ORIGINAL ARTICLE
HLA-C Expression Pattern Is Spatially Different between Psoriasis and Eczema Skin Lesions Lina Carle´n1, Kazuko Sakuraba1, Mona Sta˚hle1 and Fabio Sa´nchez1 Interactions between genetic and environmental factors underlie the immune dysregulation and keratinocyte abnormalities that characterize psoriasis. Among known psoriasis susceptibility loci (PSORS), PSORS1 on chromosome 6 has the strongest association to disease. Altered expression of some PSORS1 candidate genes has been reported but little is known about HLA-C expression in psoriasis. This study compared expression of major histocompatibility complex class Ia and HLA-C in psoriasis, allergic contact eczema, and normal skin. Although HLA-C was abundant in protein extracts from both eczema and psoriasis, a consistent and intriguing difference in the expression pattern was observed; strong immunoreactivity in the basal cell layer, polarized towards the basement membrane in psoriasis, whereas in eczema lesions HLA-C immunostaining was present mostly in suprabasal cells. Inflammatory cells in the dermis were strongly stained in both diseases. Normal skin epithelium showed less intense but similar HLA-C staining as eczema lesions. HLA class Ia expression overall resembled that of HLA-C in all samples. The distinct HLA-C expression patterns in psoriasis and eczema suggest a functional role in the specific psoriasis immune response and not only a general feature of inflammation. Journal of Investigative Dermatology (2007) 127, 342–348. doi:10.1038/sj.jid.5700549; published online 28 September 2006
INTRODUCTION Association between psoriasis and the major histocompatibility complex (MHC) region is firmly established (McMichael et al., 1978; Laurentaci et al., 1982; Henseler and Christophers, 1985). A minimal genomic segment defining the psoriasis susceptibility locus 1 (PSORS1) on chromosome 6 (Jenisch et al., 1998; Balendran et al., 1999; Oka et al., 1999; Nair et al., 2000) contains a number of proposed candidate genes, for example HLA-C, CDSN (corneodesmosin), CCHCR1 (coiled-coil alpha-helical rod protein 1), SEEK, and PSORS1C3 (Bowcock and Krueger, 2005). All of them have been investigated for strength of association to psoriasis in genetic studies but only some have been studied for expression in skin (Holm et al., 2003; Suomela et al., 2003; Capon et al., 2004). There are no published studies that describe HLA-C expression in psoriasis despite the fact that its association to disease has been known for several decades. It is known that under non-inflammatory conditions all nucleated cells express class I molecules, and that one of their important functions is to suppress self-reactivity by engaging inhibitory receptors on natural killer (NK), NK-T and CD8 þ cells (Martin and Carrington, 2005; Rajagopalan 1
Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Correspondence: Dr Fabio Sa´nchez, Molecular Dermatology, CMM L8:02, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail:
[email protected] Abbreviations: KIR, killer cell immunoglobulin-like receptor; MHC, major histocompatibility complex; NK, natural killer; PSORS, psoriasis susceptibility locus Received 22 February 2006; revised 17 May 2006; accepted 22 May 2006; published online 28 September 2006
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and Long, 2005). HLA-C but not HLA-A and B is expressed by trophoblast where it regulates maternal NK cell reactivity (Parham, 2004). HLA-C has recently gained attention in transplantation biology because it has been recognized that mismatches in the killer immunoglobulin-like receptor (KIR)HLA class I system can lead to transplant rejection (Petersdorf et al., 1997). This interaction is strongly influenced by the amino acids present at position 80 and 44 of the HLA-C and KIR molecules, respectively (Boyington et al., 2001) and is also influenced by the glycosylation state of the ligands (Baba et al., 2000). HLA-Cw*0602 has a lysine at position 80 and interacts mostly with KIRs that possess a methionine at position 44 (Winter and Long, 1997), such as KIR2DL1 (inhibitory) and KIR2DS1 (activating). Upon interaction, ligand and receptor are internalized into the effector cell (Carlin et al., 2001) which is followed by cellular activation or inhibition (Moretta and Moretta, 2004). HLA-C expression in the skin has not been described yet, although it is generally assumed to be low based on expression in other tissues (McCutcheon et al., 1995). Although several inflammatory diseases associate with polymorphisms at MHC class I genes, for example, ankylosing spondylitis with the HLA-B27 allele and subacute thyroiditis with the HLA-B35 allele (Nyulassy et al., 1977; Rubin et al., 1994), psoriasis is the only inflammatory disease that associates with HLA-C (HLA-Cw*0602). The role of MHC class Ia in the pathophysiological mechanisms of psoriasis is not well understood; however, it is clear that inflammation is a marker of disease activity (Krueger and Bowcock, 2005) and that environmental factors such as infections can trigger this disease (Wolf and Ruocco, 1999; Langley et al., 2005), which provides an immunological & 2006 The Society for Investigative Dermatology
L Carle´n et al. HLA-C Expression Pattern in Psoriasis
playground for HLA-C. In particular, streptococcal throat infections are often concomitant with onset of guttate psoriasis, which is the psoriasis subphenotype with the strongest association to HLA-Cw*0602 (Mallon et al., 2000; Holm et al., 2005). Whether these associations are circumstantial or do indeed contribute to pathophysiology remains to be established. In the late 1970s, Gross et al. (1977, 1983) reported that, in psoriasis, T-cell functions in response to in vitro exposure to streptococcal factors are influenced by HLA-C genotypes. No additional reports addressing this phenomenon are available since then. It is likely that technical difficulties arising from the high degree of homology between MHC class I genes and from the high degree of polymorphism within each gene group explain the scarcity of studies on this subject. Nonetheless, the role of HLA-C in immune surveillance (Boyington and Sun, 2002) and its importance in relation to infection grants a closer look at its expression pattern in psoriasis. RESULTS HLA-C is expressed in skin, tonsil, and adult colon epithelium but not in fetal colon epithelium
The level and pattern of HLA-C and HLA-ABC expression were investigated in normal specimens of skin, tonsil, and
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colon using antibodies recognizing HLA-C (L31) and HLA-A,B and C (W6/32). Immunohistochemical analysis showed that HLA-C staining in tonsil was strong around germinal follicles and in epithelial cells (Figure 1a). There was no HLA-C staining in fetal colon epithelium (Figure 1b), although strong staining in neighboring lymphoid tissue on the same specimen was evident, in contrast, there was very strong staining in adult colon epithelium (Figure 1c). HLA-C expression in normal skin epithelium was predominantly suprabasal with a membrane-like staining pattern (Figure 1d). Strong immunoreactivity for HLA-ABC was observed in all cells, including epithelial cells, in all tissues and in leukocytelike cells, especially large dendritic-like cells (data not shown), except in fetal colon epithelium where the staining with this antibody was faint. Psoriasis and allergic contact eczema skin lesions show spatially disparate HLA-C expression patterns
Next, we compared the HLA-C expression between plaque psoriasis, allergic contact eczema, and normal skin. Epidermal HLA-C expression in normal and eczematous tissue was stronger than in plaque psoriasis. Immunoreactivity in plaque psoriasis was consistently stronger in the basal layer, especially at the tips of rete ridges where the signal often
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Figure 1. HLA-C expression detected by immunohistochemistry with mAb L31. (a) Tonsil, (b) adult colon epithelium, (c) fetal colon epithelium, (d) normal skin, (e) plaque psoriasis, (f) allergic contact eczema (original magnification 20, Bar ¼ 100 mM, insets: 100, Bar ¼ 20 mm) (g) LCL721.221 cells expressing HLA-Cw3 before lipopolysaccharide stimulation, and after (h) 16, (i) 48, and (j) 96 hours post-stimulation (original magnification 40, Bar ¼ 50 mm).
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polarized towards the basement membrane (Figure 1e). Clear pericellular delineation, compatible with membrane staining, was observed in suprabasal keratinocytes of normal and allergic contact eczema (Figure 1f). Not all cell types in skin stained with the L31 anti-HLA-C antibody; fibroblast-like cells were mostly negative. Leukocyte-like cells as well as large dendritic-like cells stained strongly with anti-HLA-C in all sample groups. MHC class Ia expression was intense and had a similar distribution pattern to that of HLA-C, showing less intense staining in the epithelium of plaque psoriasis compared to normal and eczema skin but with relatively stronger immunoreactivity in the basal cell layer. An inverse relationship between the number of infiltrating cells and the average staining density at the basal layer was observed.
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HLA-C protein levels are increased in lesional allergic contact eczema and plaque psoriasis skin
Using the L31 antibody, a band of approximately 45 kDa, compatible with the denatured form of HLA-C, was detected by Western blot in protein extracts from lesional allergic contact eczema, plaque and guttate psoriasis, non-lesional samples for these three sample types, and normal skin samples. The range of HLA-C intensity values among the different samples was between 0.10 and 1.08 expression units. Analysis of variance revealed inter-group differences according to sample category (P ¼ 0.0039). Allergic contact eczema had the most intense HLA-C signal (average expression index ¼ 0.665, standard deviation ( ¼ 0.343), being significantly higher than in the other samples except for plaque psoriasis (average expression index ¼ 0.425, standard deviation ¼ 0.189) (Figure 2a). Overall HLA class I expression assessed by b2-microglobulin staining was also increased in allergic contact eczema compared to the other skin samples (average expression index ¼ 0.256, standard deviation ¼ 0.151, P ¼ 0.0002) (Figure 2b). A representative image of an L31-stained membrane is presented in Figure 3. DISCUSSION The contribution of the PSORS1 locus to psoriasis susceptibility has been a subject of intense research over the past two decades (Bowcock and Krueger, 2005). Although several 344
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HLA-C expression on transfected LCL721.221 cells is inducible with E. coli-derived lipopolysaccharide
In order to determine if HLA-C immunoreactivity correlated with changes in cellular functional state, LCL721.221 cells, which lack HLA class I expression, were used. LCL721.221 cells transfected with HLA-Cw3 and Cw4, as well as, nontransfected cells were stimulated with lipopolysaccharide for up to 96 hours and then tested for reactivity with the L31 antibody. There was a time-dependent increase in the frequency of L31-positive cells in HLA-Cw3 and Cw4 transfectants, which reached a peak at 48 hours (Figure 1g–j). Very faint expression was observed before lipopolysaccharide stimulation for both constructs. No increase in staining intensity or in the frequency of positive cells was observed in non-transfected cells at the set time points.
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Figure 2. HLA-C protein expression levels in total protein extracts from psoriasis, eczema and normal skin biopsies. (a) Box plot representation of HLA-C expression according to sample group, measured by densitometry on Western blot analysis. (b) Box plot representation of HLA class I expression, measured by densitometry on Western blot analysis and detected by b2microglobulin staining. LE ¼ lesional eczema, LG ¼ lesional guttate psoriasis, LP ¼ lesional plaque psoriasis, N ¼ normal, NLE ¼ non-lesional eczema, NLG ¼ non-lesional guttate psoriasis, NLP ¼ non-lesional plaque psoriasis.
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Figure 3. Representative Western blot membrane showing total protein smears and specific HLA-C bands. (a) Ponceau staining of the skin protein extracts after transfer to a membrane. (b) Specific L31 signal. C ¼ Control, LE ¼ lesional eczema, LG ¼ lesional guttate psoriasis, LP ¼ lesional plaque psoriasis, N ¼ normal, NLE ¼ non-lesional eczema, NLG ¼ non-lesional guttate psoriasis.
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genes in this locus are expressed in skin, some with differential expression between psoriasis and normal skin (HCR, CDSN), there is no conclusive explanation about their functional role in psoriasis pathogenesis (Bowcock, 2005). HLA-C has been considered a susceptibility gene in itself or a genetic marker in linkage disequilibrium with a psoriasis gene that has not yet been identified (Helms et al., 2005). If intrinsic defects in this gene are at the base of psoriasis pathogenesis then there should be evidence of altered HLA-C expression or function, otherwise this molecule might facilitate the effect of third party factors such as autoantigens. Expression analysis has been critical to understanding the role of HLA-C in other contexts than psoriasis but with the common denominator of immune regulatory functions for this molecule. For example, soluble MHC class I molecules seem to regulate lymphocyte survival through apoptosis, tumors can evade immune surveillance by modifying expression of MHC class I molecules, and HLA-C specifically contributes to regulate maternal immune reactivity against fetal tissues (Le Bouteiller, 2001; Puppo et al., 2002; GarciaLora et al., 2003). Global expression studies of RNA and protein do not indicate differential expression of HLA-C in psoriasis compared with normal or non-lesional skin (Zhou et al., 2003; Bowcock, 2005; Carlen et al., 2005), incongruent with HLA-C being a psoriasis susceptibility gene. However, qualitative as well as quantitative differences are important in defining the role of HLA-C in psoriasis pathogenesis. Different patterns of expression can emerge even in the presence of similar levels of total RNA or protein. Our findings indicate that HLA-C expression in psoriasis depends predominantly on infiltrating inflammatory cells, whereas non-lesional and normal samples express higher levels of the protein in the epidermis. It is expected that all nucleated cells express MHC class Ia molecules because they contribute to preserving peripheral self tolerance under normal circumstances, that is, no inflammation, no infection (Zimmer et al., 2005). However, it is also expected that the constitutive expression of HLA-C should be low (Neisig et al., 1998). The present study demonstrated intense staining on infiltrating inflammatory cells and variable expression levels in the epidermis. The most striking feature of the HLA-C staining pattern in this study was the polarization of the signal towards the basement membrane and the reduced expression on suprabasal keratinocytes in lesional psoriasis samples. It is known that overexpression of MHC class I molecules can downregulate effector immune cell functions (Parham, 2004); therefore, reduced expression in psoriasis epithelium might contribute to maintaining inflammation owing to inefficient downregulation of activated lymphocytes. Why would HLA-C be restricted to the basal layer in psoriasis epidermis? MHC class I clustering into lipid rafts has been reported as a requirement to binding T-cell receptors (Lebedeva et al., 2004) and lymphocytes are known to home towards the skin during psoriasis plaque formation (Davison et al., 2001), but how these cells interact with the epithelium is less well documented. HLA-C polarization in psoriasis epidermis might lead to a directional flow of inflammatory
cells towards the tip of papillae, above which microabscesses are typically formed (Kaneko et al., 1991). A relevant observation regarding this possibility is that the inflammatory infiltrate in psoriasis does not seem to affect the structure of the basal cell layer, except at the uppermost section of papillae where HLA-C expression seems lower. In contrast, the basal cell layer in eczema is characterized by infiltrating inflammatory cells throughout the epidermis. We attempted to measure the HLA-C signal intensity at the basal layer of psoriasis papillae and counted the number of infiltrating cells through this layer; we observed an inverse relationship between these variables (data not shown). Since some class I molecules, including HLA-C, are strong inhibitors of T and NK cells, the reduced epithelial HLA-C expression might lead to increased vulnerability to inflammation (Carosella et al., 2001; Le Discorde et al., 2002; Trowsdale and Betz, 2006), therefore the polarized HLA-C expression might be a compensatory mechanism to reduce lymphocyte infiltration. Support for this view comes from reproduction research indicating that HLA-C and KIR mismatches appear to fail at inhibiting NK/NK-T cells in pre-eclampsia, (Hiby et al., 2004; Parham, 2004). Also in idiopathic bronchiectasis, combinations of HLA-C and KIR associate with the progressive inflammatory damage to the lungs (Boyton et al., 2006). In addition, viral regulation of class I gene expression plays a role in viral persistence; for example, the UL18 protein from cytomegalovirus can induce HLA-C expression and inhibit HLA-A and B, which can inhibit antiviral NK/NK-T cell responses (Gewurz et al., 2001). There is mounting evidence indicating that immune surveillance of HLA-C by KIR-positive cells might be a contributing factor to psoriasis pathogenesis (Martin et al., 2002; Luszczek et al., 2004; Holm et al., 2005), but functional studies on this subject are still lacking. However, it is important to remember that an antigen-driven theory of psoriasis has been extensively discussed, where HLA-Cw6 is regarded as a cofactor in the initiation and/or maintenance of inflammation (Nickoloff et al., 2000; Lin et al., 2001; Johnston et a.l, 2004). What would be particular about HLA-Cw*0602 compared to other HLA-C alleles in this scenario? It is known that HLAC expression varies in relation to the identity of the coding alleles, but it is not yet known if HLA-Cw*0602 has unique features that would affect its protein expression. Although this study does not specifically target the psoriasis-associated allele HLA-Cw*0602, it shows that HLA-C expression in normal tissues varies depending on developmental stage and histological location and reveals that skin epithelium expresses HLA-C. The distinct HLA-C expression patterns in psoriasis and eczema suggest a functional role in the specific psoriasis immune response and not only a general feature of inflammation. It will be important to obtain a detailed description of coding and non-coding sequences of all alleles in order to identify differences at regulatory sites and design functional studies that compare HLA-Cw*0602 to other alleles. This will increase our understanding of the role of HLA-C in psoriasis pathogenesis. www.jidonline.org
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MATERIALS AND METHODS Tissue samples Details regarding patients and controls were reported previously (Carle´n et al., 2005). All study subjects provided written consent and all research procedures were performed in accordance with the Declaration of Helsinki Principles and with permission from the Ethics Committee of the Karolinska Institutet. Biopsies were taken from lesional and non-lesional skin from guttate and plaque psoriasis patients, lesional and non-lesional skin from nickel-induced contact eczema patients, and normal skin of healthy individuals. For immunohistochemistry, five normal, 12 plaque psoriasis, three non-lesional plaque psoriasis, five lesional eczema, and five nonlesional eczema samples were analyzed. In addition, one tonsil sample from a guttate psoriasis patient affected by recurrent streptococcal throat infections, two normal adult colon and one fetal colon samples were used for immunohistochemistry. For Western blot analysis, 10 normal, 12 plaque psoriasis, three nonlesional plaque psoriasis, seven guttate psoriasis, four non-lesional guttate, five lesional eczema, and four non-lesional eczema samples were considered.
Antibodies The following antibodies were used: (1) Murine mAb L31 which binds linear a1 domain epitope at position 67 of human HLA-C alleles Cw1 through Cw8 and HLA-B8 and B51 (Setini et al., 1996). Alleles from Cw9 to Cw17, and B8 and B51 do not associate with psoriasis, therefore, under-or overestimation of expression levels is expected to cancel out between patients and controls. (2) Murine mAb W6/32 (Serotec, Oxford, UK) (Brodsky et al., 1979) which binds MHC class I heavy chain associated with b-2-microglobulin. (3) Murine mAb MCA2243 (NKVFS1) (Serotec) (Spaggiari et al., 2002) which recognizes a common epitope on CD158a and CD158b (KIR2DL1, KIR2DL2), and (4) horse radish peroxidaseconjugated rabbit polyclonal P0174 (DakoCytomation, Glostrup, Denmark) which binds human b2m. As secondary antibody, horse radish peroxidase-conjugated goat anti-mouse IgG (Santa Cruz, sc-2005) was used.
Sample preparation Skin biopsies were prepared as described previously (Carle´n et al., 2005). In brief, the biopsies were kept frozen in liquid nitrogen and mechanically homogenized using a mortar and pestle. The samples were then solubilized in a buffer containing 7 M urea, 2 M thiourea, 4% SDS, reducing agents, and protease inhibitors. Protein concentration was determined using the Bradford method (BioRad Protein Assay, BioRad, Stockholm, Sweden) (Bradford, 1976).
Western blot Total protein extracts were separated, adding 7 mg of each sample to 12% SDS-PAGE gels, and then electroblotted onto nitrocellulose membranes (Whatman Schleicher & Schuell, Kent, UK). The membranes were then stained with 1% Ponceau S (Sigma, St Louis, MO) and scanned to check for loading and gel run quality. After blocking with 2% goat serum (Vector Laboratories, Burlingame, CA) and 1% BSA (Sigma, St Louis, MO) in Tris-buffered saline for 1 hour, the membranes were incubated separately overnight with L31, W6/ 32, MCA2243, or b2m antibody diluted 1:500 in TBS with 1% Tween 20. The membranes were then incubated with horse radish 346
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peroxidase-conjugated goat anti-mouse IgG (Santa Cruz Biotechnology, Santa Cruz, CA) (except for b2m) diluted 1:2,000 in blocking buffer followed by development using enhanced chemiluminescence (Amersham Pharmacia Biotech, Sunnyvale, CA) and the image acquired with a CCD camera (Fujifilm, Sendai, Japan). The immunoreactivity of the HLA-C and b2m antibodies was tested against recombinant HLA-C and b2-microglobulin. Unspecific binding of the secondary antibody was prevented by pre-incubation in normal goat serum.
Immunohistochemistry All biopsies were snap-frozen and stored at 701C until further processed. Skin samples from lesional and non-lesional eczema and plaque and guttate psoriasis, and healthy skin were included in the same experiments. In short, 6–7-mm thick cryostat sections were incubated with L31, W6/32, and MCA2243 antibody at 1:200, 1:20,000, and 1:200 dilutions, respectively. All sections were stained using the avidin: biotinylated enzyme complex technique (Vector Laboratories, Burlingame, CA) following the manufacturer’s instructions, and counterstained with Gills III hematoxylin solution. As controls, tissue sections were processed in parallel without adding primary antibody. No reactivity for secondary antibodies or signal developing reagents was observed on control histological sections.
Cell culture LCL721.221 cells were maintained in DMEM (Gibco-BRL Life Technologies, Paisley, UK) supplemented with 10% FCS (fetal calf serum; Hy-Clone, Boule Nordic AB Huddinge, Sweden) and antibiotics (PEST _ penicillin 50 U/l and streptomycin 50 mg/ml; Gibco-BRL) at 5% CO2 at 371C. HLA-Cw3 and Cw4 transfectants were kept under G418 (GibcoBRL) selection. During stimulation experiments, about 105 cells/well were grown in 12-well plates without selection with G418 for 2 days and then exposed to 1 mg/ml E. coli-derived lipopolysaccharide. HLA-C expression was detected with the L31 antibody at time 0 and 16, 48 and 96 hours after stimulation. The cells were then transferred to slides, fixed with ethanol, and further processed as described in the immunohistochemistry section above.
Data analysis Image analysis was carried out using Science Lab 99 L Process software, version 1.95 (Fujifilm, Sendai, Japan). Intensity measurements of specific signals were corrected by the total amount of protein in their corresponding lanes as derived from measurement of Ponceau staining intensities of the membranes. Variations in luminosity between images were adjusted by using an HLA-Cpositive cell line as internal control on every membrane and the density values were adjusted using the following formulae: Expression Index ¼ (corrected sample reading)/(corrected Ponceau reading). Corrected sample reading ¼ (sample density (Strongest intergel control/sample’s gel control)) Corrected Ponceau reading ¼ reading of control lane/sum of readings from all lanes in gel Statistical analysis was performed using the R language and statistics package (Ihaka and Gentleman, 1996). Mean expression indexes from different sample groups were compared by fitting a
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one-way analysis of variance model to the data, assuming a significance level of 0.05. Then a paired t-test was performed in order to identify comparisons with significant differences. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS We thank Dr Eniko¨ Sonkoly for critically reviewing this manuscript, AnnaLena Kastman for skilful technical assistance with immunohistochemistry, Dr Gunther Weber for providing HLA-C-positive cell lines and for assistance with immunoblotting, Dr Alberto Beretta for providing us with the L31 HLA-C antibody, Dr Jack Strominger, and Dr Hugh Reyburn for providing HLA-C constructs, and Dr Kalle Malmberg and Dr Hans Gustav Ljunggren for HLA-C transfected LCLs. This study was supported by funds from the Swedish Research Council, the Swedish Heart and Lung Foundation, the Swedish Psoriasis Association, A˚ke-Wibergs foundation, Serono, Biogen, Schering-Plough, the National Psoriasis Foundation, Karolinska University Hospital, and Karolinska Institutet.
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Journal of Investigative Dermatology (2007), Volume 127
