Strains Responsible for Invasive Meningococcal Disease in Patients With Terminal Complement Pathway Deficiencies.

Background: Patients with terminal complement pathway deficiency (TPD) are susceptible to recurrent invasive meningococcal disease (IMD). Neisseria meningitidis (Nm) strains infecting these patients are poorly documented in the literature. Methods: We identified patients with TPD and available Nm strains isolated during IMD. We investigated the genetic basis of the different TPDs and the characteristics of the Nm strains. Results: We included 56 patients with C5 (n = 8), C6 (n = 20), C7 (n = 18), C8 (n = 9), or C9 (n = 1) deficiency. Genetic study was performed in 47 patients and 30 pathogenic variants were identified in the genes coding for C5 (n = 4), C6 (n = 5), C7 (n = 12), C8 (n = 7), and C9 (n = 2). We characterized 61 Nm strains responsible for IMD in the 56 patients with TPD. The most frequent strains belonged to groups Y (n = 27 [44%]), B (n = 18 [30%]), and W (n = 8 [13%]). Hyperinvasive clonal complexes (CC11, CC32, CC41/44, and CC269) were responsible for 21% of IMD cases. The CC23 predominates and represented 26% of all invasive isolates. Eleven of the 15 clonal complexes identified fit to 12 different clonal complexes belonging to carriage strains. Conclusions: Unusual meningococcal strains with low level of virulence similar to carriage strains are most frequently responsible for IMD in patients with TPD.

Infections Revealing Complement Deficiency in Adults: A French Nationwide Study Enrolling 41 Patients.

Complement system is a part of innate immunity, its main function is to protect human from bacterial infection. As genetic disorders, complement deficiencies are often diagnosed in pediatric population. However, complement deficiencies can also be revealed in adults but have been poorly investigated. Herein, we describe a case series of infections revealing complement deficiency in adults to study clinical spectrum and management of complement deficiencies.A nationwide retrospective study was conducted in French university and general hospitals in departments of internal medicine, infectious diseases enrolling patients older than 15 years old who had presented at least one infection leading to a complement deficiency diagnosis.Forty-one patients included between 2002 and 2015 in 19 different departments were enrolled in this study. The male-to-female ratio was 1.3 and the mean age at diagnosis was 28 ±â€Š14 (15-67) years. The main clinical feature was Neisseria meningitidis meningitis 75% (n = 31/41) often involving rare serotype: Y (n = 9) and W 135 (n = 7). The main complement deficiency observed was the common final pathway deficiency 83% (n = 34/41). Half of the cohort displayed severe sepsis or septic shock at diagnosis (n = 22/41) but no patient died. No patient had family history of complement deficiency. The mean follow-up was 1.15 ±â€Š1.95 (0.1-10) years. Half of the patients had already suffered from at least one infection before diagnosis of complement deficiency: meningitis (n = 13), pneumonia (n = 4), fulminans purpura (n = 1), or recurrent otitis (n = 1). Near one-third (n = 10/39) had received prophylactic antibiotics (cotrimoxazole or penicillin) after diagnosis of complement deficiency. The vaccination coverage rate, at the end of the follow-up, for N meningitidis, Streptococcus pneumonia, and Haemophilius influenzae were, respectively, 90% (n = 33/37), 47% (n = 17/36), and 35% (n = 14/34).This large study emphasizes that complement deficiencies can be revealed in adults by infectious episodes. Most of them were meningococcal infections revealing common final pathway deficiency. To avoid undiagnosis or late diagnosis, adult displaying first episode of N meningitidis infection should be tested for complement deficiency.

The alternative complement pathway propagates inflammation and injury in murine ischemic stroke.

There is mounting evidence indicating an important role for complement in the pathogenesis of cerebral ischemia-reperfusion injury, or ischemic stroke. The role of the alternative complement pathway in ischemic stroke has not been investigated, and there is conflicting data on the role of the terminal pathway. In this study, we show that compared with wild-type mice, mice deficient in the alternative pathway protein factor B or mice treated with the alternative pathway inhibitor CR2-fH have improved outcomes after 60-min middle cerebral artery occlusion and 24-h reperfusion. Factor B-deficient or CR2-fH-treated mice were protected in terms of improved neurologic function and reduced cerebral infarct, demyelination, P-selectin expression, neutrophil infiltration, and microthrombi formation. Mice deficient in both the classical and lectin pathways (C1q/MBL deficient) were also protected from cerebral ischemia-reperfusion injury, and there was no detectable C3d deposition in the ipsilateral brain of these mice. These data demonstrate that the alternative pathway is not alone sufficient to initiate complement activation and indicate that the alternative pathway propagates cerebral injury via amplification of the cascade. Deficiency of C6, a component of the terminal cytolytic membrane attack complex, had no effect on outcome after ischemic stroke, indicating that the membrane attack complex is not involved in mediating injury in this model. We additionally show that the protective effect of factor B deficiency and CR2-fH treatment is sustained in the subacute stage of infarct development, adding to the clinical relevance of these findings.

A role for the NF-κB pathway in cell protection from complement-dependent cytotoxicity.

Nucleated cells are equipped with several mechanisms that support their resistance to complement-dependent cytotoxicity (CDC). The role of the NF-κB pathway in cell protection from CDC was examined. Elevated sensitivity to CDC was demonstrated in cells lacking the p65 subunit of NF-κB or the IκB kinases IKKα or IKKß, and in cells treated with p65 small interfering RNA. Pretreatment with the IKK inhibitor PS-1145 also enhanced CDC of wild-type cells (WT) but not of p65(-/-) cells. Furthermore, reconstitution of p65 into p65(-/-) cells and overexpression of p65 in WT cells lowered their sensitivity to CDC. The postulated effect of p65 on the JNK-mediated death-signaling pathway activated by complement was examined. p65 small interfering RNA enhanced CDC in WT cells but not in cells lacking JNK. JNK phosphorylation induced by complement was more pronounced in p65(-/-) cells than in WT cells. The results indicate that the NF-κB pathway mediates cell resistance to CDC, possibly by suppressing JNK-dependent programmed necrotic cell death.

Complement deficiency states and associated infections.

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.

C5b-9 complement complex in autoimmune demyelination and multiple sclerosis: dual role in neuroinflammation and neuroprotection.

Complement system activation plays an important role in innate and acquired immunity. Activation of complement leads to the formation of C5b-9 terminal complex. While C5b-9 can promote cell lysis, sublytic assembly of C5b-9 on plasma membranes induces cell cycle activation and survival. Multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE) are inflammatory demyelinating diseases of the central nervous system (CNS) mediated by activated lymphocytes, macrophages/microglia and the complement system. Complement activation may contribute to the pathogenesis of these diseases through its dual role: the ability of activated terminal complex C5b-9 to promote demyelination and the capacity of sublytic C5b-9 to protect oligodendrocytes (OLG) from apoptosis. By inducing EAE in C5-deficient mice, we showed that complement C5 promotes remyelination and protects oligodendrocytes from apoptotic cell death. These findings indicate that activation of complement C5b-9 plays a pro-inflammatory role in the acute phase of the disease, but may also be neuroprotective during the chronic phase of the disease.

Complement C7 deficiency presenting as recurrent aseptic meningitis.

BACKGROUND: Complement deficiency states are rare inherited disorders that may predispose affected individuals to angioedema, collagen vascular disease, or infection due to encapsulated organisms, especially Neisseria meningitidis. OBJECTIVES: To report the case of a 36-year-old man of Irish descent with recurrent culture-negative neutrophilic meningitis, to offer potential reasons for the inability to recover a causative pathogen, and to review the genetics and prevalence of complement deficiency states, the methods of screening for such deficiencies, the features of meningococcal infection as they relate to such deficiencies, and management strategies for clinicians caring for patients with such deficiencies. METHODS: The patient presented in 1988 and again in 2002 with culture-negative neutrophilic meningitis. His second episode was characterized by a rash suggestive of meningococcal infection, prompting immunologic evaluation. RESULTS: Immunologic evaluation revealed an undetectable CH50 level. Levels of C1, C2, and C5 through C9 were normal except for C7, which was undetectable. Further testing revealed that the patient's sister was also C7 deficient. CONCLUSIONS: Complement component deficiencies are relatively rare; individuals with collagen vascular disease and systemic neisserial infection should be screened using either the CH50 or the APH-50 assay. Key to the management of a late-complement component-deficient host is counseling, education about meningococcal infection, and discussions about the potential benefits of chemoprophylaxis and immunoprophylaxis. The ability to detect the bacterial cause of meningitis in such patients is organism dependent and may be influenced by factors such as cerebrospinal fluid bacterial concentration and previous antibiotic drug exposure.

Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis.

Abs to acetylcholine receptor (AChR) and complement are the major constituents of pathogenic events causing neuromuscular junction destruction in both myasthenia gravis (MG) and experimental autoimmune MG (EAMG). To analyze the differential roles of the classical vs alternative complement pathways in EAMG induction, we immunized C3(-/-), C4(-/-), C3(+/-), and C4(+/-) mice and their control littermates (C3(+/+) and C4(+/+) mice) with AChR in CFA. C3(-/-) and C4(-/-) mice were resistant to disease, whereas mice heterozygous for C3 or C4 displayed intermediate susceptibility. Although C3(-/-) and C4(-/-) mice had anti-AChR Abs in their sera, anti-AChR IgG production by C3(-/-) mice was significantly suppressed. Both C3(-/-) and C4(-/-) mice had reduced levels of B cells and increased expression of apoptotis inducers (Fas ligand, CD69) and apoptotic cells in lymph nodes. Immunofluorescence studies showed that the neuromuscular junction of C3(-/-) and C4(-/-) mice lacked C3 or membrane attack complex deposits, despite having IgG deposits, thus providing in vivo evidence for the incapacity of anti-AChR IgGs to induce full-blown EAMG without the aid of complements. The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization. Accordingly, severe MG and other Ab- and complement-mediated diseases could be effectively treated by inhibiting C4, thus leaving the alternative complement pathway intact.

Membrane attack complex contributes to destruction of vascular integrity in acute lung allograft rejection.

The lung is known to be particularly susceptible to complement-mediated injury. Both C5a and the membrane attack complex (MAC), which is formed by the terminal components of complement (C5b-C9), can cause acute pulmonary distress in nontransplanted lungs. We used C6-deficient rats to investigate whether MAC causes injury to lung allografts. PVG.R8 lungs were transplanted orthotopically to MHC class I-incompatible PVG.1U recipients. Allografts from C6-sufficient (C6(+)) donors to C6(+) recipients were rejected with an intense vascular infiltration and diffuse alveolar hemorrhage 7 days after transplantation (n = 5). Ab and complement (C3d) deposition was accompanied by extensive vascular endothelial injury and intravascular release of von Willebrand factor. In contrast, lung allografts from C6-deficient (C6(-)) donors to C6(-) recipients survived 13-17 days (n = 5). In the absence of C6, perivascular mononuclear infiltrates of ED1(+) macrophages and CD8(+) T lymphocytes were present 7 days after transplantation, but vascular endothelial cells were quiescent, with minimal von Willebrand factor release and no evidence of alveolar hemorrhage or edema. Lung allografts were performed from C6(-) donors to C6(+) recipients (n = 5) and from C6(+) donors to C6(-) recipients (n = 5) to separate the effects of systemic and local C6 production. Lungs transplanted from C6(+) donors to C6(-) recipients had increased alveolar macrophages and capillary injury. C6 production by lung allografts was demonstrated at the mRNA and protein levels. These results demonstrate that MAC causes vascular injury in lung allografts and that the location of injury is dependent on the source of C6.

Modulation of leukocyte recruitment and IL-8 expression by the membrane attack complex of complement (C5b-9) in a rabbit model of antigen-induced arthritis.

The complement system is thought to be a major physiological mediator of injury in a number of diseases including rheumatoid arthritis (RA). The membrane attack complex (MAC) of complement has been detected in RA tissue, suggesting that the MAC may be relevant to the pathogenesis of the disease. Deposition of sublytic concentrations of the MAC has been shown to promote the expression of proinflammatory mediators. In the present study, we utilized rabbits deficient in the complement protein C6 to elucidate the role of the MAC in mediating the pathogenesis of antigen-induced arthritis. Swelling, leukocyte accumulation, IL-8 expression, proteoglycan, and hydroxyproline content were assessed. Analysis of synovial tissue demonstrated a significant decrease in leukocyte influx and a parallel decrease in tissue associated IL-8 in joints of C6-deficient animals as compared to C6-sufficient animals. However, this did not correlate with the preservation of connective tissue. The results derived from this study provide evidence that the MAC has an important function in mediating leukocyte recruitment in antigen-induced arthritis but does not play a direct role in connective tissue breakdown.

[Clinical features of meningococcal infection in subjects with deficient terminal components of complement]. / Klinicheskie osobennosti meningokokkovoi infektsii u lits s defitsitom terminal'nykh komponentov komplementa.

AIM: To evaluate clinical characteristics of meningococcal disease (MD) in individuals with terminal complement component deficiency (TCCD) who are thousands times more susceptible to MD than complement-sufficient persons. MATERIALS AND METHODS: 61 cases of MD in TCCD patients and 200 randomly selected cases of MD in complement-sufficient patients were analyzed. RESULTS: Meningitis without meningococcemia accounted for 17% of the MD episodes in the control group of complement-sufficient patients but none in individuals with TCCD who had meningococcemia (10%) or meningococcemia with meningitis (90%). Moderate disease predominated in patients with TCCD (70%) and no episodes of fatal disease were noted, whereas severe disease was more common in the control group which had an 8% case fatality rate and frequent complications such as endotoxic shock (15% of episodes) and brain edema (26%). The severity of the disease in TCCD patients did not differ between the first and subsequent episodes, between males and females, between episodes caused by serogroup A and B meningococci, etc. CONCLUSION: In comparison to complement-sufficient persons, the course of the disease in patients with TCCD is statistically less severe.

[Homozygous C7 defect in a German family]. / Homozygoter C7-Defekt in einer deutschen Familie.

An 11 year old boy with recurrent meningitis/sepsis (once without positive bacterial culture, once with demonstration of Neisseria meningitidis in blood) was evaluated for suspected immunodeficiency. Absent activity of both the classical and alternative pathway of complement suggested a defect of the membrane attack complex. Immunochemical and functional analyses together with family studies revealed a homozygous defect of the seventh component of complement in the boy. This is the first description of C7 deficiency in a German family.