Hypocomplementemia Research Articles

Induction of Complement C3a Receptor Responses by Kallikrein-Related Peptidase 14

Activation of the complement system is primarily initiated by pathogen- and damage-associated molecular patterns on cellular surfaces. However, there is increasing evidence for direct activation of individual complement components by extrinsic proteinases as part of an intricate crosstalk between physiological effector systems. We hypothesized that kallikrein-related peptidases (KLKs), previously known to regulate inflammation via proteinase-activated receptors, can also play a substantial role in innate immune responses via complement. Indeed, KLKs exemplified by KLK14 were efficiently able to cleave C3, the point of convergence of the complement cascade, indicating a potential modulation of C3-mediated functions. By using in vitro fragmentation assays, mass spectrometric analysis, and cell signaling measurements, we pinpointed the generation of the C3a fragment of C3 as a product with potential biological activity released by the proteolytic action of KLK14. Using mice with various complement deficiencies, we demonstrated that the intraplantar administration of KLK14 results in C3-associated paw edema. The edema response was dependent on the presence of the receptor for C3a but was not associated with the receptor for the downstream complement effector C5a. Our findings point to C3 as one of the potential substrates of KLKs during inflammation. Given the wide distribution of the KLKs in tissues and biological fluids where complement components may also be expressed, we suggest that via C3 processing, tissue-localized KLKs can play an extrinsic complement-related role during activation of the innate immune response.

Successful cure of C1q deficiency in human subjects treated with hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is used to cure a number of primary immunodeficiency diseases but has never been attempted for patients with complement deficiencies because most complement factors are produced in the liver rather than the bone marrow. Inherited deficiency of the C1q component of the classical complement pathway is a severe autosomal recessive immunodeficiency disease associated with a high risk of death from either fulminant bacterial infections or systemic lupus erythematosus–like autoimmunity.

Vorsorgeuntersuchungen während intensivierter Immunsuppression bei Kindern und Jugendlichen

The increasing use of combination therapies, including disease-modifying antirheumatic drugs (DMARD) and biologicals has improved the outcome for children and adolescents in several rheumatic diseases. However, this strategy has increased the risk of drug-specific side-effects, such as an increased risk of infections. Furthermore, the underlying rheumatic disease itself often includes an increased risk of infections and some patients additionally present with immunological or organic comorbidities (e.g. complement deficiency and interstitial pulmonary disease) further increasing the susceptibility to infections. The presented review is based on an analysis of the currently available literature proposing a checklist of diagnostic procedures and immunological laboratory tests specific for the detection of patients prone to infections. The combined stratification of the underlying disease, comorbidities and the immunological mechanisms of the medication enables (1) an individual risk stratification of planned immunosuppressive therapy and (2) a prediction of the risks of infection for the patient.

Prevention of Meningococcal Infections in the First 2 Years of Life

The spectrum of disease caused by Neisseria meningitidis includes bacteremia, fulminant sepsis (meningococcemia), meningitis, and pneumonia. The incidence of meningococcal infection has long been higher in infancy than adolescents or adults older than 65 years (a third group with an increased risk based on age). Five meningococcal serogroups (A, B, C, Y, and W135) cause the great majority of human disease. Serogroup B strains cause about two-thirds of disease in children younger than 6 years. For this reason, new meningococcal vaccine formulations have been developed and evaluated in children younger than 2 years. Of four meningococcal vaccines currently licensed in the United States, two conjugate products, (MenACWY-D [Menactra], Sanofi Pasteur; HibMenCY-TT [MenHibrix], GlaxoSmithKline), are recommended for infants and toddlers younger than 2 years who have an increased risk for invasive meningococcal disease. High-risk conditions are complement deficiencies, community outbreaks, functional or anatomic asplenia, and travel to high-risk areas in which serogroup A infection is prevalent. Recommendations vary by age, dosing, and indication between these two products. Both licensed products are immunogenic and have side-effect profiles that are considered safe for use. In most cases, concomitant use with other recommended childhood vaccines does not interfere with responses to these vaccines. As of yet, there has not been universal adoption of this immunization in the infant population by parents or providers. Factors that weigh against the implementation of a national routine infant program include the prevention of only 40 to 50 meningococcal cases, two to four deaths per year, and a relatively low case fatality among infants. Some argue that costs should not be considered a barrier because infant deaths and morbidity would be prevented. The availability of a serogroup B vaccine would improve impact and cost-effectiveness of a routine infant meningococcal vaccine program. Debate over the implementation of routine infant meningococcal vaccination in the United States is ongoing. This review focuses on vaccines for the prevention of N. meningitidis infection in infants and young toddlers in the first 2 years of life.

Management of secondary immune deficiencies

Management of secondary immune deficiencies

Pathogenesis, prophylaxis and treatment of infections in patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) patients are at high risk for infections. The pathogenesis of infection in patients with this leukemia is complex and multifactorial. Patients with CLL have a number of immune system defects, including disordered B-cell function with decreased production of normal B-cells and abnormal production of immunoglobulins, suppressed T-cell function and neutropenia. Other immune abnormalities present in CLL patients include neutrophil dysfunction, and complement deficiencies. In addition, further perturbations in immune function are related to the antileukemic therapies. Immune disturbance might be common prior to CLL diagnosis and infectious agents could trigger CLL development. Current chemotherapy-based regimens are not curative and often worsen this immune suppression. The introduction of new effective therapeutic agents such as the purine analogues and monoclonal antibodies has influenced the spectrum of infections diagnosed in CLL patients. Some conditions increase the risk for the development of infections including advanced age, decreased levels of immunoglobulins, advanced Binet stage, neutropenia and treatment with more than one line of chemotherapy. Until now it is debatable whether and when antibacterial prophylaxis could be useful in CLL patients. The prevention of infection includes antimicrobial prophylaxis, as well as immunoglobulin replacement and vaccination. Antibacterial prophylaxis should be given to CLL patients with previous severe and/or relapsing bacterial infections. This article reviews the immune defects in CLL and discusses strategies aimed at prophylaxis and treatment of infections in patients with CLL.

Resistance to Streptozotocin-Induced Autoimmune Diabetes in Absence of Complement C3: Myeloid-Derived Suppressor Cells Play a Role

The contribution of complement to the development of autoimmune diabetes has been proposed recently. The underlying mechanisms, however, remain poorly understood. We hypothesize that myeloid-derived suppressor cells (MDSC), which act as regulators in autoimmunity, play a role in resistance to diabetes in absence of complement C3. Indeed, MDSC number was increased significantly in STZ-treated C3−/− mice. These cells highly expressed arginase I and inducible nitric oxide synthase (iNOS). Importantly, depletion of MDSC led to the occurrence of overt diabetes in C3−/− mice after STZ. Furthermore, C3−/− MDSC actively suppressed diabetogenic T cell proliferation and prevented/delayed the development of diabetes in arginase and/or iNOS-dependent manner. Both Tregs and transforming growth factor-β (TGF-β) are crucial for MDSC induction in STZ-treated C3−/− mice as depletion of Tregs or blocking TGF-β bioactivity dramatically decreased MDSC number. These findings indicate that MDSC are implicated in resistance to STZ-induced diabetes in the absence of complement C3, which may be helpful for understanding of mechanisms underlying preventive effects of complement deficiency on autoimmune diseases.

Maternal and fetal outcomes in women complicated with lupus nephritis

Objective To evaluate the maternal and fetal outcomes of pregnant women with lupus nephritis (LN) and the risk factors.Methods Ninety-three patients with 97 pregnancies from January 1st,1990 to December 31st,2012 in Peking Union Medical College Hospital were evaluated retrospectively.Objects of study were divided into three groups:stable lupus before pregnancy (stable group,52 cases),active lupus before pregnancy (active group,26 cases),and newly diagnosed LN during pregnancy (19 cases).Adverse maternal outcomes included exacerbated disease during pregnancy,preeclampsia,increased proteinuria and impaired renal function during pregnancy or postpartum,maternal death,thrombocytopenia and hypocomplementemia.Adverse fetal or neonatal outcomes included therapeutically termination of pregnancy,fetal loss,neonatal death,preterm labor,small gestational age and asphyxia.Statistical analysis was performed by Chi-square test or Fisher's exact test.A binary logistic regression model was used to evaluate the risk factors for adverse maternal and fetal outcomes.Results (1) Adverse maternal outcomes:There was no significant difference between exacerbated cases during pregnancies in stable group and that in active group [53.8 ％ (28/52) vs 61.5 ％ (16/26),x2 =0.417,P＞0.05].After deleting abortions before 20 weeks of gestation (5 cases in stable group and 4 cases in active group),there was no significant difference between preeclampsia incidence in stable group and that in active group [36.2％ (17/47) vs 59.1％ (13/22),x2 =3.204,P＞0.05].In nineteen newly diagnosed LN women,eighteen cases were over 20 weeks of gestation,during which preeclampsia incidence was 6/18.(2) Adverse fetal or neonatal outcomes:Therapeutically termination of pregnancy rate was higher in active group than that in stable group[42.3％(10/26) vs 7.7％(4/52),Fisher's exact test,P＜0.01].After deleting patients who required termination of pregnancy (three cases in stable group) and therapeutically termination of pregnancy (four cases in stable group and ten cases in active group),the rate of fetal loss and neonatal death was higher in active group than that in stable group [5/16 vs 6.7％(3/45),Fisher's exact test,P＜0.05].The rate of adverse fetal or neonatal outcomes was higher in active group than that in stable group [92.3％(24/26) vs50％(26/52),x2=13.483,P＜0.001].Among the nineteen newly diagnosed LN cases during pregnancy,the numbers of therapeutically termination of pregnancy and fetal loss were five and three cases respectively; among eleven live birth cases,two newborns died from severe asphyxia,and nine cases were preterm birth.(3) Binary logistic regression analysis showed that the independent risk factors for exacerbated lupus during pregnancy were hypocomplementemia (OR =0.300,95％ CI:0.104-0.863) and thrombocytopenia (OR =0.054,95％CI∶0.007-0.439).The independent risk factors for preeclampsia in LN pregnant women were thrombocytopenia (OR=0.151,95％CI:0.046-0.499) and LN recurrence or first diagnosed during pregnancy (OR=0.135,95％CI:0.027-0.679).The independent risk factors for adverse fetal or neonatal outcomes were preeclampsia (OR=0.134,95％CI:0.028-0.637) and lupus active during pregnancy (OR =0.026,95 ％ CI:0.005-0.138).Conclusions Active lupus before pregnancy is associated with poor maternal and fetal outcomes in lupus nephritis pregnancy.All pregnancies with LN should be planned,preferably after more than six months of quiescent disease.Blood pressure,renal function,proteinuria and level of platelet and serum complements should be closely monitored. Key words: Pregnancy complications; Lupus crythematosus, systemic; Lupus nephritis; Pre-eclampsia; Pregnancy outcome

AB0688 Anti-C1Q antibody as a biomarker for systemic lupus erythematosus

BackgroundSLE is the prototype of the autoimmune systemic disease. It is characterized by the production of autoantibodies against the cell nucleus components in association with multiple clinical manifestations that affect...

SP0012 Complement in the Rheumatic Disease: Complementopathies

Complement is an integral component of immunity. Inherited deficiencies in the ability to activate complement increases susceptibility to bacterial infection and autoimmunity. Examples include: meningitis and terminal component deficiency; systemic...

SAT0431 Molecular Characterization of Complement C1Q, C2, and C4 Genes in Juvenile Systemic Lupus Erythematosus

BackgroundIt was not already defined whether standard measures are sufficient to asses primary C1q, C2 and C4 deficiencies1-3.ObjectivesTo perform C1q, C2 and C4 molecular characterization in Juvenile Systemic Lupus Erythematosus...

Complement and autoimmunity

The complement system is a component of the innate immune system. Its main function was initially believed to be limited to the recognition and elimination of pathogens through direct killing or stimulation of phagocytosis. However, in recent years, the immunoregulatory functions of the complement system were demonstrated and it was determined that the complement proteins play an important role in modulating adaptive immunity and in bridging innate and adaptive responses. When the delicate mechanisms that regulate this sophisticated enzymatic system are unbalanced, the complement system may cause damage, mediating tissue inflammation. Dysregulation of the complement system has been involved in the pathogenesis and clinical manifestations of several autoimmune diseases, such as systemic lupus erythematosus, vasculitides, Sjögren's syndrome, antiphospholipid syndrome, systemic sclerosis, dermatomyositis, and rheumatoid arthritis. Complement deficiencies have been associated with an increased risk to develop autoimmune disorders. Because of its functions, the complement system is an attractive therapeutic target for a wide range of diseases. Up to date, several compounds interfering with the complement cascade have been studied in experimental models for autoimmune diseases. The main therapeutic strategies are inhibition of complement activation components, inhibition of complement receptors, and inhibition of membrane attack complex. At present, none of the available agents was proven to be both safe and effective for treatment of autoimmune diseases in humans. Nonetheless, data from preclinical studies and initial clinical trials suggest that the modulation of the complement system could constitute a viable strategy for the treatment of autoimmune conditions in the decades to come.

C5 Complement Deficiency in a Saudi Family, Molecular Characterization of Mutation and Literature Review

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. 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. 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. 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. 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.

Cost-Effectiveness of Screening for Complement Deficiency After Initial Meningococcal Infection

Cost-Effectiveness of Screening for Complement Deficiency After Initial Meningococcal Infection

Complement and Mannose-Binding Lectin 2 Polymorphism in Meningococcal Disease

Meningococcal disease is a leading cause of death due to infection in children. Differences in susceptibility and disease progression between children are unknown. The complement system plays a key role in the innate immunity against N. meningitides and could explain that differences in the response of individuals. The aim of this study was to evaluate the occurrence of complement system deficiencies and MBL2 polymorphism in patients with previous meningococcal disease. We evaluated 40 children with confirmed previous diagnosis of any form of meningococcal disease and performed quantification analysis of the complement system; C3, C4, and CH50, as well the analysis of the polymorphism of the MBL2 gene. The major deficiency was found for C4 (27.5%) followed by C3 and CH50 (2.5%). Genotyping of MBL2 showed 21 cases of homozygous wild type allele named AA, (55.3%), 14 cases heterozygous, AO (36.8%), and 3 homozygous variant alleles, OO, (7.9%). Complement deficiency and polymorphism in the MBL2 gene are possible explanations for the development of meningococcal disease in some patients. Evaluation of complement could be suggested for individuals affected by this serious disease.

Primary Immunodeficiency Diseases at Reference and High-Specialty Hospitals in the State of Guanajuato, Mexico

Background. In general, primary immunodeficiency diseases (PIDs) are underdiagnosed in most countries. The objective of this study was to describe the frequency and clinical spectrum of PID in the most important tertiary hospitals in our region. Methods. An observational, cross-sectional, with retrospective chart, review study was conducted. A total of 26 patients were included and grouped according to the updated classification of PIDs. Results. PIDs spectra were as follows: predominantly antibody deficiency diseases were the most common category (65.38%), followed by other well-defined immunodeficiency syndromes (11.55%), congenital defects of phagocyte number and/or function (7.69%), complement deficiencies (3.85%), combined T- and B-cell immunodeficiencies (3.85%), and defects in innate immunity (3.85%). The mean time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 4.65 ± 6.95 years. Conclusions. Predominant antibody deficiency disease was the most common group of PIDs, agreeing with international reports. Awareness of underdiagnosis by physicians is crucial for a prompt diagnosis and treatment, which in turn should improve the quality of life among patients with PIDs.

A Case of Meningococcal Sepsis and Meningitis with Complement 7 Deficiency in a Military Trainee

Complement component 7 (C7) deficiency leads to the loss of complement lytic function, and affected patients show increased susceptibility to encapsulated organisms infection, especially Neisseria meningitidis. Recently, we have experienced a 20-year-old military trainee with meningococcal sepsis and meningitis who was diagnosed as having C7 deficiency based upon the undetectable serum C7 protein on radioimmunoassay. This case emphasizes that although C7 deficiency is rare immune disorder, it is important to be aware of possibility about late complement deficiency among patients who present with meningococcal disease.

ADAMTS13 Variants in Atypical Hemolytic Uremic Syndrome

Abstract 490Atypical hemolytic uremic syndrome (aHUS) is a clinically defined thrombotic microangiopathic anemia (TMA) characterized by the symptom triad of renal failure, thrombocytopenia and microangiopathic hemolytic anemia in the absence of Shiga-toxin-producing bacteria as a triggering factor. Its pathogenesis is linked to dysregulation of the alternative pathway of the complement cascade, with loss-of-function mutations reported in complement regulators like factor H (CFH), membrane cofactor protein (MCP), factor I (CHI) and thrombomodulin (THBD), and gain-of-function mutations in complement activators like factor B (CFB) and complement component 3 (C3). In nearly 40% of patients, however, mutations are not identified in these genes raising the possibility of unrecognized contributory genetic causes.Genetic variants in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs) have been causally related to thrombotic thrombocytopenic purpura (TTP), another TMA characterized by the pentad of neurologic symptoms, fever, kidney failure, thrombocytopenia and microangiopathichemolytic anemia. The phenotypic similarities between aHUS and TTP can at times lead to difficulty in their clinical distinction. On this basis, we hypothesized that partial deficiency in ADAMTS13 function may coexist with abnormalities in the alternative complement pathway in patients with aHUS.To test this hypothesis, we measured ADAMTS13 functional activity in 26 patients with aHUS by fluorescence resonance energy transfer substrate-von Willebrandfactor 73mer (FRETS-VWF73) and recombinant VWF A2 domain cleavage assay. We also genotyped all patients for ADAMTS13 and alternative complement pathway genes. We transiently expressed 10 different ADAMTS13 missense variants in HEK293 cells to analyze activity and secretion of each recombinant protein.The ADAMTS13 functional activity was partially reduced (< 60%) in serum from 20 patients (77%) as measured by FRETS-VWF73 and recombinant VWF A2 cleavage assays. Genetic variants in ADAMTS13 were identified in 21 patients (81%) and included R386C, Q448E, A900V, V832M, R1060W, R7W/Q448E, A900V/Q448E, R1096H/A747V, R7W/A1033T, R7W/P618A/Q448E, R7W/P618A/A900V/Q448E, R7W/P618A/A732V/Q448E. The coexistence of both ADAMTS13 deficiency and excessive complement functional activity was present in 13 patients (50%). Activity of recombinant ADAMTS13 proteins containing the following variants was normal: R386C, Q448E, P618A, A732V, A747V, V832M, A900V, A1033T and R1060H. The R1096H variant of ADAMTS13 was associated with a reduction in functional activity by 50%. The secretion of recombinant proteins with the following variants was severely reduced: P618A, R1060H (<1%), R386C, R1096H (<10%), and A1033T (<50%) (Figures 1 and 2).This study implicates ADAMTS13 in the pathogenesis of aHUS and mandates the evaluation of ADAMTS13 in aHUS patients. Defining the role of ADAMTS13 in aHUS may aid in the development of new treatments and/or assist in clarifying whether long-term treatment with currently available anti-complement therapy is required for this disease. [Display omitted] Disclosures:Kroll:Aplagon: Membership on an entity's Board of Directors or advisory committees; Optimer: Consultancy; Leo: Honoraria, Travel Expenses, Travel Expenses Other.

Inwazyjne zakażenie Haemophilus influenzae typu b u dziecka z pełnym cyklem szczepień

Haemophilus influenzae type b (Hib) is one of the leading causes of invasive bacterial infection of young children worldwide. Especially vulnerable are children in the first years of life because of immature, T-independent immune response for polysaccharide of the capsule. Introduction of Hib protein-polysaccharide conjugate vaccines into national immunization programs has resulted in the virtual elimination of invasive Hib disease in vaccinated children and their community. Here is descripted a case of 4 years boy, who developed Hib septicemia and encephalomeningitis probably the same etiology despite of vaccination (at the age of 6, 7, 18 months). The boy was evaluated for immunoglobulin and complement deficiency at Clinic Vaccination of Risk Groups in Children's Memorial Health Institute, and no immunodeficiency was found.

Genetic and Pharmacologic Inhibition of Complement Impairs Endothelial Cell Function and Ablates Ovarian Cancer Neovascularization

Complement activation plays a critical role in controlling inflammatory responses. To assess the role of complement during ovarian cancer progression, we crossed two strains of mice with genetic complement deficiencies with transgenic mice that develop epithelial ovarian cancer (TgMISIIR-TAg). TgMISIIR-TAg mice fully or partially deficient for complement factor 3 (C3) (Tg+C3KO and Tg+C3HET, respectively) or fully deficient for complement factor C5a receptor (C5aR) (Tg+C5aRKO) develop either no ovarian tumors or tumors that were small and poorly vascularized compared to wild-type littermates (Tg+C3WT, Tg+C5aRWT). The percentage of tumor infiltrating immune cells in Tg+C3HET tumors compared to Tg+C3WT controls was either similar (macrophages, B cells, myeloid-derived suppressor cells), elevated (effector T cells), or decreased (regulatory T cells). Regardless of these ratios, cytokine production by immune cells taken from Tg+C3HET tumors was reduced on stimulation compared to Tg+C3WT controls. Interestingly, CD31+ endothelial cell (EC) function in angiogenesis was significantly impaired in both C3KO and C5aRKO mice. Further, using the C5aR antagonist PMX53, tube formation of ECs was shown to be C5a-dependent, possibly through interactions with the VEGF165 but not VEGF121 isoform. Finally, the mouse VEGF164 transcript was underexpressed in C3KO livers compare to C3WT livers. Thus, we conclude that complement inhibition blocks tumor outgrowth by altering EC function and VEGF165 expression.