Alternative Complement System Research Articles

Protein-losing enteropathy as a new phenotype in atypical hemolytic uremic syndrome caused by CD46 gene mutation.

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy. Genetic defects in the alternative complement (AP) pathway have been identified in 60-70% of individuals. Eculizumab is recommended as a first-line therapy. We collected the clinical data of a pediatric patient with aHUS accompanied by protein-losing enteropathy (PLE). Genetic testing was performed. Related literature on aHUS combined with PLE was reviewed. A 15-year-old Chinese girl was diagnosed with aHUS at 3.7years of age and experienced five episodes; her symptoms completely resolved with plasma treatment. Severe gastrointestinal symptoms and hypoalbuminemia presented after the first episode, and PLE was diagnosed. A novel homozygous CD46 variant was identified, and FACS revealed significantly decreased CD46 expression. She presented at a recent relapse with persistent GI symptoms and headache and progressed to chronic kidney failure; peritoneal dialysis was initiated. Eculizumab was given 8months after the last recurrence. Surprisingly, PLE was cured. Afterward, dialysis was discontinued, and eGFR recovered to 44.8ml/min/1.73 m2. A review of the literature indicated that PLE with thrombosis was caused by CD55 variants via hyperactivation of the AP system. We report an aHUS patient with PLE caused by CD46 variants. Symptoms of both PLE and aHUS were significantly alleviated in our patient and patients with CD55 variants treated with eculizumab, indicating that PLE was a new symptom of aHUS in our patient with a CD46 variant. Our case expands the phenotype of aHUS caused by a CD46 mutation and provides evidence of the efficacy of eculizumab after a long phase of chronic kidney failure.

HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases.

Complement cascade is a defence mechanism useful for eliminating pathogenic microorganisms and damaged cells. However, activation of alternative complement system can also cause inflammation and promote kidney and retinal disease progression. Inflammation causes tissue hypoxia, which induces hypoxia-inducible factor (HIF) and HIF helps the body to adapt to inflammation. In this study, we investigated the effect of HIF stabilizer desidustat in complement-mediated diseases. Oral administration of desidustat (15 mg/kg) was effective to reduce the kidney injury in mice that was induced by either lipopolysaccharide (LPS), doxorubicin or bovine serum albumin (BSA)-overload. Complement activation-induced membrane attack complex (MAC) formation and factor B activity were also reduced by desidustat treatment. In addition, desidustat was effective against membranous nephropathy caused by cationic BSA and retinal degeneration induced by sodium iodate in mice. C3-deposition, proteinuria, malondialdehyde, and interleukin-1ß were decreased and superoxide dismutase was increased by desidustat treatment in cBSA-induced membranous nephropathy. Desidustat specifically inhibited alternative complement system, without affecting the lectin-, or classical complement pathway. This effect appears to be mediated by inhibition of factor B. These data demonstrate the potential therapeutic value of HIF stabilization by desidustat in treatment of complement-mediated diseases.

Management of pediatric hemolytic uremic syndrome.

Classical clinical triad of hemolytic uremic syndrome (HUS) is microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury associated with endothelial cell injury. Several situations, including infections, medications, malignancies, and transplantation can trigger endothelial damage. On the HUS spectrum, atypical hemolytic uremic syndrome (aHUS) deserves special attention in pediatric patients, as it can cause endstage kidney disease and mortality. A dysfunction in the alternative complement pathway, either acquired or genetic, has been shown to be the main underlying cause. In the last decades, breathtaking advances have been made in understanding the pathophysiology of this rare disease, which has led to more efficient treatment. Recent studies have implicated genes in pathways beyond the alternative complement system, such as DGKE, TSEN2, and INF2 highlighting the importance of personalized management. Eculizumab has brought about dramatic improvements in the treatment of aHUS. Beyond eculizumab, there are many alternative therapeutics in the pipeline that target the complement system. Because of the rarity of aHUS, data from multiple patient registries are very important. The present report aimed to summarize the most important aspects of diagnosing and treating aHUS based on the Turkish national registry and the literature so as to improve clinical practice.

Atypical Hemolytic-Uremic Syndrome: Genetic Basis, Clinical Manifestations, and a Multidisciplinary Approach to Management.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) defined by the triad of hemolytic anemia, thrombocytopenia, and acute kidney injury. Microthrombi develop in the glomerular capillaries secondary to endothelial damage and exert shear stress on red blood cells, consume platelets, and contribute to renal dysfunction and failure. Per current understanding of pathophysiology, HUS is classified into infectious, secondary, and atypical disease. The most common etiology is infectious sequelae of Shiga toxin-producing Escherichia coli (STEC); other causative organisms include shigella and salmonella. Secondary HUS arises from cancer, chemotherapy, solid organ and hematopoietic stem cell transplant, pregnancy, or autoimmune disorders. Primary atypical hemolytic-uremic syndrome (aHUS) is associated with genetic mutations in complement and complement regulatory proteins. Under physiologic conditions, complement regulators keep the alternative complement system continuously active at low levels. In times of inflammation, mutations in complement-related proteins lead to uncontrolled complement activity. The hyperactive inflammatory state leads to glomerular endothelial damage, activation of the coagulation cascade, and TMA findings. Atypical hemolytic-uremic syndrome is a rare disorder with a prevalence of 2.21 to 9.4 per million people aged 20 years or younger; children between the ages of 0 and 4 are most affected. Multidisciplinary health care is necessary for timely management of its extra-renal manifestations. These include vascular disease of the heart, brain, and skin, pulmonary hypertension and hemorrhage, and pregnancy complications. Adequate screening is required to monitor for sequelae. First-line treatment is the monoclonal antibody eculizumab, but several organ systems may require specialized interventions and coordination of care with sub-specialists.

The Prevalence and Incidence of Hemolytic Uremic Syndrome: A Systematic Review.

A hemolytic uremic syndrome is an uncommon but severe condition brought on by an overactive alternative complement system, typically involving a hereditary component. It will be crucial to comprehend the epidemiology of hemolytic uremic syndrome as research advances toward bettering its diagnosis and treatment. A systematic review was conducted to evaluate the incidence and prevalence estimates of hemolytic uremic syndrome (HUS) internationally. A thorough literature search was conducted using PubMed, Springer, Cochrane Library for Systematic Reviews, and Embase databases between 2012 and 2023 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations. A further source of data was the PubMed Central search engine. To make sure that the evaluation included just the studies that were the most pertinent, a population, interventions, comparators, and outcomes (PICO) eligibility criterion was also used. Eight articles were included in this review. HUS had an annual crude incidence of 0.66 per 100,000 people and a standard annual incidence of 0.57 per 100,000 people. Females were more likely than males to develop HUS, but only marginally more frequently. Patients under 20 years old were the age group where HUS was most common. HUS had an average cost of $21,500 per patient, which was more expensive than the country's overall inpatient average cost for the same period. This is due to patients requiring supportive care, antibiotics, plasma exchange, plasma infusion, and renal replacement therapy, and it could take multiple courses of treatment before they improve. It was concluded that several variables, including the region, the age group affected, and the frequency of the underlying bacterial infection, determine the prevalence and incidence of HUS. HUS is often more common in children than adults and is more common in some nations. Overall, HUS is an uncommon disorder that can have significant repercussions for people who have it. For better results and fewer consequences, HUS must be diagnosed and treated as soon as possible.

Inhibition of C5AR1 impairs osteoclast mobilization and prevents bone loss

Age-related and chemotherapy-induced bone loss depends on cellular senescence and the cell secretory phenotype. However, the factors secreted in the senescent microenvironment that contribute to bone loss remain elusive. Here, we report a central role for the inflammatory alternative complement system in skeletal bone loss. Through transcriptomic analysis of bone samples, we identified complement factor D, a rate-limiting factor of the alternative pathway of complement, which is among the most responsive factors to chemotherapy or estrogen deficiency. We show that osteoblasts and osteocytes are major inducers of complement activation, while monocytes and osteoclasts are their primary targets. Genetic deletion of C5ar1, the receptor of the anaphylatoxin C5a, or treatment with a C5AR1 inhibitor reduced monocyte chemotaxis and osteoclast differentiation. Moreover, genetic deficiency or inhibition of C5AR1 partially prevented bone loss and osteoclastogenesis upon chemotherapy or ovariectomy. Altogether, these lines of evidence support the idea that inhibition of alternative complement pathways may have some therapeutic benefit in osteopenic disorders.

Tenebrio meal as a functional ingredient modulates immune response and improves growth performance of broiler chickens

Two experments were carried out to evaluate the use of full-fat tenebrio larvae meal (TM) in broilers diet. In experiment 1, 800 birds were assigned to 4 treatments in an open-sided poultry house, during 35 d, to evaluate performance and count of selected bacteria in ceca. Dietary treatments were as follows: negative control (NC); positive control (PC) – NC + 10 mg/kg enramycin and 66 mg/kg salinomycin; TM0.5 – NC + 0.5% TM; and TM2.0 – NC + 2.0% TM. In experiment 2, the same treatments were used; 192 birds were raised in battery cages for 21 d. At the end of the trial, birds were challenged with LPS and blood was sampled for innate immune response evaluation. PROC MIXED of SAS was used in statistical analyses and comparisons of means done using Tukey's test. In experiment 1, treatment TM2.0 resulted in increase in BWG and FI of 3.8% and 4.2% (P<0.05), and in experiment 2 the improvements were of 5.7% and 2.1% (P<0.05), compared to NC. TM2.0 improved FCR relative to NC in experiment 2 (P<0.05), but not in experiment 1. In both trials the supplementation with 0.5% TM did not improve performance. Birds non-challenged with LPS (NCLPS) and fed 2,0% TM had hemolytic activity of the alternative complement system (HACS) and myeloperoxidase activity (MPO) increased compared to NC and even PC (P<0.05). The indication of TM as a functional ingredient is ascertained by the growth improvement and innate immune response modulation in chickens fed the diet containing 2.0% TM.

Pharmacological Management of Atypical Hemolytic Uremic Syndrome in Pediatric Patients: Current and Future.

Atypical hemolytic uremic syndrome is a thrombotic microangiopathy characterized by hemolysis, thrombocytopenia, and acute kidney injury, usually caused by alternative complement system overactivation due to pathogenic genetic variants or antibodies to components or regulatory factors in this pathway. Previously, a lack of effective treatment for this condition was associated with mortality, end-stage kidney disease, and the risk of disease recurrence after kidney transplantation. Plasma therapy has been used for atypical hemolytic uremic syndrome treatment with inconsistent results. Complement-blocking treatment changed the outcome and prognosis of patients with atypical hemolytic uremic syndrome. Early administration of eculizumab, a monoclonal C5 antibody, leads to improvements in hematologic, kidney, and systemic manifestations in patients with atypical hemolytic uremic syndrome, even with apparent dialysis dependency. Pre- and post-transplant use of eculizumab is effective in the prevention of atypical hemolytic uremic syndrome recurrence. Evidence on eculizumab use in secondary hemolytic uremic syndrome cases is controversial. Recent data favor the restrictive use of eculizumab in carefully selected atypical hemolytic uremic syndrome cases, but close monitoring for relapse after drug discontinuation is emphasized. Prophylaxis for meningococcal infection is important. The long-acting C5 monoclonal antibody ravulizumab is now approved for atypical hemolytic uremic syndrome treatment, enabling a reduction in the dosing frequency and improving the quality of life in patients with atypical hemolytic uremic syndrome. New strategies for additional and novel complement blockage medications in atypical hemolytic uremic syndrome are under investigation.

THE USE OF ENVIRONMENTALLY-SAFE POLUMS IN AQUACULTURE

Introduction. In the conditions of anthropogenic pollution of water, environment-safe drugs and implementing of immunomodulatory drugs are becoming increasingly common. Schemes of their use in fisheries are being developed. The article presents and analyzes the potential use of biologically active additives (BAA), namely probiotics, prebiotics and yeasts, both domestically and internationally produced, in terms of their effect on the fish body.&#x0D; Materials and methods of research. Search for literature data on the use of biologically active substances in fish farming, namely probiotics, prebiotics and yeast.&#x0D; Research results. Considering the negative impact of prophylactic and therapeutic use of antibiotics in aquaculture, the use of dietary immunostimulants has been proposed as an alternative to antimicrobial drugs. In this sense, functional dietary supplements, including pre-, probiotics and yeasts, are receiving increasing attention as an environmental strategy to improve fish health.&#x0D; Probiotics are the objects of comprehensive scientific research and an important product on the world market. The use of probiotics as biocontrol agents in aquaculture is increasing. The benefits of such additives include increased nutritional value, inhibition of pathogens and enhanced immune response by increasing white blood cells and phagocytosis. They improve the quality of the growing environment, protect fish from biological hazards, and modulate physiological processes that ultimately contribute to the health and welfare of fish in aquaculture. Probiotics also enhance growth performance and feed utilization in aquatic animals by increasing the activity of digestive enzymes.&#x0D; The beneficial effects of prebiotics are due to by-products resulting from the fermentation of intestinal commensal bacteria. Among the many health benefits attributed to prebiotics is the modulation of the immune system. They directly enhance the innate immune response, including activation of phagocytosis, neutrophils, alternative complement system, and increased lysozyme activity.&#x0D; Another environmentally friendly product that has been proposed as a dietary supplement is yeasts. Research on yeast products in fish diets has focused on their role in nutritional and functional supplements that contribute to the immune responses and gut health of fish.&#x0D; Conclusions. Various studies of pro- and prebiotics in fish have shown the following results: effects on growth, gut microbiota, resistance to pathogenic bacteria and parameters of innate immunity such as alternative complement activity (ACH50), lysozyme activity, natural hemagglutination activity, respiratory burst, superoxide dismutase activity and phagocytic activity.All the above studies demonstrate that the addition of nutritional supplements to feed, such as immunostimulants, is an alternative method for the prevention and control of various diseases in aquaculture.

Exercise Promotes Bone Marrow Microenvironment by Inhibiting Adipsin in Diet-Induced Male Obese Mice.

Obesity is a growing global epidemic linked to many diseases, including diabetes, cardiovascular diseases, and musculoskeletal disorders. Exercise can improve bone density and decrease excess bone marrow adipose tissue (BMAT) in obese individuals. However, the mechanism of exercise regulating bone marrow microenvironment remains unclear. This study examines how exercise induces bone marrow remodeling in diet-induced obesity. We employed unbiased RNA-Seq to investigate the effect of exercise on the bone marrow of diet-induced obese male mice. Bone mesenchymal stem cells (BMSCs) were isolated to explore the regulatory effects of exercise in vitro. Our data demonstrated that exercise could slow down the progression of obesity and improve trabecular bone density. RNA-seq data revealed that exercise inhibited secreted phosphoprotein 1 (Spp1), which was shown to mediate bone resorption through mechanosensing mechanisms. Interactome analysis of Spp1 using the HINT database showed that Spp1 interacted with the adipokine adipsin. Moreover, exercise decreased BMAT, which induced osteoclast differentiation and promoted bone loss. Our study reveals that exercise improves the bone marrow microenvironment by at least partially inhibiting the adipsin-Spp1 signaling pathway so as to inhibit the alternative complement system from activating osteoclasts in diet-induced obese mice.

ODP064 Latrogenic Cushing Syndrome after Concomitant Oral Controlled-Release Budesonide and Famotidine Therapy

Abstract Introduction It has been shown that complement factors are increased in polycystic ovary syndrome (PCOS) and that these may be affected by obesity and insulin resistance. Hypothetically, this may increase cardiometabolic risk but, paradoxically, increased clotting is not a feature of PCOS. To investigate this, proteomic analysis of the complement system was undertaken, including inhibitory proteins. Methods Plasma was collected from 244 women (147 with PCOS and all 3 diagnostic features and 97 controls). Somalogic proteomic analysis was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, Factor B, Factor D, Factor H, Factor I, Mannose-binding protein C (MBL), Mannan-binding lectin serine protease 1 (MASP3), Complement decay-accelerating factor (DAF) and Complement factor H-related protein 5 (CFHR5). Results The alternative pathway of the complement system was primarily activated in PCOS, with increased C3 (p&amp;lt;0. 05), properdin and Factor B (p&amp;lt;0. 01). In addition, inhibition of this pathway was also seen in PCOS, with increase in CFHR5, Factor H and Factor I (p&amp;lt;0. 01). There were also increases in the downstream complement factors of iC3b and C3d, associated with an enhanced B cell response, and C5a, associated with inflammatory cytokine release (p&amp;lt;0. 01). Conclusion This is the most comprehensive evaluation of the complement system in PCOS to date and reveals upregulation of the alternative complement system that appears to be offset by the concurrent upregulation of its inhibitors. However, any additional dysregulation of the system, such as occurs with COVID19 infection, may give rise to an increased risk for clotting in women with PCOS. Presentation: No date and time listed

ODP141 Complement Activation and Homeostasis Works Primarily Through the Alternative Pathway in Polycystic Ovary Syndrome

Abstract Introduction It has been shown that complement factors are increased in polycystic ovary syndrome (PCOS) and that these may be affected by obesity and insulin resistance. Hypothetically, this may increase cardiometabolic risk but, paradoxically, increased clotting is not a feature of PCOS. To investigate this, proteomic analysis of the complement system was undertaken, including inhibitory proteins. Methods Plasma was collected from 244 women (147 with PCOS and all 3 diagnostic features and 97 controls). Somalogic proteomic analysis was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, Factor B, Factor D, Factor H, Factor I, Mannose-binding protein C (MBL), Mannan-binding lectin serine protease 1 (MASP3), Complement decay-accelerating factor (DAF) and Complement factor H-related protein 5 (CFHR5). Results The alternative pathway of the complement system was primarily activated in PCOS, with increased C3 (p&amp;lt;0. 05), properdin and Factor B (p&amp;lt;0. 01). In addition, inhibition of this pathway was also seen in PCOS, with increase in CFHR5, Factor H and Factor I (p&amp;lt;0. 01). There were also increases in the downstream complement factors of iC3b and C3d, associated with an enhanced B cell response, and C5a, associated with inflammatory cytokine release (p&amp;lt;0. 01). Conclusion This is the most comprehensive evaluation of the complement system in PCOS to date and reveals upregulation of the alternative complement system that appears to be offset by the concurrent upregulation of its inhibitors. However, any additional dysregulation of the system, such as occurs with COVID19 infection, may give rise to an increased risk for clotting in women with PCOS. Presentation: No date and time listed

POS-501 COMPLEMENT LEVELS IN ANCA ASSOCIATED VASCULITIS AS PREDECTOR OF RENAL SURVIVAL

During the last few years, novel findings have suggested that activation of the complement system, in particular the alternative complement system, has a significant role in ANCA associated vasculitis pathogenesis. We investigated whether low serum C3 levels can cross sectionally estimate severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and estimate the renal servival.

Mycoplasma bovis Mastitis.

Bovine mycoplasmoses, which is mostly caused by Mycoplasma bovis, is a significant problem in the dairy and beef industry. Mycoplasmal mastitis has a global occurrence with notable effects in the United States and Europe. The pathogen was first detected in a mastitis case in California, United States, and regarded as major contagious mastitis. It is highly contagious and resistant to antibiotics and lack cell wall rendering certain group of antibiotics ineffective. Outbreaks mostly originate from introduction of diseased dairy cows to a farm and poor hygienic practices that help to maintain cow to cow transmission. Rapid detection scheme is needed to be in place in dairy farms to devise preventive measures and stop future outbreaks. However; early detection is hampered by the fastidious growth of M. bovis and the need for specialized equipment and reagents in laboratory settings. Intramammary Mycoplasma bovis infections cause elevation in milk somatic cell count which is one of the important factors to determine milk quality for grading and hence dictates milk price. There are multiple attributes of M. bovis regarded as virulence factors such as adhesion to and invasion into host cells, avoidance of phagocytosis, resistance to killing by the alternative complement system, biofilm formation, and hydrogen peroxide production. Nevertheless, there are still undetermined virulence factors that hamper the development of sustainable control tools such as effective vaccine. To date, most vaccine trials have failed, and there is no commercial M. bovis mastitis vaccine. Mycoplasma bovis has been shown to modulate both humoral and cellular immune response during bovine mastitis. In the future, research seeking new immunogenic and protective vaccine targets are highly recommended to control this important dairy cattle disease worldwide.

Estrogen promotes innate immune evasion of Candida albicans through inactivation of the alternative complement system.

SummaryCandida albicans is a commensal of the urogenital tract and the predominant cause of vulvovaginal candidiasis (VVC). Factors that increase circulatory estrogen levels such as pregnancy, the use of oral contraceptives, and hormone replacement therapy predispose women to VVC, but the reasons for this are largely unknown. Here, we investigate how adaptation of C. albicans to estrogen impacts the fungal host-pathogen interaction. Estrogen promotes fungal virulence by enabling C. albicans to avoid the actions of the innate immune system. Estrogen-induced innate immune evasion is mediated via inhibition of opsonophagocytosis through enhanced acquisition of the human complement regulatory protein, Factor H, on the fungal cell surface. Estrogen-induced accumulation of Factor H is dependent on the fungal cell surface protein Gpd2. The discovery of this hormone-sensing pathway might pave the way in explaining gender biases associated with fungal infections and may provide an alternative approach to improving women's health.

Alternative C3 Complement System: Lipids and Atherosclerosis.

Familial hypercholesterolemia (FH) is increasingly associated with inflammation, a phenotype that persists despite treatment with lipid lowering therapies. The alternative C3 complement system (C3), as a key inflammatory mediator, seems to be involved in the atherosclerotic process; however, the relationship between C3 and lipids during plaque progression remains unknown. The aim of the study was to investigate by a systems biology approach the role of C3 in relation to lipoprotein levels during atherosclerosis (AT) progression and to gain a better understanding on the effects of C3 products on the phenotype and function of human lipid-loaded vascular smooth muscle cells (VSMCs). By mass spectrometry and differential proteomics, we found the extracellular matrix (ECM) of human aortas to be enriched in active components of the C3 complement system, with a significantly different proteomic signature in AT segments. Thus, C3 products were more abundant in AT-ECM than in macroscopically normal segments. Furthermore, circulating C3 levels were significantly elevated in FH patients with subclinical coronary AT, evidenced by computed tomographic angiography. However, no correlation was identified between circulating C3 levels and the increase in plaque burden, indicating a local regulation of the C3 in AT arteries. In cell culture studies of human VSMCs, we evidenced the expression of C3, C3aR (anaphylatoxin receptor) and the integrin αMβ2 receptor for C3b/iC3b (RT-PCR and Western blot). C3mRNA was up-regulated in lipid-loaded human VSMCs, and C3 protein significantly increased in cell culture supernatants, indicating that the C3 products in the AT-ECM have a local vessel-wall niche. Interestingly, C3a and iC3b (C3 active fragments) have functional effects on VSMCs, significantly reversing the inhibition of VSMC migration induced by aggregated LDL and stimulating cell spreading, organization of F-actin stress fibers and attachment during the adhesion of lipid-loaded human VSMCs. This study, by using a systems biology approach, identified molecular processes involving the C3 complement system in vascular remodeling and in the progression of advanced human atherosclerotic lesions.

Biomarkers in ANCA-Associated Vasculitis: Potential Pitfalls and Future Prospects.

Over the past 3 decades, significant advancements in the understanding of the pathophysiology of ANCA-associated vasculitis has led to the development of a multitude of potential candidate biomarkers. Accompanied by the advent of increasingly effective therapeutic strategies, the need for a dependable biomarker to help determine the extent of disease activity and risk of relapse is ever present. Implementation of such a biomarker would enable tailored therapy, optimizing disease control while helping to mitigate unnecessary exposure to therapy and potential treatment-related damage. Although far from perfect, ANCA serology and B-cell population are the two main staple biomarker tools widely used in practice to help supplement clinical assessment. Over recent years, the application and progress of more novel biomarker tools have arisen in both organ-limited and multisystem disease, including genomics, urinary proteins, degradation products of the alternative complement system, cytokines, metabolomics, and biospectroscopy. Validation studies and clinical translation of these tools are required, with serial assessment of disease activity and determination of therapy according to biomarker status correlated with patient outcomes.

C3 glomerulopathy and atypical hemolytic uremic syndrome: an updated review of the literature on alternative complement pathway disorders.

The complement system plays a significant role within the pathological process of C3 glomerulopathy (C3GP) and atypical hemolytic uremic syndrome (aHUS). In daily practice, clinicians should differentiate the subgroups of C3GP because of they should apply different treatment modalities. In the past, C3GP was considered as a part of membranoproliferative glomerulonephritis (MPGN). MPGN is defined as glomerular capillary thickening secondary to the synthesis of the new glomerular basement membrane and mesangial cellular hyperplasia with mesangial matrix expansion. Atypical hemolytic uremic syndrome is an ultra-rare disease that can be outlined by the triad of Coombs negative microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recent advances demonstrated that these diseases share common abnormalities of the control of the alternative complement system. Therefore, nowadays, most researchers advocate that there may be overlap in the pathogenesis of C3GP and aHUS. This review will provide recent novel mechanisms and treatment options in these diseases. For the purposes that we mentioned above and to help clinicians, we aimed to describe the etiology, pathophysiology, and treatment of C3GP and aHUS in this comprehensive review.

The effect of Pediococcus acidilactici on mucosal immune responses, growth, and reproductive performance in zebrafish (Danio rerio).

A completely randomized experimental design carried out to investigate the effects of different levels of Pediococcus acidilactici (PA) including 0 (basal diet as a control diet), 1 × 106, 2 × 106, 4 × 106, and 8 × 106 colony-forming unit (CFU) per gram of the diet for 60days on the mucosal immunity responses, growth, and reproductive performance, in zebrafish, Danio rerio (with mean weigh ± SE: 120 ± 10mg). The obtained results revealed that the best growth and reproduction indices were related to the concentration of 4 × 106CFUPAg-1 diet (P < 0.05). The maximum activities of mucosal immune responses including total protein, alternative complement system, IgM, and lysozyme were observed in the fish fed with 4 × 106CFUPAg-1 diet (P < 0.05). Furthermore, the maximum alkaline phosphatase activity of skin mucus was recorded in the fish fed with 8 × 106CFUPAg-1 diet (P < 0.05). Fish fed with 4 × 106CFUPAg-1 diet had the highest villus length and width of the intestine (P < 0.05). Supplementing the diet with 4 × 106CFUPAg-1 diet more significantly enhanced Cyp19a gene expression in comparison with this in other groups. Hence, PA with a concentration of 4 × 106CFUg-1 diet can be considered as a proper level of probiotic for improving the health, growth, and reproductive performance of the D. rerio.

Distinct genetic profile with recurrent population-specific missense variants in Korean adult atypical hemolytic uremic syndrome

IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA), characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and renal failure. In more than half of cases, genetic defects leading to overactivation of the alternative complement system have been identified. In this study, we investigated genetic defects in Korean adult patients with aHUS. Materials and methodsSixty-six Korean adult patients with aHUS were ascertained from the Korean TMA Registry. Genetic variants of 15 aHUS-related genes (eight core genes [CFH, CFB, CFI, CD46, C3, THBD, PLG, and DGKE] and seven candidate genes [CFP, C4BPA, and CHFR1-5]) were analyzed from exome sequencing data. Multiplex ligation-dependent probe amplification of CFH and related genes was performed to detect hybrid genes or large deletions. ResultsThirty patients (45%) had at least one aHUS-related variant (s) in eight core genes (total 40 variant alleles). The most frequently affected gene was CFH (13/40, 32%), followed by THBD (8/40, 20%) and CD46 (7/40, 18%). The two most common variants were Asp486Tyr of THBD (N = 7) and Tyr1058His-Val1060Leu of CFH (N = 5, linked on the same allele), accounting for 30% (12/40). In seven candidate genes, 19 variants were detected. When combined, 40 patients (61%) had at least one variant in 15 core or candidate genes. No patients had anti-CFH Ab or hybrid gene/CFHR1 homozygous deletions. ConclusionsThe genetic profile of Korean adult aHUS was unique with recurrent missense variants, demonstrating ethnicity- and age-dependent differences in the genetic background of aHUS.