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. [1]
Extensive research shows that parasitic worms have the ability to deactivate certain immune system cells, leading to a gentler immune response. [2] [3] [4] [5] [6] [7] [8] Often, such a response is beneficial to both parasite and host, according to Graham Rook, a professor of medical microbiology at University College London. [9] This immune "relaxation" is incorporated throughout the immune system, decreasing immune responses against harmless allergens, gut flora, and the body itself. [9]
In the past, helminths were thought to simply suppress T-helper Type 1 (Th1) cells while inducing T-helper Type 2 (Th2) cells. [9] Rook points out that this hypothesis would only explain the regulatory effects of parasitic worms on autoimmune diseases caused by Th1 cells. [10] However, helminths also regulate Th2-caused diseases, such as allergy and asthma. [10] Rook postulates that different parasitic worms suppress different Th types, but always in favor of regulatory T (Treg) cells. [10]
Rook explains that these regulatory T cells release interleukins that fight inflammation. [10] In the Journal of Biomedicine and Biotechnology, Osada et al. note that macrophages induced by Treg cells fight not only the parasitic disease, but also resist the immune system's response to allergens and the body. [11] According to Hopkin, the author of a 2009 Parasite Immunology article on asthma and parasitic worms, other immunoregulatory mechanisms are also activated, including Mast cells, eosinophils, and cytokines that invoke a strong immunoglobulin E (IgE) response. [12] All these fight a hyperactive immune response, reduce the inflammation throughout the body, and thus lead to less severe autoimmune diseases. [12]
Osada et al. state that because parasitic worms may and often do consist of allergens themselves, the degree to which they pacify or agitate the immune response against allergens is a balance of their regulating effects and their allergenic components. [11] Therefore, depending on both of these variables, some parasitic worms may worsen allergies. [11]
In their Parasite Immunology article on worms and viral infections, Kamal et al. explain why some parasitic worms aggravate the immune response. [13] Because parasitic worms often induce Th2 cells and lead to suppressed Th1 cells, problems arise when Th1 cells are needed. [13] Such cases occur with viral diseases. [13] Several examples of viral infections worsened by parasitic worms are described below in the Negative Effects section.
The positive effects of parasitic worms are theorized to be a result of millions of years of evolution, when humans and human ancestors would have been constantly inhabited by parasitic worms. [9] In the journal EMBO Reports, Rook says that such helminths "are all either things that really do us no harm, or things where the immune system is forced to give in and avoid a fight because it's just a waste of time. [14] " In the journal Immunology, Rook states that, because parasitic worms were almost always present, the human immune system developed a way to treat them that didn't cause tissue damage. [9]
The immune system extends this response to its treatments of self-antigens, softening reactions against allergens, the body, [9] and digestive microorganisms. [15] As the worms developed ways of triggering a beneficial immune response, humans came to rely on parasitic interaction to help regulate their immune systems. As developed countries advanced in technology, medicine, and sanitation, parasitic worms were mostly eradicated in those countries, according to Weinstock in the medical journal Gut. [16] Because these events took place very recently on the evolutionary timeline and humans have progressed much faster technologically than genetically, the human immune system has not yet adapted to the absence of internal worms. [9] This theory attempts to explain the rapid increase in allergies and asthma in the last century in the developed world, as well as the relative absence of autoimmune diseases in the developing world, where parasites are more common. [9]
The Hygiene hypothesis postulates that decreasing exposure to pathogens and other microorganisms results in an increase of autoimmune diseases, according to Rook. [17] This theory and the theory that certain parasitic worms pacify the immune response are similar in that both theories attribute the recent rise of autoimmune diseases to the decreased levels of pathogens in developed countries. However, the Hygiene Hypothesis claims that the absence of pathogenic organisms in general has led to this. [17] In contrast, the parasitic worm theory only analyzes helminths, and specifically ones found to have a regulating effect. [17]
Type 1 diabetes (T1D) is an autoimmune disease in which the immune system destroys the body's pancreatic beta cells. [2] In an experiment with mice, infection with parasitic worms or helminth-products generally inhibited the spontaneous development of T1D, according to Anne Cook in the journal Immunology. [2] However, results varied among the different species of parasitic worms. [2] Some helminth-products, like a protein of the nematode Acanthocheilonema viteae, didn't have any effect. [2] Another infectious agent, Salmonella typhimurium was successful even when administered late in the development of T1D. [2]
According to Hopkin, asthma involves atopic allergy, which in turn involves the release of mediators that induce inflammation. [12] In 2007, Melendez and his associates studied filarial nematodes and ES-62, a protein that nematodes secrete in their host. [3] They discovered that pure ES-62 prevents the release of allergenic inflammatory mediators in mice, resulting in weaker allergic and asthmatic symptoms. [3] In the Journal of Immunology, Bashir et al. describe their experimental findings that an allergic response against peanuts is inhibited in mice infected with an intestinal parasite. [4]
Inflammatory bowel disease (IBD) is an autoimmune disease involving the inflammation of mucus. [6] Ulcerative colitis (UC) and Crohn's disease (CD) are both types of IBD. [6] In the medical journal Gut, Moreels et al. describe their experiments on induced colitis in rats. [5] They found that infecting the rats with the parasitic worm Schistosoma mansoni resulted in alleviated colitis effects. [5] According to Weinstock, human patients of UC or CD improve when infected with the parasitic worm whipworm. [6]
In 2003, Iain McInnes et al. found that arthritic-induced mice experienced less inflammation and other arthritic effects when infected with ES-62, a protein derived from filarial nematodes, a kind of parasitic worm. [18] Similarly, in the International Journal for Parasitology, Osada et al. published their experimental findings that arthritis-induced mice infected with the parasitic worm Schistosoma mansoni had down-regulated immune systems. [19] This led to resistance to arthritis. [19]
In 2007, Jorge Correale et al. studied the effects of parasitic infection on multiple sclerosis (MS). Correale evaluated several MS patients infected with parasites, comparable MS patients without parasites, and similar healthy subjects over the course of 4.6 years. [8] During the study, the MS patients that were infected with parasites experienced far less effects of MS than the non-infected MS patients. [8]
In the journal Parasite Immunology, Kamal et al. explains that parasitic worms often weaken the immune system's ability to effectively respond to a vaccine because such worms induce a Th2-based immune response that is less responsive than normal to antigens. [20] This is a major concern in developing countries where parasitic worms and the need for vaccinations exist in large number. [20] It may explain why vaccines are often ineffective in developing countries. [20]
Because Hepatitis C virus (HCV) and the parasitic worm Schistosoma (the bloodfluke) are relatively common in developing countries, there are many cases where both are present in the human body. [21] According to Kamal, bloodflukes have been adequately shown to worsen HCV. [21] Kamal explains that, in order to maintain an immune response against HCV, patients must sustain a certain level of CD4+ T-cells. [21] However, the presence of bloodflukes closely and negatively correlates to the presence of CD4+ T-cells, and so a much higher percentage of those infected with bloodflukes are unable to combat HCV effectively and develop chronic HCV. [21] Parasitic effects of Hepatitis B virus, however, are contested—some studies show little association, while others show exacerbation of the disease. [22]
Because the two diseases are abundant in developing countries, there are many patients with both HIV (Human immunodeficiency virus) and parasites, and specifically bloodflukes. [23] In his article, Kamal relates the findings that those infected with parasites are more likely to be infected by HIV. [23] However, it is disputed whether or not the viral infection is more severe because of the parasites. [23]
According to Kamal, the human immune system needs Th1 cells to effectively fight TB. [24] Since the immune system often responds to parasitic worms by inhibiting Th1 cells, parasitic worms generally worsen tuberculosis. [24] In fact, Tuberculosis patients who receive successful parasitic therapy experience major improvement. [24]
In 2004, Sokhna et al. performed a study of Senegalese children. [25] Those infected with blood flukes had significantly higher rates of malaria attacks than those who were not. [25] Furthermore, children with the highest counts of blood flukes also had the most malaria attacks. [25] Based on this study, Hartgers et al. drew a "cautious conclusion" that helminths make humans more susceptible to contracting malaria and experiencing some of its lighter symptoms, while actually protecting them from the worst symptoms. [26] Hartgers reasons that a Th2-skewed immune system resulting from helminth infection would lower the immune system's ability to counter an initial malarial infection. [26] However, it would also prevent a hyperimmune response resulting in severe inflammation, reducing morbidity and pathology. [26]
Trichuris trichiura, Trichocephalus trichiuris or whipworm, is a parasitic roundworm that causes trichuriasis when it infects a human large intestine. It is commonly known as the whipworm which refers to the shape of the worm; it looks like a whip with wider "handles" at the posterior end. The helminth is also known to cause rectal prolapse.
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.
Schistosomiasis, also known as snail fever, bilharzia, and Katayama fever, is a disease caused by parasitic flatworms called schistosomes. The urinary tract or the intestines may be infected. Symptoms include abdominal pain, diarrhoea, bloody stool, or blood in the urine. Those who have been infected for a long time may experience liver damage, kidney failure, infertility, or bladder cancer. In children, it may cause poor growth and learning difficulties.
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.
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.
Schistosoma is a genus of trematodes, commonly known as blood flukes. They are parasitic flatworms responsible for a highly significant group of infections in humans termed schistosomiasis, which is considered by the World Health Organization to be the second-most socioeconomically devastating parasitic disease, with hundreds of millions infected worldwide.
In medicine, the hygiene hypothesis states that early childhood exposure to particular microorganisms protects against allergies by properly tuning the immune system. In particular, a lack of such exposure is thought to lead to poor immune tolerance. The time period for exposure begins before birth and ends at school age.
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.
Helminthiasis, also known as worm infection, is any macroparasitic disease of humans and other animals in which a part of the body is infected with parasitic worms, known as helminths. There are numerous species of these parasites, which are broadly classified into tapeworms, flukes, and roundworms. They often live in the gastrointestinal tract of their hosts, but they may also burrow into other organs, where they induce physiological damage.
Trichobilharzia regenti is a neuropathogenic parasitic flatworm of birds which also causes cercarial dermatitis in humans. The species was originally described in 1998 in the Czech Republic and afterwards it was detected also in other European countries, e.g. Denmark, Germany, France, Iceland, Poland, Switzerland, or Russia, and even in Iran. For its unique neurotropic behaviour in vertebrate hosts, the host-parasite interactions are extensively studied in terms of molecular biology, biochemistry and immunology.
Schistosoma mansoni is a water-borne parasite of humans, and belongs to the group of blood flukes (Schistosoma). The adult lives in the blood vessels near the human intestine. It causes intestinal schistosomiasis. Clinical symptoms are caused by the eggs. As the leading cause of schistosomiasis in the world, it is the most prevalent parasite in humans. It is classified as a neglected tropical disease. As of 2021, the World Health Organization reports that 251.4 million people have schistosomiasis and most of it is due to S. mansoni. It is found in Africa, the Middle East, the Caribbean, Brazil, Venezuela and Suriname.
Schistosoma intercalatum is a parasitic worm found in parts of western and central Africa. There are two strains: the Lower Guinea strain and the Zaire strain. S. intercalatum is one of the major agents of the rectal form of schistosomiasis, also called bilharzia. It is a trematode, and being part of the genus Schistosoma, it is commonly referred to as a blood-fluke since the adult resides in blood vessels.
Parasitic worms, also known as helminths, are large macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms that are soil-transmitted and infect the gastrointestinal tract. Other parasitic worms such as schistosomes reside in blood vessels.
Helminthic therapy, an experimental type of immunotherapy, is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth or with the eggs of a helminth. Helminths are parasitic worms such as hookworms, whipworms, and threadworms that have evolved to live within a host organism on which they rely for nutrients. These worms are members of two phyla: nematodes, which are primarily used in human helminthic therapy, and flat worms (trematodes). The theory behind helminth therapy is that these worms reduce negative immune responses due to their TH2 immune response that downregulates the overactive TH1 or TH17 response associated with autoimmune disorders. This theory ties to the Hygiene hypothesis in that the lack of exposure to bacteria and parasites such as helminths can cause a weaker immune system leading to being more susceptible to autoimmune disease.
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.
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. Other helminth proteins promote parasite survival in other ways, particularly since parasites must depend on hosts for the supply of essential nutrients. Despite their pathogenic properties, helminth proteins have potential to be co-opted to treat a number of other human diseases.
Trichuris suis is a whipworm; the variations in thickness of the anterior and posterior segments give the parasite the characteristic "whip-like" appearance. Adult females measure 6 to 8 cm and adult males 3 to 4 cm. T. suis eggs are oval and yellow-brown with bipolar plugs. T. suis is also used in helminthic therapy studies.
T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.
A Schistosomiasis vaccine is a vaccine against Schistosomiasis, a parasitic disease caused by several species of fluke of the genus Schistosoma. No effective vaccine for the disease exists yet. Schistosomiasis affects over 200 million people worldwide, mainly in rural agricultural and peri-urban areas of the third world, and approximately 10% suffer severe health complications from the infection. While chemotherapeutic drugs, such as praziquantel, oxamniquine and metrifonate both no longer on the market, are currently considered safe and effective for the treatment of schistosomiasis, reinfection occurs frequently following drug treatment, thus a vaccine is sought to provide long-term treatment. Additionally, experimental vaccination efforts have been successful in animal models of schistosomiasis.
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
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