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Anemia associated with PNH is caused by hemolysis. The C5 inhibitor eculizumab blocks intravascular hemolysis, but anemia often persists owing to extravascular hemolysis. Pegcetacoplan, an inhibitor of C3, prevents extravascular hemolysis. After 16 weeks of treatment, hemoglobin increased nearly 4 g per deciliter in 41 patients treated with pegcetacoplan, and 85% no longer needed transfusion.

This trial of pegcetacoplan, a C3 and C3b inhibitor, in patients with C3 glomerulopathy or primary immune-complex membranoproliferative glomerulonephritis showed that the drug significantly reduced proteinuria.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men 1 , whereas schizophrenia affects men with greater frequency and severity relative to women 2 . All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus 3 – 6 . Here we show that variation of the complement component 4 (C4) genes C4A and C4B , which are also at the MHC locus and have been linked to increased risk for schizophrenia 7 , generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma 8 , 9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses. Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

Purpose Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystem involvement. This study was designed to examine the effects of curcumin, a polyphenolic compound isolated from turmeric rhizomes, on inflammatory markers in SLE patients. Methods Seventy 18–60 years old SLE patients were recruited in this randomized triple-blinded placebo-controlled trial, and 62 completed the study. Curcumin group received 1000 mg curcumin daily and the placebo group received placebo capsules for 10 weeks. Dietary intakes and serum levels of complement C3 and C4, complement hemolytic 50%, rheumatoid factor, anti-double stranded DNA (anti-ds DNA), erythrocyte sedimentation rate, high-sensitivity C-reactive protein, interlukine-6 (IL-6) and tumor necrosis factor-α were assessed before and after intervention period. Results Curcumin supplementation caused a significant reduction in anti-ds DNA and IL-6 levels at the end of the trial in comparison with baseline (52.57 ± 40.21 vs. 43.27 ± 28.34, p  = 0.014 and 127.11 ± 76.63 vs. 101.49 ± 59.08, p  = 0.002, respectively). Analysis of covariance which was adjusted for confounding variables also revealed that anti-ds DNA and IL-6 levels decreased significantly in curcumin group compared to placebo group by the end of the intervention period (change:-9.30 ± 19.59 vs. -2.55 ± 17.55, p  = 0.018 and − 25.62 ± 42.33 vs. -7.34 ± 34.32, p  = 0.043, respectively). No significant changes were observed in levels of other variables during the study ( p  > 0.05). Conclusion Curcumin as an effective and safe adjuvant therapy, ameliorated the autoimmune activity and inflammation in SLE patients via reducing anti-ds DNA and IL-6 levels. Clinical trial registration irct.behdasht.gov.ir, identifier: IRCT20210425051077N1.

Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon and liver cancer, and has recently been implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA) 1 . However, the mycobiome has not been clearly implicated in tumorigenesis. Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA. PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species—but not species in the genera Candida , Saccharomyces or Aspergillus —accelerated oncogenesis. We also discovered that ligation of mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment—or knockdown of C3aR in tumour cells—were both protective against tumour growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl - (also known as Mbl2 ) or C3 -deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL. In humans and mouse models, the mycobiome of pancreatic ductal adenocarcinoma tumours is markedly enriched in Malassezia species compared to that of normal pancreas, which implicates these pathogenic fungi in oncogenesis.

The complement system plays a crucial role in retinal homeostasis. While the proteomic analysis of ocular tissues in diabetic retinopathy (DR) has shown the deposition of complement proteins, their exact role in the pathogenesis of DR is yet unclear. We performed a detailed investigation of the role of the complement system by evaluating the levels of major complement proteins including C3, C1q, C4b, Complement Factor B (CFB), and Complement Factor H (CFH) and their activated fragments from both the classical and alternative pathways in vitreous humor and serum samples from proliferative DR (PDR) patients and controls. Further, the expressions of complements and several other key pro- and anti-angiogenic genes in the serum and vitreous humor were analyzed in the blood samples of PDR and non-PDR (NPDR) patients along with controls without diabetes. We also assessed the pro-inflammatory cytokines and matrix metalloproteinases in the vitreous humor samples. There was a significant increase in C3 and its activated fragment C3bα' (110 kDa) along with a corresponding upregulation of CFH in the vitreous of PDR patients, which confirmed the increased activation of the alternative complement pathway in PDR. Likewise, a significant upregulation of angiogenic genes and downregulation of anti-angiogenic genes was seen in PDR and NPDR cases. Increased MMP9 activity and upregulation of inflammatory markers IL8 and sPECAM with a downregulation of anti-inflammatory marker IL-10 in PDR vitreous indicated the possible involvement of microglia in DR pathogenesis. Further, a significantly high C3 deposition in the capillary wall along with thickening of basement membranes and co-localization of CFH expression with CD11b activated microglial cells in diabetic retina suggested microglia as a source of CFH in diabetic retina. The increased CFH levels could be a feedback mechanism for arresting excessive complement activation in DR eyes. A gradual increase of and expression in retina with early to late changes in epiretinal membranes of DR patients indicated a major role for the alternative complement pathway in disease progression.

ObjectivesEvaluate efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that binds and neutralises membrane and soluble B-cell activating factor (BAFF) versus placebo plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE).MethodsThis phase III, 52-week study randomised 1164 patients with moderate-to-severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment—SLE Disease Activity Index ≥6 at baseline). Patients received SoC plus subcutaneous injections of tabalumab or placebo, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every two weeks (120 Q2W, n=387), 120 mg every four weeks (120 Q4W, n=389) or placebo Q2W (n=388). Primary endpoint: proportion of patients achieving SLE Responder Index 5 (SRI-5) response at week 52.ResultsSimilar proportions of patients in each group achieved SRI-5 response at week 52 (120 Q2W: 31.8%; 120 Q4W: 35.2% and placebo: 29.3%). Key secondary endpoints were not met. In a sensitivity analysis not excluding patients who decreased antimalarials or immunosuppressants, SRI-5 response was achieved with 120 Q4W (37.0% vs 29.8% placebo; p=0.021), but not 120 Q2W (34.1%; p=0.171). Significant reductions in anti-dsDNA antibodies, increases in C3 and C4, and reductions in total B cells and immunoglobulins were observed with tabalumab. No differences were observed between treatment groups in percentage of deaths (120 Q2W: 0.8%; 120 Q4W: 0.5%; placebo: 0.5%), serious adverse events (AEs) (range 11.1–14.4%) or treatment-emergent AEs (range 81.1–82.3%).ConclusionsTabalumab had biological activity—changes in anti-dsDNA, complement, B cells and immunoglobulins—consistent with BAFF pathway inhibition. Key clinical efficacy endpoints did not achieve statistical significance. Safety profiles were similar with tabalumab and placebo.Trial registration numberNCT01196091.

Emerging evidence indicates that activation of complement system leading to the formation of the membrane attack complex (MAC) plays a detrimental role in COVID-19. However, their pathogenic roles have never been experimentally investigated before. We used three knock out mice strains (1. C3 −/− ; 2. C7 −/− ; and 3. Cd59ab −/− ) to evaluate the role of complement in severe COVID-19 pathogenesis. C3 deficient mice lack a key common component of all three complement activation pathways and are unable to generate C3 and C5 convertases. C7 deficient mice lack a complement protein needed for MAC formation. Cd59ab deficient mice lack an important inhibitor of MAC formation. We also used anti-C5 antibody to block and evaluate the therapeutic potential of inhibiting MAC formation. We demonstrate that inhibition of complement activation (in C3 −/− ) and MAC formation (in C3 −/− . C7 −/− , and anti-C5 antibody) attenuates severe COVID-19; whereas enhancement of MAC formation ( Cd59ab −/− ) accelerates severe COVID-19. The degree of MAC but not C3 deposits in the lungs of C3 −/− , C7 −/− mice, and Cd59ab −/− mice as compared to their control mice is associated with the attenuation or acceleration of SARS-CoV-2-induced disease. Further, the lack of terminal complement activation for the formation of MAC in C7 deficient mice protects endothelial dysfunction, which is associated with the attenuation of diseases and pathologic changes. Our results demonstrated the causative effect of MAC in severe COVID-19 and indicate a potential avenue for modulating the complement system and MAC formation in the treatment of severe COVID-19.

Fungal dissemination into the bloodstream is a critical step leading to invasive fungal infections. Here, using intravital imaging, we show that Kupffer cells (KCs) in the liver have a prominent function in the capture of circulating Cryptococcus neoformans and Candida albicans , thereby reducing fungal dissemination to target organs. Complement C3 but not C5, and complement receptor CRIg but not CR3, are involved in capture of C. neoformans . Internalization of C. neoformans by KCs is subsequently mediated by multiple receptors, including CR3, CRIg, and scavenger receptors, which work synergistically along with C5aR signaling. Following phagocytosis, the growth of C. neoformans is inhibited by KCs in an IFN-γ independent manner. Thus, the liver filters disseminating fungi from circulation via KCs, providing a mechanistic explanation for the enhanced risk of cryptococcosis among individuals with liver diseases, and suggesting a therapeutic strategy to prevent fungal dissemination through enhancing KC functions. Patients with liver diseases are at increased risk of fungal infections. Here the authors show that Kupffer cells are critical for the filtration of fungi out of the blood and thereby for liver-mediated protection against disseminating fungal infection.

Systemic lupus erythematosus (SLE) is associated with deficiencies in the complement protein C1q. Although C1q plays a role in the clearance of apoptotic cells, there are several redundant clearance pathways. Disruption of one pathway does not lead to an autoimmune defect. In a chronic graft-versus-host disease model of SLE, Ling et al. show that C1q dampens CD8 + T cell responses to self-antigens. C1q modulates metabolism through the mitochondrial cell-surface protein p32/gC1qR. The lack of C1q during a viral infection also enhances CD8 + T cell responses. Thus, C1q plays a role as a “metabolic rheostat” for effector CD8 + T cells. Science , this issue p. 558 The initiator of the complement cascade, which protects against lupus, controls CD8 + T cell responses via mitochondrial metabolism. Deficiency of C1q, the initiator of the complement classical pathway, is associated with the development of systemic lupus erythematosus (SLE). Explaining this association in terms of abnormalities in the classical pathway alone remains problematic because C3 deficiency does not predispose to SLE. Here, using a mouse model of SLE, we demonstrate that C1q, but not C3, restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8 + T cells, which can themselves propagate autoimmunity. C1q deficiency also triggers an exuberant effector CD8 + T cell response to chronic viral infection leading to lethal immunopathology. These data establish a link between C1q and CD8 + T cell metabolism and may explain how C1q protects against lupus, with implications for the role of viral infections in the perpetuation of autoimmunity.