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Demodex and rosacea revisited
Demodex and Rosacea Revisited Ellen M. Moran B.A (Mod), PhD, Ruth Foley B.A (Mod), PhD, Frank C Powell FRCPI, FRCPEdin PII: DOI: Reference:
S0738-081X(16)30275-9 doi: 10.1016/j.clindermatol.2016.10.014 CID 7112
To appear in:
Clinics in Dermatology
Please cite this article as: Moran Ellen M., Foley Ruth, Powell Frank C, Demodex and Rosacea Revisited, Clinics in Dermatology (2016), doi: 10.1016/j.clindermatol.2016.10.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Demodex and Rosacea Revisited
Education and Research Centre, St.Vincent’s University Hospital Elm Park Dublin 4, Ireland
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Ellen M. Moran B.A (Mod), PhD. 1, Ruth Foley B.A (Mod), PhD. 2 and Frank C Powell FRCPI; FRCPEdin. 2*
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The Charles Institute of Dermatology, University College Dublin, Belfield, Dublin 4, Ireland *Correspondence: F.C. Powell. E-mail: [email protected]
Abstract
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Demodex mites are part of the vast microbiome living on and within human skin. The interaction of the various microorganisms with the skin plays a key role in the maintenance of homeostasis. The precise role and function of Demodex mites within normal and diseased
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human skin remains elusive. The emergence of ivermectin as a key therapy for rosacea has refocused interest in the role of Demodex mites in the pathogenesis of this skin disease and
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Introduction
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the ablity of Demodex to modulate the host immune system.
The skin is home to a vast array of biological life forms. These reside both on the skin surface and within the various skin appendages such hair follicles, sebaceous and sweat glands. The physical barrier of the stratum corneum, the various epidermal and specialized appendageal cells as well as the immune cells dynamically interact with the various microorganisms to maintain the homeostasis of the skin 1. Recent research relating to the Innate Immune system has focused on the cutaneous bacterial community. The presence and potential role of Demodex mites in normal and disordered human skin has been largely overlooked.
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ACCEPTED MANUSCRIPT The widely varied biogeography of the cutaneous surface suggests that organisms may play specific roles in particular biological niches (2). Demodex mites are complex organisms that
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are ubiquitously present on adult human skin, particularly in the pilosebaceous units of the
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face. We review the possible role of these mites in the orchestration of the immune response within the facial pilosebaceous unit. Topical ivermectin, an anti-parasitic agent,
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has recently been approved for the treatment of papulopustular rosacea 2. Similar to other
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rosacea treatments the exact mechanism by which it improves the clinical signs of rosacea is unclear. However the compound has been shown to display a broad range of activities; antimicrobial; anti-parasitic, anti-bacterial and anti-inflammatory 3. The advent of ivermectin as a major treatment for rosacea has stimulated renewed interest in the possible role of
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Demodex mites in the pathogenesis of this disorder and the capacity of Demodex mites to
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interact with the host immune system.
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Demodex and Healthy Skin
Mites are microscopic arthropods closely related to ticks that belong to the class Arachnida subclass Acari. They are considered to be one of the most diverse and successful of all the invertebrate groups with over 48,000 species described. They inhabit a vast range of ecological niches 4. Two species of Demodex mite are known to inhabit the human pilosebaceous unit; Demodex folliculorum and Demodex brevis. Demodex folliculorum resides within the hair follicle whereas Demodex brevis is found predominantly in the sebaceous and meibomian glands 5. Both species are ubiquitous amongst adult humans with normal skin. It has been suggested that Demodex mites are acquired after birth as a result of 2
ACCEPTED MANUSCRIPT skin contact between adults and children with numbers increasing with the age of the host and presumably maturity of the pilosebaceous unit after puberty 6, 7.
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Research into the lifecycle of Demodex mites has been limited to date due to the difficulties
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in culturing Demodex in vitro. On the basis of studies by Spickett in the early 1960s the
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lifecycle of Demodex is estimated at between 14-18 days. Spickett detailed how the male mites move about the surface of the skin mainly at night-time and copulate with females at
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the opening of hair follicles. After 12 hours the female lays eggs within the hair follicles or sebaceous glands. Larvae hatch after 3-4 days and proceed through developmental stages to become an adult in about 7 days8.
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The morphological and anatomical features of both Demodex species are well characterised These mites possess a gnathosoma, podosoma and striated opisthosoma with a transparent
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chitinous exoskeleton (Figure 1). Scanning electron microscopy has confirmed the presence
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of piercing mouthparts in Demodex folliculorum and bifid claws capable of penetrating cellular membranes and possibly keratin
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(Figure 2). Demodex mites are believed to
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perforate the skin cells (primarily keratinocytes) lining the pilosebaceous follicle and ingest their contents. They may also ingest sebum for nutrition 8. Both mite species are hypothesized to secrete salivary enzymes containing proteases that break down food sources. This is supported by the observation of specific binding of IgD and serum protease inhibitors to Demodex mites as a possible protective host response11 The presence of lipase enzymes within Demodex are probably related to the digestion of lipid material but may also have a role in digesting bacteria or other microorganisms
12, 13
(Figure 2). Demodex mites lack an anus and are thought to store their faeces internally in crystallized fashion. Large numbers of dying mites both by releasing their internal contents 3
ACCEPTED MANUSCRIPT as well as exposure of the host to the chitinous exoskeleton of the decomposing mites, may initiate an immune response by the host with subsequent inflammatory changes
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(Figure 3 & 4).
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Demodex Mites and Skin Disorders
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Only a few mite species cause dermatological issues in humans. These include the scabies, food, house dust, poultry, murine and harvest mites. Demodex mites differ in that they have
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not been proven to cause disease in man.
The causal role of Demodex mites in the generation of diseases such as mange in dogs is well established
7, 16
. In man an increased mite density of greater than 5 mites on 1cm2 of
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skin has been associated with rosacea and associated blepharitis 7, 10. Patients with perioral
mite density 17, 18.
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dermatitis caused by steroid use or other immunomodulatory drugs show increased facial
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Higher numbers of Demodex mites have also been documented in patients with alopecia,
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various malignancies, polycystic ovary syndrome, underweight and overweight patients, those undergoing immunosuppressive therapy and patients infected with HIV/AIDS
19-23
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Several reports have indicated an increased population of Demodex in patients with diabetes and the mites present were found to be larger than normal 24-28.
Evasion of the Innate Immune Response by Demodex: Clues from the Scabies mite Arthropods such as mites and ticks have evolved various mechanisms that modulate or circumvent host immune responses in order to survive within the host.
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ACCEPTED MANUSCRIPT Scabies mites secrete molecules that down regulate the human complement system and macrophage function. Scabies mite secreted complement inhibitors are also hypothesized
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to support the promotion of a microenvironment in which non-commensal pathogenic
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bacteria could flourish. These molecules also show homology to allergens of house dust mites 29, 30. In the case of Norwegian or crusted scabies there is a hyperproliferation of the
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scabies mites in and on the skin and hyperkeratotic skin crusts form. Norwegian scabies
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occurs in patients with an underlying immunodeficiency and the disease is thought to occur as a result of an inadequate host immune response to the mites 31, 32. A number of studies suggest Demodex mites may suppress the innate immune response of the host in order to evade expulsion
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. Demodex mites have been shown to express Tn
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(Figure 2). Demodex mites also appear to interact with cells of the
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surveillance
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antigen, a carbohydrate coating known to protect cancer cells and parasites from immune
pilosebaceous unit modulating the secretion of inflammatory mediators such as IL-8 and
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TNF-α, TLR expression and the recruitment of inflammatory cells
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(Figure 3 & 4). This
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suggests a mechanism through which mites may actively promote an immunosuppressed status, as well as opportunistically expanding their population when immunosuppression is caused by other factors. Suppression of the adaptive immune system may occur as evidenced by both animal and human studies. Down modulation of T cell expression and function occurs during canine demodicosis and a mouse model of inflammatory skin disease suggests defects in the TH2 response may facilitate hyper proliferation of Demodex 33, 42-45. A decrease in lymphocytes, T effector cells and NK cells has been observed in rosacea patients
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34, 46, 47
. In animals
ACCEPTED MANUSCRIPT depression of the immune system allows for a hyperproliferation of mites and disease development 48, 49 .
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Identification of Demodex by the immune system and implications for disease
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pathogenesis
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In veterinary medicine the pathogenic role of Demodex in causing mange is well established although the exact mechanisms involved are unclear
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. In human skin Demodex are
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generally considered symbiotic inhabitants and their role in mediating dermatological conditions is still under debate 19, 50, 51.
In rosacea increased numbers of mites could contribute to its pathogenesis in a number of
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ways (Figure 3). An overabundance of mites may lead to a blockage of the hair follicles and sebaceous glands resulting in cutaneous barrier disruption and tissue damage. The resulting
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increase in TLR expression and recognition of the mite’s chitin exoskeleton could trigger an
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inflammatory reaction 10, 15, 40, 52, 53 (Figure 4).
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As already pointed out the large numbers of dying mites in the follicles of patients with rosacea may increase the released internal contents including endogenous bacterial antigen load to critical levels. At such levels, the effect of mites could potentially switch from being immunosuppressive to being proinflammatory. The presence of multiple mites (both dead and alive) and their skeletal disruption could release their gut contents including various bacteria, enzymes and mite faeces into the follicular canal in contact with the keratinocytes lining with the potential to trigger a type IV hypersensitivity reaction or innate immune response
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. Disruption of the epithelium and recognition of exoskeletal chitin
may also result in a Th2 and/or Th17 response leading to tissue damage as a result of neutrophil and macrophage activation
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(Figure 3 & 4). This can be observed histologically 6
ACCEPTED MANUSCRIPT in rosacea skin whereby the enlarged hair follicle containing Demodex mites is surrounded by a significant immune cell infiltrate (Figure 3).
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Increased mite density may not be the only and/or principal factor driving skin inflammation
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as evidenced by the example of pityriasis folliculorum. In this condition despite a very high Demodex density (higher than that reported in rosacea patients) little or no skin
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inflammation is observed 10. A recent study found that Demodex density is higher in patients
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with oily versus dry skin regardless of the presence of rosacea 58. Furthermore, while there is a trend towards a higher Demodex density in erythematotelangiectatic (ETR) versus papulopustular rosacea (PPR) patients, skin sample analysis demonstrated a higher expression of inflammatory genes in PPR compared to ETR 56.
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Demodex mites as vectors of disease
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Recent studies suggest mites from rosacea patients harbour pathogenic bacteria and other
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microorganisms on their surface which drive inflammatory skin responses 59-63 and typically non-pathogenic bacteria display an altered functional profile in rosacea patients in
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comparison to normal controls
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(Figure 2). Interestingly the microbiome profile may be
specific to rosacea disease subtype
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. Furthermore, serum immunoreactivity against the
bacterium Bacillus oleronius has been significantly correlated with rosacea
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. It remains
to be determined whether this altered microbiota in rosacea is a direct cause of disease or a consequence of the altered skin environment in rosacea patients 64, 66-69. A role for bacteria in the pathogenesis of disease is supported by the response shown by patients to antibiotic therapy however it is still unclear if the antibiotics are having an anti-inflammatory or antimicrobial effect in the context of rosacea 70.
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ACCEPTED MANUSCRIPT Genetically susceptible individuals A number of studies indicate a genetic component to rosacea. The condition is more
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common in fair skinned individuals of European descent. A number of MHC class II HLA
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alleles have been associated with rosacea all of which have been associated with 71
. Gene
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autoimmune diseases such as multiple sclerosis, type 1 diabetes and retinopathy
polymorphisms in HLA-DRA and Butyrophilin-like 2 (BTNL2) have also been associated with 72
. Such variations in these molecules have been previously linked to T-cell
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rosacea
responses to mite allergens 72, 73. Associations with MHC class I molecules and Demodicosis patients have also been observed patients with a Cw2 or Cw4 phenotype were found to be more susceptible to Demodicosis and had an altered immune function phenotype whereas
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the HLA A2 phenotype were less susceptible 33, 34, 74.
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Thus there are many new studies indicating that the ubiquitous Demodex mite, previously
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considered a harmless commensal, may well play a significant role in orchestrating the host immune reactive status in the complex environment of the cutaneous microbiome of facial
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skin and possibly plays a significant role in the genesis of disorders such as rosacea.
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69) Burkhart CG. “Acne biofilms,” temperature, and microenvironments. Journal of the American Academy of Dermatology. 2005; 52:182. 70) Bhatia ND, Del Rosso JQ. Optimal management of papulopustular rosacea: rationale for combination therapy. Journal of drugs in dermatology : JDD. 2012; 11:838-844. 71) Hebbring SJ, Schrodi SJ, Ye Z, et al. A PheWAS approach in studying HLA-DRB1*1501. Genes and immunity. 2013; 14:187-191. 72) Chang ALS, Raber I, Xu J, et al. Assessment of the Genetic Basis of Rosacea by Genome-Wide Association Study. The Journal of investigative dermatology. 2015. 73) Matsuoka T, Kohrogi H, Ando M, et al. Dermatophagoides farinae-1-derived peptides and HLA molecules recognized by T cells from atopic individuals. International archives of allergy and immunology. 1997; 112:365-370. 74) Akilov OE, Mumcuoglu KY. Association between human demodicosis and HLA class I. Clin Exp Dermatol. 2003; 28:70-73.
FIGURE LEGENDS
Figure 1 – Morphological and anatomical features of Demodex mite Figure 2 – Potential Immunomodulatory features of Demodex folliculorum mites
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Figure 3: Histologic section of facial skin biopsy from patient with papulopustular rosacea showing intact and ruptured mites in inflamed follicle
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Figure 4 – Postulated interaction of Demodex mites with the host immune system in healthy vs. inflamed skin
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S0738-081X(16)30275-9 doi: 10.1016/j.clindermatol.2016.10.014 CID 7112
To appear in:
Clinics in Dermatology
Please cite this article as: Moran Ellen M., Foley Ruth, Powell Frank C, Demodex and Rosacea Revisited, Clinics in Dermatology (2016), doi: 10.1016/j.clindermatol.2016.10.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Demodex and Rosacea Revisited
Education and Research Centre, St.Vincent’s University Hospital Elm Park Dublin 4, Ireland
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Ellen M. Moran B.A (Mod), PhD. 1, Ruth Foley B.A (Mod), PhD. 2 and Frank C Powell FRCPI; FRCPEdin. 2*
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The Charles Institute of Dermatology, University College Dublin, Belfield, Dublin 4, Ireland *Correspondence: F.C. Powell. E-mail: [email protected]
Abstract
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Demodex mites are part of the vast microbiome living on and within human skin. The interaction of the various microorganisms with the skin plays a key role in the maintenance of homeostasis. The precise role and function of Demodex mites within normal and diseased
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human skin remains elusive. The emergence of ivermectin as a key therapy for rosacea has refocused interest in the role of Demodex mites in the pathogenesis of this skin disease and
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Introduction
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the ablity of Demodex to modulate the host immune system.
The skin is home to a vast array of biological life forms. These reside both on the skin surface and within the various skin appendages such hair follicles, sebaceous and sweat glands. The physical barrier of the stratum corneum, the various epidermal and specialized appendageal cells as well as the immune cells dynamically interact with the various microorganisms to maintain the homeostasis of the skin 1. Recent research relating to the Innate Immune system has focused on the cutaneous bacterial community. The presence and potential role of Demodex mites in normal and disordered human skin has been largely overlooked.
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ACCEPTED MANUSCRIPT The widely varied biogeography of the cutaneous surface suggests that organisms may play specific roles in particular biological niches (2). Demodex mites are complex organisms that
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are ubiquitously present on adult human skin, particularly in the pilosebaceous units of the
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face. We review the possible role of these mites in the orchestration of the immune response within the facial pilosebaceous unit. Topical ivermectin, an anti-parasitic agent,
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has recently been approved for the treatment of papulopustular rosacea 2. Similar to other
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rosacea treatments the exact mechanism by which it improves the clinical signs of rosacea is unclear. However the compound has been shown to display a broad range of activities; antimicrobial; anti-parasitic, anti-bacterial and anti-inflammatory 3. The advent of ivermectin as a major treatment for rosacea has stimulated renewed interest in the possible role of
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Demodex mites in the pathogenesis of this disorder and the capacity of Demodex mites to
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interact with the host immune system.
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Demodex and Healthy Skin
Mites are microscopic arthropods closely related to ticks that belong to the class Arachnida subclass Acari. They are considered to be one of the most diverse and successful of all the invertebrate groups with over 48,000 species described. They inhabit a vast range of ecological niches 4. Two species of Demodex mite are known to inhabit the human pilosebaceous unit; Demodex folliculorum and Demodex brevis. Demodex folliculorum resides within the hair follicle whereas Demodex brevis is found predominantly in the sebaceous and meibomian glands 5. Both species are ubiquitous amongst adult humans with normal skin. It has been suggested that Demodex mites are acquired after birth as a result of 2
ACCEPTED MANUSCRIPT skin contact between adults and children with numbers increasing with the age of the host and presumably maturity of the pilosebaceous unit after puberty 6, 7.
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Research into the lifecycle of Demodex mites has been limited to date due to the difficulties
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in culturing Demodex in vitro. On the basis of studies by Spickett in the early 1960s the
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lifecycle of Demodex is estimated at between 14-18 days. Spickett detailed how the male mites move about the surface of the skin mainly at night-time and copulate with females at
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the opening of hair follicles. After 12 hours the female lays eggs within the hair follicles or sebaceous glands. Larvae hatch after 3-4 days and proceed through developmental stages to become an adult in about 7 days8.
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The morphological and anatomical features of both Demodex species are well characterised These mites possess a gnathosoma, podosoma and striated opisthosoma with a transparent
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chitinous exoskeleton (Figure 1). Scanning electron microscopy has confirmed the presence
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of piercing mouthparts in Demodex folliculorum and bifid claws capable of penetrating cellular membranes and possibly keratin
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(Figure 2). Demodex mites are believed to
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perforate the skin cells (primarily keratinocytes) lining the pilosebaceous follicle and ingest their contents. They may also ingest sebum for nutrition 8. Both mite species are hypothesized to secrete salivary enzymes containing proteases that break down food sources. This is supported by the observation of specific binding of IgD and serum protease inhibitors to Demodex mites as a possible protective host response11 The presence of lipase enzymes within Demodex are probably related to the digestion of lipid material but may also have a role in digesting bacteria or other microorganisms
12, 13
(Figure 2). Demodex mites lack an anus and are thought to store their faeces internally in crystallized fashion. Large numbers of dying mites both by releasing their internal contents 3
ACCEPTED MANUSCRIPT as well as exposure of the host to the chitinous exoskeleton of the decomposing mites, may initiate an immune response by the host with subsequent inflammatory changes
4, 14, 15
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(Figure 3 & 4).
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Demodex Mites and Skin Disorders
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Only a few mite species cause dermatological issues in humans. These include the scabies, food, house dust, poultry, murine and harvest mites. Demodex mites differ in that they have
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not been proven to cause disease in man.
The causal role of Demodex mites in the generation of diseases such as mange in dogs is well established
7, 16
. In man an increased mite density of greater than 5 mites on 1cm2 of
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skin has been associated with rosacea and associated blepharitis 7, 10. Patients with perioral
mite density 17, 18.
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dermatitis caused by steroid use or other immunomodulatory drugs show increased facial
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Higher numbers of Demodex mites have also been documented in patients with alopecia,
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various malignancies, polycystic ovary syndrome, underweight and overweight patients, those undergoing immunosuppressive therapy and patients infected with HIV/AIDS
19-23
.
Several reports have indicated an increased population of Demodex in patients with diabetes and the mites present were found to be larger than normal 24-28.
Evasion of the Innate Immune Response by Demodex: Clues from the Scabies mite Arthropods such as mites and ticks have evolved various mechanisms that modulate or circumvent host immune responses in order to survive within the host.
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ACCEPTED MANUSCRIPT Scabies mites secrete molecules that down regulate the human complement system and macrophage function. Scabies mite secreted complement inhibitors are also hypothesized
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to support the promotion of a microenvironment in which non-commensal pathogenic
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bacteria could flourish. These molecules also show homology to allergens of house dust mites 29, 30. In the case of Norwegian or crusted scabies there is a hyperproliferation of the
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scabies mites in and on the skin and hyperkeratotic skin crusts form. Norwegian scabies
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occurs in patients with an underlying immunodeficiency and the disease is thought to occur as a result of an inadequate host immune response to the mites 31, 32. A number of studies suggest Demodex mites may suppress the innate immune response of the host in order to evade expulsion
33, 34
. Demodex mites have been shown to express Tn
35, 36
(Figure 2). Demodex mites also appear to interact with cells of the
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surveillance
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antigen, a carbohydrate coating known to protect cancer cells and parasites from immune
pilosebaceous unit modulating the secretion of inflammatory mediators such as IL-8 and
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TNF-α, TLR expression and the recruitment of inflammatory cells
35-41
(Figure 3 & 4). This
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suggests a mechanism through which mites may actively promote an immunosuppressed status, as well as opportunistically expanding their population when immunosuppression is caused by other factors. Suppression of the adaptive immune system may occur as evidenced by both animal and human studies. Down modulation of T cell expression and function occurs during canine demodicosis and a mouse model of inflammatory skin disease suggests defects in the TH2 response may facilitate hyper proliferation of Demodex 33, 42-45. A decrease in lymphocytes, T effector cells and NK cells has been observed in rosacea patients
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34, 46, 47
. In animals
ACCEPTED MANUSCRIPT depression of the immune system allows for a hyperproliferation of mites and disease development 48, 49 .
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Identification of Demodex by the immune system and implications for disease
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pathogenesis
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In veterinary medicine the pathogenic role of Demodex in causing mange is well established although the exact mechanisms involved are unclear
4, 44
. In human skin Demodex are
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generally considered symbiotic inhabitants and their role in mediating dermatological conditions is still under debate 19, 50, 51.
In rosacea increased numbers of mites could contribute to its pathogenesis in a number of
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ways (Figure 3). An overabundance of mites may lead to a blockage of the hair follicles and sebaceous glands resulting in cutaneous barrier disruption and tissue damage. The resulting
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increase in TLR expression and recognition of the mite’s chitin exoskeleton could trigger an
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inflammatory reaction 10, 15, 40, 52, 53 (Figure 4).
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As already pointed out the large numbers of dying mites in the follicles of patients with rosacea may increase the released internal contents including endogenous bacterial antigen load to critical levels. At such levels, the effect of mites could potentially switch from being immunosuppressive to being proinflammatory. The presence of multiple mites (both dead and alive) and their skeletal disruption could release their gut contents including various bacteria, enzymes and mite faeces into the follicular canal in contact with the keratinocytes lining with the potential to trigger a type IV hypersensitivity reaction or innate immune response
3, 4, 10, 40, 54-56
. Disruption of the epithelium and recognition of exoskeletal chitin
may also result in a Th2 and/or Th17 response leading to tissue damage as a result of neutrophil and macrophage activation
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(Figure 3 & 4). This can be observed histologically 6
ACCEPTED MANUSCRIPT in rosacea skin whereby the enlarged hair follicle containing Demodex mites is surrounded by a significant immune cell infiltrate (Figure 3).
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Increased mite density may not be the only and/or principal factor driving skin inflammation
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as evidenced by the example of pityriasis folliculorum. In this condition despite a very high Demodex density (higher than that reported in rosacea patients) little or no skin
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inflammation is observed 10. A recent study found that Demodex density is higher in patients
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with oily versus dry skin regardless of the presence of rosacea 58. Furthermore, while there is a trend towards a higher Demodex density in erythematotelangiectatic (ETR) versus papulopustular rosacea (PPR) patients, skin sample analysis demonstrated a higher expression of inflammatory genes in PPR compared to ETR 56.
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Demodex mites as vectors of disease
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Recent studies suggest mites from rosacea patients harbour pathogenic bacteria and other
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microorganisms on their surface which drive inflammatory skin responses 59-63 and typically non-pathogenic bacteria display an altered functional profile in rosacea patients in
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comparison to normal controls
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(Figure 2). Interestingly the microbiome profile may be
specific to rosacea disease subtype
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. Furthermore, serum immunoreactivity against the
bacterium Bacillus oleronius has been significantly correlated with rosacea
14, 65
. It remains
to be determined whether this altered microbiota in rosacea is a direct cause of disease or a consequence of the altered skin environment in rosacea patients 64, 66-69. A role for bacteria in the pathogenesis of disease is supported by the response shown by patients to antibiotic therapy however it is still unclear if the antibiotics are having an anti-inflammatory or antimicrobial effect in the context of rosacea 70.
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ACCEPTED MANUSCRIPT Genetically susceptible individuals A number of studies indicate a genetic component to rosacea. The condition is more
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common in fair skinned individuals of European descent. A number of MHC class II HLA
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alleles have been associated with rosacea all of which have been associated with 71
. Gene
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autoimmune diseases such as multiple sclerosis, type 1 diabetes and retinopathy
polymorphisms in HLA-DRA and Butyrophilin-like 2 (BTNL2) have also been associated with 72
. Such variations in these molecules have been previously linked to T-cell
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rosacea
responses to mite allergens 72, 73. Associations with MHC class I molecules and Demodicosis patients have also been observed patients with a Cw2 or Cw4 phenotype were found to be more susceptible to Demodicosis and had an altered immune function phenotype whereas
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the HLA A2 phenotype were less susceptible 33, 34, 74.
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Thus there are many new studies indicating that the ubiquitous Demodex mite, previously
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considered a harmless commensal, may well play a significant role in orchestrating the host immune reactive status in the complex environment of the cutaneous microbiome of facial
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skin and possibly plays a significant role in the genesis of disorders such as rosacea.
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FIGURE LEGENDS
Figure 1 – Morphological and anatomical features of Demodex mite Figure 2 – Potential Immunomodulatory features of Demodex folliculorum mites
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Figure 3: Histologic section of facial skin biopsy from patient with papulopustular rosacea showing intact and ruptured mites in inflamed follicle
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Figure 4 – Postulated interaction of Demodex mites with the host immune system in healthy vs. inflamed skin
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Podosoma
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Figure 1
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Figure 2
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Figure 3
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Figure 4
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