Original Article |
Address correspondence to Robert E. Tigelaar, Yale University School of Medicine, P.O. Box 208059, 333 Cedar St., New Haven, CT 06520-8059. Phone: 203-785-4968; Fax: 203-785-7234; E-mail: robert.tigelaar{at}yale.edu
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Abstract |
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Key Words: dermatitis TCR mast cells NOD FVB
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Introduction |
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One mechanism for controlling adaptive immune responses to such antigens is the induction of regulatory ß+ T cells that enter the systemic circulation, and upon reencountering antigen, secrete cytokines (e.g., IL-10) that down-regulate potentially tissue-damaging inflammatory responses initiated by antigen-specific effector T cells (17). Additionally, immunoregulatory functions have been demonstrated for systemic TCR-
+ cells that, in many mammals including mice and humans, constitute a minor population of circulating T cells (810). In sum, the systemic circulation harbors subsets of cells that can provoke inflammation, and those that can suppress it.
In addition to recirculating T cells, some T cells are constitutively resident within epithelia. By virtue of the large surface area of epithelia, such intraepithelial lymphocytes (IELs)*, including those in the human gut, may be among the most abundant T cell subsets. One conspicuous IEL repertoire is composed of dendritic epidermal T cells (DETC) that populate the skin of all normal mice. Most DETC express an identical V5/V
1 TCR (1113). The same V
5/V
1 TCR is expressed early in gestation (
E14-E17) on a small fraction of fetal thymocytes that can reconstitute the skin of DETC-deficient (e.g., nude) mouse recipients (12, 14, 15). Furthermore, V
5/V
1+ T cells in adult mice are apparently restricted to the skin, as such cells are not present in lymph nodes, spleen and blood, or in other epithelial sites (e.g., gastrointestinal tract, genitourinary tract, lungs) that are by contrast populated by their own distinctive subsets of
+ IELs (12, 1618).
IELs have been variously proposed to interact with epithelial cells, activated T cells, and antigen presenting cells (1922). A very recent study has provided evidence in three different mouse models of skin cancer that cells, including DETCs can function as antiepithelial tumor effector cells (23). This complements other studies demonstrating that human intestinal
+ IELs will kill human bowel carcinomas and other intestinal epithelial cell lines (24, 25), and that there is enhanced formation of chemically induced colorectal carcinomas in
-/- mice (26). In addition to protecting epithelial tissues from disruption by transformed or infected epithelial cells, it has been hypothesized that
+ IELs might likewise protect epithelial tissues from damage or disruption by systemic, proinflammatory infiltrates. Indeed, data from a variety of studies are consistent with the possibility that resident
+ IELs in the skin or the gut locally down-regulate inflammatory responses to allergens or pathogens initiated by conventional
ß T cells (2732). However, in none of those earlier studies did the experimental design critically test the hypothesis that the subset of
+ cells normally present in a particular site (e.g., V
5+ DETC in the skin) may be a critical, nonredundant regulator of a spectrum of physiological inflammatory reactions occurring within its immediate confines, i.e., that purified V
5+ DETC down-regulate different types of cutaneous inflammatory reactions, while other
+ cells do not.
To test this hypothesis, we have used several different genetic strains of / mice to examine the physiological consequences of cutaneous IEL (DETC) deficiency. The results demonstrate that some, but not other strains of
-/- mice spontaneously develop localized chronic dermatitis. The pathology is driven by
ß T cells, since mice lacking both
ß T cells and
cells are asymptomatic. Consistent with this, TCR-
-/- mice displaying spontaneous dermatitis also show augmented allergic and irritant contact dermatitis reactions. Adoptive transfer experiments in which susceptible FVB.
-/- mice received either V
5+ cells (that selectively reconstitute DETC) or other subpopulations of
cells, showed that V
5+ DETC are necessary and sufficient to down-regulate both spontaneous and irritant contact dermatitis. In sum, these studies demonstrate that a local
IEL subset can contribute a general and nonredundant role in regulating the inflammatory infiltration of tissue provoked by conventional
ß T cells. In addition, because of its strain-dependence, and because it shares several characteristics of atopic dermatitis, a common, but incompletely understood human skin disease, the experimental approach described may provide a novel animal model for studying the genetic control of inflammatory pathology.
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Materials and Methods |
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Contact Dermatitis.
To induce allergic contact dermatitis (ACD), mice were sensitized on day 0 by epicutaneous application to razor-shaved abdominal skin of 25 µl of 0.5% DNFB in a mixture of acetone:olive oil (4:1). On day 5, after measuring baseline ear thickness with an engineer's micrometer, mice were challenged by applying 10 µl of 0.2% DNFB in acetone:olive oil to each side of each ear. Ears were remeasured 24 h after challenge; data are expressed as the ear swelling response above baseline (i.e., ear thickness 24 h after challenge minus ear thickness immediately before challenge) ±1 SE of the mean (SE).
For adoptive transfer of ACD reactivity, groups of immune lymph node cell donor mice (either FVB or FVB.-/-) were sensitized by application of 25 µl of 0.5% DNFB to the shaved abdomen and 3 µl to each paw, the tip of the jaw, and each side of each ear. 5 d later, single cell suspensions were prepared from the draining lymph nodes (cervical, axillary, inguinal, and femoral) of each group of donors. Groups of normal adult FVB recipient mice were injected intravenously with graded numbers of DNFB-immune lymph node cells; 2 h later, after measuring baseline each thickness, recipient ears were challenged with 0.2% DNFB. Ears were remeasured 24 h later, and the ear swelling response above baseline calculated.
For irritant contact dermatitis (ICD) assays, after measuring baseline ear thickness, 20 nmol tetradecanoylphorbol acetate (TPA) (in 10 µl acetone) were applied to each side of each ear of adult mice. Ears were remeasured 24 h after challenge (and in indicated experiments, again at 6 d after challenge), and mean ear swelling responses above baseline calculated as above. In one study (indicated in the text and legend to Fig. 5 B) TPA was reapplied to the ears weekly for a total of three applications.
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To analyze epidermal T cell populations, separate epidermal cell suspensions were prepared as described from both ears of individual animals (13). After overnight culture to allow reexpression of trypsin-sensitive epitopes, epidermal cells were blocked with normal hamster IgG plus anti-FcR (2.4G2), and stained with hamster mAbs to CD3 (FITC-2C11; BD PharMingen), TCR- (Biotin-GL3 or FITC-GL3; BD PharMingen) and V
5 (Biotin-F536; BD PharMingen). Biotinylated antibodies were visualized with phycoerythrin-streptavidin. Isotype-matched control antibodies were used at the same concentrations as test antibodies. Analysis was performed with a FACScanTM (Becton Dickinson) with electronic gates set on live cells by a combination of forward and side light scatter and propidium iodide exclusion. A minimum of 104 live events was collected per sample and data were analyzed with CellQUESTTM software.
To analyze adult lymph node cells, aliquots from a single cell suspension of PLN (axillary and inguinal) cells from 8-wk-old FVB.ß-/- donors were blocked with normal hamster IgG and anti-FcR, and then stained with either FITC-F536, FITC-GL3, or isotype-matched control antibody. FACScanTM analysis as described immediately above documented that the suspension contained 15%
+ (GL3+) T cells, but no detectable V
5+ cells.
Statistical Analysis.
Comparisons between datasets were made using a standard Student's two-tailed t test (33), unless otherwise specified. Chi-square analysis (34) was used to compare the phenotypic presence of ear crusting after irritant challenge between groups of mice, and to compare baseline ear thickness in different groups of mice (e.g., males versus females) using as a cutoff 5 SD above the average means for "resistant" B6.
-/- and F1.
-/- mice. In all cases, P < 0.05 was considered significant.
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Results |
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To understand better the genetics governing the susceptibility to spontaneous dermatitis, NOD.-/- mice and C57BL/6.
-/- mice were mated to produce F1.
-/- offspring. F1.
-/- mice were subsequently intercrossed to produce F2.
-/- offspring, while others were backcrossed to NOD.
-/- mice to produce (F1 x NOD) and (NOD x F1) BC.
-/- animals. Ear-thickness, as a manifestation of spontaneous dermatitis, was then examined in large numbers of these mice (Fig. 2). The data have been segregated by sex, and show that baseline ear thickness in males tends to be higher than age-matched female counterparts (an expected finding given their larger size). Despite some variance observed in NOD.
-/- mice, the mean ear thickness at 812 wk of age was markedly greater than age- and sex-matched C57B/6.
-/- mice housed under identical conditions (Student's t test, unequal variance: P < 10-25), confirming the strain-dependent differences originally seen in smaller groups of animals (Fig. 1 E). F1.
-/- progeny displayed no clinical signs of spontaneous dermatitis, and their baseline ear thickness was indistinguishable from that seen in age- and sex-matched C57BL/6.
-/- mice. These results indicate that either the NOD background contributes recessive alleles that permit augmented cutaneous inflammation in the absence of
cells, and/or the C57BL/6 background contributes dominant alleles that overcome the effects of
cell deficiency.
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Further analysis of crosses between NOD.-/- and C57BL6.
-/- mice revealed that among F2.
-/- mice, 32% (26/80) of females and 17% (15/87) of males were NOD-like. Among BC.
-/- mice, 48% (55/114) of females and 36% (44/121) of males were NOD-like. These differences between the male and female incidences of the susceptible phenotype were not statistically significant. Likewise, the frequency of phenotypically susceptible mice was similar in groups of BC animals segregated according to the sex of the NOD parent (data not shown). In sum, there was no statistically significant evidence for sex-linked genes affecting the development of spontaneous dermatitis.
Strain-dependent Increases in Allergic and Irritant Contact Dermatitis Reactions in -/- Mice.
FVB.-/- and C57BL/6.
-/- mice, as well as their respective TCR-
+ controls, were next compared for their ACD responses to the allergen 2,4-dinitrofluorobenzene (DNFB). 24 h after DNFB challenge, sensitized FVB.
-/- mice showed strikingly augmented ear swelling (measured as increase above baseline thickness) compared with sensitized, and challenged FVB mice. In contrast, responses of C57BL/6.
-/- mice were indistinguishable from C57BL/6 controls (Fig. 3 A). Such enhanced ACD reactions in FVB.
-/- mice were not restricted to DNFB; ear swelling in mice sensitized and challenged with the chemically unrelated allergen dimethyl-benzanthracene (DMBA) was also significantly greater than in FVB controls (data not shown).
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Irritant contact dermatitis (ICD) reactions develop with delayed kinetics and histopathologic changes similar to ACD reactions. However, unlike ACD, ICD can be elicited in all individuals upon first exposure to sufficient concentrations of the irritant. Since ICD reactions do not require effector T cells specific for the offending chemical, they have only an elicitation phase. Thus, ICD provides an additional means by which to test whether cells regulate elicitation events. FVB.
-/- mice and C57BL/6.
-/- mice, along with counterpart TCR-
+ controls, were challenged with TPA, the active agent in the irritant croton oil, and the resulting ICD reactions compared by measuring the increase in ear thickness above baseline 24 h postchallenge. Again, irritant reactions to TPA were markedly increased in FVB.
-/- mice (Fig. 3 B), providing further evidence that
cells down-regulate contact dermatitis elicitation events. Although the contact dermatitis responses were quantitated using the conventional measurement of ear swelling above baseline (i.e., baseline ear thickness has been subtracted), it is possible that the preexisting low-grade spontaneous dermatitis of FVB.
-/- mice may have contributed to the augmented allergic and irritant responses; indeed other studies have shown that preexisting dermatitis predisposes such sites to enhanced irritant and ACD upon subsequent challenge (3638).
In contrast to the enhanced ICD reactions to TPA observed in FVB.-/- mice, TPA challenge of C57BL/6.
-/- mice resulted in ear swelling responses indistinguishable from those measured in C57BL/6 animals (Fig. 3 B), demonstrating that
cell down-regulation of contact dermatitis to irritants is also genetically controlled. Collectively, the failure of TCR-
-/- mice on the C57BL/6 background to exhibit consistent differences from their wild-type counterparts with regard to either spontaneous or chemically induced contact dermatitis reactions, suggests that the conventional use of the C57BL/6 background for analysis of the TCR-
-/- phenotype may have substantially underestimated the nonredundant roles that can be played by
cells in vivo (22).
Spontaneous and Augmented Irritant Dermatitis Responses in -/- Mice Require
ß T Cells.
To investigate whether ß T cells might directly or indirectly be targets of the antiinflammatory effects of
cells, FVB mice deficient in both in
and
ß T cells (FVB.ß-/-
-/-, backcrossed 11 generations onto the FVB background) were compared with FVB.
/ mice and FVB controls (Fig. 4). Increased baseline ear thickness (spontaneous dermatitis) was again seen in FVB.
-/- mice; in contrast, the baseline ear thickness of FVB.ß-/-
-/- mice was indistinguishable from controls, clearly indicating that
ß T cells are required for the development of spontaneous inflammation which occurs in the absence of
cells (Fig. 4 A). Similarly, while augmented irritant responses after TPA challenge were again seen in FVB.
-/- mice, the irritant response in FVB.ß-/-
-/- mice was not significantly different from that of controls (Fig. 4 B). These data demonstrate that augmented ICD responses observed in the absence of
cells also depend, at least in part, on the presence of
ß T cells. These results seen 24 h after TPA challenge were confirmed and extended by analysis of these same groups of mice several days later. 6 d after TPA challenge, the ears of all FVB.
-/- ears demonstrated histologic features of subacute dermatitis; variable amounts of scale-crust overlying a thickened epidermis with intraepidermal edema and intraepidermal mononuclear inflammatory cells, and a markedly thickened dermis containing a prominent infiltrate of mononuclear inflammatory cells and mast cells (Fig. 4 C). In contrast, ears of representative FVB and FVB.ß-/-
-/- mice exhibited equivalent, and much less striking, evidence of inflammation. Furthermore, as shown in Table I, 6 d after TPA challenge, 89% (16/18) of the ears of FVB.
-/- mice showed visible scale-crust formation (another clinical sign of severe dermatitis), whereas 0/20 ears of control mice, and only 17% (3/18) ears of ß-/-
-/- mice developed scale-crust (
2 analysis: P < 0.001 for FVB.
-/- versus controls; no significant difference for FVB.ß-/-
-/- versus controls). Moreover, in 7/18 FVB.
-/- ears, the severity of scale-crust formation was greater than that seen in any FVB.ß-/-
-/- mice. These findings demonstrate that
ß T cells are responsible for the development of the spontaneous dermatitis responses of FVB.
-/- mice, and contribute to their enhanced irritant responses. In sum, the data suggest that a major function of
cells in genetically susceptible strains is to down-regulate local inflammatory responses provoked by
ß T cells.
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Baseline ear thickness of FVB.-/- mice reconstituted with sorted V
5+ cells was indistinguishable from that measured in FVB controls, and significantly less than unreconstituted FVB.
-/- mice (Fig. 5 A). Fig. 5 B and C show that cell suspensions prepared from the spontaneously inflamed ears of FVB.
-/- mice were, as expected, devoid of
cells, but contained significant numbers of presumably proinflammatory, infiltrating
ß T cells (i.e., CD3+
-), while the noninflamed ears of control mice contained T cells which were overwhelmingly V
5+, with small, but measurable numbers of V
5-
+ cells and rare
ß+ cells. The
cells isolated from the clinically noninflamed ears of FVB.
-/- mice inoculated as newborns with sorted V
5+ fetal thymocytes were exclusively V
5+ DETC and were present in proportions indistinguishable from control mice. Thus, prototypic V
5+ DETC are clearly sufficient to restore wild-type (antiinflammatory) function to FVB.
-/- skin. The increased baseline ear thickness measured in recipients of V
5 fetal thymocytes was similar to that in uninjected FVB.
-/- mice (Fig. 5 A). However, because the ears of mice receiving V
5 fetal thymocytes were only minimally reconstituted with V
5-
+ T cells (0.15 vs. 1.5% present in normal FVB mice; Fig. 5 C, h versus f), this experimental group did not allow one to conclude that V
5-
+ cells could not also function as antiinflammatory cells within the skin, were they to be present in substantial numbers.
To address this question, an experimental approach was adopted that built on previous studies showing that the skin of experimentally manipulated mice can be repopulated by V5-
+cells, including those expressing TCRs expressed by
cells found in PLNs or spleen (13, 39, 40). Therefore, selective reconstitution of FVB.
-/- mice was again undertaken, this time including a group of newborn FVB.
-/- mice inoculated with 1.5 x 106 V
5-
+ cells obtained from adult FVB.ß/ donor PLNs, as well as a group again reconstituted with V
5+ E17 fetal thymocytes. 10 wk later, after blind measurements of baseline ear thickness (Fig. 6 A), all mice were challenged once a week with the irritant TPA, and repeat measurements taken 24 h after the third challenge (Fig. 6 B). Subsequently, epidermal cell suspensions from the ears of individual mice were again analyzed by flow cytometry for their proportions of
+ cells, CD3+
- (i.e.,
ß) cells, and V
5+ cells (i.e., prototypic DETCs) (Fig. 6 C).
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Discussion |
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This paper is consistent with several previous studies which have reported that DETC can down-regulate particular cutaneous inflammatory responses (2731). However, the experimental designs used in each of those studies did not permit the conclusion that the V5+ DETC normal resident in murine epidermis can display a unique, nonredundant, capacity to down-regulate the
ß T celldependent components of both spontaneous and chemically induced contact dermatitis. For example, Bigby et al. (28) reported that the capacities of several strains of mice to express ACD reactions after sensitization and challenge was related to the different ratios of Langerhans cells to Thy-1+ DETC in normal skin of those different strains; however, the correlative nature of this study precluded definitive assignment of a down-regulatory role to V
5+ DETC.
Likewise, Sullivan et al. (27), documented a diminished capacity to be sensitized to the allergen DNFB in mice previously injected with DNBS-conjugated Thy-1+ DETC, while similar down-regulation of ACD was not seen in recipients of haptenated Langerhans cells or haptenated keratinocytes. Nonetheless, this study also did not show that such down-regulatory capacity was unique to DETC as opposed to other subsets of cells. Moreover, the lack of evidence that prototypic V
5/V
1+ DETC migrate from the skin of adult mice to the draining lymph nodes or the systemic circulation (12) raises some questions about the biological relevance of this study as well as another (29) in which the experimental design involved intravenous transfer to normal adult recipients of a subset of
cells whose distribution in adult mice is apparently restricted to the skin.
Like this report, two previous studies have used -/- mice to investigate the role of
cells in cutaneous inflammatory responses. A report showing that C57BL/6.
-/- mice displayed augmented ACD reactions to DNFB compared with wild-type controls (31) appears a priori to conflict with our failure in this study to show consistent differences between C57BL/6.
-/- and control mice in their ACD responses to DNFB. However, while the studies reported in the present study compared inbred
-/- to inbred control mice, the controls used by Weigmann et al. for comparison to inbred C57BL/6.
-/- mice were (129 x C57BL/6)F1 animals. Given the recognized differences in the magnitude of ACD responses in different mouse strains (28), it is possible that genetic disparity, rather than the presence or absence of
cells, was responsible for some or all of the differences in ACD responses reported in that study.
Second, Shiohara and colleagues reported that C57BL/6.-/- mice failed to down-regulate the intraepidermal component of cutaneous graft-versus-host disease after reinjection into the footpad of cloned, MHC class II autoreactive CD4+
ß cells; in contrast, intraepidermal "resistance" was seen in the footpads of C57BL/6.
-/- mice previously injected with unpurified fetal thymocytes from control,
+ E1416 fetal donors (30). The apparent contrast between this phenotype obtained for C57BL/6.
-/- mice and the lack of phenotype of C57BL/6.
-/- mice shown here regarding spontaneous or chemically induced dermatitis, may reflect the very powerful proinflammatory stimulus adopted by Shiohara and colleagues. This notwithstanding, the two studies are highly consistent in attributing immunoregulatory function to DETC. Nevertheless, the present studies substantially extend those of Shiohara et al. by showing that among the various populations of cells present in the E1417 fetal thymus, V
5+ DETC precursors are sufficient for down-regulating a variety of cutaneous inflammatory responses, including those physiologic responses that occur spontaneously. By contrast, at least some other subpopulations of
cells, such as those present in the PLNs, are unable to mediate such local down-regulation, despite their ability to enter the skin in substantial numbers.
The functional importance of DETC that is revealed in this study provides a powerful complement to one previous and two more recent molecular genetic studies suggesting that the stable establishment of DETC repertoires in vivo depends on the IELs expressing a particular type of TCR (13, 44, 45). For example, in V5-/- mice, congenitally unable to express the canonical V
5/V
1 DETC receptor, a substantial fraction of the "substitute" DETC that develop utilize a novel V
1/V
1 chain pairing to encode a TCR reactive to a DETC-specific clonotypic antibody (13).
The spontaneous, localized, cutaneous inflammation that develops in some, but not other strains of -/- mice has several similarities to the dermatitis previously reported to develop in the NC/Nga mouse (4648), which has been proposed as a relevant mouse model for human atopic dermatitis, a common, chronic, and incompletely understood inflammatory skin disease with a broad socioeconomic impact throughout the world (49). Shared features of the animal model described in the present studies with human atopic dermatitis include genetic predisposition (5055); histopathology (56) dependence on
ß T cells (57); localization to areas of skin also commonly exposed to environmental irritants and/or allergens (58); and increased expression of contact dermatitis (59). Additional studies evaluating IgE levels and the effects of environmental manipulation on the development of the dermatitis, as well as more detailed genetic analyses (see below) will be required to clarify other similarities and/or differences between the present model, the NC/NGA model, and human atopic dermatitis. To date, no evidence has correlated human atopic dermatitis to either a numerical or functional deficiency in
cells; furthermore, human skin clearly is not obviously populated with a precise phenotypic homologue of the V
5+ DETC found in murine skin (60). On the other hand, recent analysis of normal human skin has revealed that cutaneous
T cells demonstrate a restricted TCR-
repertoire distinct from that of peripheral blood
T cells (61), and it is conceivable that such human cutaneous
cells represent functional equivalents of murine intracutaneous V
5+ regulatory cells. Importantly, the work presented here focuses attention on the potential for local resident cells to control the magnitude of tissue inflammation by systemic cells in a unique and nonredundant fashion.
These studies have not definitively addressed several longstanding questions in the arena of cutaneous cell immunobiology, including the relevant mechanism(s) by which these cells exert their down-regulatory effects in the skin. Do DETC down-regulate
ß-dependent inflammatory responses via direct effects on such T cells or a subset thereof (e.g., Th2 or Th1), or via indirect effects, for example on the keratinocytes with which they are in intimate contact, on other cells normally resident in the skin (e.g., mast cells), or on cells recruited into the skin in response to inflammatory stimuli (e.g., monocyte/macrophages)? Likewise, do DETC down-regulate inflammation by elaborating antiinflammatory cytokines, by directly killing infiltrating cells, and/or by rendering the local tissue resistant to inflammatory cells? One strategy to address these latter possibilities will be to compare chemical induced and/or spontaneous dermatitis in NOD.
-/- and/or FVB.
-/- mice with similar mice reconstituted as newborns with V
5+ fetal thymocytes from donors genetically deficient in specific molecules known or suspected to be produced by DETC (e.g., IFN-
, IL-10, TGF-ß, Fas-L, granzymes, perforin) (2022). Moreover, a recent large scale description of genes expressed by murine gut IELs (62) has identified other candidate molecules that may be responsible for immunoregulation by IELs, including DETC; such molecules include prothymosin ß4 (63) and monoclonal nonspecific suppressor factor (64).
Finally, the results presented herein represent the first demonstration of a strain-dependent, spontaneous phenotype developing in an antigen receptor knockout mouse. Genetic differences between C57BL/6 mice and FVB or NOD mice render the former strain phenotypically resistant, and the latter strains phenotypically susceptible to the increased cutaneous inflammation that results from cell (DETC) deficiency. Such resistance of C57BL/6.
-/- mice could mean that they lack the necessary cell(s) and/or factor(s) required to initiate and/or express spontaneous dermatitis in the absence of
cells (while NOD and FVB mice possess such cells/factors). Alternatively, C57BL/6 mice, but not either FVB or NOD mice, possess additional cell(s)/factor(s) that can down-regulate the initiation and/or expression of spontaneous inflammation in the absence of
cells. The initial genetic analyses of such differences presented in this study are consistent with a single autosomal gene being primarily responsible for controlling such resistance/susceptibility. Genome-wide microsatellite mapping studies are underway to determine the actual number and identity of relevant modifier loci in NOD.
-/- and FVB.
-/- mice. These studies should reveal whether the loci controlling spontaneous dermatitis in susceptible
-/- mice are similar to any of the loci previously linked to susceptibility either to atopic dermatitis in humans (5055) and/or to the "atopic-like" dermatitis seen in other mouse models (48, 6568). Likewise, it will be useful to compare the loci controlling spontaneous dermatitis in NOD.
-/- and FVB.
-/- mice with those regulating susceptibility of NOD mice to autoimmunity (69, 70). In conclusion, additional studies aimed at understanding the genetic, regulatory, and effector mechanisms which govern the actions of a skin-specific subset of
cells in mice, are likely to provide insights into the complex local regulation of the wide variety of inflammatory diseases which can affect the epithelial interfaces (i.e., skin, respiratory, gastrointestinal, and genitourinary tracts) of many species, including humans.
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Acknowledgments |
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This work was supported by the National Institutes of Health (to R.E. Tigelaar, A.C. Hayday, and M. Girardi), the Dermatology Foundation (to M. Girardi), the Wellcome Trust (to A.C. Hayday), and utilized core laboratory facilities of the Yale Skin Diseases Research Core Center. Mouse breeding program supported by NIH DK5 3015 (A. Hayday and C.A. Janeway).
Submitted: December 3, 2001
Revised: February 5, 2002
Accepted: February 20, 2002
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Footnotes |
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* Abbreviations used in this paper: ACD, allergic contact dermatitis; DETC, dendritic epidermal T cell; IEL, intraepithelial lymphocyte; TPA, tetradecanoylphorbol acetate.
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References |
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