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c mouse
0
INSTITUT
Res. immunol. 1996, 147, 27-38
PASTEURIELSEVIIZR
Paris 1996
Murine acariasis: I. Pathological and clinical evidence suggesting cutaneous allergy and wasting syndrome in BALB/c mouse P. Jungmann
(‘)(*), J.-L. Guenet
(*), P.-A. Cazenave
(3), A. Coutinho
(‘) and M. Huerre
(4)
(I) Unite’ d’lmmunobiologie, (2’ Unite’ de Gtknhique des Mammifsres, (3) Unite’ d’Immunochimie Analytique, and (4) Unite’ de Pathologie, CNRS URA-1961, Institut Pasteur, 75724 Paris Cedex 15
SUMMARY
We describe here a disease related to mite-associated ulcerative dermatitis in BALB/c mice, a strain previously classified as resistant to this condition. The disease was recognized by pruritic cutaneous pathology and wasting. Pathologic studies showed a marked allergic-type inflammation in the skin. The dominant histologic feature was extensive mast cell infiftration in cutaneous lesions and in fymphoid tissues, associated with a greatly elevated serum IgE concentration. The disease was secondary to infestation with an acarian ectoparasite Myocoptes musculinus, and seemed to represent an allergic reaction to the parasite-derived substances, with an associated wasting syndrome. This condition may be a useful experimental model for allergic diseases.
Key-words:
Allergy,
Mast cell, Dermatitis;
Myocoptes
musculinus,
Wasting
syn-
drome, Acariasis.
INTRODUCTION
Infestation of mice by ectoparasites is relatively common in research laboratories. The acarian parasites Myocoptes musculinus (Koch, 1844) and Myobia musculi (S&rank, 178 1) are widespread, but may not cause clinical signs of disease (Flynn, 1954; Gambles, 1952; Keegan, 1956). Thus, large numbers of parasites can be found in apparently healthy animals (Cook, 1953). Furthermore, there is no general agreement as to their pathologic significance (Gam-
Submitted
November
(*) Corresponding
author.
22, 1995, accepted March
1, 1996.
bles, 1952). These parasites are purely surface dwellers and do not penetrate the deeper layers of the skin at any stage of their life. Transmission requires close direct contact between animals. Infection by bedding is rare. (Weisbroth, 1982a). Reports of observations on M. musculinus-infected mice, however, are quite rare compared to those concerning Myobia, and none are recent. In the course of experiments involving longterm maintenance of animals, it was observed that some BALB/c mice in the breeding colony
28
P. JUNGMANN
Pasteur had an abnormal appearthe age of three months, such animals were smaller, exhibited body scratching with patches of hair loss, cutaneous lesions and progressive wasting. Siblings in the same cage differed in the manifestation of these symptoms, but further observation revealed that most mice became affected if observed for a sufficiently long period of time. Laboratory investigations of sick mice revealed striking biological and pathological alterations, and the finding of a superficial ectoparasite - M. musculinus suggested an infectious aetiology for the disease. All Myocoptes-infected BALB/c mice in our colony developed cutaneous lesions with marked systemic alterations.
ET AL. MATERIALS
at the Institut
AND METHODS
ance. After
The disease described here is similar to miteassociated ulcerative dermatitis (MAUD) (Dawson et al., 1986), described in C57BL mice and congenic strains. MAUD is thought to be caused by M. musculi (a fur mite closely related to h4. musculinus) and seems to stimulate a marked allergic reaction (Flynn, 1954 ; Gambles, 1952; Csiza and McMartin, 1976; Weisbroth et al., 1976 ; Weisbroth, 1982b; Bean-Kundsen ef aZ., 1986; Watson, 1961 ; Whiteley and Horton, 1962 ; Galton, 1963 ; Whiteley and Horton, 1965 ; Weisbroth et al., 1974 ; Friedman and Weisbroth, 1975, 1977). BALB/c mice however, were described as being a strain resistant to this condition (Dawson et al., 1986). In the present report, we describe clinical and therapeutic data and histological abnormalities in skin, lymphoid and haematopoetic tissues, as well as serum IgE concentrations associated with infestation by M. musculinus in BALB/c mice. Our data support an allergic mechanism for the disease. As the pathophysiology of this acariasis seems to involve hypersensibility to parasite-derived antigens, the study of the respective mechanisms may represent an interesting system for investigating regulatory phenomena operating in allergic inflammation.
MAUD
=
mite-associated
ulcerative
dermatitis.
Animals Adult male and female mice bred in the animal facilities of the lnstitut Pasteur were used in this study. Afflicted animals were either pure inbred BALBlc mice or progenies of the 8th to 10th backcross generations of SPE mice (a moderately inbred strain derived from A4us spretus) to the BALB/c background. Given the large number of backcross generations performed, no more than 0.01% of the M. spretus genome is likely to be carried and thus the condition is probably associated with the BALB/c background. Control animals in this study were adult BALB/c mice from different areas of our colony. Pathological
examination
Thirty-two afflicted mice were sacrificed by cervical dislocation at varying times after the onset of clinical dermatitis and submitted to complete pathologic examination with morphometric records, loco-regional observations and removal of organs, as well as tissues such as skin, joints and skeletal muscle. The histologic material was fmed in 10 % buffered formalin, routinely processed and the 5-pm paraffin sections stained with haematoxylin-eosin, periodic acid Shiff (PAS), Brown and Brenn (B&B) toluidine blue, and al&n blue, were examined by light microscopy. In viva skin microscope
examination
under
the dissecting
Due to the histological findings of cross-sections of parasitic structures on the surface of the epidermis (see below), we isolated parasites from the skin of diseased mice. Under general anaesthesia, (0.2 ml intraperitoneal injection of Avertin-2,2,2-tribromoe-
thanol), mice were subjected to direct stereomicroscopic observation of the skin lesions (mainly on the neck and eyelids). Some parasites were collected (live) with a fine needle, fixed on ethanol, and their
analysis
conducted
by Dr. Claudine
Department d’Ecologie Institut Pasteur.
des Systbmes
Perez-Eid, Vectoriels,
Haematology As pathological changes were observed in haematopoietic tissues, we verified examined blood
ALLERGY
IN MURINE
cells. Heparinized blood samples from 12 sick and 4 control mice were collected under slight ether anaesthesia by retroocular venous puncture. Red blood cells were counted on a Coulter counter analyser and white blood cells in a Biirker chamber. Blood smears were air-dried and stained by May Grunwald Giemsa. Cytomorphology of the white and red cells and the platelets was recorded. Standard haematologic techniques were used for total and differential leukocyte counts (400 leukocytes were counted on each preparation). Urine examination Urine from 12 affected and 4 control mice was tested for the presence of proteins, glucose, ketones, blood and for pH values using test strips (Laboratory Miles, Division Ames, Belgium). Radiology Radiographs were performed employing X-ray intensity that allowed definition of bone and soft tissues with image amplification. A control normal adult BALB/c mouse of the same age was simultaneously exposed in the same radiographic field. Infection
assay
In order to ascertain the infectious nature and the transmissibility of the disease, 5 BALB/c mite-free 15-day-old female mice and their mother were caged together with 3 females infected with IV. mu++ culinus. The newborns were followed for 13 months for the presence of the acarian parasite, the appearance of initial clinical signs and for the development of full-blown disease. Acaricidal
treatments
Two different therapeutic trials for acarian tations were conducted according to published mens, using Diclorvos (Dawson et al., 1986; and McMartin, 1976; Weisbroth et al., 1976; man and Weisbroth, 1975) and Ivermectin mans et al., 1988; Papini and Marconcini, Wing et al., 1985).
29
ACARIASIS
loss of fur; the second group consisted of three mice with advanced disease - ulcerative lesions, widespread hair loss and wasting; the third group was composed of three normal BALB/c mice that served as a “treated” control group for scoring putative toxic effects of the drug. After initial observation of behaviour, clinical status, weight, and the presence of the parasite, the mice were observed twice a week. In the second therapeutic trial, 200~~1 drops of a 10% solution of Ivermectin (Ivomec@, Merck Sharp & Dohme) prepared in propylene glycol (Sigma Co.) were applied to the neck. This procedure was repeated 20 days later. Two groups of adult BALB/c mice with fully developed disease were used: (1) one group of five female and two male adult BALB/c mice were treated; (2) four females and two males were left untreated to follow disease evolution. Five normal adult males were also subjected to treatment as a control group for potential toxic effects of the drug. The parameters observed were the same as above. Mice were followed up to 13 months. Food and water were provided ad Zibitum throughout both studies. Determination
of serum IgE concentration
The striking accumulation of mast cells and eosinophils in the pruritic skin lesions of mice suggested the existence of an allergic mechanism. We thus measured IgE concentration in the serum. Samples from 10 sick and 2 control mice were analysed in ELISA tests. The assays were done with flat-bottom microplates (96 wells) coated overnight at 4°C with a polyclonal sheep anti-mouse IgE antibody (AAM1) and, as secondary antibody, a biotinylated monoclonal anti-mouse IgE (MCA -419) (both antibodies were from Serotec Oxford, UK). As a standard curve, a titration of supematant of an antiDNP IgE hybridoma (HMK-11) (Liu et al., 1980) was used, while sera from pollen (Dactylis glomer-
ata)-hyperimmunized infesregiCsiza Fried(Bau1991;
In the first therapeutic trial, a strip of 1 cm2 impregnated with Dichlorvos (Neocid@) was placed in each cage and replaced every ten days for three months. Cages were covered with a filter top. Three groups of animals were treated. The first group was composed of three mice with the fully developed disease - scratching, skin wounds, ear inflammation, blepharitis and initial
mice, with a specific IgE titre
of 1280 tested by PCA at day 28 of immunization, served as a positive control.
RESULTS
Clinical
features and general
observations
BALB/c mice that developed to scratch themselves at 8-10 especially around the eyes, mouth, dorsal region. General reddening followed by superficial erosions
disease began weeks of age, nose, ears and of the skin was with crust for-
30
P. JUNGMANN
mation and eventual bleeding. Enlarged cervical lymph nodes could be detected at this stage. As the disease progressed, the mice present ruffled fur, erythema and oedema of the eyelids and conjunctiva with abundant exudate (fig. la). Similar processes were observed on the external parts of the ears, where inflammatory signs were at times so severe as to lead to necrosis and partial loss of the pinna (fig. la). In some animals, overt ulcerative skin lesions were observed, the majority of which were localized at hairless areas on the neck and shoulders. Later phases of disease were characterized by a generalized loss of fur that started on the dorsal region (fig. la) and spread throughout the body. Slow loss of muscle and soft tissue, with a hunched-back posture, were constant features. Fertility was low. Weight values for adults started at 24 g and declined progressively to 11 g. By the final phases of disease, affected mice were inac-
ET AL.
tive and cache&c. At this point, regression of the lymphadenomegaly parallel with an increase in the volume of the spleen were observed. Death usually occurred at around 16 months of age.
Macroscopic
pathology
At autopsy, sick animals had slender skeletal muscles and very thin and transparent skin with a fragile appearance. Very little adipose tissue was observed in the body. The cutaneous lesions on the neck, as well as those on the ears and eyelids, showed little variation from one animal to another. In general, they presented dermal thickening, inflammatory signs, and serohaemorrhagic crust formation with necrosis (fig. la). There was a marked enlargement of lymph nodes in the cervical and brachial regions, (fig. 2b). The thymus was pale and small and, in
Fig. 1. (top panel) M. musculinus-infected adult BALBlc mouse. a) Note erythema and oedema of the eyelids, the deep ulcer on the malar region with serohaemorrhagic exudate, a complicated ear lesion with necrosis and partial amputation of the external part. Initial hair loss with hyperhaemic dermal background is seen in the dorsal region. b) Supradiaphragmatic view of M. musculinus-infected adult BALB/c mouse: marked enlargement of cervical and brachial lymph nodes [arrows]. c) Skin section showing acarian parasites on keratin layers, hyperkeratosis, acanthosis and a chronic inflammatory cell infiltrate in the dermis. (Haematoxylin-eosin; original magnification x 10). d) Skin section showing prominent mast cell infiltration in superficial and deep dermis. (The same section stained by haematoxylin-eosin revealed strong chronic allergic inflammation with numerous plasma cells, eosinophils and lymphocytes - not shown). (Toluidine blue; original magnification X 40). Fig. 2. (bottom
panel)
Cervical
lymph node section (a, b), spleen section (c) and retroperitoneal soft tissue (d).
a) Cervical lymph node section showing massive expansion of the medullary region occupied by clusters of plasmocytoid and mature plasma cells. The lymphoid populations in the follicles and paracortical areas are pushed to the periphery of the node. (Haematoxylin-eosin ; original magnification X 10). b) Cervical lymph node section showing diffuse mast cell infiltration in medullary and paracortical regions. Infiltration of mast cells was also observed at the capsular level and in perinodal connective tissue - not shown. (Toluidine blue; original magnification x40). c) Spleen section showing an enlarged red pulp with intense extramedullar haematopoiesis. All three bone marrow cell lineages are present but erythrocytic and megakaryocytic differentiation dominates. The white pulp is represented by a clear-cut periarteriolar lymphoid sheath, but lymphoid follicles are decreased in number and in size, with poor germinal centre reaction. (Haematoxylineosin; original magnification X40). d) Retroperitoneal soft tissue (para-aortic level), showing suggestive areas of extramedullar haematopoiesis, composed of loose aggregates of myeloid precursors, mature granulocytes, eosinophils, macrophages and megakaryocytes (arrows). (Haematoxylin-eosin; original magnification x60).
ALLERGY
IN MURINE
ACARIASIS
:,r; r* ,,.. T’:.
. 1 ;
!
31
1; ‘. ..% *.
.
:
.1.
,
P. JUNGMANN
32
some advanced cases, undetectable. The spleen was darker than normal and had increased volume. On the cut surface, the firm red pulp was prominent in comparison with the inconspicuous white pulp. The bone marrow (femur) was pale and the bone structure fragile. Muscular layers of all viscera observed were very thin. All other organs and anatomical cavities were found to be grossly normal.
Stereomicroscopic examination entomological determination
of the skin and
The parasites detected on the skin surface were not numerous; however, some moving forms as well as eggs attached to the lower pole of the hair shafts were encountered. They were surrounded by viscous fluid (exudate) on a reddish dermal background. Some parasites, were harvested and prepared for entomological study. They were identified as A4. muscuhus (Koch, 1844), a fur mite (hair-clasping) of the Listrophoridae family. This mite is a common ectoparasite of the genus Mus musculus (Gambles, 1952 ; Keegan, 1956; Tiraboschi, 1904). The parasites were seen in all sick mice examined, but in none of the control mice.
Microscopic
pathology
In the keratin layers of some cases, crosssections of parasites could be identified (fig. lc). The cutaneous lesions, regardless of their localization, shared a common histological pattern. Their common features included reactive epithelial proliferation, strong accumulation of mast cells in the dermis (fig. Id) and deeper layers (only cells with toluidine blue positive granules in the cytoplasm were considered connective tissue-type mast cells), together with eosinophil and mononuclear cell infiltration. Proliferation of fibroblasts associated with mast cell accumulation was also evident. Variable histological components included necrotic areas, ulceration, granulation tissue and superficial bacterial contamination. At the level of skin free of macroscopic lesions, there existed
ET AL.
modifications characterized by local foci of hyperkeratosis, mast cell infiltration 2-fold that of controls, and variable amounts of scattered eosinophils. The hair follicles were normal in appearance. The enlarged lymph nodes showed marked expansion of the medullary region (fig. 2a) which was occupied by clusters of numerous plasmacytoid and mature plasma cells surrounded by foamy histiocytes. The ordinary lymphoid counterpart was pushed to the periphery (fig. 2a). The T-cell areas (paracortex) were hyperplastic. In B-cell areas, there was a moderate germinal centre reaction. Diffuse eosinophil infiltration was constant, Significant mast cell infiltration could be seen (fig. 2b), predominant in medullary and cortical regions but also in perinodal connective tissues. Inguinal lymph nodes did not show the same reaction but were similarly infiltrated by mast cells. Thymic histology varied according to the age and the disease stage of the mice. In advanced cases, a characteristic atrophic pattern was found and in early phases, a decreased lymphoid population could still be defined and mast cell infiltration was detected inside the medullary region (in addition to the expected resident mast cell on the septa) (Kuper et al., 1982). The spleen showed marked extramedullary haemopoiesis within splenic cords (well above background level) representative of the 3 major differentiative lines with a predominance of erythrocytic and megakaryocytic proliferation (fig. 2~). Prominent groups of plasma cells could be seen within and around the borders of haematopoietic colonies. The white pulp was essentially represented by the periarteriolar lymphoid sheet, whereas the lymphoid follicles were diminished in number and size with no prominent germinal centre reaction. In some cases, areas were seen where extramedullary haemopoiesis was suggested as small aggregates localized on retroperitoneal regions, peripancreatic and perinephritic connective tissue (fig. 2d). Mast cells were also sometimes detected at these sites. The bone marrow was occupied by the granulocytic, monocytic and megakaryocytic lineages, with erythrocytic and lymphocytic precursors being very scanty. The trabeculae and the bone matrix were normal.
ALLERGY
IN MURINE
The liver showed a variable degree of fatty infiltration and a mild sinusoidal accumulation of eosinophils. The adrenal gland had cortical hyperplasia. The male gonads showed decreased numbers of germ cells. Microcalcifications without associated lesions were observed in the lungs, liver, kidneys, prostate, gall bladder and large vessel walls. Atrophic changes were observed in visceral and skeletal muscles. No significant histologic abnormalities were detected in the joints, endocrine, cardiovascular, digestive, respiratory, urinary or nervous systems.
Haematological examination The marked extramedullary haemopoiesis led us to perform haematological profiles. Hypochromia of erythrocytes from sick mice was observed, although the number of red blood cells (8,500,000/mm3) were comparable to controls. Moderate leukocytosis was detected in sick mice (6,500-7,550 cells/mm3) as compared to normal mice (5,500 cell/mm3). Differential counts showed variable levels of lymphocytopenia, 25-55%, and granulocytosis, 30 to 60%. In control mice, 65% of leukocytes were lymphocytes and 20% granulocytes (Russel and Bernstein, 1968). The number and morphology of platelets on the smears were normal for both groups.
Other examinations In view of the poor clinical status of the mice, we searched for possible metabolic disturbances that could be revealed by urine analysis. Urine from sick mice differed from controls at pH values that were consistently acid (5.0) in contrast with the neutral pH (7.0) of controls. Mild proteinuria (+) but no glucose, ketones or blood was found in sick and control groups. The observation of microcalcifications on several tissues prompted us to perform detailed radiographic studies. The radiographic images revealed decreased volume of soft tissues and decreased bone density but no gross macrocalcifications elsewhere.
ACARIASIS
33
Infection assay and acaricidal treatment The presence of M. musculinus on sick but not healthy mice suggested an aetiological relationship between the ectoparasite and the disease. In order to assess this possibility, we performed two types of experiments: infestation of normal controls (transfer of the parasite and disease) and acaricidal treatment of sick animals. After exposing five mite-free newborn mice to mite-infested mice, 3 mice developed initial signs of disease - scratching and skin reddening - by the 4th month of age on positive parasitological examination. By 13 months, all mice had developed full disease. The severity of signs was variable, but all mice presented blepharitis, malar erosions, loss of weight and hair. One cachectic mouse died. Thus, the disease in BALB/c mice was related to infestation with M. musculinus, although individual variability was observed in the severity of its manifestations. Acaricidal therapy with Neocid” and Ivermectinm led to healing of skin lesions and scar formation as early as 10 days after the onset of treatment. Examination of skin lesions after initiation of treatment revealed fragments of mite exoskeletons and empty eggs attached to hair shafts. The mice appeared to be mite-free 2 months after the beginning of treatment. Scratching was reduced and conditions of the fur improved. Although increased survival was observed in the treated groups, the clinical status of the mice did not dramatically change. Once initiated, the wasting syndrome seemed to persist and worsen with time despite the apparent clearance of the parasites. Similar observations were reported by Pence et al. (1991) after treating M. musculi-infected Swiss-Webster mice presenting severe lesions.
Determination of serum IgE concentration As shown in figure 3, the increase in circulating IgE levels was very marked in comparison with normal mice (lOO-fold) and mice hyperim-
P. JUNGMANN Serum
IgE
DISCUSSION
concentration
1
-
1 Fig. 3. Serum IgE concentration in a normal control mouse, allergen hyperimmunized mouse, and 5 sick mice as indicated. Each bar corresponds to an individual animal. A total of 10 diseased mice and 2 controls were tested with similar results.
munized with pollen allergens that had specific IgE PCA titres of 1: 1.280 and yet had circulating IgE concentrations nearly lo-fold lower than mice afflicted with this condition. The serum concentrations of other Ig clones were also abnormal, with decreased IgM and IgG3, increased IgA, IgGl and IgG2b, and normal levels of IgG2a (table I).
Table I. Serum
Infected Control
ET AL.
The disease studied here was due to chronic infestation of BALB/c mice by the ectoparasite, M. musculinus. This was suggested by the response to acaricidal treatments and was confirmed by transfer of disease following transmission of mites from diseased to newborns. The physiopathology of this disease seemed to be allergic, since skin lesions were erythematous and pruritic, infiltrated by large numbers of mast cells and eosinophils and associated with high levels of serum IgE. In allergic responses, mast cells are both regulators and local effector cells in the inflammatory field (Galli, 1990; Swietter ef al., 1992), and cross-linking of its FceHI receptors is fundamental to the induction of signs and symptoms in allergic disorders (Swietter et al, 1992, reviewed in Galli, 1990). An allergic-type response to mite antigens was previously reported in C57BL mice infested with M. muscdi (Csiza and McMartin, 1976; Weisbroth, 1982b; Bean-Kundsen et al., 1986) based on the following observations: 1) the similarity of the lesions with those observed in allergic acarjasis in other species ; 2) the presence of “allergic accumulations” of mast cells in involved tissues ; 3) the pruritic character of the lesions; 4) the fact that although infestation occurred shortly after birth, only adult mice developed such lesions, suggesting that a period of sensitization was necessary ; 5) lesion redevelopment in healed, mitefree mice within days of experimental re-infestation with as few as 5 mites; 6) lack of a relationship between mite numbers and the severity of the lesion; 7) the fact that the disease was strain-dependent and genetically controlled (Dawson et al., 1986; Csiza and McMartin,
immunoglobulin
concentrations
Ii-N
IgG3
IgGl
71+2 174f 104
16+21 127+6
The results are means and SD of 3 mice per group,
IgG2b
4,521 f798 997f421 determined
in infected
1,052f335 173f76 by ELISA.
and control IgG2a 473 f94 238+52
mice. Id 13,209*3,684 63f51
ALLERGY
IN MURINE
1976; We&broth, 1982b; Bean-Kundsen et al., 1986 ; Friedman and Weisbroth, 1975 ; Pence et al., 1991). Furthermore, Laltoo et al. (1979), studying M. musculinus-infested SWR mice, demonstrated the presence of specific serum IgGl and IgE anti-mite antibodies and in viva degranulation of mast cells after challenge with M. musculinus antigens. Our own observations conftrm many of these points and argue against the role of the parasite itself as a primary cause of lesions. The fact that the parasites do not invade the tissue also supports a hypersensitive reaction to parasite-derived antigens which may enter the body through the skin lesions. Parasite-antigens may bind to cytophilic IgE and stimulate the release of mast cell mediators which in turn recruit other type of cells including eosinophils. Epithelial thickening due to increased mitotic activity of the epithelium (Weisbroth, 1982a; Watson, 1961; Whiteley and Horton, 1965 ; Watson, 1963) and the fibrosis found in skin lesions may have been due to effects of mast cell products known to stimulate multiplication of these cells (Franzen and Norrby, 1980; Non-by, 1983 ; Gordon and Galli, 1994). The large numbers of mast cells that accumulate in the lymph nodes (and to a lesser extent, in the thymus) represent a new aspect of the miteinduced allergic reaction. Thus, lymph nodes and thymus as compared to skin or bronchial mucosa do not appear to be suitable sites of allergic effector reactions, suggesting that mast cell accumulation in those sites may have a distinct significance. We would like to speculate that mast cells recruited into allergic reaction sites, after degranulation and proliferation, (“born-again”) (Galli, 1990; Swietter et al, 1992), may follow an alternative migratory pathway into the lymph stream, reaching draining lymph nodes. The fact that mast cells can present antigens (Frandji et al., 1993) leads us to suggest that tissue mast cells, once in lymph nodes, could contribute additional antigen transport and represent an important APC complement. However, such “quasi-recirculating behaviour” has not been described to date and remains hypothetical. Further evidence for immunological stimulation in this disease lies in lymph node enlarge-
ACARIASIS
35
ment in regions draining the most severely affected areas. The strong medullary plasmacytosis, also shown by others (Csiza and McMartin, 1976; Galton, 1963; Madden et al., 1954), suggests that there is powerful stimulation of B cells to terminal differentiation in this syndrome and it may account for the increased levels of IgE in the serum. IgE production is mostly a T-cell-dependent process (Coffman and Carty, 1986) and the hyperplasia of paracortical areas in those nodes suggests the involvement of T cells in the overall reaction. The T- and B-cell areas in the spleen show similar characteristics, suggesting that the immunological reaction is systemic and not limited to regional lymph nodes. This is also ascertained by the marked alterations in the serum levels of various Ig classes, all supporting the notion of T-cell-dependent B-cell hyperactivity. This disease also eventually involves multiple organs and body functions. Localized skin lesions progress and compromise the general status of the mice, leading to a wasting syndrome associated with fatty infiltration of the liver, hyperplasia of the adrenal cortex (Strandberg, 1982), expenditure of adipose tissue and loss of skeletal and visceral muscle mass. The low urinary pH is probably due to a chronic catabolic state. Microcalcification in several tissues, already described in similar infestations (Whiteley and Horton, 1962; Galton, 1963), along with radiologic signs of osteopenic bone, characterize metastatic calcifications due to bone catabolism (Cotran et al., 1994). The allergic component represented by numerous mast cells in the skin and in other tissues of the mice may be an important source of TNFalcachectin (Huang et al., 1990; Young et aZ., 1987), a multifunctional cytokine involved in inflammation, lipid and protein metabolism, as well as in haematopoesis (Tracey et al, 1988; Moldawer et al., 1989; Cracker and Milon, 1992) and may participate in the pathogenesis of wasting. The blood profile shows hypochromic anaemia, granulocytosis and lymphopenia, reflecting a chronic inflammatory disorder. Increased levels of TNFa could also explain granulocytosis and anaemia (Tracey et al., 1988; Moldawer et al., 1989 ; Cracker and Milan, 1992). Similar alterations in the blood profile of mite-infested mice
36
P. JUNGMANN
have been reported (Csiza and McMartin, 1976; Madden et al., 1954) associated with hypergammaglobulinaemia, hypoalbuminaemia and decreased haemoglobin concentration. The constant loss of plasma proteins through the skin exudate, on the one hand, and a persistent immunologic stimulation by the presence of the parasite on the other, could account for these findings. The presence of extramedullary haematopoiesis with a specific increase in the megakaryocytic lineage has been observed in mice infected with M. musculi (Csiza and McMartin, 1976 ; Weisberoth, 1982b ; Galton, 1963). In our cases, haematopoetic colonies were found abundantly in the spleen, in retroperitoneal connective tissues, while groups of megakaryocytes were scored in lymph nodes and liver, providing further evidence for broad haematopoetic stimulation. We would like to suggest that chronic mast cell activation by acarian antigens may contribute to these findings. It is established that mast cells are very active in cytokine production (Galli, 1993), especially those operating in haematopoiesis, such as IL3, IL4, IL6, IL5 and GM-CSF, and TNFa (Wodnar-Filipowicz et al, 1989; Plaut et al., 1989; Moore, 1992) that, if systemically active, would stimulate haematopoetic precursors in the periphery (wodnar-Filipowicz et al., 1989 ; Layton et al., 1992). Nevertheless, activated T lymphocytes, probably also involved in this immunological reaction, are able to synthesize similar factors and provide overlapping stimulation. Not all mice infested with M. musculi develop MAUD (Dawson et al., 1986). The susceptibilty to disease seems to be controlled by at least two loci: some non-H-2 linked gene(s) shared by all C57BL background strains, and a gene or genes within the H-2 complex (Dawson et al., 1986). H-2b and H-2k-linked genes were found to enhance pathogenesis of disease in the corresponding background (Dawson et al., 1986). Under the conditions of these observations, BALB/c was considered a resistant strain (Dawson et al., 1986). In contrast, we describe here observations in BALB/c mice that display an evident susceptibility to develop a “MAUD-like” condition in 100 % of the individuals after
ET AL.
13 months of observation. Thus, the apparent discrepancy may be explained by the period of observation of affected individuals, apparently much shorter in Dawson’s report (Dawson et al., 1986). In favour of this interpretation are the comparatively very low levels of disease incidence (2.1 %) in the prototype “susceptible”mouse strain (C57BL) described in that study. Second, we are dealing with a different ectoparasite. Thus, while MAUD has been described in M. musculi-infected mice, we presume we are in the presence of a monoinfestation by M. musculinus. In spite of their close structural and functional similarities, these two mites differ slightly in the type of spreading and feeding (Weisbroth, 1982a). Histopathological descriptions in M. muscuhus infestations, however, do not include ulceration and mast cell infiltration of skin lesions, nor lymphadenopathy (Weisbroth, 1982a; Watson, 1961). In contrast, our findings showing pathological patterns that are common to both conditions suggest that differences reported in the literature may be due to the reduced number of observations on M. musculinus-infested mice as compared to myobic cases. An alternative explanation for susceptibility of BALB/c mice is that different substrains, kept apart for many years, may have genetically drifted and diverged in resistance to MAUD. Nevertheless, systematic genetic approaches utilizing monospecific infestations with M. musculinus, as were performed for myobia, have not been carried out. Finally, susceptibility versus resistance is also determined by environmental conditions. The heterogeneity in disease presentation among inbred siblings shows that epigenetic factors are involved in controlling disease presentation. The discrepancy between the results of Dawson et al. (1986) and ours could thus be explained by differences in the respective microbiological or nutritional environments. In summary, we have described a MAUDlike disease in a colony of BALB/c mice infested with M. musculinus. This condition seems to have an allergic pathogenesis based on its clinical and histological presentation, and on a high serum IgE level as well. This disease also includes a systemic syndrome characterized by a
ALLERGY
IN MURINE
chronic wasting state with lymphadenopathy, granulocytosis lymphocytopenia, marked extramedullary haematopoesis and low fertility. We believe that these mite-infested mice represent a novel alternative system for studying cutaneous allergic processes and systemic effects of chronic immunological stimulation by a natural and generally non-pathogenic infestation. While in man allergic disorders are acquired after natural exposure to antigens, in most experimental systems, allergic responses are artificially induced. Thus, the spontaneous disease described here seems to be a suitable natural model for studying allergic reactions.
Acknowledgments We thank Mrs Nicole Wuscher, Unite de Pathologie, Institut Pasteur, for histotechnical assistance, and Dr Claudine Perez-Eid, Department d’Ecologie des Systemes Vectoriels for the entomological determination. This work was supported in part by a grant from ANRS. PJ was supported by a fellowship from CNPq, Brasilia, Brazil.
Acariase murine I. Elbments pathologiques et cliniques suggkrant une allergic cutanCe et une consomption chez la souris BALB/c Nous d&rivons ici une maladie similaire a la dermatite ulc6rative associ& aux acariens chez les sou-
ris BALB/c, une lignee reputee resistante & cette affection. La maladie se manifeste par un prurit et un deperissement des souris. On observe, dans la peau,
une inflammation
de type allergique
et une
infiltration massive de. mastocytes a la fois dans la lesion cutan& et dans le tissu lymphdide. Cela s’accompagne d’une augmentation importante des IgE sCriques. La maladie se manifeste B la suite d’une infestation par un acatien, Myocoptes musculinus, et semble r6unir une &action allergique a des produits parasitaires et un syndrome de consomption. Cet Ctat pathologique pourrait rep&enter un modi?le experimental intdressant pour 1’Ctude de cet-taines maladies d’origine allergique.
Mots-cl&s: Allergic, coptes musculinus,
Mastocyte, Dermatite ; MyoConsomption, Acariase.
ACARIASIS
References Baumans, V., Havenaar, R., van-Herck, H. & Rooymans, T.P. (1988), The effectiveness of ivomec and neguvon in the control of murine mites. Lab. Anim., 22, 243-245. Bean-Kundsen, D.E., Wagner, G.E. & Hall, R.D. (1986), Evaluation of the control of Myobia musculi infestation on laboratory mice with permethrin. Lab. Anim. Sci., 36, 268-270. Coffman, R.L. & Catty, J. (1986), A T-cell activity that enhances polyclonal IgE production and its inhibition by interferon-y. J. Immunol., 136, 946-954. Cook, R. (1953), Murine mange: The control of Myocoptes musculinus and Myobia musculi infestation. Br. Vet. J., 109, 113-116. Cotran, R.S., Kumar, V. & Robbins, S.L. (1994), Cellular injury and cellular death, pathologic calcification, in “Pathologic Basis of Disease” (Schoen, F.J.) (pp 303 1). W.B. Saunders Company, Philadelphia. Cracker, P.R. & Milon G. (1992), Macrophages in the control of haematopoesis, in “The natural immune system, The Macrophage” (Lewis, C.E. & McGee, J.O.D.) (pp. 115-156). IRL Press at Oxford University Press, London. Csiza, C.K. & McMartin, D.N. (1976), Apparent acaridal dermatitis in a C57BL/6 Nya mouse colony. Lab. Anim. Sci., 26, 781-787. Dawson, D.V., Whitmore, S.P. & Bresnahan, J.F. (1986), Genetic control of susceptibility to mite associated ulcerative dermatitis. Lab. Anim. Sci, 36, 262-267. Flynn, R.J. (1954), Mouse mange. Proc. Anim. Care Panel, 5, 96-105. Frandji, P., Oskeritziam, C., Cacaraci, F., Lapeyre, J., Peronet, R., David, B., Guillet, J.-G. & Mecheri, S. (1993), Antigen dependent stimulation by bone marrow-derived mast cells of MHC class II-restricted T cell hybridoma. J. Zmmunol., 15 1, 63 18-6328. Franzen, L. & Non-by, K. (1980), Local mitogenic effect of tissue mast cells secretion. Cell. tissue kinet., 13, 635-642. Friedman, S. & Weisbroth, S.H. (1975), The parasite ecology of the rodent mite myobia musculi. II. Genetic Factors. Lab. Anim. Sci., 25, 440-445. Friedman, S. & Weisbroth, S.H. (1977), The parasitic ecology of rodent mite, Myobia musculi. IV Life cycle. Lab. Anim. Sci., 27, 34-37. Galli, SJ. (1990), Biology of disease: new insights into “The riddle of the mast cells”: microenvironmental regulation of mast cell development and phenotypic heterogeneity. Lab. invest., 62, 5-33. Galli, S.J. (1993), New concepts About the mast cell. N. Engl. J. Med., 328, 251-265. Galton, M. (1963), Myobic mange in the mouse leading to skin ulceration and amyloidosis. Am. J. Pathol., 43, 855-862. Gambles, M. (1952), Myocoptes musculinus (Koch) and Myobia musculi (Schranck), Two species of mite commonly parasitizing the laboratory mice. Br. Vet. J., 108. 194-203. Gordon, J.R. & Galli, S.G. (1994), Promotion of mouse fibroblast collagen gene expression by mast cells stimulated via the FceRI. Role for mast cell derived transforming growth factor b and tumor necrosis factor a. J. Exp. Med., 180, 2027-2037.
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Huang, E., Nocka, K., Beier, D.R., Chu, T.-Y., Buck, J.Lahm, H.-W., Wellner, D., Leder, P. & Besmer, P. (1990) The hematopoietic growth factor KL is encoded by the SI locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell, 63, 225-233. Keegan, H.L. (1956), Listrophoridae-Myocoptes musculinus, myocoptic mange mite, in “Manual of Parasitic Mites of Medical or Economic Importance” (Baker, E.W, Ivans, T.M., Guld, D.G & Hull, W.B.) (pp. 149- 15 1). Technical Publication of National Pest Control Association, New York. Kuper, C.F., Beems, R.B. & Hollanders, M.H. (1982), Development and aging, thymus, rat, in “Monographs on Pathology of Laboratory Animals, Endocrine System” (Jones, T.C., Ward, J.M., Mohr, U. & Hunt, R.D.) (pp. 257-262). Springer-Verlag, Berlin. Laltoo, H., Zoost, V.T. & Kind, L.S. (1979), IgE response to mite antigens in mite infected mice. Immunol. Commun., 8, l-9. Layton, J., Cebon, J., Dyer, W., Iaria, J., Pavlovic, R. & Morstyn, G. (1992). The role of colony-stimulating factors in infection, in “Cytokines in hemopoiesis, oncology and AIDS II” (Freund, M., Link, H., Schimidt, R.E. & Welt, K.) (pp. 15-18). Springer-Verlag, Berlin. Liu, F.-T., Bohn, J., Ferry, E., Yamamoto, H., Molinaro, C., Sherman, N.E. & Katz, D. (1980), Monoclonal dinitrophenyl specific murine IgE antibody. Prepara tion, isolation, and characterization. J. Immunol., 124, 2728-2737. Madden, A.H., Tozloski, A.H. & Sweetman, H.L. (1954), Control of Myobia musculinus (S&rank) and Myocoptes musculinus (Koch) on Laboratory Mice. J. Econ. Entomol., 47,442-444. Moldawer, L.L., Marano, M.A., Wei, H., Fong, Y., Silen, M.L., Kuo, G., Manogue, K.R., Vlassara, H., Cohen, H., Cerali, A. & Lowry, S. (1989), Cachectin/tumor necrosis factor-a alters red blood cell kinetics and induces anaemia in vivo. FASEB J., 3, 1637-1643. Moore, M.A.S. (1992), Cytokine interactions in hematopoesis: An introduction and overview, in “Cytokines in Hemopoiesis, Oncology, and AIDS II” (Freund, M., Link, H., Schimidt, R.E. & Welte, K.) (pp. 3-13). Springer-Verlag. Berlin. Norrby, K. (1983), Intradermal mast cell secretion causing cutaneous mitogenesis. Virchows Arch., 42, 263-269. Papini, R. & Marconcini, A. (1991). Treatment with ivermectin in drinkirg wateragainst Myoboa musculi and Myocoptes musculinus mange in naturally infected laboratory mice. Angew. Parasitol., 32, 11-13. Pence, B.C., Demick, D.S., Richard, B.C. & Buddingh, F. (1991), The efficacy of chloropirofos (dursban) for control of Myobia musculi infestation in mice. Lab. Anim. Care, 42, 139-142. Plaut, M., Pierce, J.H., Watson, C.J., Hyde-Hanley, J., Nordart, R.P. & Paul, W.E. (1989), Mast cell lines produce lymphokines in response to cross-linkage of FCE RI or to calcium ionophores. Nature (Lorid.), 339 64-67. Russel, E.S. & Bernstein, SE. (1968), Blood and Blood Formation, in “Biology of the Laboratory Mouse”
ET AL. (Green, E.L.) (pp. 351-370). Dover Publications Inc., New York. Strandberg, B., (1982), Focal hyperplasia, adrenal cortex, rat, in “Monographs on Pathology of Laboratory Animals, Endocrine System” (Jones, T.C., Mohr, U., Hunt, R.D.) (pp. 37-40). Springer-Verlag, Berlin. Swietter, M., Mergenhagen, S.E. & Siraganian, R.P. (1992), Microenvironmental factors that influence mast cell phenotype and function. Proc. Sot. Exp. Biol. Med., 199, 22-33. Tiraboschi, C. (1904), Sous-Famille des Listrophoridae. Arch. Parasitol., 8, 326-328. Tracey, K.J., Wei, H., Manogue, K.R., Fong, Y., Hesse, D.G., Nguyen, H.T., Kuo, G.C., BeutIer, B., Cotran, R.S., Cerami, A. & Lowry, S. (1988), Cachectin/tumor necrosis factor induces cachexia, anaemia, and inflammation. J. Exp. Med., 167, 1211-1227. Watson, D.P. (1961), The effect of the mite myocoptes musculinus (C.L. Koch 1840) on the skin of the white laboratory mouse and its control. Parasitology, 51, 373-378. Watson, D.P. (1963), The effect of cysteine and B group vitamins on the skin of the white laboratory mouse infested with the mite myocoptes musculinus (Koch). Parasitology, 53, 265-272. Weisbroth, S. H. (1982a), Myocoptes musculinus (Koch), in “The Mouse in Biomedical Research” (Foster, H.L., Small, J.D. & Fox, J.G.) (pp. 397-398). Academic Press, New York, II. Weisbroth, S.H. (1982b), Myobia musculi (S&rank), in “The Mouse in Biomedical Research” (Foster, H.L., Small, J.D. & Fox, J.G.) (pp. 390-397). Academic Press, New York, II, Weisbroth, S.H., Friedman, S., Powell, M. & Scher, S. (1974), The parasitic ecology of the rodent mite Myobia musculi. I. Grooming factors. Lab. Anim. Sci., 24, 510-516. Weisbroth, S.H., Friedman, S. & Sheldon, S.(1976), The parasitic ecology of the rodent mite, myobia musculi. - III. lesions in certain host strains. Lab. Anim. Sci., 26, 726-735. Whiteley, H.J. & Horton, D.L. (1962), The effect of myobia musculi on the epidermis and hair growth cycle in the ageing CBA mouse. J. Pathol. Bact., 83, 509514. Whiteley, H.J. & Horton, D.L. (1965). Further observations on the effect of Myobia musculi on the skin of the mouse. J. Path. Bacterial., 1965, 89, 331-335. Wing, S.R., Courtney, C.H. & Young, M.D., (1985), Effect of ivermectin in murine mites. J. Am. Vet. Med. Assoc., 187, 1191-1192. Wodnar-Filipowicz, A., Heusser, C.H. & Moroni, C. (1989), Production of the haematopoetic growth factor GM-CSF and interleukin-3 by mast cells in response to IgE receptor-mediated activation. Nature (Lond.), 339, 150- 152. Young, J.D.E., Liu, CC., Butler, G., Conh, Z.A. &Galli, S.J. (1987), Identification, purification and characterization of a mast cell-associated cytolytic factor related to tumor necrosis factor. Proc. Natl. Acad. Sci. USA, 84, 9175-9181.
INSTITUT
Res. immunol. 1996, 147, 27-38
PASTEURIELSEVIIZR
Paris 1996
Murine acariasis: I. Pathological and clinical evidence suggesting cutaneous allergy and wasting syndrome in BALB/c mouse P. Jungmann
(‘)(*), J.-L. Guenet
(*), P.-A. Cazenave
(3), A. Coutinho
(‘) and M. Huerre
(4)
(I) Unite’ d’lmmunobiologie, (2’ Unite’ de Gtknhique des Mammifsres, (3) Unite’ d’Immunochimie Analytique, and (4) Unite’ de Pathologie, CNRS URA-1961, Institut Pasteur, 75724 Paris Cedex 15
SUMMARY
We describe here a disease related to mite-associated ulcerative dermatitis in BALB/c mice, a strain previously classified as resistant to this condition. The disease was recognized by pruritic cutaneous pathology and wasting. Pathologic studies showed a marked allergic-type inflammation in the skin. The dominant histologic feature was extensive mast cell infiftration in cutaneous lesions and in fymphoid tissues, associated with a greatly elevated serum IgE concentration. The disease was secondary to infestation with an acarian ectoparasite Myocoptes musculinus, and seemed to represent an allergic reaction to the parasite-derived substances, with an associated wasting syndrome. This condition may be a useful experimental model for allergic diseases.
Key-words:
Allergy,
Mast cell, Dermatitis;
Myocoptes
musculinus,
Wasting
syn-
drome, Acariasis.
INTRODUCTION
Infestation of mice by ectoparasites is relatively common in research laboratories. The acarian parasites Myocoptes musculinus (Koch, 1844) and Myobia musculi (S&rank, 178 1) are widespread, but may not cause clinical signs of disease (Flynn, 1954; Gambles, 1952; Keegan, 1956). Thus, large numbers of parasites can be found in apparently healthy animals (Cook, 1953). Furthermore, there is no general agreement as to their pathologic significance (Gam-
Submitted
November
(*) Corresponding
author.
22, 1995, accepted March
1, 1996.
bles, 1952). These parasites are purely surface dwellers and do not penetrate the deeper layers of the skin at any stage of their life. Transmission requires close direct contact between animals. Infection by bedding is rare. (Weisbroth, 1982a). Reports of observations on M. musculinus-infected mice, however, are quite rare compared to those concerning Myobia, and none are recent. In the course of experiments involving longterm maintenance of animals, it was observed that some BALB/c mice in the breeding colony
28
P. JUNGMANN
Pasteur had an abnormal appearthe age of three months, such animals were smaller, exhibited body scratching with patches of hair loss, cutaneous lesions and progressive wasting. Siblings in the same cage differed in the manifestation of these symptoms, but further observation revealed that most mice became affected if observed for a sufficiently long period of time. Laboratory investigations of sick mice revealed striking biological and pathological alterations, and the finding of a superficial ectoparasite - M. musculinus suggested an infectious aetiology for the disease. All Myocoptes-infected BALB/c mice in our colony developed cutaneous lesions with marked systemic alterations.
ET AL. MATERIALS
at the Institut
AND METHODS
ance. After
The disease described here is similar to miteassociated ulcerative dermatitis (MAUD) (Dawson et al., 1986), described in C57BL mice and congenic strains. MAUD is thought to be caused by M. musculi (a fur mite closely related to h4. musculinus) and seems to stimulate a marked allergic reaction (Flynn, 1954 ; Gambles, 1952; Csiza and McMartin, 1976; Weisbroth et al., 1976 ; Weisbroth, 1982b; Bean-Kundsen ef aZ., 1986; Watson, 1961 ; Whiteley and Horton, 1962 ; Galton, 1963 ; Whiteley and Horton, 1965 ; Weisbroth et al., 1974 ; Friedman and Weisbroth, 1975, 1977). BALB/c mice however, were described as being a strain resistant to this condition (Dawson et al., 1986). In the present report, we describe clinical and therapeutic data and histological abnormalities in skin, lymphoid and haematopoetic tissues, as well as serum IgE concentrations associated with infestation by M. musculinus in BALB/c mice. Our data support an allergic mechanism for the disease. As the pathophysiology of this acariasis seems to involve hypersensibility to parasite-derived antigens, the study of the respective mechanisms may represent an interesting system for investigating regulatory phenomena operating in allergic inflammation.
MAUD
=
mite-associated
ulcerative
dermatitis.
Animals Adult male and female mice bred in the animal facilities of the lnstitut Pasteur were used in this study. Afflicted animals were either pure inbred BALBlc mice or progenies of the 8th to 10th backcross generations of SPE mice (a moderately inbred strain derived from A4us spretus) to the BALB/c background. Given the large number of backcross generations performed, no more than 0.01% of the M. spretus genome is likely to be carried and thus the condition is probably associated with the BALB/c background. Control animals in this study were adult BALB/c mice from different areas of our colony. Pathological
examination
Thirty-two afflicted mice were sacrificed by cervical dislocation at varying times after the onset of clinical dermatitis and submitted to complete pathologic examination with morphometric records, loco-regional observations and removal of organs, as well as tissues such as skin, joints and skeletal muscle. The histologic material was fmed in 10 % buffered formalin, routinely processed and the 5-pm paraffin sections stained with haematoxylin-eosin, periodic acid Shiff (PAS), Brown and Brenn (B&B) toluidine blue, and al&n blue, were examined by light microscopy. In viva skin microscope
examination
under
the dissecting
Due to the histological findings of cross-sections of parasitic structures on the surface of the epidermis (see below), we isolated parasites from the skin of diseased mice. Under general anaesthesia, (0.2 ml intraperitoneal injection of Avertin-2,2,2-tribromoe-
thanol), mice were subjected to direct stereomicroscopic observation of the skin lesions (mainly on the neck and eyelids). Some parasites were collected (live) with a fine needle, fixed on ethanol, and their
analysis
conducted
by Dr. Claudine
Department d’Ecologie Institut Pasteur.
des Systbmes
Perez-Eid, Vectoriels,
Haematology As pathological changes were observed in haematopoietic tissues, we verified examined blood
ALLERGY
IN MURINE
cells. Heparinized blood samples from 12 sick and 4 control mice were collected under slight ether anaesthesia by retroocular venous puncture. Red blood cells were counted on a Coulter counter analyser and white blood cells in a Biirker chamber. Blood smears were air-dried and stained by May Grunwald Giemsa. Cytomorphology of the white and red cells and the platelets was recorded. Standard haematologic techniques were used for total and differential leukocyte counts (400 leukocytes were counted on each preparation). Urine examination Urine from 12 affected and 4 control mice was tested for the presence of proteins, glucose, ketones, blood and for pH values using test strips (Laboratory Miles, Division Ames, Belgium). Radiology Radiographs were performed employing X-ray intensity that allowed definition of bone and soft tissues with image amplification. A control normal adult BALB/c mouse of the same age was simultaneously exposed in the same radiographic field. Infection
assay
In order to ascertain the infectious nature and the transmissibility of the disease, 5 BALB/c mite-free 15-day-old female mice and their mother were caged together with 3 females infected with IV. mu++ culinus. The newborns were followed for 13 months for the presence of the acarian parasite, the appearance of initial clinical signs and for the development of full-blown disease. Acaricidal
treatments
Two different therapeutic trials for acarian tations were conducted according to published mens, using Diclorvos (Dawson et al., 1986; and McMartin, 1976; Weisbroth et al., 1976; man and Weisbroth, 1975) and Ivermectin mans et al., 1988; Papini and Marconcini, Wing et al., 1985).
29
ACARIASIS
loss of fur; the second group consisted of three mice with advanced disease - ulcerative lesions, widespread hair loss and wasting; the third group was composed of three normal BALB/c mice that served as a “treated” control group for scoring putative toxic effects of the drug. After initial observation of behaviour, clinical status, weight, and the presence of the parasite, the mice were observed twice a week. In the second therapeutic trial, 200~~1 drops of a 10% solution of Ivermectin (Ivomec@, Merck Sharp & Dohme) prepared in propylene glycol (Sigma Co.) were applied to the neck. This procedure was repeated 20 days later. Two groups of adult BALB/c mice with fully developed disease were used: (1) one group of five female and two male adult BALB/c mice were treated; (2) four females and two males were left untreated to follow disease evolution. Five normal adult males were also subjected to treatment as a control group for potential toxic effects of the drug. The parameters observed were the same as above. Mice were followed up to 13 months. Food and water were provided ad Zibitum throughout both studies. Determination
of serum IgE concentration
The striking accumulation of mast cells and eosinophils in the pruritic skin lesions of mice suggested the existence of an allergic mechanism. We thus measured IgE concentration in the serum. Samples from 10 sick and 2 control mice were analysed in ELISA tests. The assays were done with flat-bottom microplates (96 wells) coated overnight at 4°C with a polyclonal sheep anti-mouse IgE antibody (AAM1) and, as secondary antibody, a biotinylated monoclonal anti-mouse IgE (MCA -419) (both antibodies were from Serotec Oxford, UK). As a standard curve, a titration of supematant of an antiDNP IgE hybridoma (HMK-11) (Liu et al., 1980) was used, while sera from pollen (Dactylis glomer-
ata)-hyperimmunized infesregiCsiza Fried(Bau1991;
In the first therapeutic trial, a strip of 1 cm2 impregnated with Dichlorvos (Neocid@) was placed in each cage and replaced every ten days for three months. Cages were covered with a filter top. Three groups of animals were treated. The first group was composed of three mice with the fully developed disease - scratching, skin wounds, ear inflammation, blepharitis and initial
mice, with a specific IgE titre
of 1280 tested by PCA at day 28 of immunization, served as a positive control.
RESULTS
Clinical
features and general
observations
BALB/c mice that developed to scratch themselves at 8-10 especially around the eyes, mouth, dorsal region. General reddening followed by superficial erosions
disease began weeks of age, nose, ears and of the skin was with crust for-
30
P. JUNGMANN
mation and eventual bleeding. Enlarged cervical lymph nodes could be detected at this stage. As the disease progressed, the mice present ruffled fur, erythema and oedema of the eyelids and conjunctiva with abundant exudate (fig. la). Similar processes were observed on the external parts of the ears, where inflammatory signs were at times so severe as to lead to necrosis and partial loss of the pinna (fig. la). In some animals, overt ulcerative skin lesions were observed, the majority of which were localized at hairless areas on the neck and shoulders. Later phases of disease were characterized by a generalized loss of fur that started on the dorsal region (fig. la) and spread throughout the body. Slow loss of muscle and soft tissue, with a hunched-back posture, were constant features. Fertility was low. Weight values for adults started at 24 g and declined progressively to 11 g. By the final phases of disease, affected mice were inac-
ET AL.
tive and cache&c. At this point, regression of the lymphadenomegaly parallel with an increase in the volume of the spleen were observed. Death usually occurred at around 16 months of age.
Macroscopic
pathology
At autopsy, sick animals had slender skeletal muscles and very thin and transparent skin with a fragile appearance. Very little adipose tissue was observed in the body. The cutaneous lesions on the neck, as well as those on the ears and eyelids, showed little variation from one animal to another. In general, they presented dermal thickening, inflammatory signs, and serohaemorrhagic crust formation with necrosis (fig. la). There was a marked enlargement of lymph nodes in the cervical and brachial regions, (fig. 2b). The thymus was pale and small and, in
Fig. 1. (top panel) M. musculinus-infected adult BALBlc mouse. a) Note erythema and oedema of the eyelids, the deep ulcer on the malar region with serohaemorrhagic exudate, a complicated ear lesion with necrosis and partial amputation of the external part. Initial hair loss with hyperhaemic dermal background is seen in the dorsal region. b) Supradiaphragmatic view of M. musculinus-infected adult BALB/c mouse: marked enlargement of cervical and brachial lymph nodes [arrows]. c) Skin section showing acarian parasites on keratin layers, hyperkeratosis, acanthosis and a chronic inflammatory cell infiltrate in the dermis. (Haematoxylin-eosin; original magnification x 10). d) Skin section showing prominent mast cell infiltration in superficial and deep dermis. (The same section stained by haematoxylin-eosin revealed strong chronic allergic inflammation with numerous plasma cells, eosinophils and lymphocytes - not shown). (Toluidine blue; original magnification X 40). Fig. 2. (bottom
panel)
Cervical
lymph node section (a, b), spleen section (c) and retroperitoneal soft tissue (d).
a) Cervical lymph node section showing massive expansion of the medullary region occupied by clusters of plasmocytoid and mature plasma cells. The lymphoid populations in the follicles and paracortical areas are pushed to the periphery of the node. (Haematoxylin-eosin ; original magnification X 10). b) Cervical lymph node section showing diffuse mast cell infiltration in medullary and paracortical regions. Infiltration of mast cells was also observed at the capsular level and in perinodal connective tissue - not shown. (Toluidine blue; original magnification x40). c) Spleen section showing an enlarged red pulp with intense extramedullar haematopoiesis. All three bone marrow cell lineages are present but erythrocytic and megakaryocytic differentiation dominates. The white pulp is represented by a clear-cut periarteriolar lymphoid sheath, but lymphoid follicles are decreased in number and in size, with poor germinal centre reaction. (Haematoxylineosin; original magnification X40). d) Retroperitoneal soft tissue (para-aortic level), showing suggestive areas of extramedullar haematopoiesis, composed of loose aggregates of myeloid precursors, mature granulocytes, eosinophils, macrophages and megakaryocytes (arrows). (Haematoxylin-eosin; original magnification x60).
ALLERGY
IN MURINE
ACARIASIS
:,r; r* ,,.. T’:.
. 1 ;
!
31
1; ‘. ..% *.
.
:
.1.
,
P. JUNGMANN
32
some advanced cases, undetectable. The spleen was darker than normal and had increased volume. On the cut surface, the firm red pulp was prominent in comparison with the inconspicuous white pulp. The bone marrow (femur) was pale and the bone structure fragile. Muscular layers of all viscera observed were very thin. All other organs and anatomical cavities were found to be grossly normal.
Stereomicroscopic examination entomological determination
of the skin and
The parasites detected on the skin surface were not numerous; however, some moving forms as well as eggs attached to the lower pole of the hair shafts were encountered. They were surrounded by viscous fluid (exudate) on a reddish dermal background. Some parasites, were harvested and prepared for entomological study. They were identified as A4. muscuhus (Koch, 1844), a fur mite (hair-clasping) of the Listrophoridae family. This mite is a common ectoparasite of the genus Mus musculus (Gambles, 1952 ; Keegan, 1956; Tiraboschi, 1904). The parasites were seen in all sick mice examined, but in none of the control mice.
Microscopic
pathology
In the keratin layers of some cases, crosssections of parasites could be identified (fig. lc). The cutaneous lesions, regardless of their localization, shared a common histological pattern. Their common features included reactive epithelial proliferation, strong accumulation of mast cells in the dermis (fig. Id) and deeper layers (only cells with toluidine blue positive granules in the cytoplasm were considered connective tissue-type mast cells), together with eosinophil and mononuclear cell infiltration. Proliferation of fibroblasts associated with mast cell accumulation was also evident. Variable histological components included necrotic areas, ulceration, granulation tissue and superficial bacterial contamination. At the level of skin free of macroscopic lesions, there existed
ET AL.
modifications characterized by local foci of hyperkeratosis, mast cell infiltration 2-fold that of controls, and variable amounts of scattered eosinophils. The hair follicles were normal in appearance. The enlarged lymph nodes showed marked expansion of the medullary region (fig. 2a) which was occupied by clusters of numerous plasmacytoid and mature plasma cells surrounded by foamy histiocytes. The ordinary lymphoid counterpart was pushed to the periphery (fig. 2a). The T-cell areas (paracortex) were hyperplastic. In B-cell areas, there was a moderate germinal centre reaction. Diffuse eosinophil infiltration was constant, Significant mast cell infiltration could be seen (fig. 2b), predominant in medullary and cortical regions but also in perinodal connective tissues. Inguinal lymph nodes did not show the same reaction but were similarly infiltrated by mast cells. Thymic histology varied according to the age and the disease stage of the mice. In advanced cases, a characteristic atrophic pattern was found and in early phases, a decreased lymphoid population could still be defined and mast cell infiltration was detected inside the medullary region (in addition to the expected resident mast cell on the septa) (Kuper et al., 1982). The spleen showed marked extramedullary haemopoiesis within splenic cords (well above background level) representative of the 3 major differentiative lines with a predominance of erythrocytic and megakaryocytic proliferation (fig. 2~). Prominent groups of plasma cells could be seen within and around the borders of haematopoietic colonies. The white pulp was essentially represented by the periarteriolar lymphoid sheet, whereas the lymphoid follicles were diminished in number and size with no prominent germinal centre reaction. In some cases, areas were seen where extramedullary haemopoiesis was suggested as small aggregates localized on retroperitoneal regions, peripancreatic and perinephritic connective tissue (fig. 2d). Mast cells were also sometimes detected at these sites. The bone marrow was occupied by the granulocytic, monocytic and megakaryocytic lineages, with erythrocytic and lymphocytic precursors being very scanty. The trabeculae and the bone matrix were normal.
ALLERGY
IN MURINE
The liver showed a variable degree of fatty infiltration and a mild sinusoidal accumulation of eosinophils. The adrenal gland had cortical hyperplasia. The male gonads showed decreased numbers of germ cells. Microcalcifications without associated lesions were observed in the lungs, liver, kidneys, prostate, gall bladder and large vessel walls. Atrophic changes were observed in visceral and skeletal muscles. No significant histologic abnormalities were detected in the joints, endocrine, cardiovascular, digestive, respiratory, urinary or nervous systems.
Haematological examination The marked extramedullary haemopoiesis led us to perform haematological profiles. Hypochromia of erythrocytes from sick mice was observed, although the number of red blood cells (8,500,000/mm3) were comparable to controls. Moderate leukocytosis was detected in sick mice (6,500-7,550 cells/mm3) as compared to normal mice (5,500 cell/mm3). Differential counts showed variable levels of lymphocytopenia, 25-55%, and granulocytosis, 30 to 60%. In control mice, 65% of leukocytes were lymphocytes and 20% granulocytes (Russel and Bernstein, 1968). The number and morphology of platelets on the smears were normal for both groups.
Other examinations In view of the poor clinical status of the mice, we searched for possible metabolic disturbances that could be revealed by urine analysis. Urine from sick mice differed from controls at pH values that were consistently acid (5.0) in contrast with the neutral pH (7.0) of controls. Mild proteinuria (+) but no glucose, ketones or blood was found in sick and control groups. The observation of microcalcifications on several tissues prompted us to perform detailed radiographic studies. The radiographic images revealed decreased volume of soft tissues and decreased bone density but no gross macrocalcifications elsewhere.
ACARIASIS
33
Infection assay and acaricidal treatment The presence of M. musculinus on sick but not healthy mice suggested an aetiological relationship between the ectoparasite and the disease. In order to assess this possibility, we performed two types of experiments: infestation of normal controls (transfer of the parasite and disease) and acaricidal treatment of sick animals. After exposing five mite-free newborn mice to mite-infested mice, 3 mice developed initial signs of disease - scratching and skin reddening - by the 4th month of age on positive parasitological examination. By 13 months, all mice had developed full disease. The severity of signs was variable, but all mice presented blepharitis, malar erosions, loss of weight and hair. One cachectic mouse died. Thus, the disease in BALB/c mice was related to infestation with M. musculinus, although individual variability was observed in the severity of its manifestations. Acaricidal therapy with Neocid” and Ivermectinm led to healing of skin lesions and scar formation as early as 10 days after the onset of treatment. Examination of skin lesions after initiation of treatment revealed fragments of mite exoskeletons and empty eggs attached to hair shafts. The mice appeared to be mite-free 2 months after the beginning of treatment. Scratching was reduced and conditions of the fur improved. Although increased survival was observed in the treated groups, the clinical status of the mice did not dramatically change. Once initiated, the wasting syndrome seemed to persist and worsen with time despite the apparent clearance of the parasites. Similar observations were reported by Pence et al. (1991) after treating M. musculi-infected Swiss-Webster mice presenting severe lesions.
Determination of serum IgE concentration As shown in figure 3, the increase in circulating IgE levels was very marked in comparison with normal mice (lOO-fold) and mice hyperim-
P. JUNGMANN Serum
IgE
DISCUSSION
concentration
1
-
1 Fig. 3. Serum IgE concentration in a normal control mouse, allergen hyperimmunized mouse, and 5 sick mice as indicated. Each bar corresponds to an individual animal. A total of 10 diseased mice and 2 controls were tested with similar results.
munized with pollen allergens that had specific IgE PCA titres of 1: 1.280 and yet had circulating IgE concentrations nearly lo-fold lower than mice afflicted with this condition. The serum concentrations of other Ig clones were also abnormal, with decreased IgM and IgG3, increased IgA, IgGl and IgG2b, and normal levels of IgG2a (table I).
Table I. Serum
Infected Control
ET AL.
The disease studied here was due to chronic infestation of BALB/c mice by the ectoparasite, M. musculinus. This was suggested by the response to acaricidal treatments and was confirmed by transfer of disease following transmission of mites from diseased to newborns. The physiopathology of this disease seemed to be allergic, since skin lesions were erythematous and pruritic, infiltrated by large numbers of mast cells and eosinophils and associated with high levels of serum IgE. In allergic responses, mast cells are both regulators and local effector cells in the inflammatory field (Galli, 1990; Swietter ef al., 1992), and cross-linking of its FceHI receptors is fundamental to the induction of signs and symptoms in allergic disorders (Swietter et al, 1992, reviewed in Galli, 1990). An allergic-type response to mite antigens was previously reported in C57BL mice infested with M. muscdi (Csiza and McMartin, 1976; Weisbroth, 1982b; Bean-Kundsen et al., 1986) based on the following observations: 1) the similarity of the lesions with those observed in allergic acarjasis in other species ; 2) the presence of “allergic accumulations” of mast cells in involved tissues ; 3) the pruritic character of the lesions; 4) the fact that although infestation occurred shortly after birth, only adult mice developed such lesions, suggesting that a period of sensitization was necessary ; 5) lesion redevelopment in healed, mitefree mice within days of experimental re-infestation with as few as 5 mites; 6) lack of a relationship between mite numbers and the severity of the lesion; 7) the fact that the disease was strain-dependent and genetically controlled (Dawson et al., 1986; Csiza and McMartin,
immunoglobulin
concentrations
Ii-N
IgG3
IgGl
71+2 174f 104
16+21 127+6
The results are means and SD of 3 mice per group,
IgG2b
4,521 f798 997f421 determined
in infected
1,052f335 173f76 by ELISA.
and control IgG2a 473 f94 238+52
mice. Id 13,209*3,684 63f51
ALLERGY
IN MURINE
1976; We&broth, 1982b; Bean-Kundsen et al., 1986 ; Friedman and Weisbroth, 1975 ; Pence et al., 1991). Furthermore, Laltoo et al. (1979), studying M. musculinus-infested SWR mice, demonstrated the presence of specific serum IgGl and IgE anti-mite antibodies and in viva degranulation of mast cells after challenge with M. musculinus antigens. Our own observations conftrm many of these points and argue against the role of the parasite itself as a primary cause of lesions. The fact that the parasites do not invade the tissue also supports a hypersensitive reaction to parasite-derived antigens which may enter the body through the skin lesions. Parasite-antigens may bind to cytophilic IgE and stimulate the release of mast cell mediators which in turn recruit other type of cells including eosinophils. Epithelial thickening due to increased mitotic activity of the epithelium (Weisbroth, 1982a; Watson, 1961; Whiteley and Horton, 1965 ; Watson, 1963) and the fibrosis found in skin lesions may have been due to effects of mast cell products known to stimulate multiplication of these cells (Franzen and Norrby, 1980; Non-by, 1983 ; Gordon and Galli, 1994). The large numbers of mast cells that accumulate in the lymph nodes (and to a lesser extent, in the thymus) represent a new aspect of the miteinduced allergic reaction. Thus, lymph nodes and thymus as compared to skin or bronchial mucosa do not appear to be suitable sites of allergic effector reactions, suggesting that mast cell accumulation in those sites may have a distinct significance. We would like to speculate that mast cells recruited into allergic reaction sites, after degranulation and proliferation, (“born-again”) (Galli, 1990; Swietter et al, 1992), may follow an alternative migratory pathway into the lymph stream, reaching draining lymph nodes. The fact that mast cells can present antigens (Frandji et al., 1993) leads us to suggest that tissue mast cells, once in lymph nodes, could contribute additional antigen transport and represent an important APC complement. However, such “quasi-recirculating behaviour” has not been described to date and remains hypothetical. Further evidence for immunological stimulation in this disease lies in lymph node enlarge-
ACARIASIS
35
ment in regions draining the most severely affected areas. The strong medullary plasmacytosis, also shown by others (Csiza and McMartin, 1976; Galton, 1963; Madden et al., 1954), suggests that there is powerful stimulation of B cells to terminal differentiation in this syndrome and it may account for the increased levels of IgE in the serum. IgE production is mostly a T-cell-dependent process (Coffman and Carty, 1986) and the hyperplasia of paracortical areas in those nodes suggests the involvement of T cells in the overall reaction. The T- and B-cell areas in the spleen show similar characteristics, suggesting that the immunological reaction is systemic and not limited to regional lymph nodes. This is also ascertained by the marked alterations in the serum levels of various Ig classes, all supporting the notion of T-cell-dependent B-cell hyperactivity. This disease also eventually involves multiple organs and body functions. Localized skin lesions progress and compromise the general status of the mice, leading to a wasting syndrome associated with fatty infiltration of the liver, hyperplasia of the adrenal cortex (Strandberg, 1982), expenditure of adipose tissue and loss of skeletal and visceral muscle mass. The low urinary pH is probably due to a chronic catabolic state. Microcalcification in several tissues, already described in similar infestations (Whiteley and Horton, 1962; Galton, 1963), along with radiologic signs of osteopenic bone, characterize metastatic calcifications due to bone catabolism (Cotran et al., 1994). The allergic component represented by numerous mast cells in the skin and in other tissues of the mice may be an important source of TNFalcachectin (Huang et al., 1990; Young et aZ., 1987), a multifunctional cytokine involved in inflammation, lipid and protein metabolism, as well as in haematopoesis (Tracey et al, 1988; Moldawer et al., 1989; Cracker and Milon, 1992) and may participate in the pathogenesis of wasting. The blood profile shows hypochromic anaemia, granulocytosis and lymphopenia, reflecting a chronic inflammatory disorder. Increased levels of TNFa could also explain granulocytosis and anaemia (Tracey et al., 1988; Moldawer et al., 1989 ; Cracker and Milan, 1992). Similar alterations in the blood profile of mite-infested mice
36
P. JUNGMANN
have been reported (Csiza and McMartin, 1976; Madden et al., 1954) associated with hypergammaglobulinaemia, hypoalbuminaemia and decreased haemoglobin concentration. The constant loss of plasma proteins through the skin exudate, on the one hand, and a persistent immunologic stimulation by the presence of the parasite on the other, could account for these findings. The presence of extramedullary haematopoiesis with a specific increase in the megakaryocytic lineage has been observed in mice infected with M. musculi (Csiza and McMartin, 1976 ; Weisberoth, 1982b ; Galton, 1963). In our cases, haematopoetic colonies were found abundantly in the spleen, in retroperitoneal connective tissues, while groups of megakaryocytes were scored in lymph nodes and liver, providing further evidence for broad haematopoetic stimulation. We would like to suggest that chronic mast cell activation by acarian antigens may contribute to these findings. It is established that mast cells are very active in cytokine production (Galli, 1993), especially those operating in haematopoiesis, such as IL3, IL4, IL6, IL5 and GM-CSF, and TNFa (Wodnar-Filipowicz et al, 1989; Plaut et al., 1989; Moore, 1992) that, if systemically active, would stimulate haematopoetic precursors in the periphery (wodnar-Filipowicz et al., 1989 ; Layton et al., 1992). Nevertheless, activated T lymphocytes, probably also involved in this immunological reaction, are able to synthesize similar factors and provide overlapping stimulation. Not all mice infested with M. musculi develop MAUD (Dawson et al., 1986). The susceptibilty to disease seems to be controlled by at least two loci: some non-H-2 linked gene(s) shared by all C57BL background strains, and a gene or genes within the H-2 complex (Dawson et al., 1986). H-2b and H-2k-linked genes were found to enhance pathogenesis of disease in the corresponding background (Dawson et al., 1986). Under the conditions of these observations, BALB/c was considered a resistant strain (Dawson et al., 1986). In contrast, we describe here observations in BALB/c mice that display an evident susceptibility to develop a “MAUD-like” condition in 100 % of the individuals after
ET AL.
13 months of observation. Thus, the apparent discrepancy may be explained by the period of observation of affected individuals, apparently much shorter in Dawson’s report (Dawson et al., 1986). In favour of this interpretation are the comparatively very low levels of disease incidence (2.1 %) in the prototype “susceptible”mouse strain (C57BL) described in that study. Second, we are dealing with a different ectoparasite. Thus, while MAUD has been described in M. musculi-infected mice, we presume we are in the presence of a monoinfestation by M. musculinus. In spite of their close structural and functional similarities, these two mites differ slightly in the type of spreading and feeding (Weisbroth, 1982a). Histopathological descriptions in M. muscuhus infestations, however, do not include ulceration and mast cell infiltration of skin lesions, nor lymphadenopathy (Weisbroth, 1982a; Watson, 1961). In contrast, our findings showing pathological patterns that are common to both conditions suggest that differences reported in the literature may be due to the reduced number of observations on M. musculinus-infested mice as compared to myobic cases. An alternative explanation for susceptibility of BALB/c mice is that different substrains, kept apart for many years, may have genetically drifted and diverged in resistance to MAUD. Nevertheless, systematic genetic approaches utilizing monospecific infestations with M. musculinus, as were performed for myobia, have not been carried out. Finally, susceptibility versus resistance is also determined by environmental conditions. The heterogeneity in disease presentation among inbred siblings shows that epigenetic factors are involved in controlling disease presentation. The discrepancy between the results of Dawson et al. (1986) and ours could thus be explained by differences in the respective microbiological or nutritional environments. In summary, we have described a MAUDlike disease in a colony of BALB/c mice infested with M. musculinus. This condition seems to have an allergic pathogenesis based on its clinical and histological presentation, and on a high serum IgE level as well. This disease also includes a systemic syndrome characterized by a
ALLERGY
IN MURINE
chronic wasting state with lymphadenopathy, granulocytosis lymphocytopenia, marked extramedullary haematopoesis and low fertility. We believe that these mite-infested mice represent a novel alternative system for studying cutaneous allergic processes and systemic effects of chronic immunological stimulation by a natural and generally non-pathogenic infestation. While in man allergic disorders are acquired after natural exposure to antigens, in most experimental systems, allergic responses are artificially induced. Thus, the spontaneous disease described here seems to be a suitable natural model for studying allergic reactions.
Acknowledgments We thank Mrs Nicole Wuscher, Unite de Pathologie, Institut Pasteur, for histotechnical assistance, and Dr Claudine Perez-Eid, Department d’Ecologie des Systemes Vectoriels for the entomological determination. This work was supported in part by a grant from ANRS. PJ was supported by a fellowship from CNPq, Brasilia, Brazil.
Acariase murine I. Elbments pathologiques et cliniques suggkrant une allergic cutanCe et une consomption chez la souris BALB/c Nous d&rivons ici une maladie similaire a la dermatite ulc6rative associ& aux acariens chez les sou-
ris BALB/c, une lignee reputee resistante & cette affection. La maladie se manifeste par un prurit et un deperissement des souris. On observe, dans la peau,
une inflammation
de type allergique
et une
infiltration massive de. mastocytes a la fois dans la lesion cutan& et dans le tissu lymphdide. Cela s’accompagne d’une augmentation importante des IgE sCriques. La maladie se manifeste B la suite d’une infestation par un acatien, Myocoptes musculinus, et semble r6unir une &action allergique a des produits parasitaires et un syndrome de consomption. Cet Ctat pathologique pourrait rep&enter un modi?le experimental intdressant pour 1’Ctude de cet-taines maladies d’origine allergique.
Mots-cl&s: Allergic, coptes musculinus,
Mastocyte, Dermatite ; MyoConsomption, Acariase.
ACARIASIS
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