What is the difference between interferon and complement

Fusion of C3d to target antigens is another approach for the development of safer, more immunogenic DNA vaccines. Coupling of C3d to the secretory form of Influenza virus haemagglutinin in mice provided an effective and safer mechanism for mucosal vaccination compared to the use of other adjuvants i.

So, the use of C3d as an adjuvant can help to overcome the low immunogenicity associated with DNA vaccines, whilst maintaining their safety. In the examples where viral-mediated complement activation has been more extensively studied, a viral mechanism is often identified which protects the virus from certain antiviral functions, such as the acquisition of CD46, CD55, CD59 to protect from MAC formation or the expression of a regulatory protein to inhibit the complement cascade at various points.

The viruses which activate complement would consequently trigger the downstream antiviral effects, both intracellularly and extracellularly. Therefore, it seems plausible that these viruses would utilize a mechanism, similar to the ones described in this review, to evade this antiviral activity and promote their survival.

If such a regulatory protein or process is identified, then these may present as possible antiviral targets, similar to the targeting of the rhinovirus 3C protease with rupintrivir 6. The complex interplay between viruses and the complement system can have profound implications for protection via innate immunity and the development of effective adaptive immunity.

Such developments can also be applied for non-viral pathogens including bacteria, fungi, protozoa and to broader, more systemic functions of the complement system including: interferon signaling , , metabolism , brain development , and the coagulation system Components of the complement system form an ancient aspect of innate immunity in vertebrates and even some invertebrates , Therefore, many animals which act as viral hosts or reservoirs for zoonoses also have an active complement system for targeting pathogens i.

Further viral mechanisms of complement regulation may therefore exist which have not yet been identified and the plasticity of viral genomes could result in the emergence of novel protein regulatory functions. Identifying these novel interactions could be important for the development and augmentation of vaccines and therapeutics or even the possibility of utilizing viral-derived regulatory proteins as therapeutic complement inhibitors in other diseases The benefits from understanding complement mechanisms in viral diseases may have relevance for the current SARS-CoV-2 outbreak.

Previous research has demonstrated the impact of the complement system in coronavirus infections and other diseases, and this knowledge has led to the consideration of several complement inhibitors as therapeutics for severe cases of COVID JM wrote the manuscript and designed the tables and figures. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Fibronectin binds to the C1q component of complement. The interaction of human plasma fibronectin with a subunit of the first component of complement, C1q. PubMed Abstract Google Scholar. The proteoglycan decorin binds C1q and inhibits the activity of the C1 complex. Rainard P. Activation of the classical pathway of complement by binding of bovine lactoferrin to unencapsulated Streptococcus agalactiae.

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Structural basis of complement membrane attack complex formation. Nat Commun. Human M-ficolin is a secretory protein that activates the lectin complement pathway. The two major oligomeric forms of human mannan-binding lectin: chemical characterization, carbohydrate-binding properties, and interaction with MBL-associated serine proteases. Characterization of the complex between mannose-binding lectin trimer and mannose-binding lectin-associated serine proteases.

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Ficolins: novel pattern recognition molecules of the innate immune response. Structural insights into the recognition properties of human ficolins.

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Heteromeric Complexes of native collectin kidney 1 and collectin liver 1 are found in the circulation with MASPs and activate the complement system. Proteolytic activities of two types of mannose-binding lectin-associated serine protease.

MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. C3 adsorbed to a polymer surface can form an initiating alternative pathway convertase. Nilsson B, Nilsson Ekdahl K. The tick-over theory revisited: is C3 a contact-activated protein? Lachmann PJ. The amplification loop of the complement pathways. Adv Immunol. Quantitative modeling of the alternative pathway of the complement system. The central role of the alternative complement pathway in human disease.

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Nat Rev Immunol. Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly. The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis.

Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation. Complement factor P is a ligand for the natural killer cell-activating receptor NKp Sci Immunol. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.

Mol Immunol. A C3 H20 recycling pathway is a component of the intracellular complement system. J Clin Investig. On the functional overlap between complement and anti-microbial peptides. Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways.

The endothelium is an extrahepatic site of synthesis of the seventh component of the complement system. Clin Exp Immunol. Characteristics and biological variations of M-Ficolin, a pattern recognition molecule, in plasma. Production of complement components by cells of the immune system. Selective expression of clusterin SGP-2 and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro. Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins.

Investig Ophthalmol Vis Sci. Differential expression of complement regulatory proteins decay-accelerating factor CD55 , membrane cofactor protein CD46 and CD59 during human spermatogenesis. J Leukoc Biol. Murine CD93 C1qRp contributes to the removal of apoptotic cells in vivo but is not required for C1q-mediated enhancement of phagocytosis.

CD93 is rapidly shed from the surface of human myeloid cells and the soluble form is detected in human plasma. Activation of human neutrophils by C3a and C5A. C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway.

C3a and C5a stimulate chemotaxis of human mast cells. The human C3a receptor is expressed on neutrophils and monocytes, but not on B or T lymphocytes. Expression of a functional anaphylatoxin C3a receptor by astrocytes. J Neurochem. Activated human T lymphocytes express a functional C3a receptor. Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a-C3aR interaction. The Anaphylatoxin C3a receptor expression on human M2 macrophages is down-regulated by stimulating the histamine H4 receptor and the IL-4 receptor.

Differential expression of complement receptors on human basophils and mast cells. Human T cells express the C5a receptor and are chemoattracted to C5a. Up-regulation of C5a receptor expression and function on human monocyte derived dendritic cells by prostaglandin E2. The C1q and collectin binding site within C1 q receptor cell surface calreticulin. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro : calreticulin and CD91 as a common collectin receptor complex.

Direct interaction between CD91 and C1q. FEBS J. Expression of Complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. Tumor-promoting phorbol esters stimulate C3b and C3b' receptor-mediated phagocytosis in cultured human monocytes. Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis. Comp Inflamm.

Pascual M, Schifferli JA. The binding of immune complexes by the erythrocyte complement receptor 1 CR1. Role of complement receptor 1 CR1; CD35 on epithelial cells: a model for understanding complement-mediated damage in the kidney.

Identification of the membrane receptor for the complement fragment C3d by means of a monoclonal antibody. Structural Immunology of Complement Receptors 3 and 4. Complement receptor 3 ligation of dendritic cells suppresses their stimulatory capacity.

CR3 is the dominant phagocytotic complement receptor on human dendritic cells. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens.

The multiligand-binding protein gC1qR, Putative C1q receptor, is a mitochondrial protein. C1q-mediated chemotaxis by human neutrophils: involvement of gClqR and G-protein signalling mechanisms. Biochem J. Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR.

Analysis of the interaction between globular head modules of human C1q and its candidate receptor gC1qR. C5L2, a nonsignaling C5A binding protein. Membrane cofactor protein of complement is present on human fibroblast, epithelial, and endothelial cells. Membrane cofactor protein CD46 protects cells from complement- mediated attack by an intrinsic mechanism. Soluble forms of membrane cofactor protein CD46, MCP are present in plasma, tears, and seminal fluid in normal subjects. Nat Immunol. Complement 1 inhibitor is a regulator of the alternative complement pathway.

Human factor H and C4b-binding protein serve as factor I-cofactors both encompassing inactivation of C3b and C4b. Regulation of complement activation by C-reactive protein: targeting of the inhibitory activity of C4b-binding protein. Arthr Res Ther. C8 binding protein bears I antigenic determinants.

Ann Hematol. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Identification of the complement decay-accelerating factor DAF on epithelium and glandular cells and in body fluids. Decay-accelerating factor must bind both components of the complement alternative pathway C3 convertase to mediate efficient decay.

Decay-accelerating factor regulates T-cell immunity in the context of inflammation by influencing costimulatory molecule expression on antigen-presenting cells. Human protectin CD59 , an 18,, MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers.

CD59 functions as a signal-transducing molecule for human T cell activation. Alternative roles for CD Cell Immunol. Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9. Complement factor H: using atomic resolution structure to illuminate disease mechanisms. Adv Exp Med Biol. Insights into the effects of complement factor H on the assembly and decay of the alternative pathway C3 proconvertase and C3 convertase.

Kishore U, Sim RB. Factor H as a regulator of the classical pathway activation. Role of human factor I and C3b receptor in the cleavage of surface-bound C3bi molecules.

J Biochem. Hourcade DE. The role of properdin in the assembly of the alternative pathway C3 convertases of complement. Complement inhibition by human vitronectin involves non-heparin binding domains. Complement and bacterial infections: from molecular mechanisms to therapeutic applications. Activation of the complement system by Cryptococcus neoformans leads to binding of iC3b to the yeast.

Infect Immun. Human C1-inhibitor suppresses malaria parasite invasion and cytoadhesion via binding to parasite glycosylphosphatidylinositol and host cell receptors. A human serum mannose-binding protein inhibits in vitro infection by the human immunodeficiency virus. Virus complement evasion strategies.

Complement and viral pathogenesis. Viral-derived complement inhibitors: current status and potential role in immunomodulation. Exp Biol Med. Complement evasion strategies of viruses: an overview.

Front Microbiol. Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity. J Virol. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 Infection. Human transferrin is encoded by the TF gene.

Transferrin glycoproteins bind iron very tightly, but reversibly. Although iron bound to transferrin is less than 0. Antimicrobial peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life. Antimicrobial peptides also called host defense peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides.

These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria including strains that are resistant to conventional antibiotics , mycobacteria including Mycobacterium tuberculosis , enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics, it appears as though antimicrobial peptides may also have the ability to enhance immunity by functioning as immunomodulators.

Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure. Antimicrobial peptides generally consist of between 12 and 50 amino acids. The secondary structures of these molecules follow 4 themes, including:.

Various AMPs : These are various antimicrobial peptide structures. Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. It contains hydrophilic amino acid residues aligned along one side and hydrophobic amino acid residues aligned along the opposite side of a helical molecule. This amphipathicity of the antimicrobial peptides allows the partition of the membrane lipid bilayer.

The ability to associate with membranes is a definitive feature of antimicrobial peptides, although membrane permeabilisation is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets. The modes of action by which antimicrobial peptides kill bacteria is varied and includes disrupting membranes, interfering with metabolism, and targeting cytoplasmic components.

The initial contact between the peptide and the target organism is electrostatic, as most bacterial surfaces are anionic, or hydrophobic, such as in the antimicrobial peptide Piscidin. Alternately, they may penetrate into the cell to bind intracellular molecules which are crucial to cell living. Intracellular binding models include inhibition of cell wall synthesis, alteration of the cytoplasmic membrane, activation of autolysin, inhibition of DNA, RNA, and protein synthesis, and inhibition of certain enzymes.

However, in many cases, the exact mechanism of killing is not known. One emerging technique for the study of such mechanisms is dual polarisation interferometry.

In contrast to many conventional antibiotics these peptides appear to be bacteriocidal bacteria killing instead of bacteriostatic bacteria growth inhibiting. In general the antimicrobial activity of these peptides is determined by measuring the minimal inhibitory concentration MIC , which is the lowest concentration of drug that inhibits bacterial growth.

In addition to killing bacteria directly, they have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection, including the ability to:. Animal models indicate that host defense peptides are crucial for both prevention and clearance of infection. Several methods have been used to determine the mechanisms of antimicrobial peptide activity. In particular, solid-state NMR studies have provided an atomic-level resolution explanation of membrane disruption by antimicrobial peptides.

The most common form of autoimmune heart disease is rheumatic heart disease, or rheumatic fever. A typical mechanism of autoimmunity is autoantibodies, or auto-toxic T-lymphocyte mediated tissue destruction.

The process is aided by neutrophils, the complement system, and tumor necrosis factor alpha. Aetiologically, autoimmune heart disease is most commonly seen in children with a history of sore throat caused by a streptococcal infection. This is similar to the post-streptococcal glomerulonephritis.

Here, the anti-bacterial antibodies cross react with the heart antigens causing inflammation. Viral myocarditis : Histopathological image of myocarditis at autopsy in a patient with acute onset of congestive heart failure.

Pericarditis : Here the pericardium gets inflamed. Acutely, it can cause pericardial effusion leading to cardiac tamponade and death. After healing, there may be fibrosis and adhesion of the pericardium with the heart, leading to constriction of the heart and reduced cardiac function. Myocarditis : Here the muscle bulk of the heart gets inflamed. Inflamed muscles have reduced functional capacity. This may be fatal if left untreated, as is in a case of pancarditis. On healing, there will be fibrosis and reduced functional capacity.

Endocarditis : Here the inner lining of the heart is inflamed, including the heart valves. This may cause a valve prolapse, adhesion of the adjacent cusps, of these valves, and occlusion of the flow tracts of blood through the heart, which causes disease known as valve stenosis.

Specific clinical manifestations depend on the amount of inflammation. Therapy will involve intensive cardiac care and immunosuppressives, including corticosteroids, which are helpful in the acute stage of the disease. The chronic phase consists of mainly debility control and supportive care options. Privacy Policy. Skip to main content. Search for:.

Innate Defenders. Learning Objectives Illustrate the key points of the complement system. Key Takeaways Key Points Three biochemical pathways activate the complement system—the classical complement pathway, the alternative complement pathway, and the lectin pathway. The following are the basic functions of the complement: Opsonization enhancing phagocytosis of antigens ; chemotaxis attracting macrophages and neutrophils ; cell lysis rupturing membranes of foreign cells ; and clumping antigen-bearing agents.

Key Terms antibodies : An antibody Ab , also known as an immunoglobulin Ig , is a large Y-shaped protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.

The host may be an animal including humans , a plant, or even another microorganism. Interferons Interferons IFNs are proteins made and released by host cells in response to the presence of pathogens. Learning Objectives Identify interferons and their effects. IFNs activate immune cells natural killer cells and macrophages , increase recognition of infection and tumor cells by up-regulating antigen presentation to T lymphocytes, and increase the ability of uninfected host cells to resist new infection by virus.

Key Terms Interferons : Interferons IFNs are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites or tumor cells.

They allow for communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors. Natural Killer Cells Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. Learning Objectives Describe natural killer cells. NK cells constitute the third kind of cells differentiated from the common lymphoid progenitor generating B and T lymphocytes. NK cells provide rapid responses to virally infected cells and respond to tumor formation, acting at around 3 days after infection.

Key Terms Natural killer cells or NK cells : Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. Dandoy, Benjamin L. Laskin, Stella M. Davies; Interferon-complement loop in transplant-associated thrombotic microangiopathy.

Blood Adv ; 4 6 : — Complement and interferon interplay promotes thrombotic microangiopathy and can serve as novel therapeutic target. Combined interferon and complement blockade might improve clinical outcomes in thrombotic microangiopathy.

The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA.

In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome aHUS , where complement activation occurs largely via the alternative pathway.

Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

Here, we present novel evidence using gene expression analysis of complement activation via all complement pathways-alternative, classical, and lectin. Our data indicate important roles for activation of both complement and interferon pathways in patients with TA-TMA and offer potential new therapeutic targets for TA-TMA and other disorders presenting with thrombotic microangiopathies, especially in patients with lack of response to eculizumab therapy.

Patients are consented before transplant, prospectively enrolled, and blood samples are collected and stored starting before transplant and continuing weekly until day after HSCT. Cases and time-matched controls had available peripheral blood mononuclear cells PBMCs samples stored within 1 week before transplant conditioning chemotherapy baseline , at the time of TA-TMA diagnosis, and when eculizumab was discontinued or equivalent timepoints in controls supplemental Figure 1.

Patient demographics and disease characteristics were captured from the clinical database. A baseline sample was not used because it represents recipient PBMCs. To accurately quantify the library concentration for the clustering, the library was diluted in dilution buffer 10 mM Tris-HCl, pH 8. Individually indexed libraries were proportionally pooled million reads per sample for clustering in the cBot system Illumina, San Diego, CA.

Libraries at the final concentration of Sequence reads were aligned to the human reference genome hg19 using the TopHat2 aligner 16 and reads aligning to each known transcript were counted using Bioconductor packages for NGS data analysis.

Statistical significance of differential expressions was established for false discovery rate FDR —adjusted P values. The gene list enrichment analysis was performed in 2 steps.

A stringent Bonferroni adjustment was used for P value adjustment in this analysis. Second, the Random Set 25 enrichment analysis, as implemented in the CLEAN package, 26 of upregulated genes against all MSigDB gene sets 27 was performed to identify additional complement and interferon-related categories.

Standard FDR P value adjustment was also used in this analysis. We selected 7 autologous HSCT recipients range, years old with neuroblastoma who all received identical high-dose chemotherapy conditioning with carboplatin, etoposide, and melphalan, a regimen reported to be associated with a high-risk of TA-TMA and had stored samples available for this study. All 4 cases were treated with eculizumab and received 7 to 19 doses, after which they all had resolution of TA-TMA and normalization of their blood sC5b-9 concentration and recovery of organ function.

Eculizumab was successfully discontinued in all treated cases without any evidence of TA-TMA recurrence. All 4 cases were alive and well at 1 year after transplant.

Demographics and disease characteristics are summarized in supplemental Table 2. Demographics and relevant disease characteristic are listed in supplemental Table 3. An enrichment analysis of KEGG pathways, 21 transcription factor targets, 22,23 and MSigDB hallmark gene sets 24 identified significant activation of complement, complement-related genes, and interferon-responsive genes Table 1. The involvement of differentially expressed genes in upregulated complement and interferon-related pathways, including signal transducer and activator of transcription 1 and 2 STAT1 and STAT2 targets, is illustrated in supplemental Figure 2.

The comprehensive analysis of MSigDB identified additional complement and interferon-related gene sets enriched for upregulated genes Table 2. Upregulated pathways and transcription factor targets at the time of TA-TMA diagnosis as compared with pretransplant baseline. Focused analysis of gene expression levels of complement and interferon-related genes showed significant changes in expression of 76 complement and interferon-related genes Figure 1.

The genes that were still upregulated after resolution of TA-TMA were related to proliferation, and increased expression is likely appropriate during stem cell engraftment and blood count recovery. The figure shows a section of the heatmap that illustrates the change in complement and interferon gene expression profiles in patients with TA-TMA. Pathway analyses confirmed significant upregulation of multiple complement pathways, including upregulation of the alternative, classical, and lectin pathways at TA-TMA diagnosis as compared with pretransplant baseline.

No complement pathways were downregulated. Specifically, the data showed a marked upregulation of expression of the complement component C1Q C chain Upregulation of C2 elevated 2. Factor D was also upregulated 1. Additional changes in expression of key genes in the alternative, classical, and lectin pathways of complement activation are displayed in Figure 2. This figure illustrates gene expression in alternative, classical, and lectin complement pathways among cases with TA-TMA at the time of clinical diagnosis but before initiation of complement-blocking therapy with eculizumab.

Red letters and red outlines indicate statistically significant changes in gene expression from pretransplant baseline to the time of TA-TMA clinical diagnosis. Because of our interest in identifying new targetable endothelial injury pathways, we investigated if interferon activation was associated with TA-TMA, or just with the transplantation process itself, by comparing gene expression profiles at TA-TMA diagnosis and resolution in cases with TA-TMA and at equivalent timepoints in controls without TA-TMA.

Most of the genes in interferon related pathways were not significantly upregulated in controls without TA-TMA at equivalent timepoints posttransplant. Green bars indicate statistically significant differences between time points. Interferon pathways are not upregulated in controls without TA-TMA at matched time points after transplant.

Expression of C2, a key component of the classical pathway, was significantly elevated in cases with TA-TMA, as was CFD, a promoter of rapid activation of complement via the alternative pathway.

CFI, a negative regulator of complement, was significantly upregulated more than eightfold in controls without TA-TMA and was nonsignificantly upregulated 3. We examined only TA-TMA diagnosis and TA-TMA resolution timepoints and not the pretransplant baseline sample in these subjects because in the allogeneic HSCT setting the host genome is present before transplant and the donor genome at the latter 2 timepoints. HSCT is a planned procedure and TA-TMA is frequent in our patient population so biological samples can be collected before, during, and after TA-TMA, allowing mechanistic studies that are impossible with less predictable forms of thrombotic microangiopathies, like atypical hemolytic uremic syndrome aHUS.

The cause of endothelial injury in patients with neuroblastoma and TA-TMA is likely related to high-dose chemotherapy, and we were able to study children receiving exactly the same chemotherapy regimen to eliminate another potential source of heterogeneity. We considered at length the suitability of PBMC as a source of RNA for this study, rather than liver, traditionally thought to be the major source of complement components.

PBMC have the important advantage of being accessible for serial collection, a strategy that would not be possible with liver tissue from human patients. The complement components C1q, C7, properdin, and CFD are predominantly produced by myeloid cells, particularly monocytes and dendritic cells. All subjects undergoing HSCT likely have some degree of endothelial injury from high-dose chemotherapy, medications, and infectious agents.

In previous work, we have shown that both complement gene polymorphisms and non-Caucasian race are associated with increased risk of TA-TMA. Our new observation of the role of interferon expression in TA-TMA offers an additional potential mechanism for the association with non-Caucasian race. A recent publication from Cole et al analyzed variation in the expression of genes involved in inflammation and type I interferon using peripheral blood transcriptome profiles. This cohort study of normal young adults demonstrated increased upregulation of interferon gene expression in Blacks and Asians relative to non-Hispanic whites.

These novel findings are in agreement with the highly inflammatory clinical phenotype of children presenting with severe TA-TMA, and may explain, at least in part, incomplete response to complement blocking therapy in some patients, especially after allogeneic transplant, despite achievement of therapeutic drug concentration in the blood.

Because we purposely selected subjects that were eculizumab therapy responders, we do not directly demonstrate that anti-interferon agents are beneficial. We are hoping to document the need or benefit of interferon blockade in poor responders in the future, by testing augmentation of therapy with the targeted anti-interferon agent emapalumab in children with an inadequate or delayed response to complement blockade. Interferons and complement are both key components of innate immunity, and interferons induce expression of many complement genes.