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Regular Articles |
From the Department of Pathology and Skin Cancer Research Laboratories, Cardinal Bernardin Cancer Center, Loyola University of Chicago, Maywood, Illinois
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunodermatologists familiar with this class I association have focused predominantly on CD8+ T cells, because such cells generally recognize processed peptides displayed by antigen presenting cells in the context of class I MHC cell surface molecules.3 Many immunophenotypic studies of psoriasis have been performed, and most document the presence of CD8+ T cells in epidermis, whereas CD4+ T cells tend to predominate in the dermal compartment, with only rare incidental natural killer (NK) cells in dermis.4 Even in psoriatic lesions that are only three days old, CD8+ T cells begin accumulating in the epidermis.5 Furthermore, when peripheral blood-derived mixtures of CD4+/CD8+ T cells are injected into PN skin engrafted onto SCID mice, the induction of PP skin is characterized by preferential migration of CD8+ T cells into the hyperplastic epithelium.6 The reports identifying a clonal population of intraepidermal CD8+ but not CD4+ T cells in PP skin,7 as well as statistically significant reduction in the intraepidermal CD8+ T cell population after successful immunospecific therapy,8 all support a key role for CD8+ T cells and their interaction with epidermal cells. However, to date it has not been possible to explain the exact role of the various MHC class I alleles in psoriasis, because no one has consistently identified any specific peptide antigen responsible for causing psoriasis.9,10
Against this backdrop, it was unexpected to observe that when T cell cultures were established from the peripheral blood of five different patients, all of the CD4+ T cell lines (5/5), but none (0/5) of the CD8+ T cells lines, were capable of inducing PN-to-PP conversion using the SCID mouse model.11 By examining engrafted skin injected with CD4 + T cells, only a small fraction of the overall mononuclear population expressed the T cell acute activation marker, CD69.12 Further analysis in 2 of 5 patients revealed the majority of the CD69-positive cells were actually CD8+ cells, and these positive cells were associated with the epidermal compartment, as mid- and deep dermal lymphocytes were CD69-negative. This result suggested that, like allergic contact dermatitis reactions, which early psoriasis lesions can simulate,13 CD4+ T cells were providing critically important help signals in a regulatory fashion, whereas the actual effector cells may be CD8+ immunocytes.14 As we considered a possible role for class I MHC antigens in psoriasis, we began focusing on NK receptors (NKR) used by NK cells to interface with targets involving self/nonself determinants triggered via class I MHC recognition.15 NK cells are one of the three lineages of lymphocytes, besides T cells and B cells, that are most clearly identified with the control of viral infections and tumor development.16 Although previous investigators found only very rare NK cells in psoriatic plaques4 and no difference in NK cell activity in the blood of patients with psoriasis compared to normal individuals,17 we identified immunocytes in skin of psoriatic patients expressing NKRs. As T cell subsets in blood have been identified that express NKRs, the emphasis in other systems has been on defining the inhibitory role of these receptors, highlighting the notion that CD8+T cells bearing such inhibitory NKRs (killer inhibitory receptors)18 would not lyse autologous normal class I MHC-bearing cells.
In this report, we present several findings, including i) CD4+ but not CD8+ T cell lines derived from peripheral blood are capable of converting PN skin engrafted onto SCID mice to PP skin after intradermal injections; ii) after injection of CD4+ T cells, local restimulation of indigenous CD8+ T cells as well as CD4+ T cells occurs as intraepidermal lymphocytes are induced to express CD69 and CD25; and iii) identification of immunocytes expressing various NKRs (ie, CD94, CD158a, CD158b) in both acute and chronic lesions of psoriasis.
Based on this data we suggest a novel hypothesis for psoriasis in which direct recognition and interaction of these NKRs with class I MHC alleles may play a role in the development of psoriasis. In essence we propose that various MHC class I alleles themselves (rather than exogenous peptide antigens) are responsible for directly triggering T cells bearing the activating forms of CD94/CD158a/CD158b. Upon examination of MHC class alleles most likely involved in psoriasis, such as Cw6, and comparison of this list to the types of class I alleles that interact with NKRs, a correlation between these ligand/receptors can be appreciated.19 Taken together, these results suggest a new etiological and pathophysiological pathway in which immunocytes are postulated to be triggered to release cytokines and proliferate by using receptors typically confined to NK cells, thereby interfacing with class I MHC surface molecules on epidermal cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The psoriasis patients in this study were otherwise healthy. After obtaining their informed consent, keratome samples were obtained from symptomless (PN) skin (n = 5, 2 females, 3 males) or from untreated active psoriatic plaques (PP skin) (n = 15). Samples from normal volunteers without any skin disease (NN skin) (n = 8) were also obtained under local anesthesia. In addition, a separate set of PN skin biopsies (n = 8) was analyzed using immunohistochemical staining.
Human Skin/SCID Mouse Chimera and Tissue Processing
Human skin xenografts were orthotopically transplanted onto 7- to 8-week-old SCID mice (Taconic Farms, Germantown, NY) following previously described procedures.6 Briefly, human skin xenografts measuring 1.5 x 1.5 x 0.5 cm were sutured to the flank of SCID mice with absorbable 5–0 Vicryl Rapide suture (Ethicon, Somerville, NJ) and covered with Xeroform dressings (Kendall Co., Mansfield, MA). Dressings were removed 1 week later and animals maintained pathogen-free throughout the study. Two to three weeks after transplantation, autologous cells or reagents diluted in sterile PBS were injected intradermally (300 ul vol) into the xenograft. Human skin/SCID mouse chimeras were killed within 2–3 weeks of the last intradermal injection, and 4-mm punch biopsies (Baker's Biopsy Punch, Cummins Derm, Miami, FL) were obtained from each xenograft. Biopsies were fixed in neutral-buffered formalin for paraffin embedding and/or mounted on gum tragacanth (Sigma Chemical Co., St. Louis, MO), snap-frozen in liquid nitrogen-chilled isopentane, and stored at -80°C.
Immunostaining
Cryostat sections of skin were acetone-fixed and stained using
either a highly sensitive avidin-biotin immunoperoxidase technique with
3 amino 4-ethylcarbazole to produce a positive red reaction product as
described,6
or an indirect immunofluorescence procedure
was performed. For immunoperoxidase single antigen staining the
following antibodies were purchased to detect their respective
antigens: anti-CD3, CD4, CD8, CD16, CD25, CD57, CD69, and 
/ß TCR
(Becton-Dickinson, Mountain View, CA), and anti-CD94 (clone Hp-3B1),
CD158a (clone EB6), CD158b (clone GL183) were purchased from Coulter
Corp. (Miami, FL). Anti-CD56 was purchased from PharMingen (San Diego,
CA).
Two-color immunofluorescence staining was performed using several
different protocols. In the first method, cryostat sections were
incubated with mouse anti-human monoclonal antibodies against the
following antigens: mouse anti-CD94, mouse anti-CD158a, mouse
anti-CD158b (all Coulter Corp.), or mouse anti-CD25 or anti-CD69
(Becton-Dickinson), all at 10 ug/ml final concentration for 30 minutes
at room temperature. After washing in FA buffer (Difco, Detroit, MI), a
rhodamine-conjugated goat anti-mouse antibody was added (1:50 dilution;
Biosource International, Camarillo, CA) for 30 minutes at room
temperature. All of the cells exposing these antigens appeared red due
to the rhodamine conjugate in the reaction. To saturate unoccupied
binding sites, sections were then incubated with mouse serum (Chrompure
mouse IgG, 10 ug/ml, Jackson Immunoresearch, West Grove, PA). To
identify colabeling in the tissue sections, two different strategies
were used. Biotinylated conjugated secondary antibodies were
used to detect the following antigens: mouse anti-CD3
(Becton-Dickinson), mouse anti-CD8 (Coulter Corp.), and mouse anti-TCR
/ß (Becton-Dickinson) were added at 10 ug/ml for 30 minutes at
room temperature and washed with FA buffer. Next, streptavidin-FITC
conjugate (1:50 dilution, PharMingen) was added for 30 minutes at room
temperature, producing a green fluorescence product for these antigens.
To visualize CD4, a second reaction scheme, in which a rabbit
anti-human CD4 (Immunodiagnostics, Bedford, MA) (1:5 dilution) followed
by the secondary ab, with a goat anti-rabbit FITC-conjugated ab was
used at 1:25 dilution (Biosource International). For all these
reactions, after the last wash in FA buffer, a mounting solution was
applied (para-phenylenediamine in glycerol) before coverslipping. All
slides were examined and photographed using an Olympus AX-80
microscope.
Cell Culture Studies
Autologous immunocytes were isolated from heparinized blood by Ficoll-Hypaque (Pharmacia LKB Biotechnology, Piscataway, NJ) density centrifugation. 1–2 x 106 peripheral blood mononuclear cells (PBMC)/ml were cultured on tissue culture dishes (Corning Glass Works, Corning, NY) in complete media containing 10% heat-inactivated autologous serum in RPMI-I640 containing 24 mmol/L HEPES (GIBCO BRL, Gaithersburg, MD) supplemented with 2 mmol/L L-glutamine, 100 U/ml penicillin, 100 ug/ml streptomycin, and 50 ug/ml gentamicin (GIBCO BRL). Immunocytes were cultured in complete media with or without 1 ug/ml each of staphylococcal enterotoxins SEB and SEC2 (Toxin Technologies, Sarasota, FL) and 20 U/ml human interleukin (IL)-2 (Boehringer Mannheim, Indianapolis, IN) for 72 hours at 37°C in a humidified atmosphere containing 5% CO2. CD4+ and CD8+ T cell lines were produced by negative selection and continued exposure to IL-2. Such cells lines were >98% pure CD4+ or CD8+ T cells after the first several weeks in culture, as determined by flow cytometry. In addition, T cell lines were produced using immobilized anti-CD3 mAb and IL-2.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In preliminary experiments, while using unfractionated
Ficoll-Hypaque interface-derived immunocytes, the removal of the CD4+ T
cell population by magnetic bead selection immediately before injection
abrogated the ability of the injected immunocytes to induce psoriasis.
However, in these same two patients, removal of CD8+ T cells
from the Ficoll-Hypaque interface mononuclear cells did not alter the
conversion of PN to PP skin (data not shown). Based on these results we
further studied an additional five patients to determine whether highly
enriched specific T cell subsets were capable of inducing psoriasis
without the other cell types typically present in the Ficoll-Hypaque
interface, such as monocytes, macrophages, NK cells, B lymphocytes, or
dendritic cells. T cell lines were generated from Ficoll-Hypaque
interface cells stimulated 1–2 weeks with superantigens and IL-2. CD4+
or CD8+ T cell lines were expanded and maintained in IL-2 containing
medium following negative selection. CD4+ and CD8+ T cells were
injected into PN skin after being in culture for various durations (19,
21, 22, 25, and 35 days). Comparing the clinical and microscopic
appearance of PN grafts injected with unfractionated/acutely activated
Ficoll-Hypaque derived immunocytes (days 2–4) to PN skin injected with
CD4+ T cell lines (but not CD8+ T cells), induction of psoriasis was
seen to be similar between these populations of immunocytes (Figure 1)
. The lower horizontal panels reveal
the distribution of CD3+ T cells after injection of either CD8+ T cells
(left side), CD4+ T cells (middle), or unfractionated Ficoll-Hypaque
cells, including both CD4+ and CD8+ T cells (right side). Note that
although T cells are seen at the dermal-epidermal interface in the left
side panel, they do not trigger significant epidermal hyperplasia, but
in the middle and right side panels, numerous T cells infiltrate the
epidermis, accompanied by prominent keratinocyte hyperplasia.
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. Note that >95%
of the CD3+ lymphocytes are CD4+, with rare CD8+ T cells among these
cultured cells. In two of these five patients, we also used immobilized
anti-CD3 mAb and IL-2 (rather than bacterial superantigens) to
stimulate CD4+ and CD8+ T cells and observed that only injected
CD4+ T cells, but not CD8+ T cells, induced PN-to-PP conversion (Figure 3)
. The lack of PN-to-PP conversion by
CD8+ T cells was not due to a lack of survival or absence of stimulated
CD8+ T cells, as immunostaining of injected PN skin revealed scattered
CD8+ T cells in the upper dermis and lower epidermis (Figure 4)
. Moreover, using human leukocyte
antigen-DR (HLA-DR) expression, the PN grafts injected with the CD8+ T
cells had prominent HLA-DR staining of the lymphocytes in the upper
dermis and even focal areas of keratinocyte expression, although much
more intense and diffuse keratinocyte HLA-DR expression was seen after
injection of CD4+ T cells. This latter finding strongly suggests the
presence of 
interferon (IFN-) production by the activated dermal
mononuclear cell population. Furthermore, when these CD4+ and CD8+ T
cell lines were examined immediately before injection into PN skin,
flow cytometric analysis revealed that 22% of CD8+ T cells
versus 14% of CD4+ T cells expressed CD69, indicating that
a significant fraction of CD8+ T cells was acutely activated. Taken
together, all of these results indicated that highly purified and
activated CD4+ T cells, but not CD8+ T cells, were capable of mediating
PN-to-PP skin conversion. In the next section, we characterized the
local immunological reactions occurring after injection of CD4+ T cells
into PN skin.
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Besides the routine clinical and light microscopic findings noted
above, an immunophenotypic analysis of the PN skin grafts injected with
autologous CD4+ T cell lines was performed in samples from four of
these patients. For one patient, PN grafts were harvested at 3 and 14
days after injection of CD4+ T cells; in the other three patients, skin
grafts were harvested 2–3 weeks after injection. In one
patient, we observed a striking increase in the number of
intraepidermal CD8+ T cells 2 weeks after the injection of the CD4+
cell line (Figure 5)
. Even though
numerous CD4+ T cells were present in the upper dermis, there were more
CD8+ T cells than CD4+ T cells in the epidermal compartment. In a
second patient, CD8+ T cells appeared more abundant than routinely
observed in PN skin, but not as prominent as was observed in the first
patient. In the other two patients examined, there was no apparent
increase in the number of CD8+ T cells in the epidermis. Thus, it
should be noted that the number of intraepidermal CD8+ T cells after
intradermal CD4+ T cell injection varied among grafts. The range in the
density of intraepidermal CD8+ T cells went from <5 per high-power
field to >50 per high-power field. These results indicated that an
activation event involving resident CD8+ lymphocytes was occurring in
some of the skin samples after the injection of the CD4+ T cells that
extended beyond the response of the keratinocytes and endothelial
cells. To determine which types of immunocytes were being activated
after injection of CD4+ cells, cryostat sections were immunostained to
detect acute T cell activation markers CD25 and CD69. Because these
markers revealed similar staining profiles, only the CD69 results will
be portrayed. In preliminary studies we documented that although CD69
is rapidly induced (4–6 hours) by bacterial superantigens, it is
down-modulated in 6–8 days if no additional stimulus is
provided.20
Thus, because the CD4+ T cells are in PBS
before injection and the grafts were harvested 2–3 weeks later, we
reasoned that any CD69-positive T cells would signify a reactivation
event occurring within the local microenvironment.
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. In the third patient examined,
CD69-positive cells included both CD4+ as well as CD8+ T cells
(Figure 7)
. In the fourth
patient, CD69 was identified primarily on CD4+ T cells with
only a rare CD8+ T cell expressing CD69. It was also noted during these
immunophenotyping studies that the number of CD8 homodimer-positive
cells was greater than the number of CD8 /beta
heterodimer-positive cells. Additional studies are in progress to
further define the nature of this T cell subset that appears to express
only homodimers of chains rather than heterodimers of /beta CD8
chains. These results indicated that resident CD8+ T cells were being
acutely activated after injection of CD4+ T cells in some of the grafts
examined immediately before lesion formation. Next we sought to further
characterize the immunophenotype of the intraepidermal activated
immunocytes.
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, CD158a- (Figure 8B)
,
and CD158b- (Figure 8C)
positive immunocytes in the PN skin injected
with autologous CD4+ T cells. An immunophenotypic profile of the second
patient revealed that 3 weeks after injection of highly purified CD4+ T
cells into the dermis, numerous CD4+ and CD8+ T cells (only rare
CD8ß+) are present in the epidermis (Figure 9)
. These intraepidermal T cells express
CD25 and CD69, but there are rare or no CD57 or /
TCR + cells in
this graft. Moreover, CD94+ cells are present in the epidermis
accompanied by fewer CD158a- and CD158b-positive cells (Figure 10)
. Based on their relative frequency,
it appears that not all CD94+ T cells coexpress CD158a and/or CD158b.
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Based on these findings, we next determined the phenotype of the cells
bearing NKRs. Because there were consistently more CD94-positive
immunocytes than CD158a- and CD158b-positive cells, the two-color
immunofluorescence results reported focus on the CD94-expressing cells
in the epidermis. By two-color immunofluorescence staining, the
majority of the CD94-positive cells were also expressing CD8 (Figure 11)
, with occasional CD4+ T cells
expressing CD94, CD158a, and CD158b (data not shown). Using antibody
against the /ß chain of the TCR, CD94-positive cells were positive
for this marker of T cells (Figure 11
, inset); and CD158a- and
CD158b-positive cells were also observed to express the /ß T cell
receptor (TCR) (data not shown). The use of markers other than CD57 for
epidermal NK cells such as CD56 was not possible because of high
reactivity with surrounding keratinocytes. Similar difficulty was
encountered with CD16; because some NK cells do not express either CD56
or CD16, we cannot completely exclude the possibility that some NK
cells were present. However, using CD57 only very rare positive NK
cells were observed, and in many fields no CD57-positive cells
were present (data not shown). Thus, because NK cells do not express
TCR and only very rare CD57+ cells were detected, we believe the
NKR+ TCR+ cells in this experimental system are not traditional NK
cells.
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. Given the
overall staining profiles described above, we prefer simply to refer to
these CD94/CD158a/CD158b-positive cells with an activated cytological
appearance as immunocytes. It should be emphasized that T lymphocytes,
particularly CD8+ cells, perform many immunological functions similar
to those of NK cells and are derived from a common NK-T cell
progenitor. To our knowledge, no one has previously demonstrated the
presence of NKR-bearing lymphocytes in acute lesions of psoriatic
epidermis as described above, or documented expression of NKRs by
immunocytes in chronic psoriatic plaques as described below.
Furthermore, when the CD4+ T cell lines were examined before injection
into PN skin, only rare (<1%) of the cell population expressed either
CD94, CD158a, or CD158b (data not shown). Studies are in progress to
identify the stimulus for T cell up-regulation of these NKRs.
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To compare these unexpected findings in the acute lesions of
psoriasis using SCID mice, 15 different chronic plaques taken directly
from patients were examined. Although numerous CD3+ T cells were
abundant in the epidermis and dermis (Figure 13A)
, scattered immunocytes in
epidermis and dermis expressing CD94 (Figure 13B)
, CD158a (Figure 13C)
,
and CD158b (Figure 13D)
were present in 10 of the 15 plaques. In all
positive cases, more NKR-positive cells were seen in the epidermis than
in the dermis. Compared to the overall number of CD3+ T cells, the
NKR-positive cells were generally <10% of the entire immunocyte
population. The main difference in the appearance of these positively
labeled cells observed in examining acute versus chronic
lesions was that the immunocytes in the established plaques were
generally less conspicuous in their overall density and had fewer
cytoplasmic spikes or elongated processes than the acute lesions
obtained from the SCID mice mentioned above. By two-color fluorescence
staining, the majority of these NKR positive cells were CD8+, with only
rare CD4+ cells double positive for these NKRs (data not shown).
CD94-, CD158a-, CD158b-, and CD57-positive cells were rare to absent in
either dermis or epidermis of the PN and NN skin samples examined. A
rare dermal CD57-positive NK cell was present in PP skin (Figure 13A
,
inset).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These results using the SCID mouse model are in agreement with earlier reports documenting activated CD8+ T cells in epidermis of untreated psoriatic plaques26 and determination that clones of CD8+ T cells are present in psoriatic epidermis.7 The minimum number of intraepidermal CD8+ T cells necessary for psoriasis is currently unclear, although one study has documented that untreated psoriatic plaques had 13 CD8+ T cells per high-power field, which was reduced to <5 CD8+ T cells per high-power field with effective treatment.27 The inability of the purified CD8+ T cell lines injected into PN skin to induce psoriasis presents a paradox in that the injected CD4+ T cells induced psoriasis and activation of indigenous CD8+ T cells. One attempt to resolve this paradox is the proposal that the highly purified blood-derived CD8+ T cells maintained in vitro using this experimental protocol did not include either directly pathogenic T cell subsets, and/or have the capacity to activate resident pathogenic T cells indirectly from their dormant state. In this scenario, it is possible to postulate that CD4+ T cells may on one hand provide appropriate help signals to CD8+ T cells, and on the other hand function more directly as effector cells, as has been documented by investigators examining other skin-related immune reactions.14,28,29 Just as there are many different environmental triggering factors for psoriasis, both bacterial superantigens as well as immobilized anti-CD3 mAb could sufficiently activate the CD4+ T cells to induce psoriasis in this model system.
In addition to defining the response of engrafted PN skin with respect
to CD4/CD8 and CD25/CD69 as mentioned above, we also observed that
injection of highly purified CD4+ T cells led to appearance of
epidermal immunocytes present immediately before and during emergence
of psoriatic lesions expressing surface receptors typically confined to
NK cells (ie, CD94/CD158a/CD158b). So far, we have not identified the
skin-derived stimulus responsible for induction of these NKRs by such a
prominent number of lymphocytes, particularly those infiltrating PN
skin during lesion development. Because such induction of NKR
expression was not seen when CD8+ T cells were injected into PN skin in
the absence of psoriatic lesion formation, it appears that the
microenvironment immediately preceding the genesis of a plaque is
critically important to such expression. In another set of experiments
in which allogenic activated immunocytes were injected into normal
skin, the local psoriatic tissue reaction even spread from the human to
the adjacent murine skin and included NKR-positive T
cells.30,31
The importance of the milieu of acute
psoriatic lesions may also explain the absence of NKR-positive
lymphocytes in some of the established or chronic lesions. There is a
precedent for the importance of a local tissue environment on T cell
phenotype in that in a murine system, injection of lymph node derived
co-isogenic CD4+/CD45 RB high lymphocytes into SCID mice led to
a transdifferentiation event in the small intestine, with these T cells
acquiring CD8 but not CD8ß surface receptors accompanied by
induction of epithelial hyperplasia.32
Interestingly, in
our model we also noted a divergence in CD8 versus CD8ß
surface expression by CD4+ T cells in the acute lesion of psoriasis
produced in SCID mice and work is in progress to define this population
of T cells. It should be noted in humans that there is already a known
skin-gut connection, as some psoriatic patients also suffer from
Crohn's disease.
Even though the overall number of NKR-positive immunocytes in the engrafted PN skin that converted to PP skin was generally less than 10% of the overall T cell population, NKR-bearing T cells may still be the final effector population responsible for causing psoriasis. As has been documented in allergic contact dermatitis, the frequency of the actual antigen-specific pathogenic T cell population is <1%.33 The NKR-positive T cells may be triggered to become activated and release appropriate cytokines by recognition of various class I alleles expressed by epidermal cells. One key concept for this report is that epidermal immunocytes present during the emergence and maintenance of psoriasis express potentially activating receptors previously highlighted for their presence on NK cells. Indeed, although NK cells and T lymphocytes share a common progenitor cell and mediate similar immune reactions,15 this report clearly documents the presence of CD94, CD158a, and CD158b on immunocytes in psoriasis. Using our SCID mouse model, it was possible to identify these immunocytes within days preceding lesion formation. Their continued presence in the majority of established plaques indicates not only that they are important for producing acute lesions, but also that may also play a role in the maintenance of chronic lesions. The importance of NKR-bearing immunocytes in creation of psoriasis is suggested by the pre-injection of blocking antibody against CD94 into PN skin, which prevented induction of psoriasis in this SCID mouse model (Nickoloff, unpublished observation).
The notion that immunocytes may be directly activated by recognition of class I alleles, without the need for any additional antigen (ie, exogenous or endogenous) highlights the truly autoimmune basis for the disease.30,34 As the autoreactive NKR-positive immunocytes are triggered to release cytokines, they can recruit additional memory T cells that can amplify the initial stimulatory event and contribute to the cytokine cascade that mediates PN-to-PP phenotypic conversion. We postulate that the disease occurs because pathogenic T cells are not appropriately deleted during development because of incomplete negative selection and, when they localize to skin, become activated and recognize specific alleles such as HLA-Cw6, cytokines are released that ultimately are responsible for converting PN skin into PP skin. In contrast to previous studies that focused on the inhibitory nature of NKRs on T cells to explain why CD8+ T cells do not kill normal autologous cells,16 our studies highlight the potential activating capability of NKRs on immunocytes. Work is in progress to determine the basis for the enhanced expression of the NK receptors such as CD94/CD158a/CD158b on immunocytes in psoriatic patients, and the relative activating potential of various class I alleles that they recognize.
It should be noted that there are an increasing assortment and lineage
of class I genes that may be relevant to psoriasis and that could be
responsible for triggering the activation of appropriate immunocytes in
the skin of genetically susceptible individuals.35-41
Just as previous studies established that skin and intestinal
epithelial + T cells in the murine system can interact with
keratinocytes and epithelial cells including MHC class I- related
molecules,42-44
we postulate that ß+ T cells via
these NKRs or other NKR-like surface receptors may be important in
patients with psoriasis, with or without concomitant Crohn's disease.
Based on recent findings,31
other relevant
ligand/receptors such as CD161 and CD1d should also be investigated for
their immunological and genetic links to psoriasis.45-47
Finally, it will be of interest to determine whether these same NKRs on
immunocytes in psoriatic patients are responsible for the lower than
expected incidence/prevalence of viral infection and tumors present in
psoriatic skin,22
because such immunocytes may represent a
bridge between innate and acquired immunity.15,48
Indeed,
the amazingly rapid response by which these immunocytes bearing NKRs
become activated and trigger substantial epidermal hyperplasia and
angiogenesis may not only be effective in immune surveillance of
infections and neoplastic assaults but serve an important wound-healing
function as well.19
From this perspective, the relatively
high prevalence of psoriasis worldwide may be better understood, as
having such a subset of immunocytes may confer an advantage over the
general population in combating such assaults and promptly repairing
the skin to restore cutaneous homeostasis following injury.
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Footnotes |
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Accepted for publication March 23, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells. Science 1994, 266:1253-1255 gene usage. Science 1998, 279:1729-1733 T cells. Science 1998, 279:1737-174This article has been cited by other articles:
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  D. M. Danilenko Review Paper: Preclinical Models of Psoriasis Vet. Pathol., July 1, 2008; 45(4): 563 - 575. [Abstract] [Full Text] [PDF]
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 F. Leon, N. Contractor, I. Fuss, T. Marth, E. Lahey, S. Iwaki, A. la Sala, V. Hoffmann, W. Strober, and B. L. Kelsall Antibodies to Complement Receptor 3 Treat Established Inflammation in Murine Models of Colitis and a Novel Model of Psoriasiform Dermatitis J. Immunol., November 15, 2006; 177(10): 6974 - 6982. [Abstract] [Full Text] [PDF]
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 A. Gilhar, R. Yaniv, B. Assy, S. Serafimovich, Y. Ullmann, and R. S. Kalish Fas Pulls the Trigger on Psoriasis Am. J. Pathol., January 1, 2006; 168(1): 170 - 175. [Abstract] [Full Text] [PDF]
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 A. M. Bowcock and W. O.C.M. Cookson The genetics of psoriasis, psoriatic arthritis and atopic dermatitis Hum. Mol. Genet., April 1, 2004; 13(90001): R43 - 55. [Abstract] [Full Text] [PDF]
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 G. Krueger and K. Callis Potential of Tumor Necrosis Factor Inhibitors in Psoriasis and Psoriatic Arthritis Arch Dermatol, February 1, 2004; 140(2): 218 - 225. [Abstract] [Full Text] [PDF]
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L. Skov, K. Kragballe, C. Zachariae, E. R. Obitz, E. A. Holm, G. B. E. Jemec, H. Solvsten, H. H. Ibsen, L. Knudsen, P. Jensen, et al. HuMax-CD4: A Fully Human Monoclonal Anti-CD4 Antibody for the Treatment of Psoriasis Vulgaris Arch Dermatol, November 1, 2003; 139(11): 1433 - 1439. [Abstract] [Full Text] [PDF]
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 Y.-P. Xia, B. Li, D. Hylton, M. Detmar, G. D. Yancopoulos, and J. S. Rudge Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis Blood, July 1, 2003; 102(1): 161 - 168. [Abstract] [Full Text] [PDF]
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Y. Mizukawa, Y. Yamazaki, Y. Teraki, J. Hayakawa, K. Hayakawa, H. Nuriya, M. Kohara, and T. Shiohara Direct Evidence for Interferon-{gamma} Production by Effector-Memory-Type Intraepidermal T Cells Residing at an Effector Site of Immunopathology in Fixed Drug Eruption Am. J. Pathol., October 1, 2002; 161(4): 1337 - 1347. [Abstract] [Full Text] [PDF]
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 S. H. Jackman, S. Keerthy, and G. Perry Murine Epidermal Cell Antigen (Skn)-Directed Autoimmunity Induced by Transfer of CD4+ T Cells Ann. Clin. Lab. Sci., April 1, 2002; 32(2): 171 - 180. [Abstract] [Full Text] [PDF]
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 R. D. Granstein New Treatments for Psoriasis N. Engl. J. Med., July 26, 2001; 345(4): 284 - 287. [Full Text] [PDF]
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S. Aractingi, N. Briand, C. Le Danff, M. Viguier, H. Bachelez, L. Michel, L. Dubertret, and E. D. Carosella HLA-G and NK Receptor Are Expressed in Psoriatic Skin : A Possible Pathway for Regulating Infiltrating T Cells? Am. J. Pathol., July 1, 2001; 159(1): 71 - 77. [Abstract] [Full Text] [PDF]
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R. Bockelmann, P. Neugebauer, N. Djahan Paseban, M. Huttemann, H. Gollnick, and B. Bonnekoh Suprabasal Overexpression of the hsRPB7 Gene in Psoriatic Epidermis as Identified by a Reverse Transcriptase-Polymerase Chain Reaction Differential Display Model Comparing Psoriasis Plaque Tissue with Peritonsillar Mucosa Am. J. Pathol., February 1, 2001; 158(2): 367 - 372. [Abstract] [Full Text] [PDF]
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B. Bonish, D. Jullien, Y. Dutronc, B. B. Huang, R. Modlin, F. M. Spada, S. A. Porcelli, and B. J. Nickoloff Overexpression of CD1d by Keratinocytes in Psoriasis and CD1d-Dependent IFN-{gamma} Production by NK-T Cells J. Immunol., October 1, 2000; 165(7): 4076 - 4085. [Abstract] [Full Text] [PDF]
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B. Homey, M.-C. Dieu-Nosjean, A. Wiesenborn, C. Massacrier, J.-J. Pin, E. Oldham, D. Catron, M. E. Buchanan, A. Muller, R. deWaal Malefyt, et al. Up-Regulation of Macrophage Inflammatory Protein-3{alpha}/CCL20 and CC Chemokine Receptor 6 in Psoriasis J. Immunol., June 15, 2000; 164(12): 6621 - 6632. [Abstract] [Full Text] [PDF]
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B. J. Nickoloff The Immunologic and Genetic Basis of Psoriasis Arch Dermatol, September 1, 1999; 135(9): 1104 - 1110. [Full Text] [PDF]
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