Biomedical subjects
Publications and source records attributed to G Michaëlsson.
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BACKGROUND: A suggested role for nicotine in the pathogenesis of palmoplantar pustulosis (PPP) has been discussed. The target for the inflammation in PPP is the acrosyringium. Nicotine acts as an agonist on nicotinic acetylcholine receptors (nAChRs) and can influence a variety of cellular functions. OBJECTIVES: To study the alpha 3- and alpha 7-nAChR expression in palmar skin of patients with PPP in comparison with that in healthy smoking and non-smoking controls. METHODS: Biopsies from 20 patients with PPP, seven healthy smokers and eight healthy non-smokers were studied by immunohistochemistry with a monoclonal anti-alpha 3 and a polyclonal anti-alpha 7 antibody. RESULTS: In healthy controls both nAChR subtypes showed stronger immunoreactivity in the eccrine glands and ducts than in the epidermis. The papillary endothelium was positive for both subtypes. Epidermal alpha 3 staining was stronger and that of the coil and dermal ducts weaker in healthy smokers than in healthy non-smokers. In involved PPP skin, granulocytes displayed strong alpha 3 immunoreactivity. The normal epidermal alpha 7 staining pattern was abolished in PPP skin and was replaced by strong mesh-like surface staining, most markedly adjacent to the acrosyringium, which in controls was intensely alpha 7 positive at this level. Endothelial alpha 7 staining was stronger in PPP skin than in the controls. CONCLUSIONS: Smoking can influence nAChR expression. The altered nAChR staining pattern in PPP skin may indicate a possible role for nicotine in the pathogenesis of PPP. We hypothesize that there is an abnormal response to nicotine in patients with PPP, resulting in inflammation.
OBJECTIVES: To find out whether patients with psoriatic arthritis (PsoA) have an increased prevalence of antibodies to gliadin (AGA) and of coeliac disease. METHODS: One hundred and fourteen PsoA patients with skin disease of 20+/-13 yr and joint disease of 11+/-10 yr duration answered a questionnaire concerning their medical history and underwent clinical examination, including radiology. Serum IgA AGA and IgG AGA, IgA antibodies to endomysium and immunoglobulins, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration were determined. RESULTS: Five of the 114 patients (4.4%) had coeliac disease. After exclusion of these five patients, the mean IgA AGA concentration was significantly higher (P=0.0005) than that in a reference group. None of the patients had IgA antibodies to endomysium. The mean serum IgA concentration was significantly increased and IgM decreased. Patients with a high concentration of IgA AGA had significantly higher ESR and CRP and a longer duration of morning stiffness than those with a low AGA concentration. CONCLUSIONS: Patients with PsoA have an increased prevalence of raised serum IgA AGA and of coeliac disease. Patients with raised IgA AGA seem to have more pronounced inflammation than those with a low IgA AGA concentration.
Patients with palmoplantar pustulosis (PPP) frequently report that stress worsens their condition. A study was therefore made of the distribution and number of nerve fibres positive for protein gene product (PGP) 9.5 (a general nerve marker) and nerve fibres with substance P- and calcitonin gene-related peptide-like immunoreactivity in involved skin from patients with PPP and in skin from healthy controls. The number of mast cells in the papillary dermis was larger (P = 0.0003) in lesional palmar PPP skin than in control skin, and the number of contacts between mast cells and nerve fibres was significantly larger (P = 0.02) in PPP skin than in control skin. Image analysis of the nerve fibres around the sweat glands showed that the positively stained area as a percentage of the total area of the sweat gland (coil + surrounding nerves) was significantly lower in PPP skin (P = 0.0006). Furthermore, the nerves seemed to be fragmented. Neutrophils within and below the pustules and in the papillary dermis showed positive substance P staining. The increased number of contacts between nerves and mast cells in PPP skin and the intense substance P-like immunoreactivity of the neutrophils indicate that neuromediation may influence the inflammation in PPP, whereas the destruction of the nerve fibres around the sweat glands might be a result of the inflammation.
In a previous screening study, 16% of patients with psoriasis had IgA and/or IgG antibodies to gliadin (AGA). The aim of the present study was to evaluate the effect of a gluten-free diet (GFD) in 33 AGA-positive and six AGA-negative psoriasis patients. Of the 33 AGA-positive patients, two had IgA antibodies to endomysium (EmA) and 15 an increased number of lymphocytes in the duodenal epithelium, but in some this increase was slight. Two patients had villous atrophy. A 3-month period on a GFD was followed by 3 months on the patient's ordinary diet. The severity of psoriasis was evaluated with the psoriasis area and severity index (PASI). The examining dermatologists were unaware of the EmA and duodenal biopsy results throughout the study. Thirty of the 33 patients with AGA completed the GFD period, after which they showed a highly significant decrease in mean PASI. This included a significant decrease in the 16 AGA-positive patients with normal routine histology in duodenal biopsy specimens. The AGA-negative patients were not improved. After GFD, the AGA values were lower in 82% of those who improved. There was a highly significant decrease in serum eosinophil cationic protein in patients with elevated AGA. When the ordinary diet was resumed, the psoriasis deteriorated in 18 of the 30 patients with AGA who had completed the GFD period. In conclusion, psoriasis patients with raised AGA might improve on a GFD even if they have no EmA or if the increase in duodenal intraepithelial lymphocytes is slight or seemingly absent.
The distribution of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in involved skin in patients with palmoplantar pustulosis (PPP) and in normal palmar skin in healthy non-smokers and smokers has been studied by immunohistochemistry, especially in relation to the sweat gland apparatus. The sweat gland and its duct showed ChAT- and AChE-like immunoreactivity (LI) of varying intensity in all three groups and with stronger reactivity than in the epidermis. ChAT-LI was present in the coil and in the duct except in the corneal layer. Smokers and patients with PPP displayed significantly fewer ChAT+ acrosyringia than non-smokers. In the patients with PPP, the granulocytes in the pustules and in the papillary dermis displayed ChAT-LI. Western blot analysis of granulocytes from peripheral blood from healthy donors confirmed the presence of ChAT-like proteins in large amounts in neutrophils and small amounts in eosinophils. AChE-LI of varying intensity was found in all parts of the sweat gland apparatus in all three groups. The strongest AChE-LI in the acrosyringia was seen in the lowest part of the stratum corneum, where the PPP pustules are located. No significant differences in staining pattern or intensity were found between the coils, nerve fibres surrounding the coils or ducts. The number of mast cells in the papillary dermis was about four times larger in the patients with PPP than in the control subjects. AChE-LI was observed in about 25% of the mast cells in non-smoking control subjects and in patients with PPP, but only in 10% of those in the smoking control subjects. Our findings indicate that the (non-neuronal) cholinergic system may be involved in cutaneous inflammatory processes.
In the autosomal recessively inherited autoimmune polyendocrine syndrome type I (APS I) patients have autoantibodies directed against several endocrine and nonendocrine organs. Alopecia areata is present in about one-third of the patients and usually in the more severe forms, alopecia universalis or totalis. Sera from 39 patients with APS I, diluted 1:150, were used in indirect immunofluorescence staining of cryo-sections from normal human scalp. Two hair follicle staining patterns were observed. A cytoplasmic staining of the differentiating matrix, cuticle, and cortex keratinocytes in the anagen hair follicle was seen in five (13%) APS I sera. All these five patients had alopecia totalis, representing 63% of the eight patients with alopecia totalis (p < 0.0001). Furthermore, four (10%) of the APS I sera stained the nuclei of the melanocytes in the hair follicle. Two of these patients had vitiligo. None of 20 healthy control sera stained the keratinocyte cells or the melanocyte nuclei. These data show that many patients with APS I have high-titer autoantibodies directed against the anagen matrix, cuticle, and cortex keratinocytes and a melanocyte nuclear antigen, and also that the hair follicle keratinocyte staining is associated with alopecia, especially alopecia totalis. This study emphasizes the role of the differentiating anagen keratinocytes as an important structure in the autoimmune etiology of alopecia, both in APS I and at least in a subgroup of patients with alopecia areata unrelated to APS I.
Pustulosis palmoplantaris (PPP) is a common chronic skin disease, which is very resistant to treatment. It is not known why the lesions are located in the palms and soles. There are few studies of the disease and in particular studies of the histology. Fifty-nine patients with PPP answered a questionnaire concerning their medical history and 39 of them were clinically examined. Biopsy specimens were taken from involved skin in 22 of the 39 patients and studied immunohistologically for tryptase+ mast cells, EG2+ eosinophils, lipocalin+ neutrophils and CD3+ T lymphocytes. The sweat gland and sweat duct were visualized with AE1/AE3 antibody (cytokeratins 1-8, 10, 14/15, 16, 19). In addition to neutrophils in the pustule and lymphocytes in the upper dermis, there were also large numbers of mast cells and eosinophils in the subpustular area. Numerous eosinophils were present in the pustule. The epidermal part of the eccrine duct was not detectable in any of the specimens from patients with PPP but was present in all of the nine control persons (including two smokers). The results indicate that the acrosyringium is involved in the inflammation and also that mast cells and eosinophils participate in a hitherto unknown way. Of the 39 patients clinically examined, two had previously diagnosed thyroid disease and two had gluten hypersensitivity. Seventeen had one or several abnormal serum concentrations of thyroid-stimulating hormone, thyroxin, antibodies against thyroglobulin or thyroperoxidase and 10 had immunoglobulin (Ig) A antibodies to gliadin. The mean +/- SD for serum IgA and for eosinophil cationic protein was increased. From the questionnaire the most notable finding was that 56 of the 59 patients had been or still were smokers, all of whom had started smoking before the first signs of PPP. We hypothesize that the acrosyringium might be the target for the inflammation and that PPP is linked to autoimmune thyroid disease and smoking.
The aim of this work was to study tryptase+ mast cells and CD3+ T lymphocytes in non-involved skin in psoriasis and their possible relation to mast cells and lymphocytes in the duodenal mucosa. Skin biopsy specimens were obtained from 43 patients with psoriasis of variable severity and from 10 healthy subjects. Compared with the reference subjects, the number of mast cells in non-involved skin was clearly increased, most markedly in the papillary dermis. The increase was present both in mild, moderate and severe psoriasis. CD3+ lymphocytes were increased in non-involved skin in moderate and severe psoriasis. Patients with an increased number of duodenal intraepithelial lymphocytes had significantly more mast cells in non-involved skin than those without such an increase, and there was a significant correlation between the number of mast cells in non-involved skin and score for intraepithelial lymphocytes. However, when the 14 patients with increased intraepithelial duodenal lymphocytes were excluded-as they may represent a separate type of psoriasis-another type of correlation between the skin and the duodenal mucosa was found, namely a highly significant inverse correlation between the number of CD3+ lymphocytes in non-involved skin and the number of duodenal mast cells, which is highly elevated in psoriasis. The results might indicate an interplay between skin and intestinal mast cells and lymphocytes in a hitherto unknown way.
We have shown that the number of tryptase-positive mast cells in the duodenal mucosa in psoriasis is increased and that a subgroup of psoriasis patients showed elevated levels of antibodies to gliadin (some of whom also had increased lymphocytes in the duodenal epithelium). Duodenal biopsy specimens from 37 patients with psoriasis (eight mild, 13 moderate and 16 severe) and 22 patients with irritable bowel syndrome (IBS) were examined regarding the presence of tryptase + mast cells. Intraepithelial infiltration by lymphocytes was evaluated and scored from 0 to 3. Patients with psoriasis had 131 +/- 58 mast cells/mm2 (mean +/- SD) and those with IBS 28 +/- 18. Only in four of the 37 psoriasis patients was the number within the range of that in the IBS group. There were no signs of stromal inflammation except in one psoriasis patient. No relationship was found between degree of severity of psoriasis and number of mast cells. In 25 of the 37 specimens from psoriasis patients there was no increase in intraepithelial lymphocytes, whereas seven showed a slight increase (score 1-2) and five a moderate increase (score > or = 2-3). The number of tryptase + mast cells was similar in patients with or without increased intraepithelial lymphocytes. The number of mast cells showed no relation to the presence or absence of antibodies to gliadin. We hypothesize that there are at least two types of abnormalities in the duodenal mucosa in psoriasis, one type that is present in most psoriasis patients and characterized by an increase in mast cells and eosinophils, and another that is present in a subgroup of patients with antibodies to gliadin and an increased number of duodenal intraepithelial lymphocytes. The mechanisms underlying the increase in the number of mast cells and its relevance are not yet known.
The occurrence of EG2-positive (EG2+) eosinophils and IgE in biopsy specimens of duodenal mucosa and skin from 39 psoriasis patients was studied, with emphasis on the relation to serum eosinophil cationic protein (ECP), serum IgE and the presence or absence of serum IgA and IgG antigliadin antibodies. Psoriasis patients had significantly elevated serum levels of ECP even after exclusion of five of 37 sera which were Phadiatop positive. The elevated serum ECP was not associated with the presence of IgA or IgG antibodies to gliadin. After exclusion of Phadiatop positive sera the serum IgE values did not differ from those of a group of healthy blood donors. Patients with psoriasis had a pronounced increase of EG2+ cells in their duodenal stroma. Patients without antibodies to gliadin tended to have even more EG2+ cells than those with such antibodies and those with increased duodenal intraepithelial lymphocytes. IgE+ cells were present in most duodenal specimens, and in some specimens there were > 100 IgE+ cells/section. The number of EG2+ cells was increased in lesional skin and, in some patients, also in non-involved skin, but there was a more pronounced increase in EG2 reactivity in the duodenal than in the skin specimens. IgE reactivity was increased both in non-involved and involved skin and was significantly related to the number of IgE-positive cells in the duodenal stroma. The results of this study indicate that the gastrointestinal tract and the eosinophil granulocyte might be involved in psoriasis in a hitherto unknown way.
The function of the fixed macrophage system in 18 psoriasis patients was evaluated by measuring the elimination rate of injected autologous erythrocytes coated with iC3b or IgG. The mean half-life of iC3b-coated erythrocytes was significantly prolonged in patients with psoriasis compared with healthy controls (4.7 +/- 0.8 vs 2.7 +/- 0.2 min, P = 0.01). There was also a decrease in the total number of cells eliminated from the circulation (2.5 +/- 0.2 x 10(8) vs 3.3 +/- 0.2 x 10(8), P = 0.01). There was an even more pronounced increase in the half-life of IgG-coated erythrocytes (85 +/- 18 vs 20 +/- 5 min, P < 0.001), with normal values in only 5 of 15 patients, and 4 of these 5 patients were receiving systemic treatment. The slow elimination was interpreted as being caused by primary or secondary defects in receptor function rather than by blocking of the receptors by immune complexes, since patients with psoriasis show normal levels of circulating immune complexes. Further studies are needed to elucidate the nature of these defects.
In a screening study concerning IgA and IgG antibodies to gliadin (IgA AGA and IgG AGA, respectively) in psoriasis, raised levels of IgA and AGA were found to be more common than in a reference group. To determine whether elevated AGA levels were associated with an increased number of intraepithelial lymphocytes, 33 patients with IgA AGA (n = 28) or IgG AGA (n = 5) values above 90% of the reference values (> 50 units/ml IgA AGA and < 12 units/ml IgG AGA) underwent gastroduodenoscopy and duodenal biopsy in a prospective study. For comparison, six patients with low levels of both IgA AGA and IgG AGA were included. Five biopsy specimens were taken in each patient. Paraffin-embedded specimens were examined with regard to the degree of intraepithelial lymphocyte infiltration, and scored from 0 to 3. Biopsy specimens with a score of 0 had one mononuclear cell or less per four epithelial cells. The specimens were also examined with regard to the presence of intraepithelial CD3+ T lymphocytes and gamma/delta+ T lymphocytes. In the six patients with low IgA AGA and low IgG AGA, the biopsy score was 0. Fourteen of the 33 patients with raised AGA had a score of > or = 1; of these, 12 had raised IgA AGA and two had slightly raised IgG AGA. Two of the patients with raised IgA AGA had partial villous atrophy, but the majority had normal villous architecture. There was a significant correlation both between the biopsy score and the number of intraepithelial CD3+ cells and between the score and the number of intraepithelial gamma/delta+ positive T lymphocytes. The serum IgA AGA levels were significantly correlated with the duodenal biopsy score, the number of intraepithelial gamma/delta+ T lymphocytes, and the number of CD3+ intraepithelial T lymphocytes. Most patients had no, or only mild, gastrointestinal symptoms. Of the 14 patients with biopsy scores > or = 1, seven had severe psoriasis and five moderately severe psoriasis, whereas only two had mild psoriasis. There was no relationship between the duodenal score and haemoglobin, folate, whole blood selenium or serum zinc levels. Some of these patients improve on a gluten-free diet, but it is still too early to draw any definite conclusions concerning the type of relationship between the skin lesions, the increased number of intraepithelial lymphocytes in the duodenal mucosa and gluten hypersensitivity.
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It was recently observed that in six patients with psoriasis and one with palmoplantar pustulosis, with newly discovered gluten intolerance, a gluten-free diet had a remarkable effect on the skin lesions. This prompted us to undertake a screening investigation to discover whether increased levels of serum antibodies to gliadin are more common in patients with psoriasis than in healthy persons. IgA and IgG antibodies to gliadin (IgA AGA and IgG AGA) were quantified by a micro-ELISA method. Out of 302 patients with psoriasis, 16% (18 females, 31 males) showed serum IgA AGA levels above the 90th percentile value (51 u/ml) of the reference group. This tendency was even more marked when the proportion of patients with values > 70 u/ml was compared with the corresponding proportion of 99 reference subjects. Thus, 3% of the reference subjects but 7.9% of the patients had values > 70 u/ml. The corresponding figures for men were 1.6% and 8.9%, respectively. Men with psoriasis had a significantly higher mean IgA AGA than the male reference group. The means based on logarithmic values of the individual IgA AGA values were significantly higher in the psoriatic groups than in the reference groups. Although the mean level of IgG AGA was not increased in the psoriasis group, there was a correlation between the values for IgA AGA and IgG AGA. The serum concentrations of IgG, IgA and IgM were also measured. In the male patients, the mean IgA value was significantly increased. Women in whom IgA AGA was elevated also showed a significantly increased mean IgA.(ABSTRACT TRUNCATED AT 250 WORDS)
Topical treatment with retinoic acid (tretinoin, vitamin A acid) has been reported to partly reverse signs of photodamage. To determine whether the histochemical distribution of hyaluronan (hyaluronic acid, HYA) in the epidermis and dermis and the amounts of HYA and retinoic acid in suction blister fluid were influenced by such topical treatment, 14 subjects healthy apart from moderate photodamage were instructed to treat the lateral forearm with 0.01-0.05% retinoic acid cream for 6 months. In a study of the short-term effects, another six subjects applied 0.05% retinoic acid cream for 2 weeks. After 6 months the thickness of the vital epidermis had increased by 23%. The HYA staining was based on a specific immunohistochemical method in which hyaluronan-binding protein is used. Before treatment HYA was seen as a meshwork around the cells in the upper half of the stratum spinosum. After 6 months of treatment this meshwork had increased in thickness by 31% compared with pretreatment specimens. The HYA staining was already intense in the papillary dermis before treatment and no difference was observed after 6 months' treatment. The mean concentration of HYA in blister fluid had increased significantly (43%) after 2 weeks of treatment whereas after 6 months there was no significant difference in this respect between the treated and untreated arm. The increase in the thickness of the epidermal HYA meshwork after 6 months and the blister fluid HYA after 2 weeks may indicate that HYA is involved in the epidermal change induced by topical retinoic acid therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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