What is the difference between complement proteins and interferons

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.

In particular, the key initiators of complement activation by the classical pathway, C1QC, B, and A, are upregulated by interferons, in addition to the amplifier of cascade activation, CFD, and the classical pathway component C2. Our current data demonstrate activation of the classical, lectin, and alternative complement pathways in TA-TMA. These data contrast with findings in aHUS where complement activation is thought to occur largely via the alternative pathway.

Our previously reported clinical experience indicates that complement blockade alone allows resolution of TA-TMA in many instances, but not all, despite achievement of therapeutic drug concentration and full complement blockade, measured by a very low complement hemolytic activity CH50 in the blood of treated patients. Moreover, the benefits of complement blockade may not manifest for more than 7 days after start of therapy, and additional organ injury or even death can occur in that time.

Immediate and brief interferon blockade in severe cases might interrupt endothelial injury loop and reduce inflammation and organ injury until complement blockade can extinguish the underlying process. Our data show that gene expression returns to baseline levels with no residual elevation of complement-related pathways after eculizumab therapy in responding patients and in general TA-TMA reactivation has not occurred after stopping therapy. Data in a small group of allogeneic transplant recipients supported a similar mechanism.

These data further support our usual strategy of discontinuing eculizumab after resolution of TA-TMA. A similar strategy may identify patients with other thrombotic microangiopathies in whom short course of complement blockers or combined complement and interferon blocking therapy may also be indicated. In this report, we describe a close interaction between elevation of interferons and complement in initiating and maintaining inflammation and organ injury in TA-TMA for the first time.

Interferons promote expression of complement genes, such as C1Q, which initiates the classical complement pathway and ultimately leads to formation of the lytic membrane attack complex MAC or C5b-9 and endothelial injury presenting as TMA. Injured endothelial cells release interleukin-8 IL-8 , causing neutrophil activation and formation of neutrophil extracellular traps NETs.

NET formation promotes complement system activation via factor P. High levels of interferons administered exogenously as a therapeutic agent can be directly damaging to the endothelium and are known to result in TMA. Interferon-complement loop.

This figure displays the relationship between interferon and complement activation that perpetuates vascular endothelial injury in clinical conditions presenting with thrombotic microangiopathy where both interferon and complement pathways are activated. Our study has strengths and limitations. Our study benefited from a careful, prospective TA-TMA phenotyping in HSCT recipients using established diagnostic and risk criteria, and our experience using eculizumab in these complex patients. TA-TMA offers a unique opportunity for serial study and comparison of baseline state with disease state, a strategy that is more challenging in other microangiopathies, such as aHUS, in which there is rarely opportunity to collect samples immediately before disease presentation.

We studied a modest number of autologous HSCT cases and controls, and demonstrated similar findings in small group of allogeneic HSCT recipients, but the strength of the associations we report suggest that larger patient numbers will not importantly alter the conclusions of the study.

Moreover, neuroblastoma patients enrolled were homogeneous, with the same diagnosis and similar age, and they had been treated with the same chemotherapy regimen, an important strength of the analysis. We do recognize that although examining complement gene expression in PBMC in this clinical circumstance is valuable, there may be important changes in hepatic production of complement components that we were unable to study.

In summary, we observed that interferon gene expression in addition to the activation of all 3 complement pathways may represent new targetable mechanism of endothelial injury in thrombotic microangiopathies. It is possible that brief, combined anti-complement and anti-interferon treatment may facilitate rapid disease control in TA-TMA and other interferon- and complement-driven diseases.

Steroids can likely modify interferon production to some degree and might be considered as an adjunct to complement blocking therapy in some patients with TA-TMA like who are not receiving steroids for other clinical indications.

We speculate that response to steroids would depend on the magnitude of interferon system activation because clinical responses to the interferon blocker emapalumab are observed in patients with hemophagocytic lymphohistiocytosis, an interferon-driven disease, after failing to achieve disease remission with high-dose dexamethasone.

Also, anifrolumab is a monoclonal antibody against the type I interferon receptor that inhibits the activity of all type I interferons and is being tested in patients with systemic lupus erythematosus. The generalizability of these data to more complex clinical settings such as allogeneic stem cell transplant needs to be established, and such RNAseq studies are under way. We are also interested in additional variables such as age, presence of concomitant GVHD and infections, race, and use of specific preparative regimens; these will also be tested in specific targeted studies of interferon in the future.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Contribution: S. Conflict-of-interest disclosure: S. The remaining authors have no disclosures to report. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Key Points. Article Navigation.

Sonata Jodele , Sonata Jodele. This Site. Google Scholar. These receptors can be found in the cytosol or in the endosome. Once a virus infects a cell, the cell activates signals that lead to phosphorylation, dimerization and passage to the nucleus of the interferon response factor 3 IRF3.

Interferon response comprises a series of reactions that alter the expression of a variety of human genes. This pathway, however, does not work in isolated manner. It extensively communicates with other signal transduction pathways, therefore recruiting several effector molecules to promote a potent effect against viral infections, antiproliferative and antitumor activities, in addition to the immunomodulatory effects.

In terms of morphology, they are similar to plasmocytes, another type of cell responsible for the massive production of this cytokine. IPCs express toll-like receptors TLRs 6, 7, 9 and 10, which are critical components of innate immunity, acting as pathogen sensors.

Toll-like receptors act on innate immunity cells by detecting conserved patterns of pathogenic microorganisms. These cells, when activated by these receptors, lead to maturation of antigen-presenting cells and production of inflammatory cytokines. IPCs still differentiate into a unique type of mature dendritic cell, which allows the direct regulation of the function of T cells and links innate and adaptive immune responses.

This process occurs at a later stage of viral infection [ 11 , 17 , 18 , 19 , 20 ]. The whole process mentioned above can be summarized through the following explanation. On the following 2 days, IPCs differentiate into a type of dendritic cell called a plasmacytoid dendritic cell, which maintains the ability to produce interferon.

During the infection process, these cells cluster into the T cell areas of the draining lymph nodes. Although there is some similarity between plasmacytoid dendritic cells and myeloid dendritic cells known as conventional dendritic cells , it is believed that plasmacytoid dendritic cells do not have a substantial involvement in T cell activation in adaptive immunity, which is the main function of conventional dendritic cells.

Therefore, in the context of innate immunity, conventional dendritic cells produce relatively small amounts of type I IFN, but produce large amounts of IL, a cytokine that interacts with type I IFN to activate the NK cell response to viral infection [ 7 , 11 ].

IFNs, besides being first line of defense against viral infections, play important roles in immunosurveillance for malignant cells. More specifically, type I interferons present a potent antiviral activity, which is associated with several physiological changes. Firstly, these cytokines stimulate resistance to viral replication in all cells through cellular genes activation, with the consequent destruction of the viral mRNA and inhibition of the viral proteins translation.

Secondly, they promote an increase in ligands to NK cell receptors expression in virus-infected cells. Thirdly, they lead to NK cells to eradicate virus-infected cells [ 8 , 21 , 22 ]. It is possible to say that NK cells play, in innate immune response, similar functions than cytotoxic T cells in adaptive immune response [ 23 , 24 ]. This unique specimen of type II IFN is the primary cytokine involved in macrophage activation named as classical activation and plays a critical role in immunity against intracellular microorganisms.

In addition, B cells and professional antigen-presenting cells e. Regarding biological activities, both type I and type II IFN are essential in the immediate cellular response to viral infections. Thus, this cytokine establishes an antiviral state for long-term control, coordinating the transition from innate to adaptive immunity.

Once activated, macrophages release cytokines that participate in T cells activation, therefore initiating the adaptive immune response. This cytokine presents strong antiviral activity and has been recently described to be related to hepatitis C treatment failure. The first sign that type I IFN was somehow involved with human autoimmune diseases came from the observation of an increased incidence of autoantibodies and autoimmune diseases after type I IFN treatment.

As previously mentioned, pDCs are responsible for producing high levels of type I IFN in response to nucleic acid-containing immune complexes through the activation of TLRs 7 and 9 [ 11 ].

These immune complexes are prevalent in autoimmune conditions, such as systemic lupus erythematosus SLE , which makes this process highly relevant for the development of autoimmunity. Hence, type I IFN plays a substantial role in this kind of condition [ 16 ]. The role of this cytokine in autoimmune diseases both in promoting and suppressing the condition has been shown in several mouse models.

Due to the ability to increase immune response, type I and type II IFN have been explored in clinical trials as treatments for several conditions. It has been found that these cytokines are involved with the improvement of several conditions, such as hepatitis B and C virus infections, autoimmune diseases and certain types of leukemia and lymphomas.

Hence, this class of cytokines, which play a paramount role in the immune system, consist of valuable treatment strategy. Still, in order to obtain full advantage of the therapeutic potential of interferons, further researches are needed to elucidate the core mechanisms of their effects [ 31 , 32 ]. Tumor necrosis factor TNF is a cytokine that had the name derived from it discovery in as a molecule that caused in vitro necrosis of tumors.

Shortly thereafter, it was observed that TNF expression was promoted by immune system cells. The binding of this family of cytokines with their respective receptors triggers especially inflammatory reactions [ 33 , 34 , 35 , 36 , 37 ].

They are related to inflammatory reactions, so that a cytokine bind to the receptor, it induces the recruitment of proteins that are important for the process [ 35 , 40 ]. The production of this cytokine is performed by different cells from the immune system, which includes T cells, NK cells, macrophages and monocytes. It is primary secreted as a nonglycosylated type II membrane protein arranged as homotrimer.

TNF membrane releases a trimeric soluble cytokine a polypeptide that weighs around kDa with triangular pyramid shape through proteolytic cleavage by metalloprotease TNF-converting enzyme, and this is the circulating form that is found in blood plasma, and that allows a potent capacity to displacement in the body, thus it endocrine function. It is not well defined but from three of these circulating TNF it is possible to polymerize them forming one kD polypeptide which facilitates the binding of the cytokine with three receptors simultaneously [ 37 , 41 , 42 ].

TNF have a lot of physiologic multifunction including immune and inflammatory roles and the survival and death of different cells. The main function of cytokine is to attract and activate immune cells to sites of infections and to destroy pathogens, such as bacteria and virus.

In this context, TNF stimulate vascular endothelial cells to express adhesion molecules e. Additionally, complementing the inflammatory response, TNF induces the production of chemokines that increase the affinity of leukocyte to their ligands, the expression of IL-1 and to activate microbicidal functions of immune system cells. For all TNF importance in the inflammatory reaction, if low quantities of this cytokine are presented in the local, the containment of the infection may be impaired [ 33 , 37 , 41 , 42 , 43 ].

TNF is also well known to act in inflammatory reaction of some autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. Errors in this production are responsible for a considerable number of autoimmune, neoplastic and other diseases. Under these conditions, the treatment of these diseases are based on biologic agents targeting TNF, and thus looking for reducing the number of available TNF molecules or to block it receptors [ 33 , 35 , 40 ].

TNF also promotes necrosis of tumor cells by inducing programmed cell death, a cytolytic potential. These intracellular proteins are responsible for the release of other proteins such as pro-caspase-8, which in it activated form activate caspase-3, caspase-6, caspase-7 and other cytosolic substrates.

Evidences also suggest that TNF have the capacity to induce carcinogenesis and to stabilize tumors, an event that it is opposite of the previous explained, by DNA mutations and it mechanism of repair i. There are other biological events and actions caused by TNF. When this cytokine is produced in large scale, such as in severe infection, it may induce shock or decrease of blood pressure due to reducing vascular muscle tone and myocardial contractility.

Additionally, in high concentrations TNF can reduce blood glucose concentration, and cause intravascular thrombosis by decreasing anticoagulant capabilities of the endothelium.

It has antimicrobial activity bacteriocide, fungicide and is part of the innate defense, mainly at mucoses. In particular, lactoferrin provides antibacterial activity to human infants. Lactoferrin interacts with DNA and RNA, polysaccharides and heparin, and shows some of its biological functions in complexes with these ligands. Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. 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.

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We thank T Miwa and Y Kimura for critical evaluation of the figures. You can also search for this author in PubMed Google Scholar. Correspondence to Wen-Chao Song. Reprints and Permissions. Dunkelberger, J. Complement and its role in innate and adaptive immune responses. Cell Res 20, 34—50 Download citation.

Published : 15 December