Antibodies and complement are key drivers of thrombosis.

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcµR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.

Decreased sialylation elicits complement-related microglia response and bipolar cell loss in the mouse retina.

Sialylation plays an important role in self-recognition, as well as keeping the complement and innate immune systems in check. It is unclear whether the reduced sialylation seen during aging and in mice heterozygous for the null mutant of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (Gne+/-), an essential enzyme for sialic acid biosynthesis, contributes to retinal inflammation and degeneration. We found a reduction of polysialic acid and trisialic acid expression in several retinal layers in Gne+/- mice at 9 months of age compared to Gne+/+ wildtype (WT) mice, which was associated with a higher microglial expression of the lysosomal marker CD68. Furthermore, the total number of rod bipolar cells was reduced in 12 months old Gne+/- mice in comparison to WT mice, demonstrating loss of these retinal interneurons. Transcriptome analysis showed up-regulation of complement, inflammation, and apoptosis-related pathways in the retinas of Gne+/- mice. Particularly, increased gene transcript levels of the complement factors C3 and C4 and the pro-inflammatory cytokine Il-1ß were observed by semi-quantitative real-time polymerase chain reaction (sqRT-PCR) in 9 months old Gne+/- mice compared to WT mice. The increased expression of CD68, loss of rod bipolar cells, and increased gene transcription of complement factor C4, were all prevented after crossing Gne+/- mice with complement factor C3-deficient animals. In conclusion, our data show that retinal hyposialylation in 9 and 12 months old Gne+/- mice was associated with complement-related inflammation and lysosomal microglia response, as well as rod bipolar cells loss, which was absent after genetic deletion of complement factor C3.

[Research Progress in Complement Receptor of the Immunoglobulin Superfamily in Regulating Liver Immunity].

Kupffer cells (KC),an important subset of immune cells in the liver,are essential for maintaining tissue homeostasis and responding quickly to liver damage.The complement receptor of the immunoglobulin superfamily (CRIg) is a receptor protein on the KC membrane.CRIg can not only capture pathogens in the blood flowing through the liver by complement binding but also mediate immune responses by regulating immune cells in the liver.Recent studies have confirmed the role of CRIg in regulating liver immunity.This article reviews the main modes of action of CRIg and the research progress of CRIg in regulating liver immunity.

Unusual Presentation of Aggressive Atypical Hemolytic Uremic Syndrome With Brugada Syndrome.

Hemolytic uremic syndrome (HUS) is part of a spectrum of disorders known as thrombotic microangiopathies. These disorders are characterized by giving rise to platelet microthrombi, which subsequently develop hemolytic anemia and thrombocytopenia. In HUS, the kidneys are destroyed, mainly due to damage to the renal blood vessels. HUS can be typical or atypical, depending on the cause, and can lead to significant mortality rates. We herein report an unusual case of atypical HUS in a 15-year-old female who presented with fatigue, abdominal pain with nausea and vomiting, loss of appetite, and urine discoloration. Further tests showed low platelets with significant anemia. She was diagnosed with atypical HUS after discovering that she had no previous bloody diarrhea episode with a negative E. coli strain, O157:H7, alongside valid ADAMTS13 activity. The diagnosis was confirmed by genetic testing, and a variant of uncertain significance was found in the CFH gene. The patient, therefore, was started on eculizumab, and a follow-up was done once or twice a month through blood testing. She showed significant improvement. Due to non-compliance with the eculizumab treatment, the patient showed deterioration numerous times. A kidney biopsy was subsequently done, showing signs of acute to chronic thrombotic microangiopathy with moderate tubular atrophy and interstitial fibrosis. After many hemodialysis and plasma exchange sessions and being put on several treatments, such as prednisolone and rituximab, the patient faced death after one year.

Immune response in diseased and healthy common carp exposed to carp edema virus.

The common carp is one of the most economically valuable freshwater fish worldwide and its aquaculture can be severely affected by the koi sleepy disease (KSD)/carp edema virus disease (CEVD). This study explores a natural outbreak of CEVD in a pond containing both clinically healthy and diseased fish of various origins exposed to the virus. We investigated mRNA expression of genes associated with known antiviral immune mechanisms, such as type I interferon signalling and cell-mediated cytotoxicity, and performed a comprehensive protein expression analysis to highlight differences between the two groups in various organs. Significant differences in expression profiles of common carp with and without clinical signs were found to be strongly dependent on the organ from which the sample originated. Components of the complement cascade, including various C3 proteins, exhibited upregulation only in less affected organs, specifically the head kidney and spleen. Other complement proteins such as B/C2 and C9 showed upregulation in the kidney, spleen, and gills but not in the skin. Conversely, lysozymes C and G, were observed to be upregulated in the most affected organs of the skin and gills. This study submits the first description of the immune system related proteome using a mass spectrometry on the samples isolated from fish infected with CEV. It also offers a unique comparison of immune reaction of CEV infected and healthy fish under an infectious pressure.

Functional evaluation of rare variants in complement factor I using a minigene assay.

The regulatory serine protease, complement factor I (FI), in conjunction with one of its cofactors (FH, C4BP, MCP, or CR1), plays an essential role in controlling complement activity through inactivation of C3b and C4b. The functional impact by missense variants in the CFI gene, particularly those with minor allele frequencies of 0.01% to 0.1%, is infrequently studied. As such, these variants are typically classified as variants of uncertain significance (VUS) when they are identified by clinical testing. Herein, we utilized a minigene splicing assay to assess the functional impact of 36 ultra-rare variants of CFI. These variants were selected based on their minor allele frequencies (MAF) and their association with low-normal FI levels. Four variants lead to aberrant splicing-one 5' consensus splice site (NM_000204.5: c.1429G>C, p.Asp477His) and three exonic changes (c.355G>A, p.Gly119Arg; c.472G>A, p.Gly158Arg; and c.950G>A, p.Arg317Gln)-enabling their reclassification to likely pathogenic (LP) or pathogenic (P) based on ACMG guidelines. These findings underscore the value of functional assays, such as the minigene assay, in assessing the clinical relevance of rare variants in CFI.

Complement protein expression changes in various conditions of breast cancer: in-silico analyses-experimental research.

Introduction: Breast cancer is the most prevalent cancer diagnosed in females worldwide. The known biomarkers are insufficient to understand the actual prognosis of breast cancer, and identifying new biomarkers is desirable and valuable data to improve the patient's survival. Many inflammatory biomarkers, such as the complement system, can be regarded as prognostic values and as potent inflammatory mediators; complement proteins have a critical role in tumorigenesis. In the current study, the authors aim to investigate complement protein expression changes, particularly complement 3 (C3), complement 7 (C7), complement factor B (CFB), and complement factor D (CFD), in various conditions of breast cancer using in-silico tools. Methods: The intent data were extracted using webtools, including; Kaplan-Meier plotter, BcGenExMiner, UALCAN, cbioportal, GeneMania, and Enrichr. To select valid data, a P greater than 0.05 was considered. Results: The current study clarified that 21 complement genes correlated to survival conditions. Also, down or upregulation of extracted genes and breast cancer statuses were identified. Additionally, expression level difference of complement genes in various breast cancer four stages was detected. Ultimately, co-expression genes with complement genes were extracted and networked. Conclusion: Changes in the expression of complement proteins can strongly correlate to breast cancer's prognosis, status, and survival. Furthermore, considering the vital role of CFD and CFB complement proteins in the alternative pathway in different stages of breast cancer, CFD and CFB can be regarded as reliable prognostic values for diagnosis.

Therapeutic targets in membranous nephropathy: plasma cells and complement.

Membranous nephropathy (MN) is an antibody-mediated autoimmune disease and the most common cause of nephrotic syndrome in adults. The discovery of phospholipase A2 receptor 1 (PLA2R1) as the first target antigen in patients with MN 15 years ago has led to a paradigm shift in the pathobiological understanding of this disease. Autoantibodies against PLA2R1 as well as thrombospondin type-1 domain-containing 7A, the second identified antigen in adults, were shown to be disease-causing and act through local activation of the complement system, primarily via the classical and lectin pathways. These findings indicate that both plasma cells, the main source of antibodies and autoantibodies, as well as the complement system, the main pathogenic effector mechanism in MN, are rational and pathogenesis-based treatment targets in MN. This review summarizes pathomechanistic and clinical evidence for and against plasma cell- and complement-targeted treatments in MN.

Antibody density on bacteria regulates C1q recruitment by monoclonal IgG but not IgM.

Antibodies that trigger the complement system play a pivotal role in the immune defense against pathogenic bacteria and offer potential therapeutic avenues for combating antibiotic-resistant bacterial infections, a rising global concern. To gain a deeper understanding of the key parameters regulating complement activation by monoclonal antibodies, we developed a novel bioassay for quantifying classical complement activation at the monoclonal antibody level, and employed this assay to characterize rare complement-activating antibacterial antibodies on the single-antibody level in postimmunization murine antibody repertoires. We characterized monoclonal antibodies from various antibody isotypes against specific pathogenic bacteria (Bordetella pertussis and Neisseria meningitidis) to broaden the scope of our findings. We demonstrated activation of the classical pathway by individual IgM- and IgG-secreting cells, that is, monoclonal IgM and IgG2a/2b/3 subclasses. Additionally, we could observe different epitope density requirements for efficient C1q binding depending on antibody isotype, which is in agreement with previously proposed molecular mechanisms. In short, we found that antibody density most crucially regulated C1q recruitment by monoclonal IgG isotypes, but not IgM isotypes. This study provides additional insights into important parameters for classical complement initiation by monoclonal antibodies, a knowledge that might inform antibody screening and vaccination efforts.

Clinical characteristics and management of paroxysmal nocturnal haemoglobinuria in Latin America: a narrative review.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, complement-associated, haematological disorder. The level of knowledge about the disease and its management varies around the world. This narrative review provides an overview of available clinical data on PNH in Latin America (LATAM). A search of the PubMed, EMBASE and LILACS/IBECS databases to February 2023, and addition of author-known articles, yielded 24 relevant published articles, the majority (n = 15) from Brazil. Fourteen articles were full papers; 10 were conference abstracts. The prevalence of PNH in Brazil is estimated at 1:237,000 inhabitants. Among blood samples sent for flow cytometry screening for suspected PNH in Brazil and Colombia, 14 - 30% were positive. There is suggestion that disease subtypes may differ among LATAM populations, with classical PNH more common in Brazilian patients and PNH with aplastic anaemia more common in Mexican patients. Median age at diagnosis of PNH ranged from 24 to 41 years. Common symptoms included fatigue, haemoglobinuria, and abdominal pain, although the symptom profile varied by subtype. Three available studies indicated that eculizumab was effective at reducing haemolysis, improving anaemia, and reducing the risk of thrombosis in patients with PNH with intravascular haemolysis. A consensus document from the Brazilian Association of Hematology, Hemotherapy and Cell Therapy RBC and Iron Committee provides guidance on identifying and managing PNH patients, including appropriate selection of patients for eculizumab. Additional data on the epidemiology, natural history and outcomes of patients with PNH in LATAM countries are needed to better understand the disease and its management throughout the region.

Epidemiological estimates of paroxysmal nocturnal hemoglobinuria in Bulgaria.

Paroxysmal nocturnal hemoglobinuria is a rare clonal hematopoietic stem cell disorder with debilitating health consequences if untreated. Although cases have been described globally, precise epidemiological distribution is difficult to assess due to geographical underrepresentation in disease reporting. Evaluation of the burden of paroxysmal nocturnal hemoglobinuria in Bulgaria is currently missing. To provide epidemiological estimates, a systematic literature search for publications in the Bulgarian language or by Bulgarian authors was performed for a ten-year period (2013-2022), and clinically relevant information on case presentation was collected. Additionally, data was retrieved from the National Health Insurance Fund and National Statistical Institute on the count of registered cases with ICD-10 code "D59.5" and census for the same period. The estimated prevalence of paroxysmal nocturnal hemoglobinuria is relatively lower in the Bulgarian population than in other countries, and it is estimated to be 2.77 cases per 1,000,000 patient years. The treatment pattern mainly shows conventional blood product support use and is consistent with the pre-complement inhibition era. Underdiagnosis, lack of a reliable disease reporting system, and, until recently, restricted access to complement inhibitor therapy are significant impediments to the management of paroxysmal nocturnal hemoglobinuria in Bulgaria.

Integrated data driven analysis identifies potential candidate genes associated with PCOS.

Polycystic ovary syndrome (PCOS) is one of the most common anovulatory disorder observed in women presenting with infertility. Several high and low throughput studies on PCOS have led to accumulation of vast amount of information on PCOS. Despite the availability of several resources which index the advances in PCOS, information on its etiology still remains inadequate. Analysis of the existing information using an integrated evidence based approach may aid identification of novel potential candidate genes with a role in PCOS pathophysiology. This work focuses on integrating existing information on PCOS from literature and gene expression studies and evaluating the application of gene prioritization and network analysis to predict missing novel candidates. Further, it assesses the utility of evidence-based scoring to rank genes for their association with PCOS. The results of this study led to identification of ∼2000 plausible candidate genes associated with PCOS. Insilico validation of these identified candidates confirmed the role of 938 genes in PCOS. Further, experimental validation was carried out for four of the potential candidate genes, a high-scoring (PROS1), two mid-scoring (C1QA and KNG1), and a low-scoring gene (VTN) involved in the complement and coagulation pathway by comparing protein levels in follicular fluid in women with PCOS and healthy controls. While the expression of PROS1, C1QA, and KNG1 was found to be significantly downregulated in women with PCOS, the expression of VTN was found to be unchanged in PCOS. The findings of this study reiterate the utility of employing insilico approaches to identify and prioritize the most promising candidate genes in diseases with a complex pathophysiology like PCOS. Further, the study also helps in gaining clearer insights into the molecular mechanisms associated with the manifestation of the PCOS phenotype by contributing to the existing repertoire of genes associated with PCOS.

Structural basis for surface activation of the classical complement cascade by the short pentraxin C-reactive protein.

Human C-reactive protein (CRP) is a pentameric complex involved in immune defense and regulation of autoimmunity. CRP is also a therapeutic target, with both administration and depletion of serum CRP being pursued as a possible treatment for autoimmune and cardiovascular diseases, among others. CRP binds to phosphocholine (PC) moieties on membranes to activate the complement system via the C1 complex, but it is unknown how CRP, or any pentraxin, binds to C1. Here, we present a cryoelectron tomography (cryoET)-derived structure of CRP bound to PC ligands and the C1 complex. To gain control of CRP binding, a synthetic mimotope of PC was synthesized and used to decorate cell-mimetic liposome surfaces. Structure-guided mutagenesis of CRP yielded a fully active complex able to bind PC-coated liposomes that was ideal for cryoET and subtomogram averaging. In contrast to antibodies, which form Fc-mediated hexameric platforms to bind and activate the C1 complex, CRP formed rectangular platforms assembled from four laterally associated CRP pentamers that bind only four of the six available globular C1 head groups. Potential residues mediating lateral association of CRP were identified from interactions between unit cells in existing crystal structures, which rationalized previously unexplained mutagenesis data regarding CRP-mediated complement activation. The structure also enabled interpretation of existing biochemical data regarding interactions mediating C1 binding and identified additional residues for further mutagenesis studies. These structural data therefore provide a possible mechanism for regulation of complement by CRP, which limits complement progression and has consequences for how the innate immune system influences autoimmunity.

Complement 3a induces the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms during the development and progression of Alzheimer's disease.

As a central molecule in complement system (CS), complement (C) 3 is upregulated in the patients and animal models of Alzheimer's disease (AD). C3 will metabolize to iC3b and C3a. iC3b is responsible for clearing ß-amyloid protein (Aß). In this scenario, C3 exerts neuroprotective effects against the disease via iC3b. However, C3a will inhibit microglia to clear the Aß, leading to the deposition of Aß and impair the functions of synapses. To their effects on AD, activation of C3a and C3a receptor (C3aR) will impair the mitochondria, leading to the release of reactive oxygen species (ROS), which activates the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes. The overloading of NLRP3 inflammasomes activate microglia, leading to the formation of inflammatory environment. The inflammatory environment will facilitate the deposition of Aß and abnormal synapse pruning, which results in the progression of AD. Therefore, the current review will decipher the mechanisms of C3a inducing the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms, which facilitates the understanding the AD.

Corrigendum: Genetic investigation of Nordic patients with complement-mediated kidney diseases.

[This corrects the article DOI: 10.3389/fimmu.2023.1254759.].

Complement Receptor 1 Enhancement in Recurrent Membranous Nephropathy Following Kidney Transplantation: A Case Report.

Membranous nephropathy (MN) recurs in some kidney allograft patients, and recurrence increases graft failure rates. We present a unique case of recurrent MN in first and second allografts showing glomerular capillary wall-positivity for complement receptor 1 (CR1) consistent with immunoglobulin G (IgG). A man in his late 20s developed MN and started hemodialysis. MN recurred and caused graft loss after the first transplantation and recurred again soon after the second transplantation. The IgG subclass staining was almost consistently negative for IgG4 and phospholipase A2 receptor (PLA2R)-staining was negative. Recurrent MN of unknown etiology was considered. Mass spectrometry demonstrated that CR1 had increased in the transplanted kidney biopsies. Immunohistochemistry and immunofluorescence studies demonstrated CR1 colocalized with IgG along glomerular capillaries in this case, whereas CR1 was localized in podocytes with no colocalization of IgG in a control case of PLA2R-associated MN. Correlative light and immunoelectron microscopy showed localization of CR1 at the interface between electron-dense deposits and podocytes. Collectively, this case demonstrated a unique enhancement and localization of CR1. MN with enhancement of CR1 has not been reported to date. CR1 may be a candidate causative antigen in this case of recurrent MN, although further study is needed to investigate the pathogenesis of CR1.

Femoral nailing associated with bone marrow emboli in pigs induced a specific increase in blood IL-6 and broad inflammatory responses in the heart and lungs.

Introduction: Bone marrow embolization may complicate orthopedic surgery, potentially causing fat embolism syndrome. The inflammatory potential of bone marrow emboli is unclear. We aimed to investigate the inflammatory response to femoral intramedullary nailing, specifically the systemic inflammatory effects in plasma, and local tissue responses. Additionally, the plasma response was compared to that following intravenous injection of autologous bone marrow. Methods: Twelve pigs underwent femoral nailing (previously shown to have fat emboli in lung and heart), four received intravenous bone marrow, and four served as sham controls. Blood samples were collected hourly and tissue samples postmortem. Additionally, we incubated bone marrow and blood, separately and in combination, from six pigs in vitro. Complement activation was detected by C3a and the terminal C5b-9 complement complex (TCC), and the cytokines TNF, IL-1ß, IL-6 and IL-10 as well as the thrombin-antithrombin complexes (TAT) were all measured using enzyme-immunoassays. Results: After nailing, plasma IL-6 rose 21-fold, compared to a 4-fold rise in sham (p=0.0004). No plasma differences in the rest of the inflammatory markers were noted across groups. However, nailing yielded 2-3-times higher C3a, TCC, TNF, IL-1ß and IL-10 in lung tissue compared to sham (p<0.0001-0.03). Similarly, heart tissue exhibited 2-times higher TCC and IL-1ß compared to sham (p<0.0001-0.03). Intravenous bone marrow yielded 8-times higher TAT than sham at 30 minutes (p<0.0001). In vitro, incubation of bone marrow for four hours resulted in 95-times higher IL-6 compared to whole blood (p=0.03). Discussion: A selective increase in plasma IL-6 was observed following femoral nailing, whereas lung and heart tissues revealed a broad local inflammatory response not reflected systemically. In vitro experiments may imply bone marrow to be the primary IL-6 source.

The Plasma Levels of Protein Adiponectin (AdipoQ) and Meteorin-Like (Metrnl) in Newly Diagnosed Type 2 Diabetes Mellitus.

Purpose: This study aimed to measure the concentrations of the Adiponectin and Meteorin - Like (Metrnl) in newly diagnosed type 2 diabetes patients. Patients and Methods: A comparative cross-sectional study contained two groups: Group 1 (86 newly diagnosed diabetes mellitus type 2 patients) and group 2 (71 healthy persons). The plasma concentrations of Adiponectin and Metrnl were measured by Enzyme Link Immunosorbent Assay (ELISA). Results: The plasma level of Adiponectin of the newly diagnosed diabetes mellitus type 2 group and the healthy group were 1219.82 ng/mL (1132.43-2772.50) and 1187.25 ng/mL (1160.66-3807.50) respectively. The plasma level of Metrnl of two groups were 757.60 pg/mL (564.15-994.00) and 697.60 pg/mL (538.50-986.10) respectively. There were no significant difference between two groups. Metrnl had no correlation with glucose, HbA1c, lipid profile, BMI. Adiponectin had correlation with Metrnl and HDL-cholesterol. Adiponectin had no correlation to glucose, HbA1c, LDL-cholesterol, total cholesterol, triglyceride, BMI. People with the lower Adiponectin concentration had the higher risk of diabetes (OR=6.52; 95% CI: 2.43 -17.55). Conclusion: Adiponectin and Metrnl were not significantly different in newly diagnosed type 2 diabetes and healthy people. The lower concentration of Adiponectin might increase the risk of type 2 diabetes.

Apical tubular complement activation and the loss of kidney function in proteinuric kidney diseases.

Many kidney diseases are associated with proteinuria. Since proteinuria is independently associated with kidney function loss, anti-proteinuric medication, often in combination with dietary salt restriction, comprises a major cornerstone in the prevention of progressive kidney failure. Nevertheless, complete remission of proteinuria is very difficult to achieve, and most patients with persistent proteinuria slowly progress toward kidney failure. It is well-recognized that proteinuria leads to kidney inflammation and fibrosis via various mechanisms. Among others, complement activation at the apical side of the proximal tubular epithelial cells is suggested to play a crucial role as a cause of progressive loss of kidney function. However, hitherto limited attention is given to the pathophysiological role of tubular complement activation relative to glomerular complement activation. This review aims to summarize the evidence for tubular epithelial complement activation in proteinuric kidney diseases in relation to loss of kidney function.

Factor H-related protein 1 in systemic lupus erythematosus.

Background: Factor H (FH) is a major soluble inhibitor of the complement system and part of a family comprising five related proteins (FHRs 1-5). Deficiency of FHR1 was described to be linked to an elevated risk of systemic lupus erythematosus (SLE). As FHR1 can partially antagonize the functionality of FH, an altered FHR1/FH ratio could not only enhance SLE vulnerability but also affect the disease expression. This study focuses on the analysis of FH and FHR1 at a protein level, and the occurrence of anti-FH autoantibodies (anti-FH) in a large cohort of SLE patients to explore their association with disease activity and/or expression. Methods: We assessed FH and FHR1 levels in plasma from 378 SLE patients compared to 84 healthy controls (normal human plasma, NHP), and sera from another cohort of 84 healthy individuals (normal human serum, NHS), using RayBio® CFH and CFHR1 ELISA kits. Patients were recruited by the Swiss SLE Cohort Study (SSCS). Unmeasurable FHR1 levels were all confirmed by Western blot, and in a subgroup of patients by PCR. Anti-FH were measured in SLE patients with non-detectable FHR1 levels and matched control patients using Abnova's CFH IgG ELISA kit. Results: Overall, FH and FHR1 levels were significantly higher in healthy controls, but there was no significant difference in FHR1/FH ratios between SLE patients and NHPs. However, SLE patients showed a significantly higher prevalence of undetectable FHR1 compared to all healthy controls (35/378 SLE patients versus 6/168 healthy controls; p= 0.0214, OR=2.751, 95% CI = 1.115 - 8.164), with a consistent trend across all ethnic subgroups. Levels of FH and FHR1, FHR1/FH ratios and absence of FHR1 were not consistently associated with disease activity and/or specific disease manifestations, but absence of FHR1 (primarily equivalent to CFHR1 deficiency) was linked to the presence of anti-FH in SLE patients (p=0.039). Conclusions: Deficiency of FHR1 is associated with a markedly elevated risk of developing SLE. A small proportion of FHR1-deficient SLE patients was found to have autoantibodies against FH but did not show clinical signs of microangiopathy.