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.

The transcription factors SOX9 and SOX10 are vitiligo autoantigens in autoimmune polyendocrine syndrome type I.

Vitiligo is common in the hereditary disorder autoimmune polyendocrine syndrome type I (APS I). Patients with APS I are known to have high titer autoantibodies directed against various tissue-specific antigens. Using sera from APS I patients for immunoscreening of a cDNA library from human scalp, we identified the transcription factors SOX9 and SOX10 as novel autoantigens related to this syndrome. Immunoreactivity against SOX9 was found in 14 (15%) and against SOX10 in 20 (22%) of the 91 APS I sera studied. All patients reacting with SOX9 displayed reactivity against SOX10, suggesting shared epitopes. Among the 19 patients with vitiligo, 12 (63%) were positive for SOX10 (p < 0.0001). Furthermore, three of 93 sera from patients with vitiligo unrelated to APS I showed strong reactivity against SOX10, which may indicate a more general role of SOX10 as an autoantigen in vitiligo.

Autoimmune polyendocrine syndrome type 1 (APS I) in Norway.

OBJECTIVE: The aim of the present study was to investigate Norwegian patients with autoimmune polyendocrine syndrome type I (APS I), with respect to occurrence and clinical presentation, reactivity towards different autoantigenes and mutations in the autoimmune regulator (AIRE) gene. PATIENTS: Twenty Norwegian patients from 15 families with APS I (11 males, nine females; mean age 26 years, range 4--54) were included by contacting all major hospitals in Norway. METHODS: Clinical data was collected from both patients and their physicians by the use of questionnaires and patient records. Autoantibodies were analysed using radioimmunoassays based on antigen synthesized by in vitro transcription and translation. AIRE mutations were determined by DNA sequence analysis. RESULTS: The prevalence of APS I in Norway was estimated to be about 1 : 80,000 individuals. We found about the same distribution of disease characteristics as has been reported in Finnish patients. The diagnosis was delayed in many individuals. In two thirds of the cases, the patients were admitted in Hospital with acute adrenal insufficiency or hypocalcaemic crisis. Forty percent of these patients already had one of the main disease manifestations. Four different mutations in the AIRE gene were found in the Norwegian cohort. A 13-bp deletion in exon 8 (1085--1097(del)) was the most frequent mutation, present in 22/40 (55%) of the alleles. Eighty-five percent of the patients had either autoantibodies against 21 hydroxylase or aromatic L-amino acid decarboxylase. Five of eight women (age > 13 years) had ovarian failure, and all of these had antibodies against side-chain cleavage enzyme (P = 0.0002). CONCLUSION: Norwegian patients with APS I clinically resemble patients from Finland and other European countries. The diagnosis APS I must be considered in children and adolescents with chronic mucocutaneous candidiasis, autoimmune adrenocortical failure or hypoparathyroidism in order to avoid fatal complications. Analysis of autoantibodies and mutational analysis of the AIRE gene are valuable diagnostic tools, especially in the early stages of the disease.

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.

Identification of tyrosine hydroxylase as an autoantigen in autoimmune polyendocrine syndrome type I.

Patients with the autosomal recessively inherited autoimmune polyendocrine syndrome type I (APS I) have autoantibodies directed against several endocrine and nonendocrine organs. In this study a new autoantigen related to this syndrome, tyrosine hydroxylase, was identified in sera from patients with alopecia areata through immunoscreening of a scalp cDNA library. Immunoreactivity against in vitro expressed tyrosine hydroxylase was found in 41 (44%) of the 94 APS I patients studied and this reactivity correlated with the presence of alopecia areata (P = 0.02). These findings further stress the importance of enzymes involved in neurotransmitter biosynthesis as important immune targets in APS I.

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.

Identification of tryptophan hydroxylase as an intestinal autoantigen.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder with both endocrine and non-endocrine features. Periodic gastrointestinal dysfunction occurs in 25-30% of APS1 patients. We aimed to identify an intestinal autoantigen. METHODS: A human duodenal cDNA library was immunoscreened with serum samples from APS1 patients. A positive clone was identified and used for in-vitro transcription and translation, followed by immunoprecipitation with serum samples from 80 APS1 patients from Norway, Finland, and Sweden. Sections of normal and APS1-affected small intestine were immunostained with serum from APS1 patients and specific antibodies. An enzyme-inhibition assay was used to characterise the autoantibodies. FINDINGS: We isolated a cDNA clone coding for tryptophan hydroxylase. 48% (38/80) of APS1 patients had antibodies to tryptophan hydroxylase, whereas no reactivity to this antigen was detected in patients with other autoimmune diseases (n=372) or healthy blood donors (n=70). 89% (17/19) of APS1 patients with gastrointestinal dysfunction were positive for antibodies to tryptophan hydroxylase, compared with 34% (21/61) of patients with no gastrointestinal dysfunction (p<0.0001). Serum from antibody-positive APS1 patients specifically immunostained tryptophan-hydroxylase-containing enterochromaffin cells in normal duodenal mucosa. No serotonin-containing cells were seen in duodenal biopsy samples from APS1 patients. Serum from antibody-positive APS1 patients almost completely inhibited activity of tryptophan hydroxylase. INTERPRETATION: Tryptophan hydroxylase is an endogenous intestinal autoantigen in APS1, and there is an association between antibodies to the antigen and gastrointestinal dysfunction. Analysis of antibodies to tryptophan hydroxylase may be a valuable diagnostic tool to predict and monitor gastrointestinal dysfunction in APS1.

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.

PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.

A mouse platelet-derived growth factor A chain (PDGF-A) null allele is shown to be homozygous lethal, with two distinct restriction points, one prenatally before E10 and one postnatally. Postnatally surviving PDGF-A-deficient mice develop lung emphysema secondary to the failure of alveolar septation. This is apparently caused by the loss of alveolar myofibroblasts and associated elastin fiber deposits. PDGF alpha receptor-positive cells in the lung having the location of putative alveolar myofibroblast progenitors were specifically absent in PDGF-A null mutants. We conclude that PDGF-A is crucial for alveolar myofibroblast ontogeny. We have previously shown that PDGF-B is required in the ontogeny of kidney mesangial cells. The PDGFs therefore appear to regulate the generation of specific populations of myofibroblasts during mammalian development. The two PDGF null phenotypes also reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis.

ACE inhibition preserves renal function better than beta-blockade in the treatment of essential hypertension.

Antihypertensive treatment can slow down the decline in glomerular filtration rate (GFR) with time. In patients with diabetic nephropathy, angiotensin converting enzyme (ACE) inhibition has been shown to be more effective in this regard than conventional antihypertensive therapy. Whether this applies to the much larger population of patients with essential hypertension is not yet known. In the present study, the effects of two different antihypertensive therapies on the loss of GFR with time, determined with Cr51-EDTA clearance after 6, 12 and 24 months of treatment, were assessed in a prospective, randomised, double-blind trial in 257 patients with essential hypertension. All had normal renal function and none had diabetes mellitus or glucosuria. Proteinuria (dipstick positive or trace) was detected in 7 patients initially. The two therapeutic modalities were the ACE inhibitor cilazapril and the beta-adrenoceptor blocking agent atenolol. Both therapies were equally effective in lowering systolic blood pressure (e.g. from 168 mmHg to 152 mmHg with cilazapril and from 170 mmHg to 155 mmHg with atenolol after 6 months, p < 0.001 for both). However, atenolol was slightly but significantly more effective in lowering the diastolic blood pressure at 6, 12 and 24 months. The decline in GFR with time was significantly smaller with cilazapril than with atenolol. After 6 months the reduction in GFR was 1.0 vs. 4.0 ml/min x 1.73 m2, p = 0.008 (cilazapril vs. atenolol) and after 12 months the corresponding changes were 2.0 vs. 4.5 ml/min x 1.73 m2, p = 0.04 and after 24 months 3.0 vs. 4.0 ml/min x 1.73 m2, respectively (n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol intemperance and sudden death.

Ten years after a health screening examination was offered to 50 year old men 32 of the 2322 participants and 12 of the 454 nonparticipants had died of ischaemic heart disease. Of these, 26 and 11 respectively had suffered sudden death, for which necropsy was performed. Half of the men who had died suddenly had been registered for alcohol intemperance up to 1973, which was four times the prevalence of such registrations in the general population. Registration at both the Swedish Temperance Board and the Bureau of Social Services was associated with an odds ratio of 3.74 for sudden death as compared with not being registered at either. Logistic analysis including the classical risk factors for ischaemic heart disease together with registration for alcohol intemperance and at the Bureau of Social Services showed only the two types of registration and systolic blood pressure to be independent risk factors. On the other hand, there was no overrepresentation of subjects entered in the registers among those surviving a myocardial infarction. For non-fatal myocardial infarction blood pressure and serum triglyceride concentration were significant risk factors and serum cholesterol concentration, smoking, and body mass index probable risk factors; the two types of registration were not independent risk factors. Alcohol intemperance is strongly associated with an increased risk of sudden death after myocardial infarction.

Alcohol intemperance and social disability as risk factors for different causes of death.

At a follow-up 7-10 years after a health screening of 50-year-old men in Uppsala, 101 of the 2322 participants and 51 of the 446 non-participants had died. The incidence was thus almost three times as high among non-participants as among participants. Registration at the Temperance Board and/or the Bureau of Social Services was 2-3 times more common among the deceased subjects than among the living irrespective of participation in the health screening. A multiple logistic analysis revealed that non-participation and both types of registration were associated with an increased risk of death. For death from neoplasm only registration at the Bureau of Social Services, and not that at the Temperance Board, was a risk factor. For ischaemic heart disease (IHD), on the other hand, registration at the Temperance Board was the strongest risk factor, the other type of registration being secondary, and non-participation in the screening was a non-significant risk factor. The importance of alcohol intemperance as a risk factor for IHD was reflected in the fact that every second subject dying a sudden death (classified as IHD death) was registered at the Temperance Board. These results indicate that alcohol intemperance entails an increased risk of developing fatal complications to IHD, and social disability may carry with it a risk of both neoplasm and, to a lesser extent, death from IHD.

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.

The primary preventive study in Uppsala. Fatal and non-fatal myocardial infarction during a 10-year follow-up of a middle-aged male population with treatment of high-risk individuals.

A health survey of middle-aged men was carried out in 1970-73 in the municipality of Uppsala. Subjects with hypertension, hyperlipidaemia, reduced glucose tolerance, and smokers were invited to join various therapy groups. By 1980 this multifactorial intervention programme had thus been running for 10 years. This report describes the results of a follow-up undertaken to evaluate the efficacy of the programme. The annual rate of fatal myocardial infarction (MI) was lower among the participants (n = 2322) in the health examination as well as among participants and non-participants (n = 446) combined than among the male Swedish population of the same age (162 and 187 compared with 296 per 100 000 men, respectively). The annual rate of non-fatal MI among participants and non-participants combined was 295 per 100 000 men, which is lower than in other Swedish cities. In the hypertensive group (n = 126), six men had fatal and seven non-fatal MI. These 13 men had higher blood pressures (BPs) from the start than the other hypertensives. In addition, their BP reduction was smaller than in a control group randomly selected among the hypertensive subjects. In the hyperlipidaemic treatment group (n = 363) there were eight fatal and 10 non-fatal MIs. Nine of these events occurred in individuals who had dropped out from therapy. It is suggested that the low total mortality and the low rates of fatal and non-fatal MI in this middle-aged male population may be related to the multifactorial intervention programme, as the incidences were also low among the treated high-risk groups.

Labetalol in resistant hypertension.

In 12 patients with resistant hypertension labetalol was added to existing therapy. The average dose was 1333 mg (range 400--3600). The subjects were followed up for three and a half years. Mean supine blood pressure (BP) was reduced from 202/123 to 163/103 mm Hg and mean standing BP from 193/127 to 144/100 mm Hg. Mean BP after exercise was 134/93 mm Hg. The main side-effect was postural hypotension during exercise, causing withdrawal of labetalol in two subjects. In patients with severe hypertension, resistant to several combinations of antihypertensive drugs, the addition of labetalol may lead to satisfactory BP reduction, especially when combined with a potent diuretic.