Kurzgesagt – In a Nutshell

Sources – Allergies and Worms

We thank the following experts for their input and critical reading:

Prof. Franco H. Falcone

Justus-Liebig-Universität Gießen, Germany

Prof. Julia Esser-von Bieren

Université de Lausanne, Switzerland

Technical University of Munich and Helmholtz Munich, Germany

– You can be allergic to an incredibly diverse and weird amount of stuff. Pollen, dust, insect stings, animal hair, any kind of food, latex and even your own sweat.

#InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Overview: Allergies. [Updated 2023 Aug 8].

https://www.ncbi.nlm.nih.gov/books/NBK447112/

Quote: “Allergies arise if the body's immune system overreacts to foreign substances (allergens) that are usually harmless in most people, such as pollen or certain foods. In some cases the symptoms are quite mild, but they can also be a real nuisance and have a considerable impact in everyday life.

There are various treatment options for allergies. Some things that trigger allergies (allergens) are easy to avoid, whereas others aren't. Common allergens include the following:

Pollen
House dust mites
Pets and farm animals
The venom (poison) in insect stings and bites
Foods
Medication
Contact allergens (e.g. metals or fragrance ingredients)
Mold”

#Takahagi S, Tanaka A, Hide M. Sweat allergy. Allergol Int. 2018

https://www.sciencedirect.com/science/article/pii/S1323893018300856#sec3

Quote: “CholU is characterized by unique clinical features; pin-sized, highly pruritic wheals with surrounding erythema induced by sweating during physical exercise, taking a bath, raising the body temperature or emotional stress10. This disorder usually affects young adults and approximately half of the patients with CholU have atopic diathesis11. The precise underlying mechanism of the wheal response in CholU has not yet been clarified, but it has been proposed that the hypersensitivity to sweat may be involved in the pathogenesis. Indeed, more than 65% of patients with CholU showed positive immediate-type skin reactions when performing an intradermal skin test with autologous sweat (Table 1).12,13

A wheal and flare reaction in patients with CholU may also be produced, in the normal-appearing skin, in response to sweating induced by the intradermal injection of acetylcholine, which stimulates the muscarinic M3 receptor and induces sweating in the local site of its injection. Moreover, 66% of patients with CholU showed histamine release against the semi-purified sweat antigen,11 while 75% of patients with AD did (Table 1).8 Levels of the specific IgE binding to the semi-purified sweat antigen in sera of patients with CholU were significantly higher than those of normal controls, as seen in AD.9 Furthermore, recent reports have mentioned that omalizumab, a humanized monoclonal antibody against IgE, is effective for patients with CholU, indicating that CholU may be mediated by pathogenic IgE.14“

#Johns Hopkins Medicine. Latex Allergy. Retrieved December 2024.
https://www.hopkinsmedicine.org/health/conditions-and-diseases/latex-allergy

Quote: "What is a latex allergy?

Natural rubber latex is a milky fluid found in rubber trees. There is a protein in the fluid that can cause allergic reactions in some people. Common products made using this natural rubber latex include gloves, condoms, rubber bands, and balloons.

There are 2 types of latex allergy. One type can cause a reaction right away. For example, it's like what someone with a peanut allergy may have after eating a peanut. The other type is much more common. It causes a delayed skin rash 1 to 3 days after exposure. This is similar to a reaction that often occurs after you have been exposed to poison ivy."

– For your ancestors being infected by worms was a reality of life. We won’t get into the disgusting details – but in a world were drinking water and our poo were close buddies, some species of worms found just the perfect cycle of life.

Parasitic worms or helminths, as they are mentioned in scientific literature, include various species within flukes and tapeworms (together also known as flatworms or Platyhelminthes) and roundworms. They have worldwide coverage and still infect millions of people today. They have different appearances and life cycles.

https://www.ncbi.nlm.nih.gov/books/NBK8282/

Quote: “Helminth is a general term meaning worm. The helminths are invertebrates characterized by elongated, flat or round bodies. In medically oriented schemes the flatworms or platyhelminths (platy from the Greek root meaning “flat”) include flukes and tapeworms. Roundworms are nematodes (nemato from the Greek root meaning “thread”). These groups are subdivided for convenience according to the host organ in which they reside, e.g., lung flukes, extraintestinal tapeworms, and intestinal roundworms. This chapter deals with the structure and development of the three major groups of helminths.”

#NHS. Worms in humans. 2023.

https://www.nhs.uk/conditions/worms-in-humans

Quote: “How you catch worms

Worms are mainly spread in small bits of poo from people with a worm infection. Some are caught from food.

You can get infected by:

touching objects or surfaces with worm eggs on them – if someone with worms does not wash their hands
touching soil or swallowing water or food with worm eggs in it – mainly a risk in parts of the world without modern toilets or sewage systems
walking barefoot on soil containing worms – only a risk in parts of the world without modern toilets or sewage systems
eating raw or undercooked beef, pork or freshwater fish (like salmon or trout) containing baby worms – more common in parts of the world with poor food hygiene standards
You can catch some worms from pets, but this is rare.”

#Cox FE. History of human parasitology. Clin Microbiol Rev. 2002

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC126866/

Quote: “During our relatively short history on Earth, humans have acquired an amazing number of parasites, about 300 species of helminth worms and over 70 species of protozoa (9). Many of these are rare and accidental parasites, but we still harbor about 90 relatively common species, of which a small proportion cause some of the most important diseases in the world, inevitably, these are the ones that have received the most attention. Since most of these parasitic diseases occur mainly in the tropics, the field of parasitology has tended to overlap with that of tropical medicine, and thus the histories of these two fields are intertwined. There is, however, much more to the history of human parasitology than this, and our understanding of parasites and parasitic infections cannot be separated from our knowledge of the history of the human race. In particular, the spread and present distribution of many parasites throughout the world has largely been the result of human activities, and the advent of AIDS has added a new chapter to the history of parasitology.”

The tapeworm (Cestodes) life begins in general when the eggs are left to the environment through an infected person’s stool. These eggs then mature and are eaten by an intermediate host, animals like pigs, fish. cows. In the intermediate host, the parasite infects the tissues (typically muscle) and lives there until this host is ingested by a human, i.e. the definitive host. The parasite develops into an adult worm in the human small intestine, completing the cycle. Adult worms may live for years and sometimes decades and can reach uncomfortably large lengths and produce hundreds of thousands of eggs each day in the intestines. Some examples are Taenia saginata (the beef tapeworm) and Taenia solium (the pork tapeworm) and Diphyllobothrium latum (Fish tapeworm).

Roundworms (Nematodes) can infect people via fecal-oral routes, direct contact with infected soil or water, or ingestion of infected fish and meat. After the egg or larval stage enters the body, the parasite directly enters the vasculature, migrates to the lungs, and crosses from the capillaries into alveolar spaces. Next, the parasite ascends the airway to the pharynx. The worms are then swallowed. In the small intestine the larvae mature into adults and become fertile, laying eggs into to the bowel lumen. These eggs are expelled in the feces, completing the cycle. Some species can complete the entire cycle within a single

host, whereas others require either an intermediate host or soil larval stage. Ascaris lumbricoides, Strongyloides stercoralis or hookworms like Necator americanus and Ancylostoma duodenale organisms.

Fluke (Trematodes) infections are acquired through ingestion of contaminated water or plants (F. buski) or by eating raw fish (H. heterophyes and M. yokogawi). Eggs can contaminate fresh water through inappropriate disposal of waste, and mature there over a few weeks into free-swimming miracidia. Miracidia develop into cercariae in the tissue of snails over a period of 3 to 5 months. After the cercariae are released from the snail back into the water, they encyst on the leaves of any one of a number of common food plants (F. buski) or in the tissues of freshwater fish (H. heterophyes and M. yokogawi). When the contaminated fish are consumed uncooked, humans become infected. Adult flukes survive for approximately 1 year. They are usually found in the duodenum and jejunum. Some examples are Fasciolopsis buski, Heterophyes heterophyes and Metagonimus yokogawi.

Below are images of the general structure and the lifecycle of each of the three classes:

Tapeworms

https://www.ncbi.nlm.nih.gov/books/NBK8282/

Quote: “Whereas flukes are flattened and generally leaf-shaped, adult tapeworms are flattened, elongated, and consist of segments called proglottids. Tapeworms vary in length from 2 to 3 mm to 10 m, and may have three to several thousand segments.”

https://www.ncbi.nlm.nih.gov/books/NBK8282/figure/A4548/?report=objectonly

Quote: “Figure 86-3 Structure of tapeworms

(Modified from Jeffery HC, Leach RM: Atlas of Medical Helminthology and Protozoology. Churchill Livingstone, Edinburgh, 1968, with permission.)”

https://www.ncbi.nlm.nih.gov/books/NBK8282/figure/A4550/?report=objectonly
Quote: “Figure 86-4 Generalized life cycle of tapeworms

Hymenolepsis nana, Hdiminuta, Taenia saginata, T solium, Diphyllobothrium latum, Dipylidium craninum. Note hexacanth embryos. Cysticercus larva in cow and pig; procercoid larva in copepod, plerocercoid (sparganum) larva in fish; cysticercoid larva in insect.”

Roundworms

#Castro GA. Helminths: Structure, Classification, Growth, and Development. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 86.
https://www.ncbi.nlm.nih.gov/books/NBK8282/
Quote: “The body wall is composed of an outer cuticle that has a noncellular, chemically complex structure, a thin hypodermis, and musculature. The cuticle in some species has longitudinal ridges called alae. The bursa, a flaplike extension of the cuticle on the posterior end of some species of male nematodes, is used to grasp the female during copulation.”

https://www.ncbi.nlm.nih.gov/books/NBK8282/figure/A4552/?report=objectonly
Quote: “Figure 86-5 Structure of nematodes

(A) Female. (B) Male. Transverse sections through the midregion of the female worm (C) and through the esophageal region (D). (Modified from Lee DL: The Physiology of Nematodes. Oliver and Boyd, Edinburgh, 1965, with permission.)”

Figure 86-7 Generalized life cycle of intestinal nematodes

https://www.ncbi.nlm.nih.gov/books/NBK8282/figure/A4554/?report=objectonly

Flukes

https://www.ncbi.nlm.nih.gov/books/NBK8282/

Quote: “Flukes are leaf-shaped, ranging in length from a few millimeters to 7 to 8 cm. The tegument is morphologically and physiologically complex. Flukes possess an oral sucker around the mouth and a ventral sucker or acetabulum that can be used to adhere to host tissues. A body cavity is lacking. Organs are embedded in specialized connective tissue or parenchyma. Layers of somatic muscle permeate the parenchyma and attach to the tegument.”

https://www.ncbi.nlm.nih.gov/books/NBK8282/figure/A4545/?report=objectonly

Quote: “Figure 86-1 Structure of flukes

(A) Hermaphroditic fluke. (B) Bisexual fluke. (Modified from Hunter GW, Swartzwelder JC, Clyde DF: A Manual of Tropical Medicine. 5th Ed. WB Saunders, Philadelphia, 1976, with permission.)

https://www.ncbi.nlm.nih.gov/books/NBK8282/figure/A4546/?report=objectonly

Quote: “Figure 86-2 Generalized life cycle of flukes

All cycles involve snails as intermediate hosts. Hermaphroditic flukes - Clonorchis sinensis, Fasiolopsis buski, Paragonimys westermani, and Heterophytes heterpphyes. Metacercaria are infective for humans. Bisexual flukes: Schistosoma japonicum, S mansoni, and S hematobium. Cercariae are infective for humans. (From Castro, GA: Trematodes: schistosomiasis. p. 1710. In Kelley WN (ed): Textbook of Internal Medicine. JB Lippincott, Philadelphia, 1989, with permission.)”

#Theodore W. Schafer and Amer Skopic. Parasites of the Small Intestine. Curr Gastroenterol Rep. 2007. https://link.springer.com/content/pdf/10.1007/s11908-007-0024-1.pdf

#Luis Caraballo and Kevin Llinás‑Caballero. The Relationship of Parasite Allergens to Allergic Diseases. Current Allergy and Asthma Reports. 2023.

https://link.springer.com/article/10.1007/s11882-023-01089-8
Quote: “Most parasite allergens come from helminths, including those causing soil-transmitted infections (Ascaris lumbricoides, Strongyloides stercoralis, Trichuris trichiura, and the hookworms Necator americanus and Ancylostoma duodenalis), filarial nematodes (Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus), and platyhelminth flukes (Schistosoma haematobium, S. mansoni, S. japonicum). “

– But how do you do that? From the perspective of a cell, worms are city scale Kaijus, reaching beyond the horizon. Worse:, instead of skin, parasitic worms have an elastic protective layer, that withstands even stomach acid. You really need to pack some punch to cause damage. It takes an army to kill a worm.

For the cells of your immune system that are used to solve problems by eating the microbes that are small enough to be phagocytosed, parasitic worms are too big and require an alternate strategy.

#Fitzsimmons CM, Falcone FH, Dunne DW. Helminth Allergens, Parasite-Specific IgE, and Its Protective Role in Human Immunity. Front Immunol. 2014

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924148/pdf/fimmu-05-00061.pdf

Quote: “The parallels between allergy and the immune response to parasitic worms (helminths) have been noted for some time. Unlike most other inflammatory/infectious conditions, allergy, and helminths induce strongly Th2-skewed responses associated with cytokines such as IL-4, IL-5, and IL-13, with mastocytosis, eosinophilia, and antibody class-switching to produce IgE [reviewed in Ref. (1)]. This normally rare, tightly controlled antibody isotype is greatly elevated in helminth infection. It is widely accepted that IgE, its receptors and distinctive cellular responses did not evolve to target harmless molecules occurring in plant pollen, dust-mites, or animal dander.

Instead many believe that the IgE axis evolved to counter metazoan parasites (worms and parasitic arthropods) which are too large to be phagocytosed, and that allergy is a misdirected anti-parasite response in hypersensitive people (2). The symptoms of allergic responses; lachrymation, rhinitis, coughing, increased mucus production, and itching in response to histamine release are all responses likely to dislodge, trap, or flush out large parasites from skin or mucosa, e.g., by scratching”

#Page AP, Stepek G, Winter AD, Pertab D. Enzymology of the nematode cuticle: A potential drug target? Int J Parasitol Drugs Drug Resist. 2014
https://www.sciencedirect.com/science/article/pii/S2211320714000116
Quote: “All nematodes possess an external structure known as the cuticle, which is crucial for their development and survival. This structure is composed primarily of collagen, which is secreted from the underlying hypodermal cells.”

– We are simplifying, but basically when a worm enters your body for the first time, intelligence cells notice their presence. They move to your lymph nodes and activate specialized antibody factories called B Cells – we explained them in detail in this video. These B Cells are told that they need to fight parasites and start producing a special class of weapons: IgE antibodies – tiny protein crabs with two pinchers that connect to worms like magnets to metal.

The part of our immune system that protects us against parasitic worms is called Type 2 Immunity. We can not cover the details and the plethora of signaling molecules and cell types involved in this part but the following is a simple roadmap to see which part of the immune system we are dealing with in this section.

#Annunziato, Francesco et al. The 3 major types of innate and adaptive cell-mediated effector immunity. Journal of Allergy and Clinical Immunology. 2015.

https://www.jacionline.org/action/showPdf?pii=S0091-6749%2814%2901585-1

Type II immunity itself includes many other players but it is centered around a signaling molecule called interleukin-4 receptor α-chain (IL-4Rα).

#Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nat Rev Immunol. 2011

https://pubmed.ncbi.nlm.nih.gov/21610741/

Quote: “Why did type 2 immunity evolve?
The crucial role for TH2 cells in protection against helminths suggests that type 2 immunity is the evolutionarily appropriate response to worms. Indeed, exposure to any large metazoan, including ectoparasites, can trigger a TH2‑type immune response and its downstream consequences55, but how did a distinct pathway for multicellular pathogens evolve? Classical TH1 cell induced inflammatory mediators certainly damage worms56, but at a substantial cost in collateral damage to host tissue. Clearly, macropathogens cause extensive tissue disruption while migrating through the host. Thus, in evolutionary terms, type 2 immunity may have arisen from our innate response to tissue injury, with repair responses isolating and encapsulating macroparasites through the deposition of extracellular matrix proteins while simultaneously resolving localized damage57”

#Stear M, Preston S, Piedrafita D, Donskow-Łysoniewska K. The Immune Response to Nematode Infection. Int J Mol Sci. 2023
https://pubmed.ncbi.nlm.nih.gov/36768605/

Quote: “Following infection with gastrointestinal nematodes, dendritic cells ingest and process parasite molecules and migrate to the draining lymph node or to unencapsulated lymphoid tissue [17]. Processed parasite molecules are presented on the surface of dendritic cells by Major Histocompatibility Complex (MHC) class II molecules. MHC molecules play a crucial role in antigen presentation.
[...]
Naïve lymphocytes that recognise processed antigen on the surface of dendritic cells are activated. T cells are activated in part by dendritic cells while B cells are activated by dendritic cells and activated T cells. Activated T cells develop into a variety of specialised T cells including helper T cells (Th) or regulatory T cells (Treg) [17]. Th initiate and elaborate immune responses while Treg prevent inappropriate immune responses against self-molecules but also suppress the established immune response.
[...]
Activated B cells move within the lymph node or unencapsulated lymphoid tissue and form germinal centres where they undergo class switching and somatic mutation to produce high affinity antibodies against the specific parasite molecule that they have recognised. The activated cells leave the lymphoid tissue and migrate into the tissues, a process driven by the expression and binding of specific molecules. In the gastrointestinal tract, activated cells accumulate in the lamina propria underlying the mucosal surface. The activation process differs for different types of specialised T cell. At least three signals drive the development of naïve T cells into specialised T helper cells: The T-cell receptor (TCR) must bind to the processed parasite molecule which is presented by the class II MHC molecule; additional molecules on T cells interact with molecules on dendritic cells and provide additional signals while cytokines also bind receptors on T cells”

There are a lot of other molecules and cells involved that we don't talk about in the video. For further reading and the details, one can refer to the following papers:

#Gurram RK, Zhu J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol. 2019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460501/
Quote: [Figure Caption]“Classic model of a type 2 immune response. In allergic asthma or during helminth infection, an allergen or a helminthic antigen is phagocytosed by dendritic cells, which then migrate to the draining lymph node, where naïve CD4+ T cells recognize the processed antigen presented by the peptide-MHC-II complex along with costimulatory molecules. After recognition of antigen presented by dendritic cells (DCs), naïve CD4+ T cells differentiate into effector Th2 cells. Th2 cells migrate into the site of inflammation and produce Th2 cytokines such as IL-5, which is responsible for eosinophilia, and IL-13, which promotes mucus production and goblet cell hyperplasia. Th2 cells also produce IL-4, which is involved in antibody class switching and the production of IgE”

#Gurram RK, Zhu J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol. 2019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460501/

Quote: [Figure Caption]“Type 2 immune response from the perspective of the ILC2-DC-Th2 cell-centric axis. Pathogen sensing or tissue damaging signals induced by exposure to helminth infection or protease allergen result in the secretion of alarmins, such as IL-25, IL-33, and TSLP. ATP released from epithelial cells may also induce mast cells to produce IL-33. These alarmin cytokines activate ILC2s, resulting in the production of the type 2 cytokines IL-4, IL-5, IL-9 and IL-13. The neuropeptide neuromedin U (NMU) can also activate ILC2s. The type 2 cytokines secreted by ILC2s may support the differentiation of naïve CD4 T cells into effector Th2 cells. Additionally, DCs receive signals from IL-13 secreted by ILC2s and TSLP released by epithelial cells during pathogen sensing and become capable of inducing effector Th2 cell differentiation from the naïve CD4 T cell population. IL-9 produced by ILC2s may act on these ILC2s to promote cell expansion as well as recruit mast cells. Overall, the type 2 cytokines secreted by ILC2s and Th2 cells, especially IL-5 and IL-13, cumulatively contribute to type 2 immunopathology.”

#Yasuda K, Nakanishi K. Host responses to intestinal nematodes. Int Immunol. 2018 Mar 10;30(3):93-102. doi: 10.1093/intimm/dxy002. PMID: 29346656.

https://academic.oup.com/intimm/article/30/3/93/4807315?login=false

Quote: “Helminth infection remains common in developing countries, where residents who suffer from the consequences of such infections can develop serious physical and mental disorders and often persist in the face of serious economic problems. Intestinal nematode infection induces the development of Th2-type immune responses including the B-cell IgE response; additionally, this infection induces an increase in the numbers and activation of various types of effector cells, such as mast cells, eosinophils and basophils, as well as the induction of goblet cell hyperplasia, anti-microbial peptide production and smooth-muscle contraction, all of which contribute to expel nematodes. Innate immunity is important in efforts to eliminate helminth infection; cytokines, including IL-25, IL-33 and thymic stromal lymphopoietin, which are products of epithelial cells and mast cells, induce Th2 cells and group 2 innate lymphoid cells to proliferate and produce Th2 cytokines. Nematodes also facilitate chronic infection by suppression of immune reactions through an increased number of Treg cells. Immunosuppression by parasite infection may ultimately be beneficial for the host animals; indeed, a negative correlation has been found between parasite infection and the prevalence of inflammatory disease in humans.”

We explained B Cells and antibodies in the following video:

#How The Immune System ACTUALLY Works – IMMUNE

https://www.youtube.com/watch?v=lXfEK8G8CUI&t=452s

– IgE flood your entire body and basically begin arming a nuclear bomb. An army of really scary cells called mast cells. Mast Cells are huge bloated fellows, filled to the brink with histamine and other nasty chemicals. They pick up the IgE floating around and cover themselves with them, like angry hedgehog grenades without their safety pins. And then… they just lie and wait. Angrily. So now you have millions of bombs in your skin, lungs or gut. Until the day the mast cells meet a worm trying to enter your body. There is not much time to get rid of it, so things escalate rapidly. The mast cells with their IgE spikes grab onto the worm particles and… kind of explode.

#Krystel-Whittemore M, Dileepan KN, Wood JG. Mast Cell: A Multi-Functional Master Cell. Front Immunol. 2016

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701915/

Quote: “Mast cells upon activation release preformed and newly synthesized mediators in a phasic fashion. A variety of endogenous and exogenous agents can stimulate mast cells to release mediators immediately. Activation of mast cells occurs when an antigen crosslinks IgE molecules that are bound to FcϵRI on the surface of the mast cell. FcϵRI receptor for IgE has an affinity 100 times greater for the Fc of IgE than of IgG. Because of this, IgE is found bound to the FcϵRI receptors on the mast cell even when there are no antigens present. As a result, this makes the response of the mast cell to an antigen very fast.
[...]
There are two ways to crosslink IgE molecules on the mast cell surface. If an antigen has the same epitopes, they will crosslink IgE molecules of the same specificity. If an antigen has more than two epitopes, they will crosslink IgE molecules with different specificities (8).

Degranulation occurs a few seconds after crosslinking and results in release of the inflammatory mediators that are stored in the granules (31). Many of the mediators that are stored or newly synthesized by the mast cells attract leukocytes (eosinophils, basophils, Th2 lymphocytes, neutrophils) to the inflammatory site and amplify the inflammatory response (1). The inflammatory mediators increase the permeability of the blood vessels so that the immune cells can move from the blood stream to the affected tissue. After degranulation, mast cells resynthesize the mediators and repopulate granules (8).”

Mast cells contain 50 to 200 large granules that store inflammatory chemicals. The list is long but in the following there is a summary of the main chemicals.

Krystel-Whittemore M, Dileepan KN, Wood JG. Mast Cell: A Multi-Functional Master Cell. Front Immunol. 2016

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701915/
Quote: “IgE-mediated activation by FcϵRI causes degranulation and synthesis of many immune mediators, such as eicosanoids and cytokines, as well as other products (Figure (Figure1).1). When the mast cell is activated, it immediately releases prepackaged granules. Mast cell granules (MCG) can be compared to lysosomes in that there is a low pH and lysosomal enzymes, such as β-hexosaminidase and caspase-3 (34). Tryptase, chymase, cathepsin G, and carboxypeptidase are proteases stored in prepackaged granules that activate metalloproteases in the extracellular matrix. Activation of the metalloproteases breaks down extracellular matrix proteins and remodels the connective tissue matrix. Chymase cleaves fibronectin and collagen by activation of MMPs. β-tryptase has been shown to cleave IgE once the mast cell has been activated to down regulate the allergic response (35). Histamine and heparin are also stored in prepackaged granules and are involved with vascular permeability and smooth muscle contraction. Histamine is the most important mediator released from the mast cell involved with an allergic response. Histamine is derived from the amino acid histidine and works through three different receptors (H1, H2, H3). Stimulation of H1 receptors by the binding of histamine induces the classic allergic reaction. H1 receptors are found on smooth muscle cells and endothelial cells. Activation of H1 receptors on endothelial cells results in increased vascular permeability and activation of smooth muscle cells resulting in contraction, constriction of airways, and mucous secretion (8). TNFα, also stored in the MCG, activates macrophages, endothelium, and cytokines (36). TNF-α binds to endothelial cells and results in increased adhesion molecule expression. Leukocytes can bind to these adhesion molecules and then are brought to the site of inflammation (36, 37).
Other molecules are synthesized and released after the mast cells have been activated. IL-3, IL-5, and GM-CSF are involved with eosinophil production and activation. CCL3 is a chemotactic factor for macrophages and neutrophils (1). Eicosanoids (prostaglandins, leukotrienes, and thromboxanes) are produced by catalytic conversion of arachidonic acid by the action of phospholipase A2 on membrane phospholipids. Mast cells express COX1 and COX2, which converts arachidonic acid into prostaglandins and thromboxanes with the action of specific isomerases (38). Prostaglandins increase vascular permeability and attract neutrophils. Leukotrienes are involved with smooth muscle contraction, airway constriction, and mucous secretion (39). Eicosanoids act at the local area of mast cell degranulation. Platelet-activating factor is released after mast cell activation that acts as a chemotactic factor for leukocytes, and activates neutrophils, eosinophils, and platelets (40)."

https://thebiologist.rsb.org.uk/biologist-features/focus-on-allergies

– They release all of their dangerous chemicals all at once. A few things now happen in rapid succession: First, some of the mast cell chemicals wound the worms, ripping wounds into them and making them really unhappy. Then emergency chemicals like histamine cause massive and rapid inflammation, ordering your blood vessels to flood the battlefield with water to flush the worms out. They also order your cells that make mucus to go into overdrive and cover the worms in sticky slime.

There is not a single defense mechanism induced by mast cells against the worm. One way is to secrete chemicals that make the intestine epithelial more leaky so it is easier to push the worm out. Another effector molecule calls out for eosinophils which are also involved in defence against worms.

#McDermott JR, Bartram RE, Knight PA, Miller HR, Garrod DR, Grencis RK. Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc Natl Acad Sci U S A. 2003
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC164661/

Quote: “We provide here a compelling link between mucosal mast cells and intestinal epithelium during parasite infection. We show that an increase in intestinal epithelial paracellular permeability occurs during the course of both a primary and secondary T. spiralis infection and that this effect is induced by mast cells. In addition, we demonstrate that the kinetics of permeability changes parallels the kinetics of nematode expulsion. It has been postulated for many years that an influx of solutes and water into the gut during enteric nematode infection may be a method by which the host attempts to expel the parasite (2).”

#Shin K, Watts GF, Oettgen HC, Friend DS, Pemberton AD, Gurish MF, Lee DM. Mouse mast cell tryptase mMCP-6 is a critical link between adaptive and innate immunity in the chronic phase of Trichinella spiralis infection. J Immunol. 2008

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2969178/

Quote: “Although the innate immune function of mast cells in the acute phase of parasitic and bacterial infections is well established, their participation in chronic immune responses to indolent infection remains incompletely understood. In parasitic infection with Trichinella spiralis, the immune response incorporates both lymphocyte and mast cell-dependent effector functions for pathogen eradication. Among the mechanistic insights still unresolved in the reaction to T. spiralis are the means by which mast cells respond to parasites and the mast cell effector functions that contribute to the immunologic response to this pathogen. We hypothesized that mast cell elaboration of tryptase may comprise an important effector component in this response. Indeed, we find that mice deficient in the tryptase mouse mast cell protease-6 (mMCP-6) display a significant difference in their response to T. spiralis larvae in chronically infected skeletal muscle tissue. Mechanistically, this is associated with a profound inability to recruit eosinophils to larvae in mMCP-6-deficient mice. Analysis of IgE-deficient mice demonstrates an identical defect in eosinophil recruitment. These findings establish that mast cell secretion of the tryptase mMCP-6, a function directed by the activity of the adaptive immune system, contributes to eosinophil recruitment to the site of larval infection, thereby comprising an integral link in the chronic immune response to parasitic infection.”

#Krystel-Whittemore M, Dileepan KN, Wood JG. Mast Cell: A Multi-Functional Master Cell. Front Immunol. 2016

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701915/

Quote: “All of the mediators released upon activation results in increased vascular permeability, smooth muscle contraction, and airway constriction. These adaptations can remove parasites from the gastrointestinal tract. Due to the increased vascular permeability, increased fluid in the tissue can enhance elimination of parasites. IgE-mediated mast cell activation would result in physical expulsion of parasites.”

– Other chemicals are like air raid sirens, screaming loudly throughout your body for anti parasite soldiers, Eosinophils – first thousands, than hundreds of thousands hear the alarm and leave your blood vessels to where the mast cells are causing inflammation. Not only do they make the inflammation worse, they carry extremely toxic chemicals that they vomit at the worm, ripping open its defensive layers and causing horrible injuries. Sometimes this will straight up kill the parasite.

#Tigner A, Ibrahim SA, Murray IV. Histology, White Blood Cell. [Updated 2022 Nov 14]. https://www.ncbi.nlm.nih.gov/books/NBK563148/
Quote: “Eosinophils make up about 1 to 4% of the leukocytes on average. They are involved in chronic inflammation, allergic reactions, and host deference against parasitic infections. They also modulate potentially deleterious effects of inflammatory vasoactive mediators. This modulatory effect is via specific substances, arylsulfatase, and histaminase, enzymes that decompose leukotrienes and histamine. Eosinophils combat parasitic infections by releasing their specific granules, of which the cationic protein, a major basic protein, has toxicity against helminth parasites.[4] Last, like neutrophils and basophils, eosinophils are phagocytic; however, they commonly clear antigen-antibody complexes. ”

#Pionnier N, Sjoberg H, Furlong-Silva J, Marriott A, Halliday A, Archer J, Steven A, Taylor MJ, Turner JD. Eosinophil-Mediated Immune Control of Adult Filarial Nematode Infection Can Proceed in the Absence of IL-4 Receptor Signaling. J Immunol. 2020

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372315/

Quote: “Eosinophilia is a hallmark of the immune response against helminth parasite infection (1–5). Eosinophils are recruited to tissue sites of parasitism and have direct targeted effects on nematode worms, such as degranulation (release of granule constituents such as cytotoxic molecules or enzymes) (2, 6, 7), Ab-dependent cytotoxicity capacity (8, 9), or granuloma formation. The latter is a host protective immune mechanism by which layers of innate effector cells concatenate around excreting–secreting pores of the worm to limit worm motility and enhance effects of granulocyte degranulation (5, 10–12). Neutrophil granulocytes release extracellular DNA “traps” when in contact with Litomosoides sigmodontis, Onchocerca volvulus, or Dirofilaria immitis filarial worms or their endosymbionts, Wolbachia (13–15). Because eosinophils can also generate extracellular traps (16, 17), it is postulated that eosinophils may also contribute toward this antifilarial effector immune response.”

#Huang L, Appleton JA. Eosinophils in Helminth Infection: Defenders and Dupes. Trends Parasitol. 2016

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048491/

Quote: “Eosinophilia is a central feature of the host response to helminth infection. Larval stages of parasitic worms are killed in vitro by eosinophils in the presence of specific antibodies or complement. These findings established host defense as the paradigm for eosinophil function. Recently, studies in eosinophil-ablated mouse strains have revealed an expanded repertoire of immunoregulatory functions for this cell. Other reports document crucial roles for eosinophils in tissue homeostasis and metabolism, processes that are central to the establishment and maintenance of parasitic worms in their hosts. In this review, we summarize current understanding of the significance of eosinophils at the host-parasite interface, highlighting their distinct functions during primary and secondary exposure.”

#Ariyaratne A, Finney CAM. Eosinophils and Macrophages within the Th2-Induced Granuloma: Balancing Killing and Healing in a Tight Space. Infect Immun. 2019

https://pubmed.ncbi.nlm.nih.gov/31285249/
Quote: “Role of eosinophils. An increase in the number of eosinophils in the blood or tissue is a classic sign of helminth infection (68). These cells are thought to migrate from the bone marrow via the circulatory system to the site of infection, where they accumulate and damage parasites (68–73). However, most claims about the role of eosinophils within Th2 granulomas are based on in vitro evidence (16, 70); the role played by eosinophils in parasite clearance in vivo is less well understood (74). (i) Antiparasitic activity. Early studies concluded that in vitro, eosinophils can damage schistosomula through irreversible binding, followed by degranulation (71, 75, 76), and can damage schistosome eggs through eosinophil stimulation promoter (ESP)-mediated lysis (77). Many more in vitro studies have implicated antibody dependent cell-mediated cytotoxicity (ADCC) as the mechanism responsible (16, 71, 77). For example, in vitro, eosinophil-rich rodent peritoneal cells bind schistosomula and Dipetaloema viteae microfilaria (nematode larvae) in the presence of antibodies, resulting in parasite killing (16, 70). Antibodies can also bind human eosinophils in vitro to mediate S. mansoni killing (76). In addition, complement components and eosinophilic toxic granular contents can mediate parasite killing. Rat peritoneum-derived eosinophils have the ability to kill S. mansoni in vitro via complement C3 receptor binding (78). Major basic protein (MBP) is a cationic protein present in eosinophil granules, and its highly basic nature allows it to bind to negatively charged cell membranes (79). Purified MBP has the ability to damage/kill S. mansoni in vitro. It does so by binding parasite cell-membranes, altering their charge, disrupting the lipid bilayer, and ultimately increasing membrane permeability (79) (Fig. 2A).”

– Lastly, the anti worm coordination cell arrives, the basophil – it makes sure that the immune system doesn’t slow down but keeps attacking with violence. It keeps the inflammation going and alerts more and more attack cells to the site of battle.

#Mitre E, Nutman TB. Basophils, basophilia and helminth infections. Chem Immunol Allergy. 2006;90:141-156. doi: 10.1159/000088886. PMID: 16210908.

https://pubmed.ncbi.nlm.nih.gov/16210908/
Quote: “A growing body of evidence suggests basophils are important components of the human immune response to helminth infections. Basophil numbers are increased in several animal models of helminth infection, and basophils have been shown to release both histamine and IL-4 in response to helminths. Helminth infections typically provoke type 2 immune responses characterized by eosinophilia, elevated levels of Ag-specific and polyclonal IgE, and T cell production of type 2 cytokines such as IL-4, IL-5, and IL-13. IL-4 plays a central role in this type 2 response. As basophils are the only peripheral blood mononuclear cells with the ability to release IL-4 rapidly in response to appropriate stimuli, releasing large quantities of preformed IL-4 within minutes of surface IgE cross-linking, it appears likely that basophils play an important role in amplifying ongoing type 2 immune responses to helminth infections once Ag-specific IgE is present. Basophils may also function to initiate type 2 responses upon first exposure to helminths and to potentially re-establish these responses upon re-exposure. This article reviews basic basophil biology and physiology, evaluates the evidence for the presence of basophilia in helminth infections, and then focuses on the possible roles basophils serve in the immune response to helminth infections.”

– Zooming out, we see that the chemicals from your anti parasite forces make your smooth muscles contract rapidly, pushing everything that is inside, outside. In your intestines, combined with all the water, you notice this as diarrhoea, as your body tries to expel the stressed parasite.

#Bąska P, Norbury LJ. The Role of the Intestinal Epithelium in the "Weep and Sweep" Response during Gastro-Intestinal Helminth Infections. Animals (Basel). 2022

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772803/

Quote: ““Weep and sweep”—this term is used to describe the host response against gastro-intestinal (GI) helminths. The main features of this phenomenon are an increase in fluid in the gut lumen and enhanced smooth muscle contraction; this facilitates expulsion, rather than the killing of the intruder [1]. Although the premise of “weep and sweep” is simple, the mechanisms that regulate this phenomenon are complicated and require the interplay of the immune, endocrine, and nervous systems, not only through chemical mediators but through physical interactions. The response needs to be strong enough to efficiently terminate infection but gentle enough to only cause minor or at least acceptable injuries. A balance between the three classical Th1, Th2, and Threg responses needs to be maintained to avoid any dysregulation which may lead to immune-mediated injuries.”

#Marillier RG, Michels C, Smith EM, Fick LC, Leeto M, Dewals B, Horsnell WG, Brombacher F. IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections. BMC Immunol. 2008

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2329604/

Quote: “Actual worm expulsion, in nematode infections, is associated with increased IL-13/IL-4Rα/STAT-6 dependent intestinal smooth muscle contractions, epithelial cell turnover and goblet cell hyperplasia [11-13]. Infections of IL-4-/-, IL-13-/-, IL-4Rα-/- and Stat 6-/- mice with the nematodes Trichuris muris, Heligmosomoides polygyrus and Nippostrongylus brasiliensis have demonstrated a positive relationship between polarisation to a TH2 immune response, goblet cell hyperplasia and worm expulsion [14-19]. In support of a role for goblet cell derived mucus in worm expulsion in vitro experiments have demonstrated increased viscosity of mileu surrounding N. brasiliensis at an equivalent density to intestinal mucus inhibits worm movement [20]. Moreover, isolation of the goblet cell secreted protein RELMβ/FIZZ2 and incubation with parasitic nematodes in vitro results in impaired chemotactic function in the worm [21]. These observations have led to TH2 induced goblet cell hyperplasia being considered a key mechanistic factor in resolving gastrointestinal related nematode infections [22-24]”

#Bouchery T, Harris NL. Only Two Can Tango: Mast Cells Displace Epithelial Cells to Dance with ILC2s. Immunity. 2017

https://pubmed.ncbi.nlm.nih.gov/28514681/
Quote: “ Intestinal mast cells bound extracellular ATP released from epithelial cells that underwent apoptotic cell death in response to invasion of the intestinal wall by helminth larvae (Figure 1A). IL-33 released by mast cells activated ILC2s to produce the type 2 cytokine, IL-13. IL-13 is known to be effective at promoting the expulsion of adult worms from the intestinal lumen, in part due to its ability to promote the expansion of mucous producing goblet cells (Figure 1A). Extracellular ATP is well known as a danger signal resulting from its ability to activate immune cells via P2 purinergic receptors; however, this report demonstrates that ATP can elicit IL-33 production by mast cells. Of note, mast cells also secrete proteases that convert full-length IL-33 into its bioactive form (Lefranc¸ ais et al., 2014), and IL-33 can act directly on mast cells to promote their maturation, elicit cytokine production, and amplify IgEinduced degranulation (Reber et al., 2015). IL-33 can also elicit IL-9 production by ILC2s (Mohapatra et al., 2016), and IL-9 increases IL-2 production by mast cells, leading to further ILC2 expansion (Moretti et al., 2017). Thus, it is likely that IL-33, mast cells, and ILC2s together participate in a positive feedback loop that further amplifies type 2 immunity.”

#Artis, D., Grencis, R. The intestinal epithelium: sensors to effectors in nematode infection. Mucosal Immunol 1, 252–264 (2008).

https://doi.org/10.1038/mi.2008.21

Quote: “TH2 cytokines control intestinal epithelial cell effector mechanisms against intestinal nematode parasites. TH2 cells release IL-4, IL-9 (and IL-3), which act in concert with stem cell factor and TGF-β1 to cause differentiation, maturation, and activation of intraepithelial mucosal mast cells, inducing release of mmcp-1. This alters tight junction integrity, leading to increased intestinal permeability. IL-13 from TH2 cells (and intraepithelial NK cells) induces goblet cell differentiation, expression of RELMβ, and is associated with mucus release into the gut lumen. IL-13 from TH2 cells increases epithelial cell turnover and in conjunction with IL-4, induces alternatively activated macrophages that can “entrap” parasites within the submucosa."

– In your respiratory tract, loads of mucus and water flood outside, trying to take the worm with them. If this happens under your skin, your tissue is red, hot and itchy as your immune system is trying to commit murder.

#Weatherhead JE, Gazzinelli-Guimaraes P, Knight JM, Fujiwara R, Hotez PJ, Bottazzi ME, Corry DB. Host Immunity and Inflammation to Pulmonary Helminth Infections. Front Immunol. 2020

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606285/

Quote: “Mucosal Barrier (Epithelium, Smooth Muscle, Mucus Production) Direct helminth-induced damage to and death of lung epithelial cells can be one of the initial triggering events in helminth infection, leading to release of epithelial derived alarmins IL-25, IL-33, thymic stromal lymphopoietin (TSLP), and chemokines CXCL1, CXCL2, CXCL8, and eotaxins (42, 43). These alarmins signal to innate cell populations such as Innate lymphoid cells type 2 (ILC2), basophils, eosinophils, neutrophils, macrophages, and dendritic cells during the early phases of infection (43). The influx of type-2 cytokines into the lung compartment as a result of innate immune cell activation, particularly through the action of IL-4, IL-9, and IL-13, aids in goblet cell hyperplasia andmucin production needed for helminth expulsion and epithelial turn-over and repair (37, 43). In Schistosoma mansoni infection in the lung, rapid influx of IL-9 leads to robust generation of goblet cell hyperplasia (44). IL-4 receptor alpha (IL-4Rα) signaling via IL-4 and IL-13 cytokines also plays a role in mucin production and smooth muscle responsiveness during Nippostrongylus infection (45). Smooth muscle cells responding to IL-4Rα activation on smooth muscle leads to airway hyperresponsiveness, the exaggerated tendency of the airway to constrict, during Nippostrongylus infection in addition to T cell recruitment to the lungs (45). Mice deficient in smooth muscle IL-4Rα lack coordination of acetylcholine responsiveness with reduced M3 muscarinic receptor expression, delayed goblet cell hyperplasia, reduced type-2 cytokine production, and have a delayed ability to expel Nippostrongylus ( 46). Independent of IL-4Rα signaling, secreted proteins Ym1 and Restin-link molecule alpha (RELMα/Fizz1) from epithelial cells in the lungs contribute to lung repair through inducing IL-17A and neutrophilic infiltration promoting type-2 immunity and remodeling (47). Pulmonary tuft cells, termed brush cells, along the airway epithlium contain microvilli and potentially function as chemosensory cells playing an additional role in innate epithelial immunity (48). Tuft cells in the intestines have been shown to be involved in the generation of type-2 immunity to helminths (49). However, more research is needed to evaluate the interaction between helminths and pulmonary tuft cells.”

Figure Caption. "Activated innate and adaptive immune pathways in the lungs during helminth infection. Innate phase of immune activation to helminths in the lungs is mediated by antigen presenting cells including dendritic cells and macrophages in addition to release of alarmins from damaged epithelium that drive a type-2 immune response. Release of type-2 cytokines IL-4, IL-5, and IL-13 contributed from granulocytes and type 2 innate lymphocytes promote a lung phenotype with goblet cell metaplasia and mucus hypersecretion and smooth muscle hypertrophy. T lymphocytes including Th2, Th17 in combination with B lymphocyte aiding immunoglobulin class switching further contribute to type-2 immune response promoting parasite killing and clearance as well as tissue repair and recovery."

– Parasitic worms don’t love being ripped apart by millions of bombs. And as all living things do, they adapted to the deadly attacks on them. In a nutshell, worms release a plethora of chemicals to manipulate your immune system. They make it weaker and much less angry. Like immune system weed. Which is pretty bad for your survival because you have to fight off all sorts of intruders every day.

Apart from their large size and mobility, which can readily help them evade defence mechanisms, parasitic worms can also secrete chemicals that for example can make the blood coagulate slower, or suck the nutrients ripping the host off of the benefits, or again due to size they can block the flow of blood or lymph, causing pressure atrophies.

#Wakelin D. Helminths: Pathogenesis and Defenses. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 87.

https://www.ncbi.nlm.nih.gov/books/NBK8191/

Quote#1: “Many of the pathogenic consequences of worm infections are related to the size, movement and longevity of the parasites, as the host is exposed to long-term damage and immune stimulation, as well as to the sheer physical consequences of being inhabited by large foreign bodies.

Intestinal worms cause a variety of pathologic changes in the mucosa, some reflecting physical and chemical damage to the tissues, others resulting from immunopathologic responses. Hookworms (Ancylostoma and Necator) actively suck blood from mucosal capillaries. The anticoagulants secreted by the worms cause the wounds to bleed for prolonged periods, resulting in considerable blood loss. Heavy infections in malnourished hosts are associated with anemia and protein loss. Protein-losing enteropathies may also result from the inflammatory changes induced by other intestinal worms. Diversion of host nutrients by competition from worms is probably unimportant, but interference with normal digestion and absorption may well aggravate undernutrition. The tapeworm Diphyllobothrium latum can cause vitamin B12 deficiency through direct absorption of this factor.”

Quote#2: “Despite their immunogenicity, many helminths survive for extended periods in the bodies of their hosts. Some of the reasons have already been mentioned (size, motility), but we now know that worms employ many sophisticated devices to render host defenses ineffective (Fig. 87-4). Some worms (schistosomes) disguise their outer surface by acquiring host molecules which reduce their antigenicity; intrinsic membrane changes also make these worms resistant to immune attack. Filarial nematodes acquire serum albumin on their cuticle, which may act as a disguise. Many worms release substances that depress lymphocyte function, inactivate macrophages, or digest antibodies. Larval cestodes appear to prolong their survival by producing anticomplement factors which protect their outer layers from lytic attack. Antigenic variation in the strict sense is not known to occur, but many species show a stage-specific change of antigens as they develop, and this phenomenon may delay the development of effective immune mechanisms. All helminths release relatively large amounts of antigenic materials, and this voluminous production may divert immune responses or even locally exhaust immune potential. Irrelevant antibodies produced by the host may block the activity of potentially protective antibodies, as has been shown to be the case in schistosome infections.”

– Our ancestors were basically unable to prevent regular worm infections. So as the worms adapted to us, our bodies had to adapt to them. To balance out any weakening worm chemicals, one adaptation might have been to make our immune system more aggressive so it could still defend against other invaders.

#Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nat Rev Immunol. 2011

https://pubmed.ncbi.nlm.nih.gov/21610741/

Quote: “The immune system has evolved to defend us from the full spectrum of pathogens, including microorganisms, such as viruses, bacteria, fungi and protozoal parasites, and macropathogens, such as multicellular helminths and ectoparasites. Each of these pathogens poses a very different problem for the immune system to resolve and, correspondingly, we have evolved specialized mechanisms and cell populations to best address the challenge encountered in each setting. When operating optimally, the immune system interweaves the innate and adaptive arms of immunity, at both sensitization and effector levels, in a continuous dialogue that selects, calibrates and terminates the response in the most appropriate manner. Many pathogens, however, have developed complex evasion strategies and, when the immune response falls short, it may be necessary for the host to enter a damage limitation state, accommodating infection in order to minimize pathology. Moreover, most parasite immune evasion mechanisms themselves depend on a form of molecular dialogue between pathogen and host and, in turn, many parasites depend on host molecular signals for their development.”

– Worms still infect up to 2 billion people, mostly in underdeveloped rural regions or slums with unsanitary conditions and dirty water.

#WHO. Soil-transmitted helminth infections. 2023.

https://www.who.int/news-room/fact-sheets/detail/soil-transmitted-helminth-infections

Quote: “Soil-transmitted helminth (STH) infections are among the most common infections worldwide with an estimated 1.5 billion infected people or 24% of the world’s population. These infections affect the poorest and most deprived communities with poor access to clean water, sanitation and hygiene in tropical and subtropical areas, with the highest prevalence reported from sub-Saharan Africa, China, South America and Asia. They are transmitted by eggs present in human faeces, which in turn contaminate soil in areas where sanitation is poor. Over 260 million preschool-age children, 654 million school-age children,108 million adolescent girls and 138.8 million pregnant and lactating women live in areas where these parasites are intensively transmitted, and are in need of treatment and preventive interventions.”

#CDC Yellow Book 2024. Helminths, Soil-Transmitted. Travel-Associated Infections & Diseases

https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/helminths-soil-transmitted

Quote: “Globally, ≈2 billion people are infected with ≥1 STH, which together account for most parasitic disease burden worldwide. STH have widespread global distribution and are endemic in countries with tropical or subtropical climates and where sanitation is poor, human feces are used as fertilizer (“night soil”), or water supplies are contaminated. Although all travelers to endemic countries have some risk for STH infection, risk increases for long-term travelers and expatriates going to countries with poor general sanitation. Travelers can minimize risk by taking preventive measures.”

– And while IgE, mast cells, basophils and eosinophils also have other jobs, a major reason for their existence has now gone away. But they kind of act as if worms are around – only that they now attack other dangerous foes – like shrimps.

Following paper reviews functions, development and characteristics of each of the cell type.

#Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010
https://pmc.ncbi.nlm.nih.gov/articles/PMC2847274
Quote: "Mast cells, basophils and eosinophils express many of the same receptors and cytokines, yet have different effector functions. Mast cells are tissue resident cells and uniquely required for immediate hypersensitivity. Basophils are largely circulating cells, but home to areas of allergic inflammation during the late phase response. Eosinophils are resident to the GI tract, but also home to allergic inflammatory sites. The dominant cytokines produced by these cells differ: basophils express abundant IL-4 and IL-13, but little IL-5, whereas mast cells produce IL-5 and IL-13, but little IL-4. Although eosinophils can express a range of cytokines, their production of cytotoxic granule proteins is thought to be their major effector function. Differences in trafficking, activation and mediator production contributes to each cell's unique role."

Following study searched for similarities among 2712 proteins known to cause allergies and more than 70,000 proteins from 31 species of parasites and 2445 parasite proteins turned out to be very similar to allergenic proteins. For instance, scientists found a protein in the worm Schistosoma mansoni that closely resembles one in birch pollen that makes people sneeze. They also tested this finding with people with parasite infections and found that one in six of them produced antibodies that recognized the pure worm protein.

#Tyagi N, Farnell EJ, Fitzsimmons CM, Ryan S, Tukahebwa E, Maizels RM, Dunne DW, Thornton JM, Furnham N. Comparisons of Allergenic and Metazoan Parasite Proteins: Allergy the Price of Immunity. PLoS Comput Biol. 2015

https://pubmed.ncbi.nlm.nih.gov/26513360/

Quote: ”Allergic reactions can be considered as maladaptive IgE immune responses towards environmental antigens. Intriguingly, these mechanisms are observed to be very similar to those implicated in the acquisition of an important degree of immunity against metazoan parasites (helminths and arthropods) in mammalian hosts. Based on the hypothesis that IgE-mediated immune responses evolved in mammals to provide extra protection against metazoan parasites rather than to cause allergy, we predict that the environmental allergens will share key properties with the metazoan parasite antigens that are specifically targeted by IgE in infected human populations. We seek to test this prediction by examining if significant similarity exists between molecular features of allergens and helminth proteins that induce an IgE response in the human host. By employing various computational approaches, 2712 unique protein molecules that are known IgE antigens were searched against a dataset of proteins from helminths and parasitic arthropods, resulting in a comprehensive list of 2445 parasite proteins that show significant similarity through sequence and structure with allergenic proteins. Nearly half of these parasite proteins from 31 species fall within the 10 most abundant allergenic protein domain families (EF-hand, Tropomyosin, CAP, Profilin, Lipocalin, Trypsin-like serine protease, Cupin, BetV1, Expansin and Prolamin). We identified epitopic-like regions in 206 parasite proteins and present the first example of a plant protein (BetV1) that is the commonest allergen in pollen in a worm, and confirming it as the target of IgE in schistosomiasis infected humans. The identification of significant similarity, inclusive of the epitopic regions, between allergens and helminth proteins against which IgE is an observed marker of protective immunity explains the ‘off-target’ effects of the IgE-mediated immune system in allergy. All these findings can impact the discovery and design of molecules used in immunotherapy of allergic conditions.”

– This is exactly what happens when you have an allergic reaction to a shrimp. Your immune system picks up shrimp proteins and produces IgE antibodies – against shrimps. The antibodies then arm mast cells, turning them into bombs. So you have millions of bombs in your skin, your lungs or your gut, with a licence to choose violence, even when provoked a little bit. Until one day you eat another shrimp. Your anti parasite forces flip on like a switch. Only, there is no Kaiju to attack. This is what you experience when you have an allergic reaction – extremely powerful weapons now target your own body.

The whole process is a tad bit more complicated and manifests differently for different types of allergies, but the following image briefly summarizes the cascade of events and cells involved in mounting an allergic reaction.

#Ballegaard AR, Bøgh KL. Intestinal protein uptake and IgE-mediated food allergy. Food Res Int. 2023 https://www.sciencedirect.com/science/article/pii/S096399692201208X

Quote: "The pathogenesis of IgE-mediated food allergy is composed of two phases; a sensitisation phase and an elicitation phase (Fig. 2). To evoke an immune reaction, allergens must access our body and immune system. It is well-accepted that food allergy may develop through both oral and skin route of exposure and to a lesser extent through the respiratory route (Asero and Antonicelli, 2011, Dunkin et al., 2011, Ramirez and Bahna, 2009, Tordesillas et al., 2014). Hence, sensitisation may occur after ingestion and involves a primary exposure to the dietary protein or their digested peptide fragments that are transported though the gut lumen for uptake and presentation by innate immune cells to cells of the adaptive immune system leading to a cascade of events resulting in the production of specific IgE by plasma cells, as outlined in Fig. 2. Elicitation involves re-exposure to the culprit dietary protein or a cross-reacting protein, which binds and cross-links FcԑRI-bound IgEs on the surface of mast cells or basophils, leading to a degranulation response and the release of an array of mediators, such as histamine, proteases, cytokines, leukotrienes and prostaglandins, which are responsible for the symptoms characterising IgE-mediated food allergy (Stone et al., 2010) (Fig. 2). Symptoms can occur within minutes to hours and involve one or more organs. The most common site of food allergy manifestation is the skin (urticaria) followed by the gastrointestinal tract (vomiting, diarrhoea, abdominal pain) and the respiratory tract (wheezing, coughing) (Ahrens et al., 2012). In severe cases several organs are involved, and may result in the systemic reaction anaphylaxis which may be fatal (Fiocchi et al., 2010)."

– Under your skin your blood vessels suddenly turn leaky. Fluid streams into your tissue, your skin swells up and turns red, often in itchy hives. You immediately feel hot and unwell. In your digestive system the mast cells can cause nausea, cramps and sharp pain, as water floods into your intestines and triggers intense diarrhoea and vomiting.

#Food allergy. Mayo Clinic. Retrieved November 2024.
https://www.mayoclinic.org/diseases-conditions/food-allergy/symptoms-causes/syc-20355095
Quote: "Symptoms

For some people, an allergic reaction to a particular food may be uncomfortable but not severe. For other people, a food allergy reaction can be frightening and even life-threatening. Food allergy symptoms usually develop within a few minutes to two hours after eating the offending food. Rarely, symptoms may be delayed for several hours.

The most common food allergy symptoms include:

Tingling or itching in the mouth.

Hives, itching or eczema.

Swelling of the lips, face, tongue, and throat or other parts of the body.

Belly pain, diarrhea, nausea or vomiting.

Wheezing, nasal congestion or trouble breathing.

Dizziness, lightheadedness or fainting."

#Australasian Society of Clinical Immunology and Allergy. Angioedema. 2024.
https://www.allergy.org.au/patients/skin-allergy/angioedema
Quote: "Q 1: What is angioedema?
Angioedema is a condition where small blood vessels leak fluid into the tissues under the skin, causing swelling in different parts of the body. It can develop because of an allergic reaction and is usually accompanied by hives (urticaria). Up to 20% of people will develop hives at some time in their life, and around one in three of these will have angioedema as well. It is possible to develop angioedema without also developing hives.
Although the swelling can be quite severe, it is temporary. Angioedema is not usually caused by a serious underlying disease and is not likely to cause illness or damage to vital organs such as kidneys, liver, or lungs. There is no known cure, but with the right diagnosis and management with appropriate medication, it can usually be prevented."

#Vicki Contie. NIH. Unexpected role for the nervous system in anaphylaxis. 2023.
https://www.nih.gov/news-events/nih-research-matters/unexpected-role-nervous-system-anaphylaxis
Quote: "A research team led by Dr. Soman N. Abraham of Duke University Medical Center examined the mechanisms that underlie the rapid drop in body temperature seen in mice with anaphylaxis. Earlier studies had hinted that a neural circuit that helps to regulate body temperature might play a role. But to date, only the immune system—and not the nervous system—had been implicated in anaphylaxis. The findings were published online in Science Immunology on March 17, 2023.

In a series of experiments, the researchers found evidence that during anaphylaxis, heat-sensing nerve cells in mice became highly activated, despite the fact that no heat was being applied. This created a false signal that the body was overheating.

Further study revealed that during anaphylaxis, mast cells release an enzyme called chymase, which interacts with a protein called TRPV1 on a subset of sensory nerve cells. This interaction triggers a sudden shutdown of heat-generating brown fat cells. The result was a rapid drop in body temperature characteristic of anaphylaxis.

To validate these findings, the scientists showed that mice lacking chymase or TRPV1 were protected against a sudden drop in body temperature during anaphylaxis. Direct activation of TRPV1 nerve cells led to a rapid drop in body temperature even without exposure to allergens.

“By demonstrating that the nervous system is a key player—not just the immune cells—we now have potential targets for prevention or therapy,” says first author Chunjing “Evangeline” Bao. “This finding could also be important for other conditions, including septic shock, and we are undertaking those studies.”"

#Johns Hopkins Medicine. Anaphylaxis. Retrieved November 2024. https://www.hopkinsmedicine.org/health/conditions-and-diseases/anaphylaxis
Quote: "Anaphylaxis, also called allergic or anaphylactic shock, is a sudden, severe and life-threatening allergic reaction that involves the whole body. The reaction is marked by constriction of the airways, leading to difficulty breathing. Swelling of the throat may block the airway in severe cases. Gastrointestinal symptoms, such as severe abdominal pain, vomiting and diarrhea, may also occur. Histamines, the substances released by the body during an allergic reaction, cause the blood vessels to expand, which in turn causes a dangerous drop in blood pressure. Fluid can leak into the lungs, causing swelling (pulmonary edema). Anaphylaxis can also cause heart rhythm disturbances. Any allergen can cause this reaction, but the most common ones are insect bites, food and drugs.
Symptoms

Symptoms develop suddenly and escalate in seconds:

Difficulty breathing

Confusion

Rapid heart beat

Swelling of the lips, tongue, throat

Wheezing

Slurred speech

Confusion

Bluish skin (cyanosis)

Light-headedness, dizziness, fainting

Hives and generalized itching

Anxiety

Heart palpitations

Nausea, vomiting

Diarrhea

Abdominal pain or cramping

Cough"

– Your respiratory tract swells up making breathing hard. Way more dangerously, histamine and other chemicals can cause the smooth muscles in your lungs to tense up.

#Patel RH, Mohiuddin SS. Biochemistry, Histamine. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
https://www.ncbi.nlm.nih.gov/books/NBK557790/
Quote: “H1 receptors are widespread throughout the body, including neurons, smooth muscle cells of the airways, and blood vessels. Activation of the H1 receptors causes the stereotypical allergic/anaphylactic physiological reactions: increased pruritus, pain, vasodilation vascular permeability, hypotension, flushing, tachycardia, and bronchoconstriction. Also, H1 receptors regulate sleep-wake cycles, food intake, thermal regulation, emotions/aggressive behavior, locomotion, memory, and learning.[1] These receptors also mediate most of the effects of histamine that are relevant to asthma and can also include features of smooth muscle spasms, mucosal edema, inflammation, and mucous secretion.[2] H1 receptor antagonists have also been studied and identified in the management of benign forms of allergic conjunctivitis.[10]”

#Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, Church MK and Saluja R (2018) The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets. Front. Immunol.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01873/full
Quote:"The H1R is ubiquitously expressed and is involved in allergy and inflammation. H1R is expressed in many tissues and cells, including nerves, respiratory epithelium, endothelial cells, hepatic cells, vascular smooth muscle cells, dendritic cells, and lymphocytes (8, 19). Histamine activates H1R through Gαq/11, which then activates phospholipase C and increases intracellular Ca++ levels. As a consequence, histamine elicits the contraction of smooth muscle of the respiratory tract, increases vascular permeability, and induces the production of prostacyclin and platelet activating factor by activating H1R (Figure 1) (58). Thus, almost all immediate hypersensitivity reactions, including symptoms observed in the skin, such as erythema, pruritus, and edema, may be elicited by the activation of H1R (59)."

– Mast cells all over your body unload their bombs all at once, causing an anaphylactic shock. Your blood loses so much water that your blood pressure drops to dangerous levels. This alone is life threatening. In combination with the things going on in your lungs, anaphylaxis is a life or death emergency – often with just a small time window to do anything about it.

#Hammett, E. Medical emergencies: anaphylaxis. BDJ Team 4, 17158 (2017). https://www.nature.com/articles/bdjteam2017158
Quote: "We have small amounts of histamine in our system normally and it is important for various vital functions of the body including regulating stomach acid and as a neurotransmitter in our nerve cells. However, larger amounts of histamine being released leads to symptoms such as sneezing, blocked nose, itching... the sort of symptoms often associated with hayfever and mild allergies. Antihistamine medication can work effectively at resolving these symptoms. However, antihistamine medication typically takes around 15 minutes to work.

Life threatening and systemic allergic reactions are caused by the body producing even more histamine, which dilates small blood vessels and causes them to leak, resulting in swelling in areas such as the lungs – leading to breathing problems. Sufferers may have a rash and be flushed due to the increased blood supply to the skin. Their blood pressure could drop dramatically and they may collapse."

– Yet we still don’t know why some people produce a lot of IgE antibodies against certain substances and others don’t. We don’t know why some adults develop new allergies later in life or why some allergies disappear over time. And we are not sure if the lack of worms is the main culprit, only that the cells that evolved to fight them are responsible for the symptoms of allergies. There are other ideas, like less diverse microbiomes or increased pollution – maybe it's just a combination of all of them.

#Ballegaard AR, Bøgh KL. Intestinal protein uptake and IgE-mediated food allergy. Food Res Int. 2023 https://www.sciencedirect.com/science/article/pii/S096399692201208X
Quote: “Several factors have been suggested as contributing causes to the increase in food allergy seen in the Western countries during the last decades, and relate to changes in both environmental and lifestyle parameters, such as increased pollution, decreased physical activity, increased hygiene, increased use of drugs, increased psychological stress and changes in the diet (Granum et al., 2020; Lozano-Ojalvo et al., 2019b; Marshall, 2004; Platts-Mills, 2015). Why and how these external factors contribute to the increased prevalence of food allergy remains to be fully resolved, but may be attributed to a direct effect on the host or an indirect effect on the host triggered by changes in the microbiota composition (Platts-Mills, 2015; Reitsma et al., 2014).”

Some researchers suggested that allergic reactions are part of an internal food control system gone wrong. Immune system operates through an inherently error prone “guilty by association” mechanism. The benefits of detecting potentially harmful substances outweigh the cost of rejecting harmless food, which might have led to a highly sensitive but less specific system for monitoring food quality that prefers “better safe than sorry” approach.

#Florsheim et al. Food allergy as a biological food quality control system

https://www.sciencedirect.com/science/article/pii/S0092867420316779

Quote: “Allergies have long been assumed to be mistargeted responses to innocuous environmental antigens, with the normal counterpart being the defense against parasitic worms. This assumption is largely based on the fact that anti-parasitic and allergic responses are mediated by the same effector arm of the immune system; namely, by the type 2 immune response. An alternative view, originally proposed by Profet (1991), is that allergy is a defense against environmental toxins. Indeed, all symptoms of allergic reactions,

including rhinitis, sneezing, coughing, vomiting, diarrhea, and itching, have one thing in common: they are defense mechanisms designed to remove harmful environmental substances from the skin and the respiratory and GI tracts (Palm et al., 2012).

Here we extend and reconcile these views by suggesting that allergic responses are a form of defense that normally protects from noxious substances but becomes pathological when exaggerated or mistargeted. Examples of exaggerated allergic responses include anaphylaxis, edema, and hives. Examples of mistargeted allergic responses include many instances of reactivity toward innocuous antigens that are targeted because of prior association with noxious substances (see below). Thus, we suggest that the physiological counterpart of food allergies is the food quality control system that limits exposure to harmful substances in foods. Normal operation of this system does not result in clinical symptoms and, therefore, is not recognized as a distinct mode of function of ‘‘allergic immunity.’’ Pathological food allergies, on the other hand, are exaggerated versions of this defense system that result in clinical symptoms. ”

– But what we clearly see is that allergies and their more serious cousin, autoimmune diseases, have been rising massively in the last 100 years.

#Ballegaard AR, Bøgh KL. Intestinal protein uptake and IgE-mediated food allergy. Food Res Int. 2023 https://www.sciencedirect.com/science/article/pii/S096399692201208X
Quote: “Food allergy is defined as an immune-mediated adverse reaction to otherwise harmless dietary proteins, caused by a failure in the immune system to develop tolerance after food protein exposure or by an abrogation of an already established oral tolerance (Lozano-Ojalvo et al., 2019b; Yu et al., 2016; Boyce et al., 2010). Food allergy is a major health problem affecting around 5–8 % of young children and 2–4 % of adults (Sicherer & Sampson, 2014, 2018), and appears to be increasing worldwide (Kotz et al., 2011; Loke et al., 2016; McWilliam et al., 2015; Osborne et al., 2011; Sasaki et al., 2018)."

#Gutowska-Ślesik J, Samoliński B, Krzych-Fałta E. The increase in allergic conditions based on a review of literature. Postepy Dermatol Alergol. 2023
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9993206/
Quote: “One of the first survey-based epidemiological studies was conducted in 9,000 families in the United States in the period 1928–1931. The resulting analyses showed 0.5% of children aged 5–9 years to suffer from bronchial asthma. Subsequent studies, conducted in the period from 1976 to 1980, demonstrated an increased prevalence of asthma in children and adolescents aged 3–17 years. Asthmatic symptoms were reported in 9.5% of children among a total of 7,300 respondents. Fourteen years later, 15.9% of children aged 5–17 years had been diagnosed with bronchial asthma [7]. In comparison with the 1983 data, the prevalence of asthma had increased by 6.7% in this population [8]. By the beginning of the 21st century, the total number of bronchial asthma patients in the United States had increased by 60% in comparison with the data from the early 1980s [9]. Meanwhile, the rates of allergic rhinitis ranged from 9% to 42% in the study population [10]. The current incidence is very high in the population of under-18-year-olds, 41% of whom suffer from asthma, 11.6% from atopic dermatitis, 10% from allergic rhinitis, 8.4% from hay fever, and 5.4% from food allergies [11].”

#Miller FW. The increasing prevalence of autoimmunity and autoimmune diseases: an urgent call to action for improved understanding, diagnosis, treatment, and prevention. Curr Opin Immunol. 2023 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9918670/
Quote: “Consistent with the ANA findings above, which argue against the notion that increased physician recognition of autoimmune diseases alone may be causing their apparent rises, local, national, and international epidemiologic studies have discovered similar increases in the frequencies of most autoimmune diseases. Estimates of the yearly increases in the overall worldwide incidence and prevalence of autoimmune diseases are 19.1% and 12.5%, respectively [26]. Despite the limitations noted above in obtaining accurate estimates, prevalence data collated from multiple investigations of various autoimmune diseases in many global locations have confirmed an overall rising trend (Figure 2). Perhaps the best studied of these is type 1 diabetes [27], where investigations found a consistent 3–4% annual increase in incidence over the last three decades [28]. Not only are core currently recognized autoimmune diseases increasing, but the range of autoimmune and chronic inflammatory diseases continues to expand in number and scope, as additional disorders are found to have laboratory or clinical features implicating involvement of the immune system and autoimmune signatures [10].

[...]

Taken together, the confluence of growing evidence points to many environmental factors that are possibly related to the development of autoimmunity and autoimmune diseases [45–48]. Of most concern are the major changes in our diets and the effects on microbiomes [49–52], xenobiotic contacts [53,54], infections [55,56], personal lifestyles and attendant increased obesity rates [57] and sleep deprivation [58], stress [59], air pollution [60], and the impacts of climate change [61], as possible contributing factors to these increases.”

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