The complement system is an important part of the body’s innate immunity. It consists of more than 50 soluble proteins and membrane-bound proteins. It plays an important role in enhancing the humoral immune response and other life activities. Complement receptors are a class of membrane proteins that are mainly expressed on the surface of immune cell membranes. They combine with activated complement components to enhance the recruitment of leukocytes to sites of inflammation, promote phagocytosis to clear pathogenic microorganisms, and clear immune complexes produced at sites of infection or in the blood system and so on. Among them, the complement receptor 3 and the complement component 5 receptor have received much attention.

C5aR is a membrane glycoprotein with a molecular weight of 42 kda, belonging to a seven-transmembrane G protein-coupled receptor with high affinity for C5a and C5a-desarg.

Human CD4+ T cells have two C5 active components, C5a and C5a-desArg, and two C5a receptors, C5aR2 (GPR77 C5L2) and C5aR1 (CD88). Among them, C5aR1 is mainly distributed in the plasma membrane, while C5aR2 exists in the cell and plasma membrane. Studies have confirmed that cathepsin D (CTSD) can cleave C5 to generate the active component C5a, while cathepsin G (CTSG) can enzymatically degrade C5aR1 and inactivate it. In the resting state, human CD4+ T cells store a lower content of C5 and its active component C5a, while C5a receptors are dominated by C5aR2. When CD4+ T cells were stimulated by the outside world, the intracellular C5a content increased, and the C5aR receptor also turned to C5aR1. Intracellular C5a and C5aR1 are transported to the cell membrane and combined with each other, on the one hand, they can induce mitochondria to produce ROS, and on the other hand, they can promote the assembly of NLRP3 inflammasome to activate the autocrine of il-1β, and finally induce the production of interferon-γ. When the stimulation is terminated, the expression level of C5aR2 is restored and it forms a dimer with C5aR1, which can not only negatively regulate the above-mentioned intracellular signaling pathway mediated by C5aR1, but also inhibit the extracellular ERK1/2 signaling pathway mediated by C5aR1. The expression of interferon-γ in T cells decreased and the expression of il-10 increased, which promoted the rapid recovery of cells from the activated state to the resting state.

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Since the first outbreak of NiV, it has appeared in Malaysia, Singapore, Bangladesh, India and the Philippines in five countries, resulting in severe infection and high mortality in the population. Currently, there are no specific therapeutic drugs and preventive vaccines, and continuous monitoring of animal hosts and environments in high-risk areas of infection can help detect early signs of infection and control disease outbreaks.

NiV Gene Structure

NiV belongs to the paramyxoviridae family Henipavirus genus. It is an enveloped virus with a polymorphic shape and an average diameter of 500 nm (range 180 nm to 1 900 nm), with an envelope and spikes, and an unsegmented single-negative-stranded RNA genome. The genome encodes six structural proteins from the 3′ end, which are nucleoprotein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), glycoprotein (G) and large protein (L). Among them, the P gene also encodes three non-structural proteins C, V and W. The viral nucleocapsid is composed of three proteins, N, L, and P, and the envelope is composed of M, G, and F proteins.

NiV Detection Method

Currently, laboratory diagnosis is the only way to confirm NiV infection, which can be detected by techniques such as virus isolation, histopathology, serology, molecular diagnosis, and immunohistochemistry.

Virus Isolation and Culture

Virus isolation is the gold standard for laboratory diagnosis. NiV virus isolation can help identify new cases or identify new hosts. Infected samples are usually derived from acute-phase patient cerebrospinal fluid, blood, nasal/pharyngeal swabs, urine, or infected animal tissue (lymph nodes, lung, kidney, spleen, etc.). NiV grows well in Vero cells, and cytopathic effect (CPE) can be observed within 3 days of virus infection.  CPE is mainly manifested as syncytia composed of 20 or more nuclei, with the nucleocapsid and nuclei usually surrounding the cells, and this phenomenon is more pronounced in the later stages of infection. It is worth noting that the CPE will vary slightly depending on the strain and cell line used.

Molecular Diagnosis

PCR detection Molecular diagnostic techniques such as PCR and genome sequencing play an important role in the detection of viral infections in human and animal diseases due to their high sensitivity and fast detection speed. Before the establishment of real-time quantitative PCR (qPCR) detection methods for NiV, conventional PCR methods have been used for the detection and diagnosis of Henipavirus. The PCR method designed by the US CDC based on the conserved N gene of NiV can be used to detect nucleic acids in different types of specimens, including cerebrospinal fluid, urine, various swabs, and fresh or fixed tissues. Sequencing of PCR products facilitates the rapid identification of virus isolates from tissue supernatants. A nested PCR detection method targeting the N gene with an internal control reduces false negative results due to PCR inhibitors in the sample, thereby improving the detection accuracy and monitoring reliability.

Genome Sequencing

Sanger sequencing plays an important role in the diagnosis of NiV and the identification of potential mutation sites in target regions of the genome, and next-generation sequencing (NGS) has become the first choice for rapid whole-genome sequencing of new Henipavirus isolates. Using sequencing technology, it was found that the NiV strains isolated in Malaysia originated from different hosts such as bats, pigs and humans, but their genome sequences were very similar. The sequences of the NiV strains isolated from Bangladesh and India later were very different from those of the Malaysian strains. Large, genetic evolution analysis indicates that NiV has two main lineages: the Malaysian NiV and the Bangladeshi NiV.

Serological Testing

Enzyme-linked immunosorbent assay Currently, enzyme-linked immunosorbent assay (ELISA) has been widely used to detect NiV antigen and antibody responses. Indirect ELISAs developed using viral antigens for serological detection (IgM and IgG) have been used for sero-antibody transformation in humans and field studies in bats and other animals. Recombinant protein can be used as antigen instead of whole virus for ELISA detection. The expression of recombinant NiV N, F and G proteins in E.coli can react with the convalescent sera of NiV-infected patients, and the recombinant NiV G protein can also react with the sera of late-onset NiV-infected patients.

ELISA detection is fast, safe, low-cost, and high-throughput, but the sensitivity and specificity of the detection are slightly worse than molecular detection, and it is prone to false positives, and positive samples need to be verified by neutralization tests. Nonetheless, ELISA is currently the primary method for serological detection, facilitating NiV epidemiological studies and ongoing surveillance.

Serum Neutralization Test

The Serum neutralization test (SNT) is the reference standard for serological testing and needs to be performed at a BSL-4 facility. Traditional SNT uses Vero cells as host cells, and serum that can reduce or eliminate CPE is considered to have neutralizing activity. In order to reduce the biosafety level of the experimental operation, an improved version of SNT based on the rapid immune plaque test was established. The culture plates obtained in BSL-4, after inactivation by γ-irradiation, can be stained in BSL-2, so that SNT is no longer dependent on the BSL-4 facility, improving experimental operability. In addition, pseudovirus neutralization assays can also replace serum neutralization assays for infectious NiV in areas lacking BSL-4 facilities with high sensitivity and safety. The vesicular stomatitis virus (VSV) vector was used to construct recombinant pseudovirus particles expressing NiV F and G proteins and carrying green fluorescent protein (GFP), which can be used as known viral antigens to detect NiV serum samples . NiV antibody plaque inhibition test can be established by using the pseudovirus expressing NiV F or G protein constructed by this gene recombination technology.

Immunohistochemistry 
Anti-NiV antibodies can be used to detect NiV antigens in formalin-fixed tissues. NiV infection in ferrets causes lesions in the respiratory tract, lymphoid tissue, kidney and liver of the body, and viral antigens even exist in neurons and vascular endothelial cells. Therefore, immunohistochemical specimens should include brain, lung, mediastinal lymph nodes, spleen, and kidney. If testing a pregnant animal, the specimen should also include the uterus, placenta, and fetus. The Australian Animal Health Laboratory (AAHL) conducted a comparative study using different antisera and found that the highly immune rabbit serum prepared from NiV recombinant N protein had the best immunohistochemical staining effect on different tissues infected with Henipavirus.Immunohistochemical method for accurate pathogen location is helpful for histopathological research, high safety and traceability is helpful for retrospective pathogen analysis.

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This type of fat is the brown fat that has attracted attention since its discovery, and the beige fat that was discovered later. There are a large number of mitochondria in brown adipose tissue, and it is these mitochondria that play a role in producing heat. Subsequently, a large number of studies hope to explore the formation mechanism of brown fat and find a way to make the body more inclined to produce brown fat instead of white fat.

Recently, a study published in the journal Nature revealed the key mechanism of brown fat production. The study found that a cytokine can cause fat cells to brown and produce heat. This discovery is expected to provide a new target for the treatment of obesity, type 2 diabetes and other diseases.

In this study, in order to find factors that affect the production of brown fat, the researchers screened the sera of obese people and found cytokines whose expression was significantly decreased, including interleukin 27 (IL-27). IL-27 is a member of the IL-12 cytokine family. It is a heterodimeric cytokine composed of the expression product of Epstein-Barr virus inducible gene 3 (EBI3) and IL-27p28. IL-27 is expressed by antigen-presenting cells and interacts with a specific cell surface receptor complex called IL-27 receptor (IL-27R). Existing studies have shown that IL-27 plays an important role in inflammation and anti-inflammatory processes. However, recent studies have found that the nucleotide sequence encoding IL-27 is associated with body mass index and insulin resistance. What’s more interesting is that after patients undergoing bariatric surgery and losing weight, their levels of IL-27 have risen significantly. This series of phenomena all show that IL-27 seems to be closely related to the obesity process.

In order to verify the role of IL-27 in this process, the researchers constructed genetically engineered mice that knock out the IL-27 receptor. After they provided a high-fat diet, they found that these genetically engineered mice that knocked out the IL-27 receptor were more likely to be obese than normal mice in the control group, and had more serious glucose intolerance and insulin resistance. Therefore, the relationship between IL-27 and obesity has been confirmed. So, how does this cytokine affect the metabolic process? Through further research, it was found that under the condition of normal food intake, the energy expenditure of these IL-27 receptor-deficient mice was significantly reduced compared with ordinary mice. In addition, these mice are less resistant to cold environments, which means that the process of generating heat through energy consumption is inhibited. In addition, the level of uncoupling protein 1 (UCP1) in IL-27 knockout mice was significantly reduced regardless of whether they were fed high-fat food or normal food. Mitochondrial protein UCP1 is known to be indispensable in the thermogenesis of brown and beige fat. After re-injection of IL-27, UCP1 levels were also restored. These phenomena indicate that IL-27 affects the body’s metabolism by promoting the thermogenesis of brown and beige fat.

In addition, this research has also subverted our usual understanding of cytokines. This is also the first discovery that this cytokine can directly act on fat cells, breaking the inherent view that IL-27 specifically targets immune cells. The study found that IL-27 can promote the browning of white fat cells and the ability of brown or beige fat cells to produce heat. Furthermore, it reveals the signaling pathway that IL-27 affects the production of brown and beige fat. Using this pathway to provide new targets and potential drugs for the treatment of obesity and related metabolic diseases is the main direction of the next research.

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CD24 and Cancer

The usual purpose of the “don’t eat me” signal is to prevent macrophages from attacking normal cells in the body. In the past decade, researchers have identified three other “don’t eat me” proteins, namely PD-L1, CD47 and B2M, which cancer cells use to escape macrophages. Most types of immunotherapies that have been used target white blood cells called T cells, which are a key component of the body’s second immune defense system (called adaptive immunity). In contrast, CD24-inhibiting macrophages are part of the innate immune system—the body’s first line of defense against infection and abnormal cells.
In a new study before, scientists discovered that a protein called CD24 is a new “don’t eat me” signal, which they believe is a potential target for cancer immunotherapy. The research team’s findings indicate that the well-known intractable ovarian cancer and triple-negative breast cancer are cancers that can be targeted for treatment by blocking CD24. Macrophages that infiltrate the tumor pass through a receptor called Siglec-10 Interact with CD24 to recognize the “don’t eat me” signal.

CD24 and COVID-19

In addition to CD24 can be used for cancer treatment, recent studies have found that it can also be used for the treatment of severely ill patients with new coronary pneumonia. In patients with mild and common symptoms of the new coronavirus, most of the damage to the human body is caused by the virus invading the lungs, intestines or other organs. However, in severely ill (and part of the general type) patients, many injuries are caused by the patient’s own excessive immune response. The new coronavirus has triggered an over-reaction of the immune system, causing the immune system to over-attack itself, causing a severe storm of inflammatory factors, and eventually death.
Therefore, drugs for the treatment of new coronaviruses can generally be divided into two categories, one is for the virus and the other is for inflammatory factors. The former are more antiviral treatments, which are generally used for mild and common patients, such as remdesivir, and monoclonal antibodies. Because severe stage treatment is the core point to calm the inflammatory factors, remdesivir and monoclonal antibodies have no effect on the severe disease. So what kind of medicine is generally used for severe Covid-19 illness? Dexamethasone, which is the only drug approved by the WHO to reduce mortality. Of course, the side effects of hormone drugs are also obvious. Besides, there is also tocilizumab. Tocilizumab can target interleukin 6 (an inflammatory factor secreted by white blood cells is responsible for the transmission of messages between immune cells). Since most of the human body’s immune response depends on interleukins, tocilizumab just targets this interleukin to eliminate inflammation. Therefore, it can also suppress the inflammatory factor storm caused by the new crown by targeting interleukin 6. However, it should be noted that these drugs themselves are not effective against the virus, and for patients who do not have an inflammatory factor storm, it will reduce their usual autoimmunity.

The recent Israeli study of the special drug “EXO-CD24” for the treatment of severely ill patients with new coronary disease also has a similar effect, mainly through the CD24 protein to reduce the immune response and eliminate the inflammatory factor storm. Among them, EXO-CD24 is a combination of CD24 protein and exosomes. CD24 can reduce the effect of the immune system, while exosomes are small lipid vesicles, which are mainly used as transport vehicles for CD24. The drug is inhaled through the nose and mainly acts on the patient’s lungs. The principle is to suppress the “immune storm” that is common in severely ill patients with new coronary disease, so that the immune system can clear the virus more safely. However, due to limitations in the number of patient studies, double-blind design, placebo group, and age distribution in this study, further studies are needed to determine the true efficacy of the drugs.

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Symptoms of a cytokine storm

The daily work of the immune system is to clear the infection, but if the immune system is activated to the limit or loses control, it will harm the host. An extreme immune attack is a cytokine storm.

The cytokine storm is a signal for help, and the purpose is to ask the immune system to fight tooth and nail at once. This kind of suicide attack can damage the virus, but will also leave a lot of wounds to the host. The blood vessels withstood the most important offensive, in which the cytokine storm makes the blood vessel wall easier to penetrate. Therefore arteries, veins, and capillaries all begin to leak blood and plasma. The cytokine storm also triggers a massive release of nitric oxide, which will further dilute the blood and destroy blood vessels. All of these factors combine to lower blood pressure to a dangerous level, so the patient does not die from blood loss, but from a symptom similar to severe septic shock.

Cytokine storm plays an important role in the chronicles of human diseases

The concept of cytokine storm first appeared in graft-versus-host disease (GvHD) in 1993. GvHD shows the symptom that immune cells in the transplant treat the host as a foreign body and attack the host cells. Later, humans gradually discovered that viruses (such as SARS virus and MERS virus) and bacterial infections can also cause cytokine storms. At this time, it is the patients’ own immune cells that attack the host cells.

COVID-19 can trigger a cytokine storm

When SARS-CoV-2 infects humans for the first time, the human immune system has no ability to recognize this virus. Once the virus invades into normal cells, the immune system will not be able to distinguish between friends and foes. When the virus multiplies rapidly and the immune system becomes intolerable and chooses to work hard to clear the virus, a cytokine storm may break out. From this point of view, a virus’s toxicity depends on how destructive the immune response it induces.

Human ACE2 stable cell line is frequently used in research of SARS-CoV-2 since studies have shown that SARS-CoV-2 enters the cell through angiotensin-converting enzyme 2 (ACE2), so the lung tissue with high expression of ACE2 and easy access has become the main invasion target of these viruses. After invading the lungs, the immune system sends a large number of immune cells to the lung tissue to kill the enemy, thus forming pneumonia, and some symptoms appear such as fever, coughing, and expiratory dyspnea.

However, because these immune cells are not capable of destroying the virus accurately, they can only attack indiscriminately and summon more immune cells to kill the enemy, leading to the result that more and more immune cells and cytokines gather together. Once a cytokine storm is formed, the immune system may not be able to kill these viruses, but it will definitely kill a large number of normal cells in the lungs, severely destroying the ventilation function of the lungs, and large white shadows will appear on the lung CT scan, which is known as “white lung”. The patient will have respiratory failure until death from hypoxia.

Diagnosis of cytokine storm

The diagnosis of cytokine storm mainly depends on the detection of inflammatory factors in the blood. However, in fact, different viruses do not trigger cytokine storms through exactly the same mechanism, so they will cause different cytokine changes. For example, SARS-related cytokine storms are mainly related to IL1B, IL6, IL12, IFNγ, IP10, and MCP1, while MERS CoV-induced cytokine storms are mainly related to IFNγ, TNFα, IL15, and IL17. The performance of COVID-19 is different from the above two. On January 24, 2020, The Lancet published a retrospective study of 41 COVID-19 pneumonia in Wuhan University Zhongnan Hospital. In this study, compared with patients with mild symptoms, the expression levels of multiple plasma pro-inflammatory factors (IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, TNFα) in severe cases were significantly higher, and these inflammatory indicators suggested that cytokine storms occurred in patients with severe COVID-19.

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Muramyl dipeptide (MDP) is a peptidoglycan motif present in all Gram-positive and Gram-negative bacteria. Animal studies have shown that MDP has a wide range of immunomodulatory activities, including enhanced antibody production, increased cell-mediated immunity, increased non-specific immunity to bacteria and increased release of cytokines. It was found that MDP can interact with cytoplasmic PRR NOD2 (nucleotide-binding oligomerization domain 2) to transmit cellular signals, while NOD2 is highly expressed in APC, which is a necessary of humoral response to MDP adjuvant antigen. Since CFA is toxic to human, and MDP can replace the activity of the entire killed mycobacteria in complete Freund’s adjuvant (CFA), the vaccine field is working to develop a safer adjuvant based on MDP. Among them, MDP-derived moradyl ester, threonyl-MDP, and muramyl tripeptide were tested in clinical trials as adjuvants against HIV-1 and influenza virus vaccines. Clinical findings have found that a large amount of reactogenicity, including fever and other systemic reactions, has been observed in a proportion of vaccines and has hindered the further development of MDP adjuvants for human vaccines.

Mechanism of Causing Fever

In order to better develop MDP-based adjuvants, it is necessary to understand the mechanism of MDP-induced fever. When microbial products activate PRR, macrophages produce pyrogenic cytokines such as interleukin 1β (IL-1β), IL-6 and tumor necrosis factor-α. The pyrogenic cytokines released by macrophages are transported by blood flow to the hypothalamic anterior ventricle, where the release of the pyrogenic lipid mediator-prostaglandin E is induced. In addition to being produced in the central brain, PGE 2 can also be produced by macrophages in surrounding tissues, including liver Kupffer cells. Studies have shown that locally produced PGE2 can transmit a fever signal by binding to the PGE2 receptor.

The key role of PGE 2 in tissue inflammatory response has been well established: PGE 2 promotes vascular permeability and promotes the flow of neutrophils, macrophages and mast cells from the bloodstream, causing swelling and edema infection at this site. It also stimulates the sensory nerves to increase the pain response and promote fever. Studies of human monocytes activated by TLR agonists suggest that circulating monocytes may be a major source of PGE2.

In addition, the study also found that the T cell-derived soluble glycoprotein GPIbα activates the PLC/InsP 3 / InsP 3 R pathway by triggering Mac-1 in monocytes and induces calcium release from the endoplasmic reticulum. An increase in cytosolic calcium provides a second signal that is critical for the increase in COX2 transcription in MDP-activated monocytes and subsequent PGE2 production.This is also the main cause of MDP-induced fever.

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PD-1/PD-L1 inhibitor

Anti-PD-1 mAb mainly blocks the combination of PD-1 receptor and PD-L1 (B7-H1) or PD-L2 (B7-DC) to release T cell activity. The inhibition will promote the attack of activated T cells on tumor cells. Programmed death-1 (PD-1) and its ligand (PD-L1) inhibitors are immune checkpoint drugs, and the breadth, depth, and persistence of their responses show great potential in clinical. It is a hot spot in the research of tumor immunotherapy in recent years. The marketed nivolumab and pembrolizumab are PD-1 inhibitors. Nivolumab is a monoclonal antibody that binds to programmed death receptor-1 (PD-1) and blocks PD-1 by blocking the interaction between PD-1 and its ligands. Pathway-mediated immunosuppressive responses include anti-tumor immune responses. Therefore, the anti-tumor of cell immune is improved. In 2014, Nivolumab was approved by the US FDA for melanoma patients. In 2015, it was approved by the US FDA for the treatment of non-small cell lung cancer (NSCLC). It is the first lung cancer immunotherapy drug. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligand and is an IgG4 kappa immunoglobulin. The drug is suitable for the treatment of unresectable or metastatic melanoma. In addition, PD-L1 is also a target of blocking the immune inhibitory. And its inhibitors atetolizumab, durvalumab and avelumab have been approved for the treatment of urothelial carcinoma.

Side effects of PD1/PDL1 immunosuppressive agents

Although the treatment of immunosuppressive agents has brought new hopes for the treatment of cancer, the toxicity of these drugs has attracted people’s attention. Immunosuppressive therapy can kill the tumor cell by removing inhibition of body’s own immune system. However, the enhanced immune system will induce excessive immune in body, so the adverse events associated with the immunological checkpoint inhibitor include almost all organs. During inflammatory processes, PDL1 is critical for maintaining an immunosuppressive environment, and any tissue stimulated by interferon expresses PDL1 to alleviate the damage caused by T cells during inflammation. If a PDL1 inhibitor is administered to a patient, the system’s immunosuppression will be ineffective, which increases the likelihood of inflammatory damage surrounding the tumor. Since PDL1 expression is in a wider scope, treatment with a PDL1 inhibitor will result in a higher incidence of side effects and autoimmune events, while PD1 inhibitors primarily affect T cells and therefore do not cause unwanted autoimmune events in the body.

Creative Diagnostics offers PD1 / PDL1 / PDL2 related  antibodies and conjugates validated for use in a variety of common applications including WB, FC, IHC, ICC, IF, IP, and more.

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Figure 1. Fc Receptor

Plasma cells produce five classes of antibodies, IgA, IgD, IgE, IgG and IgM. Fc receptors with an Ig superfamily related structure exist that correspond to each of these classes of immunoglobulins. They include the IgG receptors (FcγR), high-affinity IgE receptor (FcεR), IgA receptor (FcαR) and polymeric immunoglobulin receptor for IgA and IgM. The second category of Fc receptors is the neonatal Fc receptor for IgG (FcRn), which is a unique FcR that has three major functions with respect to IgG; IgG transport across epithelial barriers, protection of IgG from catabolism and antigen presentation.

Creative Diagnostics provides Fc receptor related products for research use.

FcγRIA	FcγRIIA	FcγRIIA
FcγRIB	FcγRIIB	FcγRIIB
FcαR	FcεRIα	FcεRIγ
FcεRII	FcεRIIα	FcRn
Magict Fc Receptor Blocker

FcγR (Fc-gamma receptors）

All of the Fcγ receptors (FcγR) belong to the immunoglobulin superfamily and are the most important Fc receptors for inducing phagocytosis of opsonized (marked) microbes. This family includes several members, FcγRI (CD64), FcγRIIA (CD32), FcγRIIB (CD32), FcγRIIIA (CD16a), FcγRIIIB (CD16b), which differ in their antibody affinities due to their different molecular structure. For instance, FcγRI binds to IgG more strongly than FcγRII or FcγRIII does. FcγRI also has an extracellular portion composed of three immunoglobulin (Ig)-like domains, one more domain than FcγRII or FcγRIII has. This property allows FcγRI to bind a sole IgG molecule (or monomer), but all FcγR must bind multiple IgG molecules within an immune complex to be activated. FcγRs play an important role in determining the therapeutic activity of monoclonal IgG antibodies (mAbs) by their ability to activate the cytotoxic activity of FcγR-positive cells such as NK cells, monocytes, macrophages and neutrophils and by increasing antigen presentation by DC when ligated by the Fc portion of therapeutic antibodies. Recent studies in Fc receptor-deficient nude mice show that the anti-tumor effects of mAbs such as those directed at-CD20 (Rituximab) and HER2 (Herceptin) require the presence of the signal transducing Fcγ chain that is involved in the activation of FcγRI and FcγRIII receptors that are expressed on monocytes, macrophages, and NK cells.

FcαR (Fc-alpha receptors)

Only one Fc receptor belongs to the FcαR subgroup, which is called FcαRI (or CD89). FcαRI is found on the surface of neutrophils, eosinophils, monocytes, some macrophages (including Kupffer cells), and some dendritic cells. It is composed of two extracellular Ig-like domains, and is a member of both the immunoglobulin superfamily and the multi-chain immune recognition receptor (MIRR) family. It signals by associating with two FcRγ signaling chains. Another receptor can also bind IgA, although it has higher affinity for another antibody called IgM. This receptor is called the Fc-alpha/mu receptor (Fcα/μR) and is a type I transmembrane protein. With one Ig-like domain in its extracellular portion, this Fc receptor is also a member of the immunoglobulin superfamily.

FcεR (Fc-epsilon receptors)

There are two types of FcεR are known- FcεRI and FcεRII, FcεRI is a member of the immunoglobulin superfamily (it has two Ig-like domains). FcεRI is found on epidermal Langerhans cells, eosinophils, mast cells and basophils. As a result of its cellular distribution, this receptor plays a major role in controlling allergic responses. FcεRI is also expressed on antigen-presenting cells, and controls the production of important immune mediators called cytokines that promote inflammation. FcεRII (CD23) is a C-type lectin. FcεRII has multiple functions as a membrane-bound or soluble receptor; it controls B cell growth and differentiation and blocks IgE-binding of eosinophils, monocytes, and basophils.

FcRn (neonatal Fc receptor)

The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus. In addition, throughout life, FcRn protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum. In recent years, it has become clear that FcRn is expressed in various sites in adults, where its potential function is now beginning to emerge. In addition, recent studies have examined the interaction between FcRn and the Fc portion of IgG with the aim of either improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. The neonatal Fc receptor for IgG (FcRn) is responsible for the transfer of passive humoral immunity from the mother to the newborn in rodents and humans. Throughout life, FcRn contributes to effective humoral immunity by recycling IgG and extending its half-life in the circulation.

References:

1 Atsuhiro Masuda, Masaru Yoshida, “Role of Fc Receptors as a Therapeutic Target.” Inflamm Allergy Drug Targets. 2009, 03; 8(1): 80–86.

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Types of Interferons

Table 1. Types of Interferons and the receptors

On the basis of this criteria the IFNs were initially classified into two types—the type I family composed of the acid-stable forms IFNα and IFNβ, whereas the acid-labile form, IFNγ, was classified as the lone type II IFN. In recent years, a third type of IFN has been described, IFNλ. Originally termed interleukin (IL)- 28a/b and IL-29 these proteins have been re-classified as IFNs based on the similar modes of induction and anti-viral activities they share with the type I and type II IFNs.3 However, although the type I and type III IFNs are induced during a viral infection and are, at least in part, involved in host defense against viruses, the type II IFN is primarily involved in the allergic response, in host defense against intracellular pathogens and in control of tumors.

Interferon receptors

Figure 1. Representation of the distinct receptor systems employed by IFNs for signal transduction.

All interferons mediate their biological effect by binding to high-affinity cell surface receptors. Binding is followed by initiation of signal transduction, culminating in an altered level of expression of several IFN-responsive genes. The three IFN types are distinguished by the use of distinctive but related multi-chain cell-surface receptor complexes (see Figure 1). All receptors involved in IFN signal transduction are classified as class II helical cytokine receptors (hCRs) sharing homologous structural folds and basic structural elements with other proteins including tissue factor, and the receptors for IL-10, IL-20 and IL-22. In the extracellular region, all members of this class of hCR have tandem domains consisting of B100 amino acids each housing a type III fibronectin (FBN-III) domain with topology analogous to the immunoglobulin constant domain. With the exception of IFNAR1, which has a four-domain architecture, all other IFN receptors consist of two FBN-III domains. Interestingly, although the receptors are unique to each IFN type, components of each signaling complex, namely IFNAR1, IFNAR2, IFNGR2 and IL10RB. All IFN-stimulated genes are characterized by the upstream presence of an interferon stimulated response element (ISRE). Signal transduction culminates in the binding of specific regulatory factors to the ISRE, which stimulates RNA polymerase II-mediated transcription of the IFN-sensitive genes. The induced gene products then mediate the anti-viral, immunomodulatory and other effects characteristically induced by IFNs.

Effects of Interferons during Immune Responses

Generally, IFNs are produced by the body to fight infection or in an allergic response. The most pronounced effect of type I IFNs relates to their anti-viral activity, as well as their anti-proliferative effect on various cell types, including certain tumour cell types. Anti-tumour effects are likely due not only to a direct anti-proliferative effect on the tumour cells themselves but also due to the ability of type I IFNs to increase natural killer (NK) cell and T cytotoxic cell activity. These cells can recognize and destroy cancer cells.

Of the IFNs, the type I IFNs have the broadest range of biological activities having both protective and counter-protective effects in different immune situations. Although type I IFNs are protective in viral infection, IFNβ signaling causes lethality during certain bacterial infections but protection against certain protozoa and fungi. In contrast to the type I IFNs, IFNγ is induced in NK and NKT cells, CD8 T cells and Th1 CD4 effector T cells, has roles in immunity against viruses, intracellular bacteria and tumors and is generally anti-inflammatory in allergy and asthma.

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An autoimmune disease is a condition arising from an abnormal immune response to a normal body part, it releases “autoantibodies” that attacks and destroys healthy body organs, tissues or cells by mistake. Autoimmune diseases are the third most common category of disease in the United States after cancer and heart disease, they affect approximately 5%–8% of the population or 14–22 million persons. There are over 100 types of autoimmune diseases that affect human’s life. The characteristics of autoimmune disease as follow:

• There are high titer autoantibodies or sensitized lymphocytes can be detected in the patient blood.
• Autoantibodies or the sensitized lymphocytes interact with target antigens in the tissues and cells, resulting pathological damage and dysfunction in the corresponding tissues and organs.
• A similar model can be replicated in animal experiments.
• The disease and autoimmune response intensity is closely related.
• Most unexplained autoimmune diseases are often recurrent and chronic persistent.
• There is a genetic predisposition.

Common autoimmune diseases

1. Type 1 diabetes: The pancreas produces the hormone insulin, which helps regulate blood sugar levels. In type 1 diabetes, the immune system attacks and destroys insulin-producing cells in the pancreas. High blood sugar can damage blood vessels, as well as organs like the heart, kidneys, eyes, and nerves.
2. Rheumatoid arthritis (RA): In rheumatoid arthritis (RA), the immune system attacks the joints. This attack causes redness, warmth, soreness, and stiffness in the joints.
3. Psoriasis/psoriatic arthritis: Skin cells normally grow and then shed when they’re no longer needed. Psoriasis causes skin cells to multiply too quickly. The extra cells build up and form red, scaly patches called scales or plaques on the skin. About 30 percent of people with psoriasis also develop swelling, stiffness, and pain in their joints. This form of the disease is called psoriatic arthritis.
4. Multiple sclerosis: Multiple sclerosis (MS) damages the myelin sheath — the protective coating that surrounds nerve cells. Damage to the myelin sheath affects the transmission of messages between your brain and body. This damage can lead to symptoms like numbness, weakness, balance issues, and trouble walking. The disease comes in several forms, which progress at different rates. About 50 percent of people with MS need help walking within 15 years after getting the disease.
5. Systemic lupus erythematosus (lupus): Although doctors in the 1800s first described lupus as a skin disease because of the rash it produces, it actually affects many organs, including the joints, kidneys, brain, and heart. Joint pain, fatigue, and rashes are among the most common symptoms.

Diagnosis

Autoimmune disease is a common multiple disease, because of its clinical symptoms of occult difficult to diagnose. And early diagnosis and treatment is very important, Creative Diagnostics provides autoantibody-related detection kits for autoimmune diseases research use. There are types of Autoimmune Elisa Kits for detection of autoantibodies. The antinuclear antibody test is often the first test that doctors use when symptoms suggest an autoimmune disease. A positive test means you likely have one of these diseases. Other tests look for specific autoantibodies produced in certain autoimmune diseases.

Browse more resource about autoimmunity.

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