Hypocomplementemia Research Articles

Protective role of host complement system in Aspergillus fumigatus infection.

Invasive aspergillosis (IA) is a life-threatening fungal infection for immunocompromised hosts. It is, therefore, necessary to understand the immune pathways that control this infection. Although the primary infection site is the lungs, aspergillosis can disseminate to other organs through unknown mechanisms. Herein we have examined the in vivo role of various complement pathways as well as the complement receptors C3aR and C5aR1 during experimental systemic infection by Aspergillus fumigatus, the main species responsible for IA. We show that C3 knockout (C3-/-) mice are highly susceptible to systemic infection of A. fumigatus. Intriguingly, C4-/- and factor B (FB)-/- mice showed susceptibility similar to the wild-type mice, suggesting that either the complement pathways display functional redundancy during infection (i.e., one pathway compensates for the loss of the other), or complement is activated non-canonically by A. fumigatus protease. Our in vitro study substantiates the presence of C3 and C5 cleaving proteases in A. fumigatus. Examination of the importance of the terminal complement pathway employing C5-/- and C5aR1-/- mice reveals that it plays a vital role in the conidial clearance. This, in part, is due to the increased conidial uptake by phagocytes. Together, our data suggest that the complement deficiency enhances the susceptibility to systemic infection by A. fumigatus.

Analysis of the relationship between human complement components C3 & C4 deficiency and C– reactive protein levels as an indicator of the increase of microbial infections

The complement system is an important component of the immune system that consists of a group of plasma proteins produced by the liver and serving a defense function. As a result, the deficiency in any of the complement system components leads to the loss of the function of the deficient protein causing a specific clinical problem or disease. For that reason, this study was designed to investigate C3 and C4 deficiencies in young patients and to inspect the possibility of using C-Reactive Protein (CRP) test and the variation of C3 and C4 concentrations in children`s blood as an indicator of the onset of infection. This study was conducted in the children hospital in Benghazi city, Libya. The blood samples were collected from 446 children in all hospital units to examine the proportion of complement deficiency among those children and C3, C4 deficiency was set as an indicator of infection occurrence. The results of this study have shown a deficiency in complement proteins C3 and C4 were in 44 (10%) samples and 2 (0.4%) samples respectively, the female candidates had a higher rate of C3 and C4 deficiency than males. In addition, the CRP levels were elevated in 167 (55.9%) cases. Furthermore, the association between the increase of CRP levels and low levels of C3 and C4 was observed in 26 (8.7%) cases and 2 (0.6%) cases. These results suggest a strong association between complement proteins C3 and C4 deficiency and an elevation of CRP levels (P-Value=0.00), which supports the concept of using such association as an indicator of microbial infection

Anaphylatoxins spark the flame in early autoimmunity.

The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to specific receptors on innate and adaptive immune cells, the activation of which translates the initial humoral innate immune response (IR) into cellular innate and adaptive immunity. Dysregulation of the CS has been associated with the development of several autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ANCA-associated vasculitis, and autoimmune bullous dermatoses (AIBDs), where complement drives the inflammatory response in the effector phase. The role of the CS in autoimmunity is complex. On the one hand, complement deficiencies were identified as risk factors to develop autoimmune disorders. On the other hand, activation of complement can drive autoimmune responses. The anaphylatoxins C3a and C5a are potent mediators and regulators of inflammation during the effector phase of autoimmunity through engagement of specific anaphylatoxin receptors, i.e., C3aR, C5aR1, and C5aR2 either on or in immune cells. In addition to their role in innate IRs, anaphylatoxins regulate humoral and cellular adaptive IRs including B-cell and T-cell activation, differentiation, and survival. They regulate B- and T-lymphocyte responses either directly or indirectly through the activation of anaphylatoxin receptors via dendritic cells that modulate lymphocyte function. Here, we will briefly review our current understanding of the complex roles of anaphylatoxins in the regulation of immunologic tolerance and the early events driving autoimmunity and the implications of such regulation for therapeutic approaches that target the CS.

CME exam: Complement Genetics for the Practicing Allergist Immunologist: Focus on Complement Deficiencies

CME exam: Complement Genetics for the Practicing Allergist Immunologist: Focus on Complement Deficiencies

Demographic and clinical characterization of pediatric group patients with inborn errors of the immune system in a Colombian tertiary hospital.

In recent decades, there has been a growing increase in the diagnosis of patients with inborn errors of the immune system, formerly known as primary immunodeficiency disorders (PIDs). Timely diagnosis remains a challenge due to low clinical suspicion and poor education on the subject. It is estimated that between 70% and 90% of these pathologies remain underdiagnosed in our environment. The objective of this study is to characterize the demographic and clinical presentation of pediatric group patients with inborn errors of the immune system in a Colombian tertiary hospital. Retrospective descriptive study of 306 patients with a diagnosis of innate errors of the immune system who consulted the PID clinic between 2011 and 2018 in a high-complexity institution in Cali, Colombia. Three-hundred and six patients were included. The median age was 4 years (IQR 2.3-7.7 years), and 59.5% of the patients were male. According to the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency classification for inborn errors of the immune system, the most common group was antibody deficiency in 74.8% (n˂229), especially in the age group between 1 and 5 years. The least frequent in our population was complement deficiency. Of the warning signs stipulated for these pathologies, the most frequent were the (1) need for intravenous antibiotics (32%), (2) difficulty growing (15.7%), (3) four or more episodes of ear infection (10.8%), and (4) abscesses in organs or cutaneous abscesses (12.7%). No patient reported two or more episodes of pneumonia or sinusitis, and only 5.8% of the patients received a bone marrow transplant. Innate errors of the immune system require an early diagnosis with follow-up from an early age to ensure adequate management and follow-up in order to reduce morbidity and mortality. It is imperative to sensitize the medical population about the existence of these pathologies so that early intervention can be carried out, which improves the quality of life of patients and their families.

Vaccination prophylaxis for recurrent invasive meningococcal diseases

Meningokokkenerkrankungen sind selten, führen jedoch zu einer hohen Morbidität und Mortalität. Das Risiko, sich erneut mit einem anderen oder dem gleichen Serotyp zu infizieren, ist nach durchgemachter Infektion und bei bestimmten Vorerkrankungen wie Komplementdefekten deutlich erhöht.Die Kommission hält folgendes Vorgehen für sinnvoll:Kinder und Jugendliche ohne vollständigen Meningokokkenimpfstatus sollten unmittelbar nach Ausheilung einer invasiven Meningokokkenerkrankung eine Impfung mit 4CMenB (Bexero®, Trumenba®) und/oder eine Impfung gegen die Serogruppen A, C, W und Y (Menveo®, Nimenrix®, MenQuadfi®) nach Vorgabe der Fachinformationen erhalten. Ein vorheriges isoliertes Screening auf Komplementdefekte ist für die Impfentscheidung bei diesen Patienten nicht erforderlich.

Moyamoya Disease Associated with a Deficiency of Complement Component 6

ObjectivesComplement component 6 (C6) deficiency is a very rare genetic defect that leads to significantly diminished synthesis, secretion, or function of C6. In the current report, we demonstrate a previously undescribed, homozygous missense mutation in exon 17 of the C6 gene (c.2545A>G p.Arg849Gly) in a 35-year-old Japanese woman with moyamoya disease and extremely low levels of CH50 (<7.0 U/mL). Materials and MethodsThe complement gene analysis using hybridization capture-based next generation sequencing was performed. CH50 was determined in patient's plasma mixed with plasma from a healthy donor or purified human C6 protein. Western blot was performed on patient's plasma using polyclonal antibodies against C6, with healthy donor's plasma and purified human C6 protein as positive controls while C6-depleted human serum as a negative control. The carriage of ring finger protein 213 variant (c.14576G>A p.Arg4859Lys), a susceptibility gene for moyamoya disease, was examined by direct sequencing. ResultsCH50 mixing test clearly showed a deficiency pattern, being rescued by addition of only 1% healthy donor's plasma or 1 μg/mL purified human C6 protein (1/50-1/100 of physiological concentration). Western blot revealed the absence of C6 protein in the patient's plasma, confirming a quantitative deficiency of C6. The ring finger protein 213 variant was not detected. ConclusionsOur data implies that unrecognized complement deficiencies would be harbored in cerebrovascular diseases with unknown etiologies.

Screening for Immunodeficiencies in Children With Invasive Pneumococcal Disease: Six-year Experience From a UK Children's Hospital.

A previous study showed that investigation of children with invasive pneumococcal disease (IPD) revealed an immunodeficiency in up to 10% of cases. Following this report, we implemented a protocol to investigate children with IPD, to assess the proportion with an immunodeficiency in our setting. We retrospectively identified patients who presented with IPD from January 2015 to November 2020 and collected data from medical records. Immunological investigations included complement C3 and C4 levels, classical and alternative pathway complement function, IgG, IgA and IgM levels, specific IgG levels (H. influenza B, tetanus and pneumococcal serotypes), peripheral blood film, lymphocyte subsets, and CD62L-shedding upon activation with Toll-like receptor-agonists in selected cases. We identified a total of 68 children with IPD, with a mortality of 6%. Immunological investigations were performed in 51 children. Four children (8%) had abnormal findings that were deemed of clinical significance. Two children had complement deficiencies (Factor I and C2 deficiency), one child had specific antibody deficiency, and another child had low IgM, low NK-cells and poor persistence of serotype-specific anti-pneumococcal IgG concentrations. Of the 17 children with IPD who were not tested for immunodeficiencies, 4 died and four had possible explanations for the infection. We identified clinically relevant abnormal immunological findings in 4/51 (8%) of children with IPD. Our results support the recommendation to perform immunological investigations in children with IPD, since this might reveal underlying immunodeficiencies, allowing for necessary preventive measures and close follow-up.

The Genetic Landscape of Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune connective tissue disease that can exist as a disease entity or within the context of systemic lupus erythematosus (SLE). Over the years, efforts to elucidate the genetic underpinnings of CLE and SLE have yielded a wealth of information. This review examines prior studies investigating the genetics of CLE at the DNA and RNA level and identifies future research areas. In this literature review, we examined the English language literature captured within the MEDLINE and Embase databases using pre-defined search terms. First, we surveyed studies investigating various DNA studies of CLE. We identified three predominant areas of focus in HLA profiling, complement deficiencies, and genetic polymorphisms. An increased frequency of HLA-B8 has been strongly linked to CLE. In addition, multiple genes responsible for mediating innate immune response, cell growth, apoptosis, and interferon response confer a higher risk of developing CLE, specifically TREX1 and SAMHD1. There was a strong association between C2 complement deficiency and CLE. Second, we reviewed literature studying aberrations in the transcriptomes of patients with CLE. We reviewed genetic aberrations initiated by environmental insults, and we examined the interplay of dysregulated inflammatory, apoptotic, and fibrotic pathways in the context of the pathomechanism of CLE. These current learnings will serve as the foundation for further advances in integrating personalized medicine into the care of patients with CLE.

The yin and the yang of early classical pathway complement disorders.

The classical pathway of the complement cascade has been recognized as a key activation arm, partnering with the lectin activation arm and the alternative pathway to cleave C3 and initiate the assembly of the terminal components. While deficiencies of classical pathway components have been recognized since 1966, only recently have gain-of-function variants been described for some of these proteins. Loss-of-function variants in C1, C4, and C2 are most often associated with lupus and systemic infections with encapsulated bacteria. C3 deficiency varies slightly from this phenotypic class with membranoproliferative glomerulonephritis and infection as the dominant phenotypes. The gain-of-function variants recently described for C1r and C1s lead to periodontal Ehlers Danlos syndrome, a surprisingly structural phenotype. Gain-of-function in C3 and C2 are associated with endothelial manifestations including hemolytic uremic syndrome and vasculitis with C2 gain-of-function variants thus far having been reported in patients with a C3 glomerulopathy. This review will discuss the loss-of-function and gain-of-function phenotypes and place them within the larger context of complement deficiencies.

Complement C3 deficiency enhances anti-CD47 efficacy in murine ovarian cancer model.

Abstract Epithelial ovarian cancer (OC) is the most lethal gynecological malignancy. While OC is an immunogenic tumor, single-agent anti-PD-1 have limited efficacy in recurrent OC. Blockade of the CD47/SIRPα pathway, a phagocytosis checkpoint in macrophages and other myeloid cells, can enhance myeloid-driven antitumor immunity and tumor control. However, the benefit of targeting CD47/SIRPα in recurrent OC has been limited. Prior work from our lab and others point to complement priming of innate immune responses as a barrier to T-cell-driven anti-tumor immunity. However, in the specific context of anti-CD47 therapy, complement opsonization of tumor cells could augment the capacity of myeloid cells to phagocytose or injure tumor cells. The role of complement deficiency with anti-CD47 therapy in tumor control is a gap in the field, we therefore evaluated the efficacy of anti-CD47 in female wild-type (WT) versus C3−/− and C5aR1−/− with syngeneic OC (ID8). Mice (n=8–10 per group) were administered IP ID8 tumor cells followed by anti-CD47 or isotype twice weekly for 3 weeks and were monitored for the ascites development and survival. On day 84, all WT mice treated with isotype had ascites by visual inspection and 3 of 10 died. The proportion of mice with ascites varied in other groups, C3−/− mice treated with anti-CD47 having the lowest proportion, 4 of 9 mice with ascites and no deaths (Fisher’s test, WT-isotype vs C3−/− + anti-CD47, p= 0.01). A limitation is the potential endogenous complement production by tumor cells, which will be evaluated. These results suggest a potential benefit for dual targeting of the CD47/SIRPα and complement pathways in OC. Additional studies will probe immunologic correlates and survival benefits of these therapies in OC. This work was supported by Roswell Park Cancer Center Support Grant P30CA016056 and Apellis Pharmaceuticals, Inc

Secondary Complement Deficiency Impairs Anti-Microbial Immunity to Klebsiella pneumoniae and Staphylococcus aureus During Severe Acute COVID-19.

A high incidence of secondary Klebsiella pneumoniae and Staphylococcus aureus infection were observed in patients with severe COVID-19. The cause of this predisposition to infection is unclear. Our data demonstrate consumption of complement in acute COVID-19 patients reflected by low levels of C3, C4, and loss of haemolytic activity. Given that the elimination of Gram-negative bacteria depends in part on complement-mediated lysis, we hypothesised that secondary hypocomplementaemia is rendering the antibody-dependent classical pathway activation inactive and compromises serum bactericidal activity (SBA). 217 patients with severe COVID-19 were studied. 142 patients suffered secondary bacterial infections. Klebsiella species were the most common Gram-negative organism, found in 58 patients, while S. aureus was the dominant Gram-positive organism found in 22 patients. Hypocomplementaemia was observed in patients with acute severe COVID-19 but not in convalescent survivors three months after discharge. Sera from patients with acute COVID-19 were unable to opsonise either K. pneumoniae or S. aureus and had impaired complement-mediated killing of Klebsiella. We conclude that hyperactivation of complement during acute COVID-19 leads to secondary hypocomplementaemia and predisposes to opportunistic infections.

Hypocomplementemia in primary Sjogren’s syndrome: association with serological, clinical features, and outcome

ObjectiveThe aim of the present study was to assess the clinical characteristic of hypocomplementemia (HC) in primary Sjogren’s syndrome (pSS), and to address possible risk factors and the prognosis associated with HC in pSS patients.MethodspSS patients with HC in Hebei General Hospital from September 2016 to March 2019 were retrospectively analyzed and compared to those with normocomplementemia (NC). Logistic regression analysis was used to detect risk factors.ResultsOf the 333 patients with pSS, 84 patients (25.23%) were presented with HC at diagnosis. The presence of hyper-IgG and anti-Ro52 antibodies was significantly more common in patients with HC. In addition to systemic involvement, pSS patients with HC had more hematological, renal, and nervous system involvement, and received more immunosuppressant treatments than NC group (p < 0.05). ESSDAI score was significantly higher in patients with HC (p < 0.05). Multivariate logistic analysis indicated that leukopenia (OR = 2.23) and hyper-IgG (OR = 2.13) were independent risk factors for pSS with HC. In addition, profound CD16/CD56+ NK-cell lymphopenia was found in pSS-HC patients. More pSS patients developed SLE in the HC group than NC group (4.76% vs. 0.80%, p = 0.04) during the follow-up.ConclusionHC was not an uncommon manifestation of pSS and had an independent association with the main clinical and immunological features. Patients with pSS-HC had an increased possibility to develop SLE that required more positive treatment with glucocorticoids and immunosuppressants.Key Points:• Hypocomplementemia had an independent association with the main clinical and immunological features in primary Sjogren’s syndrome patients.• ESSDAI score was significantly higher in patients with hypocomplementemia.• The pSS patients with hypocomplementemia had an increased possibility to develop SLE.

Myasthenia gravis complement activity is independent of autoantibody titer and disease severity.

Acetylcholine receptor (AChR) autoantibodies, found in patients with autoimmune myasthenia gravis (MG), can directly contribute to disease pathology through activation of the classical complement pathway. Activation of the complement pathway in autoimmune diseases can lead to a secondary complement deficiency resulting in reduced complement activity, due to consumption, during episodes of disease activity. It is not clear whether complement activity in MG patients associates with measurements of disease activity or the titer of circulating pathogenic AChR autoantibodies. To explore such associations, as a means to identify a candidate biomarker, we measured complement activity in AChR MG samples (N = 51) using a CH50 hemolysis assay, then tested associations between these values and both clinical status and AChR autoantibody titer. The majority of the study subjects (88.2%) had complement activity within the range defined by healthy controls, while six patients (11.8%) showed reduced activity. No significant association between complement activity and disease status or AChR autoantibody titer was observed.

Complement Genetics for the Practicing Allergist Immunologist: Focus on Complement Deficiencies

Complement deficiencies have been considered to be rare for many decades, but this assumption is changing year by year. Recognition of these conditions significantly increases thanks to the availability of different testing approaches and due to clinical awareness. Furthermore, sequencing technologies (including Sanger sequencing, targeted gene panels, and whole exome/genome sequencing) may facilitate the identification of the underlying disease-causing genetic background. On the other hand, functional characterization of the identified possibly pathogenic variations and performing family studies, as illustrated by some of our cases, remain similarly important to establish a precise clinical diagnosis facilitating the most appropriate management. Here, we present 4 illustrative cases with complement deficiencies of diverse etiologies and also provide an educative, step-by-step description on how to identify the underlying cause of complement deficiency based on the results of complement laboratory testing.

Meningococcal Vaccination:: An Update on Meningococcal Vaccine Recommendations for the Primary Care Physician.

Neisseria meningitidis is an aerobic, gram-negative, diplococcus bacterium that is a leading cause of meningitis and sepsis in the United States. Particularly at-risk groups include those with complement deficiencies, people using complement inhibitors, individuals with anatomic or functional asplenia, patients with HIV infection and travelers to endemic countries. There are currently three quadrivalent meningococcal vaccines (Serogroups A, C, W, Y) and two recombinant serogroup B vaccines available for use in the United States, and recommendations for vaccine use have changed rapidly in the past 10-15 years. This article summarizes updated ACIP recommendations for meningococcal vaccination for the primary care provider.

Genetic workup as a complementary tool for the diagnosis of primary complement component deficiencies: a multicenter experience.

Awareness of risk factors for primary complement deficiencies, even at the first infectious episode, should facilitate prompt immune and genetic workup, commencing diagnosis and proper treatment for the patient and family. •Deficiencies in the classical terminal complement components increase susceptibility to invasive meningococcal infections. • Recurrent meningococcal infections mandate a diagnostic workup of the complement system. •Genetic workup can be utilized for prompt diagnosis of complement deficiencies. •High rates of consanguinity, even in the presence of a single meningococcal infection, should promote immune and genetic workups.

The Spectrum of Inborn Errors of Immunity in the United Arab Emirates: 5 Year Experience in a Tertiary Center.

PurposeInborn Errors of Immunity (IEI) are heterogeneous disorders of immunity with variable clinical presentation and outcome. This is the first comprehensive report from the United Arab Emirates aiming to describe the demographics, clinical characteristics, categories, treatment modalities and outcome of patients with IEI.MethodsThis retrospective study was conducted on patients who attended Tawam Hospital between 2016-2020.ResultsWe identified 162 patients with IEI, of whom 152 were children. The age of onset of symptoms ranged between birth to 38 years. About two-thirds of patients were Emirati nationals, 64.2% had consanguineous parents and 38.3% of cases were familial. Patients were classified as; immunodeficiencies affecting cellular and humoral immunity (20.4%), combined immunodeficiencies with associated or syndromic features (38.3%), predominantly antibody deficiencies (16%), immune dysregulation (4.3%), congenital defects of phagocytes number or function (8.6%), defects in intrinsic and innate immunity (1.9%) autoinflammatory disorders (1.9%), complement deficiency (6.2%), bone marrow failure (1.9%) and phenocopies of inborn errors of immunity (0.6%). Genetic testing was performed in 85.2% of patients with a diagnostic yield of 92.7%. Complications included bronchiectasis, neoplasia, and vaccine-related infections. Immunoglobulin therapy and antimicrobial prophylaxis were both used in (51.9%) of patients while (20.4%) underwent hematopoietic stem cell transplantation (HSCT). The overall mortality rate was 10.5%.ConclusionThis report highlights the burden of IEI in the UAE. Ongoing education of physicians, establishment of a national registry and considering changes to early BCG vaccination are measures recommended to improve outcomes.

Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort

BackgroundTerminal complement pathway deficiencies often present with severe and recurrent infections. There is a lack of good-quality data on these rare conditions. This study investigated the clinical outcome and genetic variation in a large UK multi-center cohort with primary and secondary terminal complement deficiencies.MethodsClinicians from seven UK centers provided anonymised demographic, clinical, and laboratory data on patients with terminal complement deficiencies, which were collated and analysed.ResultsForty patients, median age 19 (range 3–62) years, were identified with terminal complement deficiencies. Ten (62%) of 16 patients with low serum C5 concentrations had underlying pathogenic CFH or CFI gene variants. Two-thirds were from consanguineous Asian families, and 80% had an affected family member. The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections. Nine (22%) were treated in intensive care for meningococcal septicaemia. Two patients had died, one from intercurrent COVID-19. Twenty-one (52%) were asymptomatic and diagnosed based on family history. All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics.DiscussionThe genetic etiology and clinical course of patients with primary and secondary terminal complement deficiency are variable. Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important. Only half of the patients develop septicaemia, but all should have a clear management plan.

Risk Factors for Invasive Meningococcal Disease Belonging to a Novel Urethritis Clade of Neisseria meningitidis—United States, 2013–2017

Abstract We describe cases of invasive meningococcal disease caused by nongroupable Neisseria meningitidis belonging to a novel phylogenetic clade associated with urethritis. Seven cases were identified, comprising 0.6% of sequenced invasive meningococcal disease isolates from 2013 to 2017. Five patients had a known or likely immunocompromising condition, including 2 with a complement deficiency.