The Role of Bradykinin Receptors in Hereditary Angioedema Due to C1-Inhibitor Deficiency.

BACKGROUND: Hereditary angioedema (HAE) is a rare, genetic disease caused by the decreased level or function of the C1 inhibitor. The primary mediator of symptoms in HAE is bradykinin acting through its two receptors, namely receptors 1 (BR1) and 2 (BR2). Although BR2 is well characterized, the role of BR1 remains unclear. OBJECTIVE: To study the role of bradykinin receptors 1 (BR1) in the etiopathogenesis of HAE. METHODS: A total of 70 individuals, 40 patients with HAE, and 30 healthy subjects were recruited to the study. HAE was diagnosed in accordance with the international guideline. The level of bradykinin receptors was determined in populations of CD3+, CD4+, CD8+, and CD14++CD16-, CD14++CD16+ monocytes. In addition, the level of disease activity-specific markers was measured. RESULTS: There were statistically significant differences in the subpopulation of lymphocytes and monocytes between patients with HAE compared to healthy subjects. The level of BR1 and BR2 on PBMCs was comparable in healthy subjects and HAE patients during remission with significant overexpression of both receptors, triggered by HAE attack. Moreover, a significant increase in TNF-alpha and IL-1 plasma levels was observed among HAE patients. CONCLUSIONS: BR1 expression may play an important role in the pathomechanism of HAE.

Allergic contact dermatitis to metal allergens in the South of Poland between 2008-2018.

Allergic contact dermatitis (ACD) is a common skin disorder caused by contact with an exogenous substance that elicits a hypersensitivity response in susceptible individuals. Changing fashion trends, the process of industrialization as well as official legislations restricting the use of metals in recreational and occupational products change the epidemiological patterns in the European countries. AIM: The aim of the study was to estimate the current prevalence of isolated and concurrent sensitization to nickel sulfate, cobalt chloride and potassium dichromate, as well as to investigate their associations with potentially predisposing epidemiological and clinical factors. MATERIALS AND METHODS: 1200 patients with suspected ACD were enrolled for this study. Medical records were taken on the basis of the standardized questionnaire to collect epidemiological and clinical variables. All patients were tested with T.R.U.E. TEST Panel 1.2 and Panel 2.2, including the total of 24 allergens. RESULTS: We observed statistically significant difference in mean age between women allergic to cobalt (41 vs 49; p<0.001) and nickel (41 vs 50; p<0.001) than among women not allergic to metals . Female gender was a significant risk factor for an allergy to nickel (OR 3.7909, CI95%: 2.4081 - 5.9677; p<0.001). Chi2 test showed that atopic dermatitis may influence the prevalence of allergic reaction to cobalt in a group of women and men, as well only among women or men - the most significant association was noted among men (OR=3.8472, CI95%: 1.1518 - 12.8503; p=0.0285). The sensitization any metal was a significant risk factor for an allergy to other metallic allergens. CONCLUSIONS: Our study gives a valuable insight into the metal allergy prevalence in Polish population and sheds some light on the associated risk factors. The results serve to raise questions concerning the relevance of metal allergies and to highlight the need for more effective preventive measures.

The Role of Bradykinin Receptors in the Etiopathogenesis of Chronic Spontaneous Urticaria.

Background and Objectives: Chronic spontaneous urticaria (CSU) is a distressing skin condition, which manifests as red, swollen, itchy, and sometimes painful hives or wheals appearing on skin. Recently, CSU has been associated with bradykinin release, which was previously discovered to be the main trigger of hereditary angioedema attacks. To study the role of bradykinin receptors 1 (BR1) and 2 (BR2) in the etiopathogenesis of CSU. Materials and Methods: A total of 60 individuals, 30 patients with CSU and 30 healthy subjects, were recruited to the study. CSU was diagnosed in accordance with the standardized protocol of dermatological assessment of skin symptoms. The level of bradykinin receptors was determined in populations of CD3+, CD4+, and CD8+ lymphocytes as well as in CD14++CD16-, CD14++CD16+ and CD14+CD16+ monocytes. In addition, urticaria activity score summed over 7 days (UAS-7) was assessed and correlated with BR1 and BR2 expression. Results: A statistically significant higher concentration of BR1 expression in lymphocytes was found in patients with CSU, compared to the control group (p < 0.001). Moreover, a statistically significant positive correlation was observed between UAS-7 and BR1/BR2 expression in CD14++CD16- cells (p = 0.03, R = 0.4). Conclusions: Bradykinin receptors are elevated in selected populations of lymphocytes in symptomatic CSU patients compared to healthy controls, indicating their role in the etiopathogenesis of the disease.

Participation of the coagulation system and fibrinolysis as well as selected biomarkers in pathogenesis of chronic urticaria with various activity degree.

INTRODUCTION: Chronic urticaria is a complex disease process in which chronic spontaneous urticaria (CSU) and chronic inducible urticaria are distinguished. Its etiopathogenesis still remains unknown. Some recent studies indicated a significant participation of vitamin D in the etiopathogenesis of urticaria. In 40-50% of patients with CSU on the basis of the positive result of the autologous serum skin test (ASST), autoimmunological background of the disease is diagnosed. Moreover, numerous test results confirm involvement of the coagulation system/fibrinolysis and non-infectious inflammatory factors in the pathophysiology of CSU. AIM: To determine whether some factors may play a role in pathogenesis and contribute to the severity of chronic spontaneous urticaria. MATERIAL AND METHODS: One hundred and forty-two patients with diagnosed CSU were enrolled in the study. The activity of urticaria was assessed using the UAS-7 (Urticaria Activity Score). The study participants were divided into 4 groups depending on the UAS-7. ASST was performed and blood was collected to determine the biomarkers (CRP, vitamin D, D-dimers, fibrinogen, MPV, PLT). RESULTS: Statistical analysis was performed using Statistica 13. A statistically significant difference between groups with various activity of urticaria in D-dimer concentration average values (p < 0.05) was observed. Moreover, a statistically significant negative correlation between activity of urticaria and vitamin D concentration (p < 0.001) was noted. CONCLUSIONS: Our results might support the possible involvement of both coagulation and fibrinolysis pathway and vitamin D in the urticaria pathomechanism. Further prospective studies in larger populations conducted at multiple centres are required to expand further our findings.

Is vitamin D concentration an indicator of the severity of atopic dermatitis and chronic spontaneous urticaria in adults?

Atopic dermatitis (AD) and chronic spontaneous urticaria (CSU) are common chronic and recurrent dermatoses. The role of vitamin D in the immunological processes, including the development of inflammation, has been the subject of numerous studies. The feasible measurement of vitamin D serum concentration and possibly supplementation necessitates the assessment of its impact on the clinical severity of mentioned diseases. AIM: The aim of the study was to determine the relationship between blood serum vitamin D concentration and the severity of clinical symptoms in the group of adults suffering from AD or CSU. MATERIALS AND METHODS: The study was conducted in 2018 on groups of patients suffering from AD or CSU. Serum vitamin D concentration was determined by electrochemiluminescence assay. Student's t-test was adopted to compare vitamin D levels between groups. Spearman's rank correlation coefficient was used to assess the correlation between vitamin D concentration and the severity of AD (according to the SCORAD scale) and CSU (according to the UAS 7 scale). RESULTS: There was not found any statistically significant relationship between the severity of skin lesions scores in the course of AD and CSU and serum vitamin D concentration.

Bacillary Angiomatosis in Renal Transplant Recipient: A Case Report.

INTRODUCTION: Bacillary angiomatosis (BA) is a rare, opportunistic infectious disease caused by the aerobic Gram-negative bacilli Bartonella henselae or Bartonella quintana. The main reservoir for those microbes are cats. The disease mostly affects immunocompromised patients with human immunodeficiency virus infection, after organ transplantation, undergoing corticosteroid and methotrexate therapy or with oncological history. CASE REPORT: We represent the case of a 65-year-old man who reported to the Department of Dermatology with a high fever and numerous nodular skin lesions on the 5th month of kidney transplantation. At that time, his immunosuppressive therapy consisted of tacrolimus 6 mg/day, mycophenolate mofetil 2 g/day, and prednisone 5 mg/day. Laboratory tests revealed an increased leukocyte count and elevated values of acute-phase proteins, but blood cultures were negative. Skin biopsy was performed and BA was diagnosed. The patient was given oral doxycycline 100 mg twice a day. During antibiotic therapy, his body temperature normalized and skin lesions began to resolve. The patient continued the above treatment for the next 3 months with good tolerance, and no relapse occurred in 1 year. CONCLUSION: BA should be listed among possible opportunistic infections in organ transplant recipients.

Bradykinin and oxidative stress in patients with hereditary angioedema due to C1 inhibitor deficiency.

INTRODUCTION: Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by genetic dysfunction of C1 inhibitor (C1-INH) due to mutations in the SERPING1 gene. The disorder is mediated mainly by bradykinin. The clinical course of the disease is varied and not related to genetic changes. OBJECTIVES: We aimed to evaluate redox homeostasis of peripheral blood mononuclear cells (PBMCs) in patients with HAE due to C1-INH deficiency (C1 INH HAE) by measuring the levels of reactive oxygen species (ROS) of PBMCs as well as plasma advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs). We also aimed to assess the effect of bradykinin on ROS levels. PATIENTS AND METHODS: We enrolled 30 adults with C1-INH-HAE and 15 healthy individuals. The levels of ROS were measured by flow cytometry, while the plasma levels of AGEs and AOPPs were determined spectrophotometrically by enzyme­ linked immunosorbent assays. RESULTS: Basal and hydrogen peroxide (H2O2)-induced ROS levels were higher in patients with HAE when compared with controls (P = 0.002 and P = 0.001, respectively), indicating abnormalities in redox homeostasis. Plasma AOPP and AGE levels were similar in both groups. Bradykinin reduced basal and H2O2-induced ROS generation in PBMCs only in patients with HAE (P = 0.03). CONCLUSIONS: The higher basal and H2O2-induced ROS levels in patients with C1 INH HAE indicate redox imbalance. However, by reducing basal and H2O2-induced ROS levels, bradykinin shows antioxidant action in this disorder.

What's New in the Pathophysiology of Alopecia Areata? The Possible Contribution of Skin and Gut Microbiome in the Pathogenesis of Alopecia - Big Opportunities, Big Challenges, and Novel Perspectives.

The term "microbiome" defines the collective genome of all commensal, symbiotic, and pathogenic microbes living in the human body. The composition of microbiota in the gut and skin is influenced by many factors such as the stage of life, nutrition, lifestyle, and gender. In the past few years, several scientific papers have demonstrated an implication of microbiota in many immune-mediated diseases, for example, diabetes, ulcerative colitis, and multiple sclerosis. The alterations in the proportion of gut microbiota have emerged as potential immunomodulators with the capacity to induce physiologic as well as pathologic immune responses against the human body, causing inflammation and destruction of tissues or organs. The microbiota influences the differentiation of adaptive immune cells not only in the gut but also in the skin. Alopecia areata (AA) is a dermatologic disorder which causes hair loss in most cases resistant to treatment. There are some clinical and experimental evidences indicating that AA is the demonstration of autoimmune attack against hair follicles. The factors that may implicate such an autoimmunity in AA still remain unknown. Despite more and more evidences demonstrate that human microbiome plays a key role in human health and diseases, to the best of our knowledge, no study has been conducted to analyze an implication of microbiome in the pathogenesis of AA. Undoubtedly, there is a need to performing a study which might explain the involvement of gut and skin microbiota in the unclear pathogenesis of AA and lead to alternative treatment options for numerous patients suffering from current treatment limitations.

Level of inflammatory cytokines tumour necrosis factor α, interleukins 12, 23 and 17 in patients with psoriasis in the context of metabolic syndrome.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease with immunologic etiology. AIM: To investigate the levels of the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 23 (IL-23) and IL-17 in patients with psoriasis and psoriatic arthritis with concomitant metabolic syndrome. MATERIAL AND METHODS: This study included 60 patients with severe psoriasis. RESULTS: In patients with arterial hypertension concomitant with psoriasis, no statistically significant differences in cytokine levels were observed. On the other hand, in the group of patients diagnosed with diabetes, an increased level of IL-17 was observed. In patients with lipid disorders, the results were similar to the results of patients with diabetes. CONCLUSIONS: It is very important to study immunologic mechanisms responsible for the presence and severity of psoriasis, in order to personalize the therapy in the future and optimize the effect of action on the basic disease and on concomitant disorders.

The level of proinflammatory cytokines: interleukins 12, 23, 17 and tumor necrosis factor α in patients with metabolic syndrome accompanying severe psoriasis and psoriatic arthritis.

INTRODUCTION: The incidence of metabolic syndrome is estimated at 15-24% in the general population and at 30-50% in patients with psoriasis. A probable cause of the described correlation is a constant release in chronic dermatosis of proinflammatory cytokines and their influence on individual systems and organs. AIM: Assessment of the concentration of the proinflammatory cytokines (IL-12, IL-23, IL-17 and TNF-α) in blood serum and their correlation with the intensity of skin lesions, the presence of psoriatic arthritis and the risk of development of obesity and metabolic syndrome. MATERIAL AND METHODS: The concentrations of subunit p70 IL-12, IL-17 and IL-23, and TNF-α in subjects with psoriasis and metabolic syndrome were determined. RESULTS: The level of the studied cytokines, IL-17, IL-23 and TNF-α was higher in patients diagnosed with psoriasis. Higher levels of IL-17, IL-23 and TNF-α were observed in patients with metabolic syndrome accompanying psoriasis. A higher level of IL-17 and IL-23 was found in sera of patients with psoriatic arthritis in comparison to normal psoriasis. CONCLUSIONS: In the study, a higher level of IL-17 and IL-23 was also shown in patients with psoriatic arthritis in comparison to patients with normal psoriasis. The effectiveness of anti-IL12/23 drugs in psoriatic arthritis is a confirmation of the obtained results of the studies. Additionally, the increased level of IL-17, both in patients with metabolic syndrome and with psoriasis, could indirectly indicate an increased cardiovascular risk in patients with affected joints in comparison to psoriasis affecting only the skin.

Robust pro-inflammatory immune response is associated with serological cure in patients with syphilis: an observational study.

OBJECTIVES: Approximately 15% of adequately treated patients with early syphilis remain serofast. Pathogenesis and clinical significance of this phenomenon is unclear. The objective of this study was to determine whether there is any association between host immune response and treatment outcome (serofast state or proper serological response). METHODS: Forty-four patients with secondary syphilis were enrolled to this study. Levels of pro-inflammatory cytokines such as interferon-γ, tumour necrosis factor-α and interleukin-6 were measured before treatment and 8 hours after injection of antibiotic. RESULTS: After 1 year, based on the serological response patients were stratified into two groups: (1) proper serological response (n=31) and (2) serofast state (n=9). The serological cure rate was 77.5% at 12 months after treatment. Patients with proper serological response had significantly higher levels of analysed cytokines (at baseline and 8 hours after treatment) compared with the serofast state group (p<0.05). CONCLUSIONS: We showed that robust host pro-inflammatory immune response to infection may be the predictive factor of serological cure. The treatment outcome may be also associated with the magnitude of immune reaction occurring during the treatment.

Contact eczema of hands caused by contact with potato protein.

INTRODUCTION: Protein contact dermatitis (PCD) is an IgE-dependent allergic reaction which, despite enormous progress in knowledge, remains a 'non-diagnosed' nosologic unit in contemporary medicine. Skin lesion, with a chronic and recurring course, are analogous with the clinical picture in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD); skin patch tests, however, are usually negative. This makes the diagnostics difficult, prevents a correct diagnosis and treatment based on the avoidance of allergen. CASE DESCRIPTION: A 48-year-old woman presented with erythemato-squamous skin lesions, accompanied by a strong itching, occurring on hands for about 6 months. The patient attributed the occurrence of skin lesions to household chores, above all - cooking and contact with food. The contact allergy was not confirmed. Positive results of the prick-by-prick test were observed for potato. Based on the above results, contact eczema induced by potato protein was diagnosed. Allergen elimination and use of emolients were prescribed. A complete remission of skin lesions was obtained. DISCUSSION: PCD is rarely diagnosed, which is why there is no substantial epidemiologic data. It is estimated that about 50% of cases are related to atopy. This occurs more often in patients with a damaged dermal-epidermal barrier. Most often, the same products eaten by subjects do not produce any effects. A correct assessment of the substance provoking the occurrence of skin lesions is very important, as most often the products concerned are those commonly used in the household. A detailed PCD diagnostics is very important for obtaining the optimal treatment results.

Palisaded neutrophilic and granulomatous dermatitis - cutaneous manifestation of Lyme disease or connected with CTD? Case report.

INTRODUCTION: Palisaded neutrophilic and granulomatous dermatitis (PNGD) are terms which include such diseases as rheumatoid nodules, Churg-Strauss granuloma, and interstitial granulomatous dermatitis with arthritis. This heterogeneous group was first described in 1965. It is associated with immunological diseases. There are reported cases of coexistence with systemic lupus erythematosus, rheumatoid arthritis, Wegener's granuloma, inflammatory bowel disease, generalized vascular inflammation, and lymphoproliferative disorders. The etiology of the disease is unknown. It is probable that the deposition of immune complexes in blood vessels leads to cutaneus leukocytoclastic vasculitis, degeneration of collagen fibres and palisaded granulomatous inflammation. Ultimately, this leads to fibrosis of the skin. OBJECTIVE: The aim of the study is to present a patient with skin lesions and histopathological features of palisaded neutrophilic and granulomatous dermatitis during the course of infection Borrelia burgdorferi. Several cases of this disease have been reported worldwide (30 entries in the PubMed database). To-date, there have been no reports of PNGD in Polish literature. MATERIALS AND METHOD: The patient, aged 72, was admitted to hospital because of erythematous, indurated lesion of the skin on the side surface of the left thigh. Diagnosis of PNGD was made on the basis of typical histopathologic features due to clinical symptoms. CONCLUSIONS: Clinical diagnosis of PNGD is difficult, and is based mainly on the histopathological picture. Systemic therapy is incorporated mainly due to the systemic disease. The patient requires further observation in the direction of associated systemic disorders.

Autoimmunogenicity during anti-TNF therapy in patients with psoriasis and psoriatic arthritis.

INTRODUCTION: The tumor necrosis factor (TNF-α) was initially described as lymphotoxin or cachectin. The discovery of therapies blocking the action of TNF-α, in 1988, started a new era in the therapy. One of often reported adverse effects related to the use of TNF-α antagonists is induction of the formation of autologous antibodies and antibodies neutralizing anti-TNF drugs. The development of anti-TNF-induced lupus or classical drug-induced lupus is more rarely reported. AIM: To evaluate the presence and the level of anti-nuclear antibodies in patients with psoriasis and psoriatic arthritis and the influence of anti-TNF therapy used on the concentration of antinuclear antibody (ANA). MATERIAL AND METHODS: A total of 28 subjects were included in the study. 71.4% of subjects were diagnosed with psoriatic arthritis and 28.6% with plaque psoriasis. RESULTS: Among the patients with plaque psoriasis, the antinuclear antibodies were found in 25% of subjects and in 80% of patients with psoriatic arthritis. After the treatment an increase in the titer or appearance of antibodies was found in 66.7% in the infliximab group, 18.2% in the etanercept group and 54.7% in the adalimumab group. No subjects developed symptoms of drug-induced systemic lupus. CONCLUSIONS: Our findings have shown that all anti-TNF therapies induced ANA in psoriatic arthritis and psoriatic patients. Considering a mild course of lupus induced by anti-TNF treatment and, usually intrinsic, resolution of symptoms, the biological therapy still appears as a safe treatment for patients.

[Melkersson-Rosenthal syndrome--diagnostic and therapeutic problems]. / Zespól Melkerssona-Rosenthala - problemy diagnostyczne i lecznicze.

It is very difficult to differentiate Melkersson-Rosenthal syndrom and macrochelitis granulomatosa. Two neurologists: Ernt Melkersson and Curt Rosenthal in 1928 and 1931 described classical symptoms of this syndrom: recurring facial paralysis, swelling of the face and lips and the development of folds and furrows in the tongue. In 1945 Miescher described a few cases of primary interstitial inflammation of the lips and gave them the name macrochelitis granulomatosa. Some patients had paralysis of the facial nerve, others folds of the tongue. In the present study the etiopatho-genesis, diagnostic and therapeutic problems are presented.

[Nickel allergy in contact and atopic dermatitis]. / Alergia na nikiel w wyprysku kontaktowym i atopowym.

The study is aimed to determine the importance of type I and type IV allergy in eczema caused by allergy to nickel. The study was performed at 55 patients (42 women, 13 men, aged 16-58 yrs) suffering from hand dermatitis (19 cases), disseminated eczema (22 cases) and atopic dermatitis (14 cases) with positive skin patch test to 2.5% nickel sulphate. In each patients history of illness was analyzed, total serum IgE level (tIgE) was estimated and specific IgE (sIgE) for nickel and also absolute blood eosinophils and basophils counts were estimated for the evaluation of the atopy features. In each patient patch skin test with different nickel sulphate dilutions were performed as well as skin prick tests with different dilutions of nickel sulphate. The following oral provocation tests were carried out with the nickel sulphate in doses 0.56 mg, 1.12 mg, 2.24 mg, 5.6 mg and 11.2 mg. The test was stopped at the dose provoking the symptoms of illness. Positive family history, the increased tIgE serum level as well as absolute counts of eosinophils and basophils were present in some patients with atopic and contact dermatitis and they were not useful in differential diagnosis of this forms of skin allergy. Skin patch test with different concentrations of nickel sulphate was helpful to establish the degree of contact sensitivity in all patients. The oral provocation test with different dose of nickel sulphate also provoked symptoms in some patients in each observed groups, but the reaction to the lowest dose was observed only in patients with atopic dermatitis. Specific IgE to nickel as well as skin prick testing also with different dilutions of nickel sulphate are not useful in the diagnosis of nickel allergy. In the all examined patients they were negative. It seems that both types of allergy (type I and IV) may take part in the patho-mechanism of atopic and contact skin allergy with alternate prevalence of one of its depending on patient condition.

[Prevalence of allergic diseases in primary school children in Cracow and surroundings--risk factors]. / Wystepowanie chorób alergicznych u dzieci w szkolach podstawowych Krakowa i okolic--próba okreslenia glównych czynników ryzyka.

Prevalence of allergic diseases has been increasing over recent decades, especially in developed countries. The aim of this study was to assess prevalence of bronchial asthma and allergic rhinitis in children of Krakow at school age, depending on home and school environment conditions. The study was carried out in two stages: questionnaire based on ISAAC questionnaire and skin prick tests in children with symptoms suggesting allergic disease were performed. Altogether 532 children from 4 primary schools (2 in central and 2 in peripheral parts of the city) were included. Symptoms suggestive of allergic disease were reported by 304 children (57.1%), including asthma in 145 (27.2%) and allergic rhinitis in 288 children (54.1%). Asthma and allergic rhinitis was previously diagnosed in 19 (4%) and 138 (26%) children respectively. In younger age groups more children reported symptoms suggestive of asthma. Pupils from schools in the center of Krakow exposed to high level of traffic significantly more frequently reported asthma and had diagnosed allergic rhinitis. Increased prevalence of allergic rhinitis symptoms was observed in children exposed to passive smoking. Skin prick tests were positive only in 29.7% of children qualified for them. The results of the study suggest that in pupils with allergic rhinitis in whom skin prick tests are weakly positive for inhaled allergens, environmental factors may play an important role in the development of clinical symptoms.