement component defects.

Selective C7 complement deficiency causing recurrent meningococcal infection.

We report on two sisters both with complete absence of the 7th component of complement. This congenital immunodeficiency disorder is associated with recurrent bacterial infection, especially that due to Neisseria species. These cases illustrate many of the well-recognised features of this disorder, but in one patient the illness was complicated by infective endocarditis due to N. meningitidis, a feature not previously reported.