Eva Hagforsen

Palmoplantar Pustulosis: an Autoimmune Disease Precipitated by Smoking?

Ninety-five percent of patients with palmoplantar pustulosis are smokers at onset of the disease. The aim of this study was to determine whether these patients have serum antibodies to nicotinic acetylcholine receptors (nAChR ab) and if their sera induce a specific immunofluorescence in normal palmar skin. Sera from 45 patients with palmoplantar pustulosis and 23 patients with chronic hand eczema were analysed for muscle nAChR ab, and immunofluorescence was performed on healthy palmar skin. Forty-two percent of the patients with palmoplantar pustulosis but none of the eczema patients had raised levels of nAChR ab. Immunofluorescence showed staining on endothelial cells in the papillary dermis in 47% of all sera from patients with palmoplantar pustulosis and in those with nAChR ab in 68%. On palmar skin from smokers there was also a staining of the sweat duct. Sera from patients with chronic hand eczema were negative. Our findings indicate that palmoplantar pustulosis is an autoimmune disease, possibly induced by smoking.

Patients with palmoplantar pustulosis have increased IL-17 and IL-22 levels both in the lesion and serum

Abstract:u2002 Recent findings about the pathogenesis of pustulosis palmaris et plantaris (PPP), also known as palmoplantar pustulosis, suggest that IL‐17 expression in the acrosyringium as well as infiltration of IL‐17 positive cells, e.g. Langerhans cells may play important roles. However, to date, it has not been established whether circulating IL‐17 related cytokines are involved in PPP. We studied the circulating IL‐17 related cytokines as well as the mRNA levels in lesional skin. IL‐17 related cytokine mRNAs were increased in the PPP lesions compared with the control tissues (five patients vs five controls). The serum levels of TNF‐alpha, IL‐17, IL‐22 and IFN‐gamma also were significantly increased in PPP, but not IL‐23 and IL‐8 (48 patients vs 20 controls). Our findings document that not only the serum IL‐17 but also tissue IL‐17 are elevated in PPP and may be in the pathogenesis of this disorder.

Novel findings of Langerhans cells and interleukin-17 expression in relation to the acrosyringium and pustule in palmoplantar pustulosis

Backgoundu2002 Palmoplantar pustulosis (PPP) is a chronic and intensely inflammatory skin disease with pustules, erythema and scaling localized to the palms and soles. To date, no specific treatment is known. Earlier findings indicate the acrosyringium as the target for the inflammation.

Women with palmoplantar pustulosis have disturbed calcium homeostasis and a high prevalence of diabetes mellitus and psychiatric disorders : A case-control study

Palmoplantar pustulosis is characterized by pustule formation in the acrosyringium. Nearly 50% of palmoplantar pustulosis sera produce immunofluorescence of the palmar papillary endothelium from healthy subjects, but also of the endothelium of normal parathyroid gland. With a case-control design the levels of calcium and parathyroid hormone in serum were measured in 60 women with palmoplantar pustulosis and 154 randomly selected population-based control women. One-third of the controls had been smokers, whereas 95% of the cases were or had been smokers. Mean age-adjusted serum calcium was increased in the patients compared with the controls (2.43 vs 2.36 mmol/l; p<0.0001), whereas the parathyroid hormone concentration was suppressed (23.2 vs 31.1 ng/l; p<0.0001). The plasma levels of parathyroid hormone-related protein were normal in patients but there was a strong expression of this protein in the acrosyringium both in palmoplantar pustulosis and control skin. As even a marginal elevation of serum calcium is associated with an increased risk for diabetes, cardiovascular disease and psychiatric disease, we analysed the risk for these disorders in palmoplantar pustulosis patients compared with that in the control group. Both diabetes mellitus and psychiatric disorders were associated with palmoplantar pustulosis with an odds ratio of 8.7 (95% CI 3.3-22.8) and 5.6 (95% CI 2.2-14.4), respectively. Palmoplantar pustulosis is a complex disease with an increased risk for several non-dermatological disorders. The role of the mildly increased serum calcium for the high risk for diabetes and depression deserves to be studied.

Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis.

Backgroundu2002 An alternative approach to retinoid therapy is to inhibit the cytochrome P450 (CYP)‐mediated catabolism of endogenous all‐trans retinoic acid in the skin by applying retinoic acid metabolism blocking agents such as talarozole (R115866).

Granzyme H Is a Novel Protease Expressed by Human Mast Cells

Background: Many of the functions attributed to mast cells depend on the various pro-inflammatory mediators that are secreted upon mast cell activation. These include a panel of mast cell-specific proteases. In addition, recent studies have indicated that murine mast cells also express granzyme D, a protease previously thought to be confined to cytotoxic lymphocytes. Here, we address the human relevance of the latter findings by investigating whether human mast cells express granzyme H, the granzyme that may represent the functional counterpart to murine granzyme D. Methods: Cord blood-derived mast cells, LAD2 cells and skin mast cells in situ were evaluated for their expression of granzymes using quantitative PCR, Western blot analysis and immunostaining. Mast cells were activated by either calcium ionophore stimulation or IgE receptor cross-linking. Results: Cord blood-derived mast cells and LAD2 cells were shown to express granzyme H and B mRNA, while granzyme A, K and M expression was undetectable. Mast cell activation by either calcium ionophore or IgE receptor cross-linking caused down-regulated expression of granzyme H. In contrast, granzyme B expression was up-regulated by the same stimuli. Granzyme H expression was also confirmed at the protein level, as shown by both Western blot analysis and confocal microscopy. Further, we show that granzyme H is expressed by human skin mast cells in situ. Conclusions: The present findings implicate granzyme H as a novel protease expressed by human mast cells and support earlier findings obtained in natural killer cells suggesting that granzymes B and H are reciprocally regulated.

Ablation of human skin mast cells in situ by lysosomotropic agents.

Mast cells are known to have a detrimental impact on numerous types of inflammatory skin diseases such as contact dermatitis, atopic eczema and cutaneous mastocytosis. Regimens that dampen skin mast cell‐mediated activities can thus offer an attractive therapeutic option under such circumstances. As mast cells are known to secrete a large array of potentially pathogenic compounds, both from preformed stores in secretory lysosomes (granules) and after de novo synthesis, mere inhibition of degranulation or interference with individual mast cell mediators may not be sufficient to provide an effective blockade of harmful mast cell activities. An alternative strategy may therefore be to locally reduce skin mast cell numbers. Here, we explored the possibility of using lysosomotropic agents for this purpose, appreciating the fact that mast cell granules contain bioactive compounds prone to trigger apoptosis if released into the cytosolic compartment. Based on this principle, we show that incubation of human skin punch biopsies with the lysosomotropic agents siramesine or Leu‐Leu methyl ester preferably ablated the mast cell population, without causing any gross adverse effects on the skin morphology. Subsequent analysis revealed that mast cells treated with lysosomotropic agents predominantly underwent apoptotic rather than necrotic cell death. In summary, this study raises the possibility of using lysosomotropic agents as a novel approach to targeting deleterious mast cell populations in cutaneous mastocytosis and other skin disorders negatively influenced by mast cells.

Autoantibodies Targeting a Collecting Duct–Specific Water Channel in Tubulointerstitial Nephritis

Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.

Somatostatin receptors are strongly expresssed in palmoplantar sweat glands and ducts: studies of normal and palmoplantar pustulosis skin

Background.u2002 The acrosyringium is the target for inflammation in the chronic and intensely inflammatory skin disease palmoplantar pustulosis (PPP). The sweat‐gland apparatus seems to be an immunocompetent structure that probably contributes to skin defence. Furthermore, the sweat gland and duct may be a hitherto unrecognized neuroendocrine organ.

Normal and PPP-affected palmoplantar sweat gland express neuroendocrine markers chromogranins and synaptophysin differently

Earlier findings indicate the acrosyringium as the target for the inflammation in the chronic and intensely inflammatory skin disease palmoplantar pustulosis (PPP). The sweat gland apparatus seems to be an immune-competent structure that probably contributes to the defence of the skin. Furthermore, the sweat gland and duct may be a hitherto unrecognized neuroendocrine organ because it expresses cholineacetyl-transferase and acetylcholinesterase, nicotinic receptors, beta-adrenergic and angiotensin receptors. The aim of this study was to obtain further information about neuroendocrine properties of the sweat gland apparatus by examining the expression of common neuroendocrine markers synaptophysin and chromogranins A and B in healthy palmar skin and in PPP skin. Synaptophysin and chromogranins were expressed in the sweat glands and ducts with some variation in the pattern and intensity of the expression. In PPP skin the expression differed, being higher and lower, depending on the part of the sweat duct. Chromogranins were further expressed in the epidermis, endothelium and inflammatory cells, but its intensity was weaker in epidermis than in the sweat gland apparatus. In most cases, chromogranins in epidermis in involved PPP were weakly expressed compared to healthy controls. The presence of synaptophysin and chromogranins in palmoplantar skin may have marked neuroendocrine effects, and the palmoplantar skin is likely to have important neuroimmuno-endocrine properties. Moreover, the altered chromogranin expression in PPP skin might influence both the neuroendocrine and neuroimmunologic properties of palmoplantar skin in these patients. These results indicate important neuroendocrine properties of the palmoplantar skin.