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he immuno-pathological conversions of canine demodicosis
hanker K. Singha,b,∗, Umesh Dimrib
Department of Veterinary Clinical Medicine, College of Veterinary Science and Animal Husbandry, DUVASU, Mathura 281 001, UP, IndiaDivision of Medicine, Indian Veterinary Research Institute, Izatnagar 243 122, UP, India
a r t i c l e i n f o
rticle history:eceived 17 January 2014eceived in revised form 26 February 2014ccepted 1 March 2014
eywords:poptosisemodicosis
L-10mmunosuppressionxidative stressGF-�
a b s t r a c t
Canine demodicosis is a common but exigent noncontagious parasitic dermatosis caused byoverpopulation of the host-specific follicular mites of various Demodex species. Receptivityof dogs to demodicosis and progression of the clinical disease are influenced by numerousfactors including; genetic defect, alteration of skin’s structure and biochemistry, immuno-logical disorders, hormonal status, breed, age, nutritional status, oxidative stress, lengthof hair coat, stage of oestrus cycle, parturition, endoparasitism and debilitating diseases.Of these, the immune status is thought to be the most significant. Thus, in the presentreview we intended to edify the immuno-pathological conversions of canine demodico-sis. Generalized demodicosis requires a cutaneous environment that is ecologically andimmunologically favorable for extreme colonization of demodectic mites. Demodex canismites can down regulate the CD4+ T cells; possibly by an increased rate of apoptosis orimmunological exhaustion of CD4+ T cells. An increased apoptosis of peripheral leukocytesconfers progression of the clinical manifestations. Mites induced elevation of TGF-� andinhibition of TNF-� mRNA expression might be a key factor for revealing the difference
in the mechanism of onset between localized and generalized demodicosis. Moreover, anelevated serum level of IL-10 could be accountable for the recurrence as well as occur-rence of demodicosis in dogs. Over production of reactive oxygen species can corroborateimmunological discrepancies in dogs with demodicosis.
Canine demodicosis is a common but exigent nonconta-gious parasitic dermatosis caused by overpopulation of thehost-specific follicular mites of various Demodex species.Recently it has been validated, that Demodex mite is thenormal cutaneous microfauna in most of the healthy dogs(Ravera et al., 2013) and pups acquire the parasite fromthe bitch during the first days of life (Greve and Gaffar,1966). Three types of Demodex mites have been describedin dogs. Demodex canis mites inhabiting mainly in hair folli-cle are encountered in most of the clinical cases (Plant et al.,2011), while the long-bodied Demodex injai residing withinthe sebaceous glands is also implicated (Desch and Hillier,2003; Sastre et al., 2013). It is more commonly seen inadult onset demodicosis (Robson et al., 2003; Ordeix et al.,2009). A short-bodied Demodex mite resides in the mostsuperficial layer of the epidermis has also been identifiedin some cases of canine demodicosis (Chen, 1995; Chesney,1999; Saridomichelakis et al., 1999; Tamura et al., 2001).Recently it was suggested, that the short-bodied Demodexmites could also be D. canis but may inhabit the surface ofthe epidermis or in the follicular ostiae (Bourdeau, 2010).
Canine demodicosis is differentiated into a localizedversus a generalized form. Localized demodicosis hasa good prognosis, with the overwhelming majority ofcases spontaneously resolving without miticidal treatment(Scott et al., 2001). Generalized demodicosis may be asevere and potentially life-threatening disease (Muelleret al., 2012). Generalized demodicosis is commonly com-plicated with a secondary bacterial folliculitis and/orfurunculosis (Kuznetsova et al., 2012). The dogs with gener-alized demodicosis showing spontaneous cure is unknownpresently, albeit evidence for spontaneous remission ina subset of cases was recently presented (Bruzinska-Schmidhalter and Nett-Mettler, 2011). The number ofmites is kept low by a dog’s immune system. Despite var-ious studies demonstrating numerous aspects of caninedemodicosis; immuno-pathological conversions are stillmatter of discussion to manage the ailment contentedly.The aim of this paper is therefore to review recent investi-gations establishing the immuno-pathological conversionsimplicated in the progression as well as susceptibility ofcanine demodicosis and their possible impact on the man-agement of the disease.
2. Immuno-pathological conversions
Pups acquire the parasite from the bitch during thefirst days of life and the parasite resides as normal cuta-neous microfauna in the dogs (Greve and Gaffar, 1966).Cutaneous microenvironment plays an important rolein the development of the diseases condition. Receptiv-ity of dogs to demodicosis is influenced by numerousfactors. The predisposing factors of canine demodicosisinclude, genetic defect, alteration of skin’s structure andbiochemistry, immunological disorders, hormonal status,
Please cite this article in press as: Singh, S.K., Dimri, U., The imVet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2014.0
breed, age, length of hair coat, stage of oestrus cycle, par-turition, endoparasitism and debilitating diseases (Scottet al., 2001; Ghubash, 2006; Mederle et al., 2010; Plantet al., 2011). Reference textbooks repeatedly make a
PRESSsitology xxx (2014) xxx–xxx
statement that a genetically preprogrammed immunolog-ical defect is responsible for the exaggerated replicationof mites in demodicosis (Scott et al., 2001). This hypoth-esis is not in the agreement with clinical experienceand scientific publications reporting that a majority ofdogs do not relapse after an appropriately long treatment(Mueller et al., 2012; Miller et al., 2013). Additionally, nutri-tional status, immunological aberrations and misbalanceof oxidant/antioxidant status of the affected dogs may beassociated in the progression of clinical disease condition(Dimri et al., 2008; Camkerten et al., 2009; Singh et al.,2010, 2011a). The exact pathogenesis of generalized caninedemodicosis is unknown but an aberration in immune sta-tus is thought to be the most significant (De Bosschere et al.,2007). However, immunological abnormalities have notbeen noted in dogs with localized demodicosis (Scott et al.,2001). Alternatively, the immuno-containment bestowingprogression of the clinical diseases could also be due to theDemodex mites itself (Barriga et al., 1992; Paulík et al., 1996;Singh et al., 2010, 2011a).
2.1. Immunosuppressive hypothesis
Canine generalized demodicosis entails a cutaneousmicroenvironment favoring ecologically and immunolog-ically for extreme colonization of demodectic mites. It isconsidered to be a consequence of a severe overgrowth ofD. canis mites due to a still poorly characterized hereditaryimmunodeficiency or acquired immunosuppression (Itet al., 2010; Miller et al., 2013). Factor coffering a defect inthe skin immune system or systemic immuno-containmentand/or immuno-exhaustion allows the overpopulation ofmites in hair follicles, resulting in clinical manifestationsof graded severities (Singh et al., 2011a). It has been pos-tulated that the cell-mediated immune response plays animportant role in the pathogenesis of Demodex mite infes-tation (Caswell et al., 1997). Krawiec and Gaafar (1980)endorsed the theory regarding the existence of a fac-tor (�-� globulin) in the serum of infected dog. Thisfactor is responsible for the immunosuppression of T lym-phocytes. Additionally, possibility of the Demodex mitesinduced immuno-incompetence cannot be snubbed. Manyimmunosuppressed dogs never develop demodicosis, andin many cases an underlying cause may not be found. Thelack of pathological changes at the site of mites residencein healthy individuals might be due to local immunosup-pression stimulated by the mites, which allows them tosurvive in the host skin (Akilov et al., 2005). When mitesstart to proliferate, it induces the secretion of a humoralfactor which suppresses the immune response against theparasite, thus allowing its proliferation (Ginel, 1996).
2.2. T-cells misbalance hypothesis
Recent studies on the function of T lymphocytes andtheir involvement in the immune response of dogs withclinical disease provide an explanation to the cellu-
muno-pathological conversions of canine demodicosis.3.008
lar reactions which occur in demodicosis (Fukata et al.,2005). Recently, we have demonstrated the specific down-regulating activity of D. canis mites on CD4+ T cellsand hypothesized the possibility of an increased rate
f apoptosis or immunological exhaustion of CD4+ Tells in demodicosed dogs (Singh et al., 2010). Similarly,ther parasitic infections like Leishmania infantum inducededuction of CD4+ T cells and the CD4+/CD8+ ratio in symp-omatic dogs has been reported (Papadogiannakis et al.,010). Detrimental effects caused by apoptosis can be trig-ered by parasitic infection, depending upon the specificost–parasite situations (Bienvenu et al., 2010). The para-ites have evolved a variety of strategies to modulate theost cells apoptosis. An apoptosis can be either initiatedr down-regulated by the parasite, thereby contributingo dissemination within the host, inhibiting or modulatingost immune responses, or facilitating the survival of theathogen. Moreover, we have also endorsed an increasedpoptosis of peripheral leukocytes of dogs with demodico-is conferring the progression of the clinical manifestationsSingh et al., 2011a). Therefore, Demodex mites could alsonduce immuno-incompetence in the demodicosed dogsnd thus can lead to the flare-up of clinical disease.
The evaluation of cytokine messenger RNA expressionn mononuclear cells from the peripheral blood of dogs
ith demodicosis was performed using RT-PCR and semi-uantitative PCR (Tani et al., 2002). Results of PCR analysisuggest that increased TGF-mRNA expression might be aey factor for revealing the difference in the mechanismf onset between localized and generalized demodico-is (Tani et al., 2002). In accordance, Yarim et al. (2013)ave also demonstrated markedly increased circulatingoncentrations of TGF-�1 in dogs with generalized demod-cosis compared to healthy ones. TGF-� is the prototypical
ember of a superfamily of pleiotropic cytokines, whichegulate a multitude of biological processes includingissue homoeostasis, angiogenesis, migration and differ-ntiation. TGF-� acts as a potent immunosuppressor byegulating the proliferation and survival of many cellsf the immune system. Tani et al. (2002) also demon-trated down regulation of TNF-� in dog with demodicosis.NF-� is a pleiotropic pro-inflammatory cytokine thatxerts multiple biological effects. At low level expres-ion of TNF-� participates in beneficial tissue remodelingnd host defense response. The expression of TNF-� isightly controlled, because systemic over production ofNF-� activates inflammatory response to infection andnjury, and mediates hypotension, diffused coagulation and
idespread tissue damage. Additionally, Tani et al. (2002)uggest that IL-5 may be a key factor in monitoring theisease. Recently, Felix et al. (2013) revealed that elevatederum levels of IL-10 are strongly associated with recurrentemodicosis in dogs. They also demonstrated elevated lev-ls of IL-10 in dogs encountered with demodicosis for therst time. IL-10 cytokine is an essential molecule in theechanism underlying suppression mediated by T regu-
atory cells (Moore et al., 1990). IL-10 is also called the
Please cite this article in press as: Singh, S.K., Dimri, U., The imVet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2014.0
ytokine synthesis inhibitor factor, since it has the abil-ty to inhibit the synthesis of Th1 cytokines (IL-1, IFN-�,nd TNF-�) as well as inhibiting the function of NK cellsHoward and O’garra, 1992). It has anti-inflammatory and
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suppressive effects on the most of hematopoietic cells. Itindirectly suppresses cytokine production and prolifera-tion of antigen-specific CD4+ T effector cells, by inhibitingthe antigen-presenting capacity of various types of pro-fessional antigen-presenting cells (Roncarolo et al., 2006).IL-10 mainly targets on Th1 cells, B cells, macrophages, NKcells, mast cells, and thymocytes (Tizard, 2002). Therefore,the association of Demodex mites induced overproduc-tion of immunosuppressive cytokines IL-10 and TGF-� anddown regulation of TNF-� in the flare-up of clinical diseaseand proliferation of mites is reasonable.
2.4. Oxidative stress and immuno-containmenthypothesis
Various substances known as reactive oxygen species(ROS) are constantly generated in vivo as an integral partof metabolism, as part of controlled inflammatory reac-tions and by exposure to environmental factors (Nemecet al., 2000). Oxidative stress (OS) results when produc-tion of ROS exceeds the capacity of cellular antioxidantdefenses to remove these toxic species. Thus, OS is a dis-turbance of the cellular redox balance in favor of thepro-oxidants, and can lead to disruption of cellular macro-molecules (e.g., degradation of proteins, cross-links in DNA,and membrane fatty acid peroxidation). Oxidants suchas ROS are balanced against this antioxidative defensesystem that consists of enzymes and metabolites in all sub-cellular compartments (Halliwell, 2006). It is known thatinflammatory cells are increased as a result of inflamma-tion in animals with mange; recruited neutrophiles andmacrophages produce reactive oxidants such as hydrogenperoxide (H2O2), hypochlorite and oxygen radicals. Thesereactive oxygen substances produced by cells of immunesystem shows potent cytotoxic effects on parasites andas well as on other pathogenic organisms (Gurgoze et al.,2003). Free radicals can also induce or contribute adverseeffects on the skin, including edema, erythema, wrinkling,inflammation, autoimmune reaction, hypersensitivity, andkeratinization abnormalities (Bickers and Athar, 2006). OShas been implicated in various mites infestations includingcanine demodicosis (Dimri et al., 2008; Camkerten et al.,2009; Singh et al., 2011b, 2012).
The current literature does clearly support the gen-eral concept that oxidative stress causes extensive cellulardamage throughout the body and can result in compro-mised immune and inflammatory reactions (Victor et al.,2004; Nicolls et al., 2007). Immune cells are sensitive tooxidative stress as their membranes contain high concen-trations of polyunsaturated fatty acids that are vulnerableto lipid peroxidation and they produce large quantities ofreactive oxygen metabolites when stimulated (Spears andWeiss, 2008). ROS, in addition to imparting oxidative insultby damaging structural and functional components of cel-lular systems, is also able to induce apoptosis (Czaja, 2002).Elevated ROS may lead to membrane lipid peroxidation,mitochondrial DNA cleavage and impaired ATP genera-
muno-pathological conversions of canine demodicosis.3.008
tion with resulting mitochondrial damage and induction ofapoptosis during stress situations and aging (Huang et al.,1999; Takahashi et al., 2004). Recently, we have demon-strated a tilting of oxidative/antioxidative balance toward
oxidative status as well as an increased apoptosis of periph-eral leukocytes of dogs with demodicosis (Dimri et al.,2008; Singh et al., 2011a). Moreover, elevated ROS con-centrations can also act in signal transduction (Thevenod,2009). Numerous cytokines and growth factors have beendescribed to generate ROS to transmit information uponbinding to their receptors (Thannickal and Fanburg, 2000).In fetal rat hepatocytes, TGF-� induces cell death through amechanism dependent on ROS production (Sánchez et al.,1996). ROS are also responsible for the execution of themitochondrial pathway of apoptosis (Herrera et al., 2004),at least in part, through modulation of different mem-bers of the Bcl-2 family (Ramjaun et al., 2007; Kang et al.,2007). Therefore, shifting of oxidant/antioxidant balancein demodicosed dogs toward oxidative status could beinvolved in the progression of canine demodicosis.
3. Conclusion
Immunosuppression is an imperative feature ofcanine demodicosis. Circumstances favoring an immuno-containment in dogs could endow the developmentof demodicosis owing to unrestrained proliferation ofthe mites. Additionally, Demodex mites can also induceimmunological aberration itself through hastening apo-ptosis of the cells of immune system, regulating cytokinesexpressions and overproduction of ROS in demodicoseddogs and thus corroborate the progression of the clinicaldisease. The veterinary clinicians may consider theseimmuno-pathological conversions while managing thevexing canine demodicosis.
References
Akilov, O.E., Butov, Y.S., Mumcuoglu, K.Y., 2005. A clinicopathologicalapproach to the classification of human demodicosis. J. Dtsch. Der-matol. Ges. 8, 607–614.
Barriga, O.O., Al-Khalidi, N.W., Martin, S., Wyman, M., 1992. Evidence ofimmunosuppression by Demodex canis. Vet. Immunol. Immunopathol.32, 37–46.
Bickers, D.R., Athar, M., 2006. Oxidative stress in the pathogenesis of skindisease. J. Invest. Dermatol. 126 (12), 2565–2575.
Bourdeau, P., 2010. Variation in size in Demodex canis: from the longest tothe shortest forms. In: 24th Annual Congress of the ESVD/ECVD 2010,Florence, p. 213.
Bruzinska-Schmidhalter, R., Nett-Mettler, C.S., 2011. Spontaneous remis-sion in canine generalized demodicosis-predisposing factors. Vet.Dermatol. 22, 301 (Abstract).
Camkerten, I., Sahin, T., Borazan, G., Gokcen, A., Das, A., 2009. Evaluationof blood oxidant/antioxidant balance in dogs with sarcoptic mange.Vet. Parasitol. 161, 106–109.
Caswell, J.L., Yager, J.A., Parker, W.M., Moore, P.F., 1997. A prospectivestudy of the immunophenotype and temporal changes in the histo-logic lesions of canine demodecosis. Vet. Pathol. 34, 279–287.
Chen, C., 1995. A short-tailed demodectic mite and Demodex canis infes-tation in a Chihuahua dog. Vet. Dermatol. 6, 227–229.
Chesney, C.J., 1999. Short form of Demodex species mite in the dog: occur-rence and measurements. J. Small Anim. Pract. 40, 58–61.
Please cite this article in press as: Singh, S.K., Dimri, U., The imVet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2014.0
Czaja, M.J., 2002. Induction and regulation of hepatocyte apoptosis byoxidative stress. Antioxid. Redox. Signal. 4, 759–767.
De Bosschere, H., Casaer, J., Neukermans, A., Baert, K., Ceulemans, T., Tav-ernier, P., Roels, S., 2007. Severe alopecia due to demodicosis in roedeer (Capreolus capreolus) in Belgium. Vet. J. 174, 665–668.
PRESSsitology xxx (2014) xxx–xxx
Desch, C.E., Hillier, A., 2003. Demodex injai: a new species of hair folliclemite (Acari: Demodecidae) from the domestic dog (Canidae). J. Med.Entomol. 40, 146–149.
Dimri, U., Ranjan, R., Kumar, N., Sharma, M.C., Swarup, D., Sharma, B.,Kataria, M., 2008. Changes in oxidative stress indices, zinc and cop-per concentration in blood in canine demodicosis. Vet. Parasitol. 154,98–102.
Felix, A.O.C., Guiot, E.G., Stein, M., Felix, S.R., Silva, E.F., Nobre, M.O., 2013.Comparison of systemic interleukin 10 concentrations in healthy dogsand those suffering from recurring and first time Demodex canis infes-tations. Vet. Parasitol. 193, 312–315.
Fukata, T., Fuoki, S., Yoshikawa, H., Kambayashi, Y., Kito, K., Kitagawa, H.,2005. Significance of the CD4/CD8 lymphocytes ratio in dogs sufferingfrom demodicosis. J. Jpn. Vet. Med. Assoc. 58, 113–116.
Ghubash, R., 2006. Parasitic miticidal therapy. Clin. Tech. Small Anim.Pract. 21, 135–144.
Ginel, P., 1996. Demodicose beim Hund (Demodicosis in dogs). WalthamFocus 6, 2–7 (in German).
Greve, J.H., Gaffar, S.M., 1966. Natural transmission of Demodex canis indogs. J. Am. Vet. Med. Assoc. 148, 1043–1045.
Gurgoze, S.Y., Sahin, T., Sevgili, M., Ozkutlu, Z., Ozan, S.T., 2003. The effectof ivermectin or doramectin treatment on some antioxidant enzymesand the level of lipid peroxidation in sheep with natural sarcoptic scab.Yuzuncu. Yil. Univ. Vet. Fac. Derg. 14, 30–34.
Halliwell, B., 2006. Reactive species and antioxidants. Redox biology is afundamental theme of aerobic life. Plant Physiol. 141 (2), 312–322.
Herrera, B., Murillo, M.M., Alvarez-Barrientos, A., Beltrán, J., Fernández,M., Fabregat, I., 2004. Source of early reactive oxygen species in theapoptosis induced by transforming growth factor-beta in fetal rathepatocytes. Free Radic. Biol. Med. 36, 16–26.
Howard, M., O’garra, A., 1992. Biological properties of interleukin 10.Immunol. Today 13, 198–200.
Huang, T.T., Carlson, E.J., Raineri, I., Gillespie, A.M., Kozy, H., Epstein, C.J.,1999. The use of transgenic and mutant mice to study oxygen freeradical metabolism. Ann. N. Y. Acad. Sci. 893, 95–112.
It, V., Barrientos, L., López-Gappa, J., Posik, D., Diaz, S., Golijow, C., Gio-vambattista, G., 2010. Association of canine juvenile generalizeddemodicosis with the dog leukocyte antigen system. Tissue Antigens76, 67–70.
Kang, H.R., Cho, S.J., Lee, C.G., Homer, R.J., Elias, J.A., 2007. Transforminggrowth factor (TGF)-beta1 stimulates pulmonary fibrosis and inflam-mation via a Bax-dependent, bid-activated pathway that involvesmatrix metalloproteinase-12. J. Biol. Chem. 282, 7723–7732.
Krawiec, D.R., Gaafar, S.M., 1980. Studies on the immunology of caninedemodicosis. J. Am. Anim. Hosp. Assoc. 16, 669–676.
Kuznetsova, E., Bettenay, S., Nikolaeva, L., Majzoub, M., Mueller, R., 2012.Influence of systemic antibiotics on the treatment of dogs with gen-eralized demodicosis. Vet. Parasitol. 188 (1–2), 148–155.
Mederle, N., Darabu, G., Oprescu, I., Morariu, S., Ilie, M., Indre, D., Mederle,O., 2010. Diagnosis of canine demodicosis. Sci. Parasitol. 11 (1), 20–23.
Miller, W.H., Griffin, C.E., Campbell, K.L., 2013. Muller and Kirk’s SmallAnimal Dermatology. Elsevier, St Louis, pp. 304–313.
Moore, K.W., Vieira, P., Fiorentino, D.F., Trounstine, M.L., Khan, T.A., Mos-mann, T.R., 1990. Homology of cytokine synthesis inhibitory factor(IL-10) to the Epstein–Barr virus gene BCRFI. Science 248, 1230–1234.
Mueller, R.S., Bensignor, E., Ferrer, L., Holm, B., LeMarie, S., Paradis, M.,Shipstone, M.A., 2012. Treatment of demodicosis in dogs: 2011 clinicalpractice guidelines. Vet. Dermatol. 23, 86–96.
Nemec, A., Brobnic-Kosorok, M., Skitek, M., Pavlica, Z., Galac, S., Butinar,J., 2000. Total antioxidant capacity (TAC) values and their correlationwith individual antioxidants in serum of healthy beagles. Acta Vet.Brno 69, 297–303.
Nicolls, M.R., Haskins, K., Flores, S.C., 2007. Oxidant stress, immune dys-regulation, and vascular function in type I diabetes. Antioxid. RedoxSignal. 9, 879–889.
Ordeix, L., Bardagí, M., Scarampella, F., Ferrer, L., Fondati, A., 2009. Demodexinjai infestation and dorsal greasy skin and hair in eight wirehaired foxterrier dogs. Vet. Dermatol. 20, 267–272.
Papadogiannakis, E., Andritsos, G., Kontos, V., Spanakos, G., Koutis, C.,Velonakis, E., 2010. Determination of CD4+ and CD8+ T cells in theperipheral blood of dogs with leismaniosis before and after prolongedallopurinol monotherapy. Vet. J. 186 (2), 262–263.
Paulík, S., Mojzisová, J., Bajová, V., Baranová, D., Paulíková, I., 1996.Lymphocyte blastogenesis to concanavalin A in dogs with local-ized demodicosis according to duration of clinical disease. Vet. Med.(Praha) 41 (8), 245–249.
muno-pathological conversions of canine demodicosis.3.008
Plant, J.D., Lund, E.M., Yang, M., 2011. A case–control study of the riskfactors for canine juvenile-onset generalized demodicosis in the USA.Vet. Dermatol. 22, 95–99.
amjaun, A.R., Tomlinson, S., Eddaoudi, A., Downward, J., 2007. Upregula-tion of two BH3-only proteins, Bmf and Bim, during TGF beta-inducedapoptosis. Oncogene 26, 970–981.
avera, I., Altet, L., Francino, O., Sánchez, A., Roldán, W., Villanueva, S.,Bardagí, M., Ferrer, L., 2013. Small Demodex populations colonize mostparts of the skin of healthy dogs. Vet. Dermatol. 24 (1), 168–172.
obson, D.C., Burton, G.G., Bassett, R., Mueller, R.S., 2003. Eight cases ofdemodicosis caused by a long-bodied Demodex species (1997–2002).Aust. Vet. Pract. 33, 64–72.
oncarolo, M.G., Gregory, S., Battaglia, M., Bachetta, R., Fleischhauer, K.,Levings, M.K., 2006. Interleukin-10-secreting type 1 regulatory T cellsin rodents and humans. Immunol. Rev. 21, 28–50.
ánchez, A., Alvarez, A.M., Benito, M., Fabregat, I., 1996. Apoptosis inducedby transforming growth factor-beta in fetal hepatocyte primary cul-tures: involvement of reactive oxygen intermediates. J. Biol. Chem.271, 7416–7422.
aridomichelakis, M., Koutinas, A., Papadogiannakis, E., Papazachariadou,M., Liapi, M., Trakas, D., 1999. Adult-onset demodicosis in two dogsdue to Demodex canis and a short-tailed demodectic mite. J. SmallAnim. Pract. 40, 529–532.
astre, N., Ravera, I., Ferreira, D., Altet, L., Sánchez, A., Bardagí, M., Fran-cino, O., Ferrer, L., 2013. Development of a PCR technique specificfor Demodex injai in biological specimens. Parasitol. Res. 112 (9),3369–3372.
cott, D.W., Miller Jr., W.H., Giriffin, C.E., 2001. Canine demodicosis.In: Muller, Kirk’s (Eds.), Small Animal Dermatology. W.B. Saunders,Philadelphia, pp. 457–474.
Please cite this article in press as: Singh, S.K., Dimri, U., The imVet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2014.0
ingh, S.K., Dimri, U., Sharma, M.C., Sharma, B., Saxena, M., 2010. Determi-nation of CD4+ and CD8+ T cells in the peripheral blood of dogs withdemodicosis. Parasitology 137, 1921–1924.
ingh, S.K., Dimri, U., Sharma, M.C., Swarup, D., Kumar, M., Tiwary, R.,2012. Psoroptes cuniculi induced oxidative imbalance in rabbits and
PRESSsitology xxx (2014) xxx–xxx 5
its alleviation by using vitamins A, D3 E, and H as adjunctive remedial.Trop. Anim. Health. Prod. 44 (1), 43–48.
Singh, S.K., Dimri, U., Sharma, M.C., Swarup, D., Sharma, B., 2011b. Deter-mination of oxidative status and apoptosis in peripheral blood of dogswith sarcoptic mange. Vet. Parasitol. 178, 330–338.
Singh, S.K., Dimri, U., Sharma, M.C., Swarup, D., Sharma, B., Pandey, H.O.,Kumari, P., 2011a. The role of apoptosis in immunosuppression of dogswith demodicosis. Vet. Immunol. Immunopathol. 144, 487–492.
Spears, J.W., Weiss, W.P., 2008. Role of antioxidants and trace elements inhealth and immunity of transition dairy cows. Vet. J. 176, 70–76.
Takahashi, A., Masuda, A., Sun, M., Centonze, V.E., Herman, B., 2004.Oxidative stress induced apoptosis is associated with alterations inmitochondrial caspase activity and Bcl-2-dependent alterations inmitochondrial pH (pHm). Brain. Res. Bull. 62, 497–504.
Tamura, Y., Kawamura, Y., Inoue, I., Ishino, S., 2001. Scanning electronmicroscopy description of a new species of Demodex canis spp. Vet.Dermatol. 12, 275–278.
Tani, K., Morimoto, M., Hayashi, T., Inokuma, H., Ohnishi, T., Hayashiya,S., Nomura, T., Une, S., Nakaichi, M., Taura, Y., 2002. Evaluation ofcytokine messenger RNA expression in peripheral blood mononuclearcells from dogs with canine demodicosis. J. Vet. Med. Sci. 64, 513–518.
Thannickal, V.J., Fanburg, B.L., 2000. Reactive oxygen species in cellsignalling. Am. J. Physiol. Lung Cell. Mol. Physiol. 279, L1005–L1028.
Thevenod, F., 2009. Cadmium and cellular signaling cascades: to be or notto be? Toxicol. Appl. Pharm. 238 (3), 221–239.
