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

BACKGROUND: 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. OBJECTIVES: To identify specific features of the PPP inflammatory cell infiltrate and mediators of inflammation, which might provide insight into the pathogenesis and possible future treatment of the disease. METHODS: Skin biopsies were taken from 23 patients with typical PPP (23 from involved skin and seven from noninvolved skin) and from 18 healthy controls (10 nonsmokers, eight smokers). Cell infiltrates and inflammation mediators were studied with immunohistochemistry. RESULTS: A strong inflammation was observed in lesional skin of PPP. Our main findings of Langerhans cells and interleukin-17 close to or in the acrosyringium differs from findings in psoriasis vulgaris. Other inflammatory cells such as CD4+, CD8+, regulatory T cells and CD11a+ cells were also accumulated close to the sweat duct in epidermis and papillary dermis. More CD4+, CD8+, Langerhans cells, plasmacytoid dendritic cells and a higher proportion of regulatory T cells/CD3+ cells were seen in noninvolved palmar skin from patients with PPP compared with healthy controls. CONCLUSIONS: Our novel findings indicate that the inflammation in PPP is initiated by the 'stand-by' innate immune system at the acrosyringium.

Antibodies against hair follicles are associated with alopecia totalis in autoimmune polyendocrine syndrome type I.

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.

Pteridin-dependent hydroxylases as autoantigens in autoimmune polyendocrine syndrome type I.

Autoimmune polyendocrine syndrome type I (APS I) is characterized by autoantibodies, often directed towards tissue-specific enzymes in the affected organs. We have earlier reported the identification of tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) as autoantigens in APS I associated with intestinal dysfunction and alopecia, respectively. These two enzymes, together with phenylalanine hydroxylase (PAH), constitute the group of biopterin-dependent hydroxylases, which all are involved in the biosynthesis of neurotransmitters. A clone encoding PAH was used for in vitro transcription/translation, followed by immunoprecipitation with sera from 94 APS I patients and 70 healthy controls. Of the APS I patients, 25% had PAH antibodies, and no reactivity was detected in the controls. No association with the main clinical components of APS I was found with PAH antibodies. Altogether, 59 sera from the 94 APS I patients reacted with at least one of TPH, TH, or PAH, whereas 35 showed no reactivity. Nineteen of the sera contained antibodies towards all enzymes, 12 to TPH only and 12 to TH only. No sera showed antibodies that reacted to only PAH. An immunocompetition assay demonstrated that the reactivity against PAH represents a cross-reactivity with TPH, whereas antibodies against TPH and TH are directed towards epitopes unique for the two enzymes.

Serum triglycerides are a risk factor for myocardial infarction but not for angina pectoris. Results from a 10-year follow-up of Uppsala primary preventive study.

At a follow-up 7-10 years after a health survey of men born in 1920-1924 in the municipality of Uppsala, 31 of the participants (n = 2322) had died from ischaemic heart disease (IHD). In response to a letter to all men alive in 1980, 106 men declared that they had had a myocardial infarction (MI) (verified or suspected). In 58 cases MI was verified from the hospital records. 28 other men had had typical central chest pain (angina pectoris) only. In another 20 men other diagnoses explained the chest pain for which they were treated in hospital. The health screening values for S-cholesterol and S-triglycerides, blood pressure and smoking habits were analysed in relation to the occurrence of IHD. In this prospective study, smoking, hypertension, S-cholesterol and S-triglycerides were identified as risk factors for fatal and non-fatal MI. The risk factor values were similar in subjects suffering from angina pectoris only to those in subjects who also developed ECG and/or transferase changes, with the exception of S-triglyceride concentration, which was normal in the group with angina pectoris. The subjects who had a fatal MI had a significantly higher blood pressure than those with non-fatal MIs, but otherwise these two groups did not differ. The results emphasize the importance of scrutinizing questionnaire data with regard to chest pain and of selection of end-points when risk factor patterns are described for cardiovascular diseases.

Long-term renal preservation in essential hypertension. Angiotensin converting enzyme inhibition is superior to beta-blockade.

Antihypertensive treatment is known to slow down the decline in glomerular filtration rate (GFR) with time. Angiotensin converting enzyme (ACE) inhibition has been shown to be more effective in this regard than conventional antihypertensive therapy. In a recent prospective, randomized, double blind trial in 257 patients with essential hypertension, the loss of GFR, determined with 51Cr-EDTA clearance, was significantly less with an ACE inhibitor (cilazapril) than with a beta-adrenoceptor blocker (atenolol) during the first year of treatment. However, after 2 years, the two therapies were equally effective in this regard, thereby creating doubts about the long-term superiority of ACE inhibition in this regard. In order to elucidate whether the superior renal preservation with the ACE inhibitor was a transient effect, GFR was measured after 1 more year of treatment, i.e., after 36 months. At that time, the decline in GFR was significantly smaller in the ACE inhibitor group as compared to the beta-adrenoceptor blocker group (-3.0 [-5.5, -1.0; 95% CI] v -7.0 [-9.0, -4.5; 95% CI] mL/min x 1.73 m2; P = .026). This demonstrates that in the treatment of essential hypertension ACE inhibition preserves GFR significantly better than beta-adrenoceptor blockade during long-term therapy.

Inheritance of type-III hyperlipoproteinemia. Lipoprotein patterns in first-degree relatives.

The lipoprotein (LP) patterns were studied in the families of 19 index cases with type-III hyperlipoproteinemia (HLP). Seventy adult first-degree relatives (93% ascertainment) to the 19 probands were analyzed. The diagnosis of HLP type III among the first-degree relatives was based on three criteria, all of which had to be fulfilled to make the diagnosis: (1) presence of a slow-moving band in very-low-density LP (VLDL) on agarose gel electrophoresis migrating in beta or close to beta position; (2) A cholesterol/triglyceride ratio (mg/100 ml: mmoles/liter) in VLDL greater than 29.0; and (3) A "III-index" [cholesterol/triglycerides in VLDL x 10 divided by cholesterol/triglycerides in low-density LP (LDL)] greater than 1.30. When defined according to these criteria there was a marked over-representation of HLP type III among the relatives (27%). There was also an increased frequency of hypertriglyceridemia (28% against expected 15%), mainly because of a high prevalence of HLP type IV (24%). On agarose gel electrophoresis a "late pre-beta" band, probably indicative of an increased amount of intermediary LP particles, was frequently present (47%) among relatives not classified as HLP type III. Type-III patients with hypertriglyceridemia were characterized by a significantly higher body weight than those with normotriglyceridemic type III. However, there was no qualitative difference in the composition of the lipoproteins in normotriglyceridemic and hypertriglyceridemic type-III patients. A genetic analysis of the LP patterns within the families showed several examples of vertical transmission of HLP type III. There was no sex linkage. Six of thirteen analyzed parents showed LP patterns classified as HLP type III. Another two parents were most probably carriers of the gene. Of the siblings to the probands, 23% showed a type-III pattern and another four (7%) showed LP patterns very similar to type III, fulfilling two of three criteria for HLP type III. The data support the concept that HLP type III is inherited as an autosomal dominant gene. It was indicated that HLP type IV with a late pre-beta band in VLDL may represent another expression of the gene for HLP type III. It is suggested that HLP type III may be a pathogenetically heterogenous group of lipid disorders. A separation of type III into two subgroups with low or normal and high LDL cholesterol concentration, respectively, may facilitate the understanding of the inheritance of type III as well as of the pathogenesis behind this LP abnormality.

Cardiovascular risk factors and hearing loss. A study of 1,000 fifty-year-old men.

The hypothesis that cardiovascular risk factors might be of importance in the development of sensori-neural hearing loss was tested in a material of 1000 fifty-year-old men. No significant correlations were found. The present study confirmed the well-known observation that the left ear usually is poorer than the right. Hearing loss in the right ear was found to be related to the smoking habits in the groups with no history of noise exposure. The explanation for this is discussed. Hearing loss was more common in social class 3 than in the other social classes. This difference was principally referable to noise exposure but also to conductive hearing loss. A prospective study of this material will further analyze the question concerning a possible relationship between cardiovascular risk factors and hearing loss.

Dietary and drug treatment of hyperlipidaemia. A feasibility study in asymptomatic middle-aged men.

83 middle-aged men with different types of hyperlipoproteinaemia were recruited from a health examination survey. They were treated with diet for 3 months and with diet and drugs in combination over a 2-year period (63 men used drugs). The serum lipid reductions after the dietary period were 14% and 27% for serum cholesterol and triglycerides, respectively. After 2 years the corresponding reductions were 21% and 42%, indicating an additional effect of diet and drugs. There was an average body weight reduction of 4.3% during the first 3 months which was maintained over the 2-year period. Special considerations in treating asymptomatic individuals are discussed.

Serum lipoprotein concentration and composition in healthy 50-year-old men.

The classification of hyperlipoproteinaemias (HLP) is based on arbitrary limits between "normolipidaemia" and "hyperlipidaemia". 92 randomly selected healthy 50-year-old men were studied regarding serum lipoprotein (LP) lipid composition to define limits for "normality". Cholesterol and triglyceride concentrations were determined and the individual ratios between cholesterol and triglycerides were calculated in the ultracentrifugally isolated LP density classes. A significant linear correlation between cholesterol and triglyceride concentrations was found in the very low density lipoproteins (VLDL) and low density lipoproteins (LDL) but not in the high density lipoproteins (HDL). When different percentile limits for LDL cholesterol and VLDL triglycerides were used as cut-off points for "normality" not only the absolute prevalence but also the relative frequency of different types of HLP was influenced. 26 overweight men studied separately showed significantly increased VLDL cholesterol and triglyceride levels with maintenance of the normal ratio cholesterol/triglycerides of this LP class compared with non-obese subjects. Three different kinds of "extra bands" were occasionally seen on agarose electrophoresis: a "double pre-beta" band in whole serum (3%), a "sinking pre-beta" band with density greater than 1.006 (17%) and a "late pre-beta" band in VLDL (22%). While "sinking pre-beta" is identical with Lp (a) LP the "late pre-beta" band probably represents a certain accumulation of "intermediary particles".

Detection and characterization of hyperlipoproteinaemia in middle-aged men.

Serum lipoprotein (LP) concentrations were determined and LP patterns were classified in 261 middle-aged men, recruited from a health examination survey, with serum lipid values above the 80th percentile of the same population. Individuals with hyperlipoproteinaemia (HLP) and normolipidaemic controls were characterized also regarding family history of cardiovascular disease, socio-economic factors and clinical and laboratory variables. Subjects with HLP type IV-V and IIB were overweight and showed hyperuricaemia and hyperinsulinaemia compared with normolipidaemic controls and subjects with HLP type IIA. The latter showed elevated erythrocyte sedimentation rate. In spite of being overweight, subjects with HLP type III showed normal fasting values of insulin and uric acid in serum and normal early insulin response to intravenous glucose. The glucose tolerance did not differ significantly between the groups. Men with HLP types IV-V had predominantly sedentary occupations, in contrast to those with type IIA. There were significantly more smokers in the groups with HLP type IIB and IV-V than in the control group. Thus, individuals with different types of HLP tend to show different metabolic profiles but also different socioeconomic and clinical patterns, suggesting that exogenous factors are of importance in the expression of the LP abnormalities.

Lipoprotein composition and lipoprotein interrelations in 50-year-old men with hyperlipoproteinaemia.

The serum lipoprotein (LP) composition and LP lipid interrelations were studied in 50-year-old men with different types of hyperlipoproteinaemia (HLP) and in randomly sampled health controls from the same population. The ratio cholesterol/triglycerides in very low density lipoproteins (VLDL)was high in HLP type III. The other types of HLP showed ratios not significantly different from the controls. The low density lipoprotein (LDL) cholesterol concentration was similar in controls, type III and type IV while, by definition, higher values were seen in type II A and II B. All types of HLP showed statistically significantly higher LDL triglycerides than the controls. HLP type II A and II B showed cholesterol/triglyceride ratios in LDL similar to the controls. The corresponding ratio in type IV was lower than in the control subjects but the lowest ratio was seen in type III with a mean value below the 5th percentile of healthy controls. The high density lipoprotein (HDL) cholesterol concentration was decreased in HLP type IV. Apparently elevated HDL triglyceride levels were seen in all types of HLP with the highest mean value in type III. The LP lipid interclass relationships were analysed in the random sample of health men and compared to corresponding relationships in the different types of HLP. Apart from HLP type III and HLP type IV with low LDL cholesterol levels all other types of LP interconversions. Intype IV a significant negative correlation between VLDL concentration and LDL cholesterol concentration and the cholesterol/triglyceride ratio in VLDL. There were no significant correlations between LDL cholesterol concentration and VLDL lipid variables in other types of HLP and normolipidaemia.

Dopamine-beta-hydroxylase and plasma renin activity in twenty hypertensive subjects.

Dopamine-beta-hydroxylase (DBH), the enzyme responsible for the biosynthesis of noradrenalin from dopamine, was assayed in the blood plasma of 20 men with primary hypertension. At the same time plasma was taken for measurement of plasma renin activity. Renin release as well as the plasma level of DBH is dependent upon the activity of the sympathetic nervous system, at least to some extent. A possible relationship between the two enzymes was therefore investigated. However, no relationship could be found in this series of 20 hypertensive patients. Another aim was to study the levels of DBH in venous and arterial blood simultaneously. No difference in the DBH level was found in venous and in arterial blood in 11 patients undergoing heart catheterization.