Inflammatory And Immune Responses

When feeding from the host skin surface, acarine parasites inject or secrete into the host an array of immunogenic and pharmacokinetic molecules. Likewise, acarine parasites that live in the skin, hair follicles, sebaceous glands, and respiratory tree and lungs release immunogenic molecules both while living and after death, from their disintegrating bodies. Substances injected or released may induce an inflammatory (i.e., innate) and/or immune (i.e., adaptive) response by the host. Pharmacokinetic molecules can modulate specific aspects of the host immune or inflammatory responses.

Innate Immune Response

After a person has been bitten by a parasitic acarine, a red (or erythematous) swollen (i.e., edema), and irritated (i.e., painful) lesion may develop at the bite site. These symptoms may be the result of a localized innate inflammatory reaction and not an adaptive immune reaction. In an inflammatory reaction, components of the saliva and body secretions of mites that feed from the skin surface or in tissue (e.g., follicle or scabies mites) cause cells of the skin (epidermis and dermis) such as ker-atinocytes, fibroblasts, and antigen-presenting cells (Langerhans, macrophages, natural killer cells) to release an array of chemical mediators (cytokines, kinins, and others). These substances cause arterioles to dilate, which results in increased blood flow to the tissue. Increased blood flow to the skin where a mite has bitten or is located imparts a red appearance. In addition, the tight junctions between endothelial cells of the capillary wall become less tight, which allows fluid from the blood to leak from the capillary lumen into the surrounding tissue, causing it to swell. These cytokines also cause local endothelial cells in the capillaries and white blood cells that pass by in the capillaries to express or increase expression of adhesion molecules (i.e., the receptors) in their surface membranes. White blood cells in the blood vessels stop and adhere to the endothelial cells of the capillary. These cells (cellular infiltrate) then migrate out of the capillary space between endothelial cells to the source of the molecules that induced the reaction. The infiltrating cells may include neu-trophils, eosinophils, macrophages, and lymphocytes. The molecules from damaged or stimulated cells and secreted cytokines from the infiltrating cells stimulate pain receptors in the vicinity, causing an irritating sensation. This type of a host response is referred to as innate immunity, and it is not altered with repeated exposure to a particular mite or tick. The time and intensity of the response reaction is the same each time the individual is challenged.

Adaptive Immune Response

In contrast, the molecules introduced into the body by acarine parasites may induce an adaptive immune response that is highly specific for a particular epitope (sequential or structural) on an immunogenic molecule (antigen) from the parasite. An epitope is the part of the antigen that receptors on B and T lymphocytes recognize. The adaptive immune response is stronger and quicker with successive exposures and involves T and B lymphocytes and memory cells of each type. It may be accompanied by an inflammatory reaction too that can be delayed. With the help of type 2 T-helper cells (Th2) B cells become plasma cells that produce antibody directed at the offending molecules from the mite. Activated Th1-type helper cells activate cytotoxic T cells (Tc) that perform functions that kill the parasite directly or damage it. Helper T cells release specific cytokines such as Interleukin 2 (IL-2), interferon Y (IFN-y), and other interleukins (IL-4, IL-6, IL-10, and IL-13), which act as signals to activate Tc and B cells.

PARASITIC MITES Family Trombiculidae

Chiggers are the parasitic larval stage of prostigmatid mites that belong to the family Trombiculidae (Fig. 1). Chiggers are also known as harvest bugs in Europe and scrub-itch mites in Asia and Australia. Trombiculid mites are prevalent in moist, warm temperate climates and in tropical climates worldwide. These mites live in moist soil covered with vegetation such as grassy and weedy areas. More than 3000

Dovid Scharf
FIGURE 1 Tromicula alfreddugesi, the mite that causes chiggers. (Photograph © David Scharf.)

species of chiggers are known, but only about 15 species frequently bite humans and cause a cutaneous reaction.

Unlike many mites, male and female chiggers do not copulate directly. Instead, males deposit a stalked sper-matophore (sperm packet) on the substrate. Females insert it into their genital pores to fertilize the eggs, which are then deposited on moist soils. Larva emerge from the eggs and complete development into an active hexapodal (six-legged) larva (chigger). The larva is parasitic and must feed from a mammal, bird, or reptile host before development can progress to the nymphal stages and the adult. The active nymphal stages and adults are predators and prey on small arthropods (insects and mites) or their eggs. The larval stage (chigger) generally feeds on rodents, mice, birds, and reptiles, and some species bite humans.

Chiggers can cause dermatitis and transmit the agent Rickettsia tsutsugamushi, which causes scrub typhus in humans. Scrub typhus is characterized by an ulcer at the site of the bite, high fever, and headache. Scrub typhus is present in tropical climates such as parts of India, Pakistan, Southeast Asia, Philippines, Indonesia, Korea, Japan, China, some Pacific Islands, and coastal Queensland, Australia. The principal vectors are species of the chigger genus Leptotrombidium. The reservoir hosts for this disease are rodents (mainly rats). In nature, the pathogen is transferred from rodent to rodent by many chiggers species. Humans become infected when they venture into an enzootic area and are bitten by infected larva. The larval stage feeds only once and acquires the pathogen from infected moles, mice, rats, and other small rodents. Therefore, chiggers can only acquire the rickettsia or, if they were already infected, transmit it, but not both. The rickettsia acquired by the larva is carried (trans-stadially) throughout the developmental stages to the adult. Rickettsia acquired by the larva multiply in the subsequent developmental life stages and infect the ovaries of the adult, from which they are passed to the egg (transovarially) and then to the larva of the next generation. The rickettsia in transovarially infected larva infect the salivary gland and are transmitted to humans when the larva feed.

The chigger feeds from the surface of the skin much like a tick. Its piercing mouth-parts (chelicerae) are inserted through the epidermis into the dermis. Saliva is introduced into the host during feeding. In humans, these salivary components induce both an innate inflammatory reaction and an adaptive immune response. These reactions are characterized by the production of circulating antibody and by cellular infiltration into the feeding lesion. Repeated exposures result in a more rapid and intense adaptive immune response. It is unclear whether chiggers induce an innate inflammatory response independent of the immune response. Clinically, however, the bite manifests as a reddish (erythematous), swollen (edema), and epidermally-thickened papular and irritating lesion. Histologically, the feeding lesion appears as a cylinder of tightly packed cells surrounding a strawlike channel that extends from the dermis to the skin surface where the chigger is located. The chigger sucks fluids from the surface of the channel until it is engorged, and then it drops off the host. Chiggers do not feed on blood; rather, they feed on extracellular fluid from the dermis.

Family Demodicidae

The prostigmatid mites of the family Demodicidae are small (approx. 100 |lm in length) and have an elongated, wormlike body. The podosoma bears retractible, short, stumpy, telescoping legs. The opistosoma is transversly striated and elongate. Two species, Demodex folliculonum and D. brevis, parasitize humans and are commonly called follicle mites. Both species are most often obtained from the face, particularly along the nose, forehead, scalp, and eyelids. D. folliculonum lives in the hair follicle alongside the hair shaft and is positioned with its capitulum (mouthparts) down in the follicle. D. brevis resides in the sebaceous gland off the follicle. The entire life cycle is completed in the follicle and sebaceous gland. Generally, these mites cause little pathology in humans who practice good facial hygiene and are not immunocompromised. However, they may be associated with acne, blackheads, and acne rosacea.

Families Laelaptidae, Dermanyssidae, and Macronyssidae

The Mesostigmata contains many species of mites that are parasitic on reptiles, birds, and mammals. Included are hematophagous (blood-feeding) species in the families Laelaptidae, Dermanyssidae, and Macronyssidae. Among these are Dermanyssus gallinae (chicken mite), Ornithonyssus bacoti (tropical rat mite), O. bursa (tropical fowl mite), O. sylviarum (northern fowl mite), Echinolaelaps echidninus (spiny rat mite), Liponyssus sanguineus, Haemogamasus pontiger, and

Eulaelaps stabularis. These species are attracted to warm objects and usually live on their host or in the nest of their host. Some of these species will attack humans if their normal hosts are not available. This situation may result after roosts and nests of birds (e.g., pigeons, sparrows, starlings) and nests of rodents (mice, rats, squirrels) in homes (attics, behind shutters, etc.) are destroyed. In the absence of a natural host, the mites invade homes and attack humans. Also, species that infest poultry (O. sylviarium, O. bursa, O. gallinae) can be a problem for workers who handle infected chickens and turkeys. Bites of these mesostigmatid mites can cause an irritating inflammatory reaction. There may also be an allergic reaction in some individuals, but this remains to be confirmed. Siponyssoides sanguineus parasitizes house mice and rats and can transmit Rickettsia abari, which causes rickettsial pox in humans. Western equine encephalitis and St. Louis encephalitis viruses have been isolated from D. gallinae, but there are no documented cases of transmission of these viruses to humans.

Species in the families Rhinonyssidae, Entonyssidae, and Halarachnidae live in the nasal cavity and lungs of birds and some mammals (e.g., dogs, monkeys, seals, baboons). Human infections by these mites have not been reported.

Family Sarcoptidae

The astigmatid mites, (e.g., Sarcoptes scabiei) are permanent obligate parasites that live in the stratum corneum of the skin of at least 17 families of mammals. These mites cause a disease known as scabies. Scabies is a common contagious disease of humans. There is little morphological difference between the strains of S. scabiei that parasitize different host mammals, and at this time, the strains from different host species are not considered to be different species by most experts. However, the strains from different host species are host specific and generally cannot permanently infest an unnatural host. For example, the strain from dogs causes only temporary self-limiting infestations in humans, cats, pigs, cattle, goats, and mice, yet scabies naturally occurs on these host species. The host factors and physiological differences between mite strains that do not allow one strain to establish an infestation on strange hosts are not known.

Scabies mites are small. The male and female are 213 to 285 |lm and 300 to 504 |lm in length, respectively. The life cycle, consisting of egg, larvae, protonymph, tritonymph, and adult males and females, is completed in about 10 to 13 days on the host. All active stages are oval, with a characteristic tortoise like body with stout dorsal setae, cuticular spines, and cuticular striations.

When separated from the host at room temperature, scabies mites must infest a new host within 24 to 36 h to survive. Under cool (4 or 10°C) and humid conditions, females of the strain that infests humans (var. hominus) remain infective for at least 4 days. Therefore, fomites (i.e., clothing, bedding, and furniture that harbor dislodged mites) can be important sources of infection for humans. Body odor and temperature attract these mites to a host. Once on the host skin, females begin to burrow into the skin within minutes, and they can be completely submerged within the stratum corneum within a half-hour. Males, nymphs, and larval stages penetrate more quickly than females.

Scabies is common in nursing homes, day-care centers, and among the general population in the United States. It often mimics other skin diseases and is difficult to diagnose. Scabies is prevalent in some populations in Africa, Central America, South America, Egypt, India, and Australia. Human scabies infestations are manifested in the vicinity of the burrowing mite by itching, red, papular and vesicular lesions. These symptoms generally develop in 6 to 8 weeks after a primary (first) infestation, but they are evident within a few days of a subsequent infestation. Lesions most commonly occur on the interdigital, elbow, and chest (breast area) skin. However, other areas that may be infested are the penis, buttocks, knees, soles and insteps of the feet, wrists, waistline, and axillae.

Scabies mites induce both cell-mediated (Th1) and circulating antibody (Th2) immune responses and an associated inflammatory reaction. The cell-mediated/inflammatory response is characterized by a mixed cellular infiltrate in the skin lesion that consists of plasma cells, lymphocytes, mast cells, neutrophils, Langerhans cells, and eosinophils.

An infestation with scabies induces some immune resistance to subsequent infestations. The balance between the Th1 and Th2 responses appears to be a key aspect in protective immunity. Hosts that develop protective immunity exhibit up-regulated Th1 and weaker Th2 responses. In contrast, hosts that do not develop protective immunity exhibit strongly up-regulated Th2 response (circulating antibody) but a weaker Th1-cell-mediated response. Infected hosts produce serum antibodies to at least 12 antigens from sarcoptic mites. Some of these antigens are cross-reactive with antigens from the related house dust mites Dermatophagoides farinae, D. pteronyssinus, and Euroglyphus maynei. In some humans, antigens from S. scabiei can also induce an IgE-mediated allergic reaction and circulating IgE-type antibody.

Family Pyemotidae

Pyemotid mites are prostigmatids that have an elongate cigar-shaped body with the first two pair of legs widely spaced from the posterior two pair of legs. They have stylettiform (needlelike) chelicerae and are usually parasitic on the larvae of insects. Unlike other mites, pyemotid female mites retain internally the eggs from which the immatures hatch and pass through all developmental stages. As a result, the female's opisthosoma (region behind the last pair of legs) becomes enormously swollen before the offspring are born.

Pyemotes tritici (straw itch mite) and P. ventricosus (grain itch mite) are parasitic on the larvae of grain moths, boring and stored grain beetle larvae, and other insects. Humans may contact these species when working with grain and hay. Also, hordes of these insects may emerge from the flowers of cattails brought into a home to make a floral arrangement. These mites will attack humans and cause red, itchy inflammatory dermatitis.

Families Tetranychidae and Eriophyidae

Many species of prostigmatid mites such as those in the families Eriophyidae and Tetranychidae parasitize plants and can become an economic problem on food crops (e.g., fruit trees; vegetable and grain crops) and yard/garden and green houseplants. Humans come into contact with these mites when working in fields, orchards, greenhouses, gardens, and yards, when handling infested food crops/produce, or by living near an area in which food crops are grown. The importance to human health of most of these pest species has yet to be determined. However, it is clearly documented that a few species are the source of allergens that induce allergic reactions in predisposed individuals. Farmers working in apple orchards and children living around citrus orchards have become sensitized and/or had allergic reactions to Tetranychus urticae (two-spotted spider mite) and Panonychus ulmi (European red mite) and P. citrilis (citrus red mite).

Family Phytoseiidae

Humans come into contact with predaceous mites that are used for biological control of pest species such as the tetranychids just mentioned. The predaceous mite Phytoseilus persimilis, which feeds on spider mites, can cause allergic reactions.

Family Hemisarcoptidae

Hemisarcoptes cooremani is an astigmatid mite that is a predator of scale insects that parasitize woody plants. The body of this mite is the source of at least two allergenic proteins. Close contact with these mites can result in production of serum IgE and allergic symptoms. Therefore, gardeners and nursery workers may become sensitized to this mite and have allergic reactions.

NONPARASITIC MITES Family Pyroglyphidae

The family Pyroglyphidae contains mainly species of astigmatid mites that live in the nests of birds and mammals, where they feed on the epidermal detritus (skin, feathers) left by the host. Three species, Dermatophagoides farinae, D. pteronyssinus, and Euroglyphus maynei, are commonly found in homes of humans. In homes, these mites are most prevalent in high-use areas, where shed skin scales collect and serve as their food. Therefore, the greatest densities are found in carpets around sofas and easy chairs, in fabric-covered overstuffed furniture, and in mattresses. However, they may also be found in bedding, on pillows, on clothing, on automobile and train seats, and sometimes in schools and in the workplace. Each species is the source of multiple potent allergens that sensitize and trigger allergic reactions in predisposed people. These allergens cause perennial rhinitis, asthma, and atopic dermatitis.

Ambient relative humidity is the key factor that determines the prevalence and geographical distribution of these mites. This is because water vapor in humid air is the main source of water for their survival. They survive and thrive well at relative humidities above 50% but desiccate and die at relative humidities below this. Therefore, dust mites and the allergies they cause are a significant problem only for people who live in humid, tropical, and temperate geographical areas. D. farinae and/or D. pteronyssinus are prevalent in homes in the United States, Europe, South America, and Asia. Most homes are coinhabited by multiple species. However, the most prevalent species varies both between homes in a geographical area and between geographical areas. For example, in the United States, both D. farinae and D. pteronyssinus are prevalent in homes. However, in South America, D. pteronyssinus is prevalent in homes, whereas D. farinae is not.

In temperate climates, population densities of D. farinae and D. pteronyssinus exhibit pronounced seasonal fluctuations that parallel the seasonal fluctuations in indoor relative humidity. High densities occur during the humid summer and low densities during winter.

The life stages of the dust mites are egg, larva, protonymph, tritonymph, and adult male and female. Length of the life cycle is temperature dependent when relative humidity is above 60%. At 23°C the life cycle takes 34 and 36 days to complete for D. farinae and D. pteronyssinus, respectively. Females produce 2 or 3 eggs daily during the reproductive period at 23°C. D. pteronyssinus takes 23 and 15 days to complete development at 16 and 35°C, respectively. D. farinae does not develop well at 16 and 35°C.

A desiccant-resistant quiescent protonymphal stage can develop that allows survival during long periods (months) under dry (low relative humidity) conditions. When relative humidity conditions become optimal, the quiescence is broken and development continues.

Allergens from these mites are associated with fecal material, body secretions, and body anatomy. Fourteen different groups of mite allergens have been characterized. The frequency of reactivity to most of these allergens is above 40% among patients sensitive to dust mites. Sensitivity to allergens varies both within and between individuals. Allergens from one species may be species specific, or they may cross-react with allergens from another mite species. Most patients with sensitivities are allergic to multiple allergens of a species and to multiple mite species.

Families Acaridae, Glycyphagidae, Carpoglyphidae, Echimyopididae, and Chortoglyphidae

Many species of the astigmatid families Acaridae, Glycypha-gidae, Carpoglyphidae, Echimyopididae, and Chortoglyphidae are medically important because they are the sources of potent allergens. Many species of these mites are often referred to as "storage mites" because they occur in stored hay, grain, and straw, in processed foods made from grain (flour, baking mixes), and in dust in grain and hay at storage, transfer, and livestock feeding facilities. Humans may be exposed to storage mites, and their allergens, occupationally and in the home. Inhalation or contact on the skin with allergens from storage mites can induce allergic reactions. These mites and their allergens can also occur in bread, pancakes, cakes, pizza, pasta, and bread made from ingredients contaminated with mites. Humans have had anaphylactic reactions after eating these mite-contaminated foods.

Species known to be the sources of allergens include Blomia tropicalis (Echimyopididae); Acarus siro, Tyrophagus putrescentiae, T. longior, and Aleuroglyphus ovatus (Acaridae); Lepidoglyphus destructor and Glycyphagus domesticus (Glycyphagidae); Carpoglyphus spp. (Carpoglyphidae); Chortoglyphus arcuatus (Chortoglyphidae); and Suidasia medanensis (Suidasiidae). T. putrescentiae is the source of 14 allergens, with the number recognized as allergens by individuals ranging from 5 to 11. B. tropicalis, which is common in house dust in tropical climates and may be more prevalent than pyroglyphid mites, has been reported in small numbers in some homes in the southern subtropical United States. Several allergens from B. tropicalis have been characterized and/or produced by recombinant technology. There is little cross-reactivity between storage mites and house dust mites. However, many patients are sensitive to both storage mites and the pyroglyphid house dust mites.

See Also the Following Articles

Medical Entomology • Mites • Ticks • Veterinary Entomology Further Reading

Arlian, L. G. (1989). Biology, host relations, and epidemiology of Sarcoptes scabiei. Annu. Rev. Entomol. 34, 139—161. Arlian, L. G. (1992). Water balance and humidity requirements of house dust mites. Exp. Appl. Acarol. 6, 15-35. Arlian, L. G. (1996). Immunology of scabies. In "The Immunology of Host-Ectoparasitic Arthropod Relationships." (S. Wikel, ed.), pp. 232-258. CAB International, Wallingford, U.K. Arlian, L. G. (2002). Arthropod allergens and human health. Annu. Rev.

Entomol. 47, 395-433. Arlian, L. G, Bernstein, D., Bernstein, I. L., et al. (1992). Prevalence of dust mites in homes of people with asthma living in eight different geographic areas of the United States. J. Allergy Clin. Immunol. 90, 292-300. Arlian, L. G., Neal, J. S., Morgan, M. S., et al. (2001). Reducing relative humidity is a practical way to control dust mites and their allergens in homes in temperate climates. J. Allergy Clin. Immunol. 107, 99-104. Johansson, E., Johansson, S. G. O., and van Hage-Hamsten, M. (1994). Allergenic characterization of Acarus siro and Tyrophagus putrescentiae and their cross reactivity with Lepidoglyphus destructor and Dermatophagoides pteronyssinus. Clin. Exp. Allergy 24, 743-751. Kim, Y. K., Lee, M. H., Jee, Y. K., et al. (1999). Spider mite allergy in apple-cultivating farmers: European red mite (Panonychus ulmi) and the two-spotted spider mite (Tetranychus urticae) may be important allergens in the development of work-related asthma and rhinitis symptoms. J. Allergy Clin. Immunol. 104, 1285-1292.

Lee, M. H., Cho, S. H., Park, H. S., et al. (2000). Citrus red mite (Panonychus citrilis) is a common sensitizing allergen among children living around citrus orchards. Ann. Allergy Asthma Immunol. 85, 200—204.

Radovsky, F. J. (1994). The evolution of parasitism and the distribution of some dermanyssoid mites (Mesostigmata) on vertebrate hosts. In "Mites, Ecological and Evolutionary Analysis of Life-History Patterns." (M. A. Houck, ed.), pp. 186-217. Chapman & Hall, New York.

Thomas, W. R., and Smith, W. (1999). Towards defining the full spectrum of house dust mite allergens. Clin. Exp. Allergy 29, 1583-1587.

Wikel, S. K., Ramachandra, R. N., and Bergman, D. K. (1996). Arthropod modulation of host immune responses. In "The Immunology of Host-Ectoparasitic Arthropod Relationships." (S. Wikel, ed.), pp. 107-130. CAB International, Wallingford, U.K.

Wrenn, W. (1996). Immune responses to manger mites and chiggers. In "The Immunology of Host-Ectoparasitic Arthropod Relationships." (S. Wikel, ed.), pp. 259-289. CAB International, Wallingford, U.K.

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