**5. Host-Parasite Interaction,** *Demodex canis versus* **dog**

Because they are natural inhabitants of the skin of mammals, mites of the genus *Demodex* usually do not generate adverse reactions to the host due to the capacity of the animal's immune system [6, 11, 17, 26, 56]. This is due to the recognition of mite chitin by host keratinocytes through their toll-like receptors (TLR), specifically TLR2, triggering an innate immune response. In addition, studies report that the immune systems of healthy dogs are especially effective at detecting the lipases and proteases secreted by *Demodex* mite, possibly stimulating the adaptive immune response, which is more specific and effective for the control of the *Demodex* mite [17, 57].

**81**

factor.

circulating CD4+ [17].

to generalised demodicosis [56].

*Clinical and Immuno-Pathology Aspects of Canine Demodicosis*

probable that there is impaired cellular immunity [7, 57].

synthesis of cytokines and helper 1 T cells (Th1) [22].

not eliminating or containing the proliferation of the mite.

The reason for the progressive evolution of the disease in some dogs has not been completely elucidated. The most accepted hypothesis is that immune system dysfunctions play an important role in the manifestation of clinical signs of the disease in its different forms [7, 11, 13–15]. The proposition that the host immune system is the main mediator in the overpopulation of *Demodex* is sustained by the occurrence of the disease in patients who have undergone prolonged treatments with immunosuppressive drugs, in addition to clinical signs in immunodeficient mice, as well as in people and animals with chronic degenerative diseases [17, 56, 57]. However, studies in dogs indicate that immunosuppression occurs at various times in the course of the disease and may be induced by the action of the mite itself on the hair follicles and/ or sebaceous glands and not as a primary trigger for parasitic proliferation [14, 17, 32, 42, 57]. This explains why not all immunosuppressed dogs develop clinical demodicosis and indicates that the manifestation of the disease may involve more than one

Unlike humans, there is little evidence of humoral immune response being involved in canine demodicosis and although Ravera et al. [58] have shown the existence of immunoglobulin (Ig) G against *D. canis* with generalised juvenile demodicosis, the real meaning of this response remains unclear. On the other hand, dogs with generalised demodicosis tend to present functional immunodeficiency in T lymphocytes [7, 18]. Many of the studies indicate that the main mechanism of *Demodex* population control is cell mediated. When mite proliferation occurs, it is

This immune dysfunction is defined by the exhaustion of T cells. This type of depletion is not uniform and is generally characterised by high levels of suppressor cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β, low production of stimulatory interleukins, such as IL-2 and IL-21 and a reduction in

Higher serum levels of IL-10 were observed in dogs with relapsing demodicosis, compared to healthy dogs and those with first manifestation. This change culminates in T cell suppression and antigen presentation ability by inhibiting the

Lemarié et al. [59] observed a reduction in the expression and in vitro production of IL-2 resulting from a decrease in Th1 cell response and pointed to a functional irregularity of this class of lymphocytes, directly affecting the balance between Th1 and Th2 responses during the course of the disease. The establishment and perpetuation of demodicosis was attributed to suppression of the Th1 response to Th2, resulting in an inflammatory process capable of inducing tissue damage but

The decrease in transcription of cytokines TNF-α and IFN-γ, and the unprecedented increase in IL-5, as evidenced by Tani et al. [20], appears to be due to Th2 lymphocyte overexpression in the presence of *Demodex* [59]. In addition, Yarim et al. [23] and Tani et al. [20] demonstrated an increase in circulating TGF-β concentrations in dogs with generalised disease compared to healthy animals. Elevated TGF-β levels may compromise the regulation of various biological processes, such as tissue homeostasis, angiogenesis, and cell differentiation, especially in cases of chronic disease, allowing the evolution of localised

Considering that most of these previously described changes were observed in dogs with generalised demodicosis, a recent study investigated the serum levels of a selection of proinflammatory cytokines in dogs with localised and generalised demodicosis in order to observe the levels of certain proteins. There was no difference in serum cytokine levels between groups of diseased animals, but IL-6 was significantly higher in dogs with localised disease than in healthy animals. Thus,

*DOI: http://dx.doi.org/10.5772/intechopen.88763*

*Parasitology and Microbiology Research*

clinical lesions [8]. As the disease progresses, mural folliculitis occurs due to the infiltration of lymphocytes and histiocytes into the follicular wall, causing injury to follicular keratinocytes. Hydropic degeneration, follicular keratinocyte apoptosis and follicular exocytosis occurs [9, 50]. Mural folliculitis, which has been reported most frequently in dogs with the localised disease [8], is observed to be a consistent and an important lesion pattern of active demodicosis. The histological lesion generated is often associated with diseases in which immune response is recognised

*(A) Generalised demodicosis in dog with cutaneous hyperpigmentation, alopecia and desquamation. (B) Pyoderma and generalised demodicosis in facial region of dog. (C) Demodex in the interior of the hair* 

Finally, multiplication of *Demodex* in the interior of the hair follicles induces follicle dilation causing rupture and releasing mites into the dermal interstitium [10]. The observation of mural folliculitis and multifocal pyogranulomatous furunculosis more frequently in dogs with localised demodicosis indicates that the histological stages of follicular inflammation may have similar severity in the different clinical

Because they are natural inhabitants of the skin of mammals, mites of the genus *Demodex* usually do not generate adverse reactions to the host due to the capacity of the animal's immune system [6, 11, 17, 26, 56]. This is due to the recognition of mite chitin by host keratinocytes through their toll-like receptors (TLR), specifically TLR2, triggering an innate immune response. In addition, studies report that the immune systems of healthy dogs are especially effective at detecting the lipases and proteases secreted by *Demodex* mite, possibly stimulating the adaptive immune response, which

as important in its pathogenesis [10, 50, 54, 55].

*follicles and folliculitis. H&E, 10×. (D) Furunculosis. H&E, 10×.*

**5. Host-Parasite Interaction,** *Demodex canis versus* **dog**

is more specific and effective for the control of the *Demodex* mite [17, 57].

forms of the disease [8].

**Figure 2.**

**80**

The reason for the progressive evolution of the disease in some dogs has not been completely elucidated. The most accepted hypothesis is that immune system dysfunctions play an important role in the manifestation of clinical signs of the disease in its different forms [7, 11, 13–15]. The proposition that the host immune system is the main mediator in the overpopulation of *Demodex* is sustained by the occurrence of the disease in patients who have undergone prolonged treatments with immunosuppressive drugs, in addition to clinical signs in immunodeficient mice, as well as in people and animals with chronic degenerative diseases [17, 56, 57]. However, studies in dogs indicate that immunosuppression occurs at various times in the course of the disease and may be induced by the action of the mite itself on the hair follicles and/ or sebaceous glands and not as a primary trigger for parasitic proliferation [14, 17, 32, 42, 57]. This explains why not all immunosuppressed dogs develop clinical demodicosis and indicates that the manifestation of the disease may involve more than one factor.

Unlike humans, there is little evidence of humoral immune response being involved in canine demodicosis and although Ravera et al. [58] have shown the existence of immunoglobulin (Ig) G against *D. canis* with generalised juvenile demodicosis, the real meaning of this response remains unclear. On the other hand, dogs with generalised demodicosis tend to present functional immunodeficiency in T lymphocytes [7, 18]. Many of the studies indicate that the main mechanism of *Demodex* population control is cell mediated. When mite proliferation occurs, it is probable that there is impaired cellular immunity [7, 57].

This immune dysfunction is defined by the exhaustion of T cells. This type of depletion is not uniform and is generally characterised by high levels of suppressor cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β, low production of stimulatory interleukins, such as IL-2 and IL-21 and a reduction in circulating CD4+ [17].

Higher serum levels of IL-10 were observed in dogs with relapsing demodicosis, compared to healthy dogs and those with first manifestation. This change culminates in T cell suppression and antigen presentation ability by inhibiting the synthesis of cytokines and helper 1 T cells (Th1) [22].

Lemarié et al. [59] observed a reduction in the expression and in vitro production of IL-2 resulting from a decrease in Th1 cell response and pointed to a functional irregularity of this class of lymphocytes, directly affecting the balance between Th1 and Th2 responses during the course of the disease. The establishment and perpetuation of demodicosis was attributed to suppression of the Th1 response to Th2, resulting in an inflammatory process capable of inducing tissue damage but not eliminating or containing the proliferation of the mite.

The decrease in transcription of cytokines TNF-α and IFN-γ, and the unprecedented increase in IL-5, as evidenced by Tani et al. [20], appears to be due to Th2 lymphocyte overexpression in the presence of *Demodex* [59]. In addition, Yarim et al. [23] and Tani et al. [20] demonstrated an increase in circulating TGF-β concentrations in dogs with generalised disease compared to healthy animals. Elevated TGF-β levels may compromise the regulation of various biological processes, such as tissue homeostasis, angiogenesis, and cell differentiation, especially in cases of chronic disease, allowing the evolution of localised to generalised demodicosis [56].

Considering that most of these previously described changes were observed in dogs with generalised demodicosis, a recent study investigated the serum levels of a selection of proinflammatory cytokines in dogs with localised and generalised demodicosis in order to observe the levels of certain proteins. There was no difference in serum cytokine levels between groups of diseased animals, but IL-6 was significantly higher in dogs with localised disease than in healthy animals. Thus,

characterising the nonspecific inflammatory reaction that occurs shortly after tissue injury precedes the acquired immune response in the acute phase of the disease [16].

Moreover, a modern approach supports the involvement of the cholinergic pathway in the immunopathogenesis of canine demodicosis. In addition to acting as a neurotransmitter, acetylcholine (Ach) plays an important role as a mediator in the inflammatory process by inhibiting the release of certain proinflammatory cytokines, without affecting the production of inhibitory cytokines such as IL-10. The increased activity of its indirect biomarker, acetylcholinesterase, in the serum of dogs with demodicosis, has established the overproduction of Ach in diseased dogs, resulting in immunosuppression [26, 56].

Finally, it is known that TLR receptors play an important role in the identification and control of *Demodex* proliferation in the skin of healthy dogs [17]. However, in a recent study involving animals with demodicosis, important changes in the function of these receptors were detected. Kumari et al. [60] showed elevated expression of mononuclear type 2 TLRs (lymphocytes and monocytes), as well as a decrease in the expression of TLR types 4 and 6. These effects were directly attributed to the action of the mites, but it is not yet known how the mite stimulates or decreases the production of TLR receptors in the disease process [12, 60].

## **6. Conclusion**

Although the *D. canis* mite is considered a commensal inhabitant of dog's skin, demodicosis is one of the most frequent parasitic diseases in this species. Clinical signs such as alopecia, desquamation, erythema and crusting are common in dogs with localised and generalised demodicosis and may be aggravated by secondary bacterial infection. Pyoderma produces severe dermal microscopic inflammation; however, the histopathological findings of dogs with localised and generalised disease tend to be similar. In addition, the increase in the parasitic load of mites in the canine tegument induces the clinical disease, but does not define the severity of the lesions, indicating that the predisposing factor for the mite proliferation likely relates to the immunocompetence of the host.

Low production of stimulating cytokines and high levels of suppressor cytokines coupled with reduced numbers of CD4+ lymphocytes are invariably observed in dogs that develop clinical signs of demodicosis, indicating T-cell depletion. However, due to the multifactorial nature of the disease, immunological mechanisms that allow the excessive growth of the parasites in the dog skin is still misunderstood and this limitation in the understanding of the host-mite interaction makes that the impediment of diseased animals reproduction prevail as the main strategy of control until now.

Currently, research groups from different countries have suggested several mechanisms to understand the immunopathogenesis of demodicosis and although the various hypotheses raised are not yet enough to establish the determining cause of clinical disease development, observed together they allow for new hypotheses that may serve as starting points for subsequent studies in the area.

**83**

**Author details**

Valéria Régia F. Sousa\*, Naiani D. Gasparetto and Arleana B.P.F. Almeida Universidade Federal de Mato Grosso, UFMT, Mato Grosso, Brazil

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: regia@ufmt.br

provided the original work is properly cited.

*Clinical and Immuno-Pathology Aspects of Canine Demodicosis*

*DOI: http://dx.doi.org/10.5772/intechopen.88763*

*Clinical and Immuno-Pathology Aspects of Canine Demodicosis DOI: http://dx.doi.org/10.5772/intechopen.88763*

*Parasitology and Microbiology Research*

dogs, resulting in immunosuppression [26, 56].

relates to the immunocompetence of the host.

strategy of control until now.

disease [16].

**6. Conclusion**

characterising the nonspecific inflammatory reaction that occurs shortly after tissue injury precedes the acquired immune response in the acute phase of the

Moreover, a modern approach supports the involvement of the cholinergic pathway in the immunopathogenesis of canine demodicosis. In addition to acting as a neurotransmitter, acetylcholine (Ach) plays an important role as a mediator in the inflammatory process by inhibiting the release of certain proinflammatory cytokines, without affecting the production of inhibitory cytokines such as IL-10. The increased activity of its indirect biomarker, acetylcholinesterase, in the serum of dogs with demodicosis, has established the overproduction of Ach in diseased

Finally, it is known that TLR receptors play an important role in the identification and control of *Demodex* proliferation in the skin of healthy dogs [17]. However, in a recent study involving animals with demodicosis, important changes in the function of these receptors were detected. Kumari et al. [60] showed elevated expression of mononuclear type 2 TLRs (lymphocytes and monocytes), as well as a decrease in the expression of TLR types 4 and 6. These effects were directly attributed to the action of the mites, but it is not yet known how the mite stimulates or

Although the *D. canis* mite is considered a commensal inhabitant of dog's skin, demodicosis is one of the most frequent parasitic diseases in this species. Clinical signs such as alopecia, desquamation, erythema and crusting are common in dogs with localised and generalised demodicosis and may be aggravated by secondary bacterial infection. Pyoderma produces severe dermal microscopic inflammation; however, the histopathological findings of dogs with localised and generalised disease tend to be similar. In addition, the increase in the parasitic load of mites in the canine tegument induces the clinical disease, but does not define the severity of the lesions, indicating that the predisposing factor for the mite proliferation likely

Low production of stimulating cytokines and high levels of suppressor cytokines

coupled with reduced numbers of CD4+ lymphocytes are invariably observed in dogs that develop clinical signs of demodicosis, indicating T-cell depletion. However, due to the multifactorial nature of the disease, immunological mechanisms that allow the excessive growth of the parasites in the dog skin is still misunderstood and this limitation in the understanding of the host-mite interaction makes that the impediment of diseased animals reproduction prevail as the main

Currently, research groups from different countries have suggested several mechanisms to understand the immunopathogenesis of demodicosis and although the various hypotheses raised are not yet enough to establish the determining cause of clinical disease development, observed together they allow for new hypotheses

that may serve as starting points for subsequent studies in the area.

decreases the production of TLR receptors in the disease process [12, 60].

**82**
