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Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation within the liver. While studying aging CFH-deficient (fH-/-) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged fH-/- males. Examination of fH-/- livers (3-24 months) for evidence of complement-mediated inflammation revealed widespread deposition of complement-activation fragments throughout the sinusoids, elevated transaminase levels, increased hepatic CD8+ and F4/80+ cells, overexpression of hepatic mRNA associated with inflammatory signaling pathways, steatosis, and increased collagen deposition. Immunostaining of human HCC biopsies revealed extensive deposition of complement fragments within the tumors. Investigating the Cancer Genome Atlas also revealed that increased CFH mRNA expression is associated with improved survival in patients with HCC, whereas mutations are associated with worse survival. These results indicate that CFH is critical for controlling complement activation in the liver, and in its absence, AP activation leads to chronic inflammation and promotes hepatic carcinogenesis.

Acute hemorrhagic leukoencephalitis (AHLE) is a rare, fulminant neuroinflammatory disease with high mortality rate. It most often occurs after infections; however, the exact etiology of the disease remains unclear. We highlight that complement factor I (FI) deficiency may be a possible cause of AHLE. We describe a 9-year-old patient presenting with fever, headache, dizziness, ataxia, and diplopia, who developed rapid neurologic decline and refractory intracranial pressure elevation. Based on clinical, laboratory, and MRI findings, AHLE was diagnosed. Successful treatment included therapeutic plasma exchange (PEX) and early decompressive craniectomy. At one year of follow-up, the patient showed complete recovery. Complement testing of the patient revealed complete FI deficiency. Genetic workup uncovered a germline pathogenic variant in the gene. As AHLE is an emerging phenotype of complement FI deficiency, with only a few previously reported cases in the literature, high clinical suspicion and awareness among clinicians are needed. To control the complement system, prompt blockade with complement FI substitution via PEX and early decompressive craniectomy may be life-saving. In neuroinflammatory diseases with unknown etiology, complement testing is recommended.

Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral–host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality—effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection. A combination of clinical and molecular analyses supports an association between disorders of immune complement or coagulation with poor outcome in patients with SARS-CoV-2 infection.

Excessive intake of fat causes accumulation of fat in liver, leading to non-alcoholic fatty liver disease (NAFLD). High-fat diet (HFD) upregulates the expression of Factor D, a complement pathway component, in the liver of mice. However, the functions of Factor D in liver are not well known. Therefore, the current study investigated the relationship between Factor D and hepatic lipid accumulation using CRISPR/Cas9-mediated Factor D knockout (FD-KO) mice. Factor D deficiency downregulated expression of genes related to fatty acid uptake and de novo lipogenesis in the liver. Furthermore, Factor D deficiency reduced the expression of inflammatory factors ( Tnf and Ccl2 ) and fibrosis markers and decreased accumulation of F4/80-positive macrophages. These data suggest that the Factor D deficiency improved hepatic lipid accumulation and hepatic inflammation in HFD-fed mice.

Background Complete complement factor I (CFI) deficiency is an inborn error of immunity (IEI) that results in heightened susceptibility to infections and immune dysregulatory disorders. This systematic review seeks to enhance our understanding of the clinical characteristics, genotype–phenotype correlations, and treatment outcomes in patients with complete CFI deficiency, including three novel cases. We conducted a comprehensive literature review of cases published from 1996 to November 2024, identifying 49 patients with homozygous or compound heterozygous mutations in the CFI gene. Results Among the 49 patients, the mean age at initial presentation was 7.19 (± SD: 9.75) years. Most patients presented with infectious manifestations (n: 37, 75.5%), particularly sepsis (n: 18, 36.7%). The predominant pathogens were encapsulated organisms, particularly Neisseria meningitidis . Immune dysregulatory manifestations involved rheumatologic (n: 14, 28.57%), neurologic (n: 11, 22.4%), and renal (n: 8, 16.3%) disorders. Immunological evaluations showed low or absent levels of C3 and CFI in most patients. Genetic analysis identified 45 distinct mutations; less deleterious mutations, such as missense and splicing variants, were more common in those with immune dysregulation. Notably, three patients treated with eculizumab demonstrated significant clinical improvement. Conclusion Complete CFI deficiency presents a varied clinical spectrum, from asymptomatic to recurrent infections and immune dysregulation. Early diagnosis and targeted therapies, such as eculizumab, may improve patient outcomes. These findings underscore the necessity for further research into the nature of complete CFI deficiency and the development of optimal management strategies.

Deficiency of complement factor I is a rare immunodeficiency that typically presents with increased susceptibility to encapsulated bacterial infections. However, non-infectious presentations including rheumatological, dermatological and neurological disease are increasingly recognized and require a high-index of suspicion to reach a timely diagnosis. Herein, we present two contrasting cases of complement factor I deficiency: one presenting in childhood with invasive pneumococcal disease, diagnosed using conventional immunoassays and genetics and the second presenting in adolescence with recurrent sterile neuroinflammation, diagnosed via a genomic approach. Our report and review of the literature highlight the wide spectrum of clinical presentations associated with CFI deficiency and the power of genomic medicine to inform rare disease diagnoses.

Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to Gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1β and IL-8 were more dependent on complement than IFN-γ and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-γ inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to Gram-negative bacteria.

ObjectiveComplement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM.MethodsThe study population included 105 patients with JDM and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and qPCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 patients with JDM and seven controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR.ResultsSignificantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed in JDM versus controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of patients with JDM compared with 18.2% of controls (OR=3.00 (1.87 to 4.79), p=8.2×10−6). Patients with JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.0025). Microarray profiling of blood RNA revealed upregulation of type I interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A-deficient or DR3-positive patients.ConclusionsComplement C4A deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background.

Objective: To evaluate the frequency of primary immunodeficiencies (PID) in juvenile systemic lupus erythematosus (JSLE) patients. Methods: Some 72 JSLE patients were analyzed for levels of immunoglobulin classes and IgG subclasses and early components of the classical complement pathway. Determination of C4 gene copy number (GCN) and detection of type I C2 deficiency (D) were also performed. Results: PID was identified in 16 patients (22%): C2D in three, C4D in three, C1qD in two, IgG2D (<20 mg/dl) in four, IgAD (<7 mg/dl) in three, and IgMD (<35 mg/dl) in three; one of these patients presented IgA, C2 and C4D. Two patients had low C4 GCN and two had type I C2D. Demographic data, family history of autoimmune disease and PID, JSLE clinical findings, occurrence of infections, disease activity and therapies were similar in patients with and without PID (p > 0.05). Remarkably, the median of Systemic Lupus International Collaborating Clinics/ACR-damage index (SLICC/ACR-DI) was significantly higher in JSLE patients with PID compared with patients without these abnormalities (p = 0.0033), likewise the high frequency of SLICC/ACR-DI > 1 (p = 0.023). Conclusions: A high frequency of PID was observed in JSLE patients, suggesting that these defects may contribute to lupus development. Our findings indicate that these two groups of PID should be investigated in severe pediatric lupus.

Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q− and 17p−). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P <0.01; n =52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels ( P <0.0001; n =9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy.