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A helminth protein, or helminthic antigen, is a protein derived from a parasitic worm that causes an immune reaction. When secreted, these proteins may modify the host's immune response in order to promote longevity of the parasite. Helminth proteins can result in a deregulated response to infection, and are implicated in reduced reactivity to other antigens. [1] Other helminth proteins promote parasite survival in other ways, particularly since parasites must depend on hosts for the supply of essential nutrients. [2] Despite their pathogenic properties, helminth proteins have potential to be co-opted to treat a number of other human diseases. [3]
Helminth proteins modulate the immune response of their hosts, but do not suppress it entirely. A number of proteins are able to induce production of IL-10, an anti-inflammatory cytokine. [4] IL-10 is partially responsible for reducing expression of co-stimulatory molecules such as CD86 on macrophages. CD86 is one of the proteins which interact with CD28 to activate T helper cells; without it, T helper cell response is mitigated. [3] Schistosome proteins also contain abundant proteases which and cleave IgE antibodies. Alpha-1, a protein released by schistosome eggs, can also be a chemokine binding protein, preventing the recruitment of other immune cells like neutrophils. T. canis C-type lectins are additionally able to bind to mammalian carbohydrates, suggesting that they may promote evasion of the host's immune system by preventing the migration of host immune cells.
A number of helminth species also secrete high levels of antioxidants to avoid phagocytosis; those antioxidants are needed because phagocytes like macrophages frequently produce reactive oxygen species like oxygen radicals, superoxide, and hydrogen peroxide to attack parasites. Additionally, many nematodes residing in the gut may secrete acetylcholinesterase, which is responsible for the degradation of acetylcholine to terminate neuronal signals. Acetylcholinesterase may prevent parasite clearance from the gut by preventing acetylcholine-mediated signaling from stimulating the production of intestinal chloride and mucus.
Parasites like helminths do not synthesize their own fatty acids or sterols, and are consequently dependent on their hosts for essential nutrients. A number of different classes of lipid-binding proteins have been investigated and characterized. Of these, NPA (nematode polyprotein antigen/allergen) FAR, and Sj-FABPc demonstrate different binding affinities for fatty acids and/or retinoids. Ov-FAR-1, which is produced by the riverblindness parasite Onchocerca volvulus binds retinol with great affinity, and this activity may result in the pathology it causes. Ov-FAR-1, however, binds fatty acids with less affinity. On the other hand, Sj-FABPc, found in Schistosoma japonicum , binds fatty acids with high affinity, but does not bind to retinol. All three of these proteins are able to deliver lipids to acceptor membranes, but this transfer process in Ov-FAR-1 and ABA-1A1 (a type of NPA) requires an aqueous diffusion step. Sj-FABPc uses a collision mechanism, and transfer is not affected by changing salt concentrations, suggesting that it may be important to intracellular targeted transport and metabolism of fatty acids. Ov-FAR-1 and ABA-1A1 may instead behave similarly to extracellular lipid-binding proteins. [2]
The Helminth Secretome Database (HSD) is a repository for helminth proteins predicted using expressed sequence tags (ESTs). Previously identified ESTs, which correspond to known helminth proteins, are used to predict the location and function of newly discovered helminth proteins based on genomic sequencing. Additionally, the database can also be used to develop protein targets for new drugs to treat helminth infections. [5]
Given the modulatory properties of helminth proteins, it has been suggested that they may be co-opted to successfully treat other human diseases, particularly those associated with auto-immunity disorders. [3] In particular, immunization with P28GST, a schistosome glutathione S-transferase enzyme in rats has been shown to reduce colitis lesions and expression of pro-inflammatory cytokines by eosinophil responses to inflammation. P28GST is thus a promising potential therapeutic for treating inflammatory bowel diseases like Crohn's disease and ulcerative colitis. [6]
Additionally, injection of proteins secreted by Fasciola hepatica in nonobese diabetic mice prevented the onset of type I diabetes, with 84% of the mice showing normal glucose levels 26 weeks after injection. This phenomenon is attributed to the suppression of interferon-gamma secretion from autoreactive T cells following the activation of regulatory M2 macrophages. This result supports the possibility of eventually using helminth products to treat type I diabetes in humans as well. [7]
In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.
Tumor necrosis factor is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain.
Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.
Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.
CD36, also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is encoded by the CD36 gene. The CD36 antigen is an integral membrane protein found on the surface of many cell types in vertebrate animals. It imports fatty acids inside cells and is a member of the class B scavenger receptor family of cell surface proteins. CD36 binds many ligands including collagen, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, oxidized low density lipoprotein, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.
In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.
The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.
In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.
Heligmosomoides polygyrus, previously named Nematospiroides dubius, is a naturally occurring intestinal roundworm of rodents. It belongs to the family Trychostrongylidae, and male and female worms are morphologically distinguishable. The parasite has a direct lifecycle, with its larval form being the infective stage. H. polygyrus has the ability to establish chronic infections in rodents and alter host immune responses. This nematode is widely used as a gastrointestinal parasitic model in immunological, pharmacological, and toxicological studies.
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.
Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTES. RANTES was first described by Dr. Tom Schall who named the protein, the original source of the name Rantes was from the Argentine movie Man Facing Southeast about an alien who shows up in a mental ward who was named Rantés, the rather clunky acronym was only made to fit the name.
Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.
An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.
Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors, HCA1 and HCA3, HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA2.
Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis. The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 1013 to 1014 bacteria, roughly equivalent to the number of human cells, and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.
C-type lectin domain family 10 member A (CLEC10A) also designated as CD301 is a protein that in humans is encoded by the CLEC10A gene. CLEC10A is part of the C-type lectin superfamily and binds to N-Acetylgalactosamine (GalNAc). It is mainly expressed on myeloid cells and also on oocytes and very early stages of embryogenesis. CLEC10A is used as a marker of the CD1c+ dendritic cell subgroup, also called cDC2. The actions of CLEC10A are diverse, depending on the ligand and environment.
The effects of parasitic worms, or helminths, on the immune system is a recently emerging topic of study among immunologists and other biologists. Experiments have involved a wide range of parasites, diseases, and hosts. The effects on humans have been of special interest. The tendency of many parasitic worms to pacify the host's immune response allows them to mollify some diseases, while worsening others.