Novel homozygous variants in the SERPING1 gene in two Turkish families with hereditary angioedema of recessive inheritance.

Hereditary angioedema as a result of deficiency of the C1 inhibitor (HAE-C1INH; MIM# 106100) is a rare autosomal disorder and affected individuals are generally heterozygous for dominant negative variants in the SERPING1 gene. Homozygosity for SERPING1 pathogenic variants was long considered to be embryonically lethal; however, five nonrelated families with a recessive HAE pattern have been described in the last decade. In this report, we functionally characterized two newly reported nonrelated, consanguineous families with a recessive presentation of HAE attributed to SERPING1 variants in the reactive center loop (family D; S438F) and gate (family A; I379T) regions. S438F heterozygotes (family D) showed variable levels of intact 105-kDa and cleaved/inactive 96-kDa isoforms of C1INH, whereas their homozygous relative presented only the 96-kDa band. Functional studies showed that S438F reduced C1INH interaction with target proteases in heterozygous (C1s, 32-38% of controls and FXIIa, 28-35% of controls) and homozygous (C1s, 18-24% of controls and FXIIa, 4-8% of controls) carriers, which is consistent with the more severe presentation of HAE in the family and decreased C1q levels in homozygous patients. By contrast, plasma C1INH from I379T heterozygotes (family A) showed normal C1INH/C1s binding (84-94% of controls) and no significant reduction in C1INH/FXIIa complexes (50-70% of controls). However, the homozygote failed to inhibit both C1s (25-42% of controls) and FXIIa (14-18% of controls). This profile is concordant with the less severe presentation of HAE in the family and the conserved C4 and C1q levels in heterozygous and homozygous patients.

Deletions in SERPING1 Lead to Lower C1 Inhibitor Function: Lower C1 Inhibitor Function Can Predict Disease Severity.

BACKGROUND: How genotype affects phenotype in hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) has not been totally clarified. In this study, we investigated the relationship between different types of mutations and various phenotypic characteristics. METHODS: Clinical data from 81 patients from 47 families were recorded. Complement proteins were analyzed from 61 untreated patients. The coding exons and the exon-intron boundaries of the SERPING1 gene were sequenced, and deletion/duplication analysis with multiple ligation dependent probe amplification was performed. The relationship of complement protein with the mutation type was analyzed by using generalized estimating equations. RESULTS: Thirty-five different mutations (15 novel and 2/15 homozygous) were identified. There was no causative mutation in 6 patients (7.4%). Patients with deletion and large deletion had the lowest (5.05%, 0-18.7; 5.8%, 0-16.5%, respectively), and the none mutation group had the highest C1 inhibitor function (23.3%, 11-78%, p < 0.001). C1 inhibitor function levels decreased as the age of the disease progressed (r = -0.352, p = 0.005). Lower C1 inhibitor function levels caused severer disease (r = -0.404, p = 0.001) and more frequent annual attacks (r = -0.289, p = 0.024). In the off-attack period, C1q levels were lower than normal in 9.8% of the patients. CONCLUSION: Deletion mutations may represent the most unfavorable effect on C1 inhibitor function. The earlier disease onset age could be a sign for lower C1 inhibitor function levels in adult life. C1q levels could also be low in C1-INH-HAE patients, as in acquired angioedema. Lower C1 inhibitor function can predict disease severity and may have negative impacts on the course of C1-INH-HAE.

Misleading Allergens in the Diagnosis of Latex Allergy: Profilin and Cross-Reactive Carbohydrate Determinants.

BACKGROUND: It has been suggested that latex-specific IgE analysis may lead to false-positive results, especially in patients with pollen allergy. In the present study, the reasons underlying clinically irrelevant latex-specific IgE positivity were investigated. METHODS: Thirty patients with latex allergy (group 1), 89 patients sensitised to aeroallergens (group 2a), and 98 healthy individuals without allergy (group 2b) were enrolled. Participants from all 3 groups were subjected to skin prick tests with aeroallergens including latex, latex-specific IgE analysis (ImmunoCAP), and nasal provocation test with latex. All cases demonstrating positive latex-specific IgE also underwent specific IgE tests (ImmunoCAP) with latex profilin, birch pollen profilin, peach lipid transfer protein, and pineapple bromelain as cross-reactive carbohydrate determinants. RESULTS: Comparison of the atopic and healthy control groups showed that the rate of positive latex-specific IgE was significantly higher in group 2a. Latex profilin-, birch pollen profilin-, and bromelain-specific IgE were remarkably higher in group 2a. CONCLUSION: False positivity to latex-specific IgE in ImmunoCAP analysis may be observed in approximately 19% of patients with pollen allergy. Profilins and bromelain are the main contributors to clinically irrelevant positive latex-specific IgE.

CD31 expression on peripheral blood stem cells predicts both early neutrophil and platelet engraftments.

No detailed information currently exists about the immune phenotypic profiles of peripheral blood stem cells (PBSCs) obtained by different mobilization regimens. The effects of these profiles on the outcome of transplantation are largely unknown. In this prospective study, the surface immune phenotypic features (CD11a, CD18, CD31, CD38, CD44, CD62e, CD62L, CD90, CD117, CD135 and CD184 expression) of sorted PBSCs that had been mobilized by growth factor with (group I and group II) or without (group III) disease-specific chemotherapies were investigated. The immune phenotypic features on mobilized PBSCs in groups I, II and III were not significantly different. The CD31 (platelet endothelial cell adhesion molecule-1) positivity ratio on PBSCs inversely correlated with both the duration of neutrophil (r=-0.32, p=0.03) and platelet (r=-0.36, p=0.02) engraftment. No relationship was found between the engraftment (neutrophil and platelet) durations and CD184 (chemokine receptor CXC motif receptor 4 [CXCR4]) expression on PBSCs. We demonstrated that the surface immune phenotypic profiles on PBSCs obtained by several mobilization regimens were not different. To our knowledge, this is the first study to demonstrate that CD31 expression on human PBSCs may positively affect both neutrophil and platelet engraftment. Contrary to our expectations, CD184 (CXCR4) expression on PBSCs has no effect on neutrophil or platelet engraftment. Considered together, our results suggest that additional surface antigens (such as CD31) may be more effective in the homing process.

Diagnostic value of specific IgE analysis in latex allergy.

BACKGROUND: The precision of the methods used to diagnose latex allergy is of great importance due to false-positive results. Neither the skin prick test (SPT) nor the latex-specific IgE assay has 100% diagnostic accuracy. We analysed the diagnostic value of latex-specific IgE by the first-ever concomitant use of the SPT and nasal provocation test (NPT). METHODS: Twenty-seven latex-sensitive patients (group 1), 46 aeroallergen-sensitive patients (group 2a) and 33 healthy subjects (group 2b) participated in the study. All groups underwent an SPT with latex and aeroallergens and an NPT with latex. Latex-specific IgE and total IgE levels were measured by the ImmunoCAP assay. RESULTS: Latex-specific IgE was positive in 92.6, 30.4 and 9.1% of groups 1, 2a and 2b, respectively. The 11 aeroallergen-sensitive patients in group 1 and all of the patients in group 2a were predominantly sensitised to pollens (grass, weed and tree) and reacted to a lesser degree to house dust mite, moulds and animal dander. Combined pollinosis was remarkably more prevalent in patients with positive latex-specific IgE in group 2a than in those with negative latex-specific IgE (p = 0.001). The NPT was positive in 84.6% of group 1 and negative in all control subjects. The sensitivity, specificity, negative predictive value and positive predictive value of the latex-specific IgE assay were 90.9, 72.2, 96.3 and 50%, respectively. CONCLUSION: The high rate of false-positive results for latex-specific IgE by ImmunoCAP should be taken into account when making a diagnosis of latex allergy in patients with pollinosis, especially in those sensitised to more than one pollen species.

Desensitization effect of preseasonal seven-injection allergoid immunotherapy with olive pollen on basophil activation: the efficacy of olive pollen-specific preseasonal allergoid immunotherapy on basophils.

BACKGROUND: It has previously been demonstrated that subcutaneous immunotherapy with allergoids positively affects clinical and immunological parameters even after 7 preseasonal injections. However, its effect on basophil activation remains unclear. We investigated the effect of preseasonal allergoid immunotherapy on basophils and concomitantly assessed its clinical and immunological efficacy in olive pollen-monosensitized patients. METHODS: This study enrolled 437 consecutive patients with respiratory allergy and positive skin prick tests (SPTs); 212 (48.5%) patients were sensitized to olive pollen, and 33 (7.5%) patients were sensitized to olive pollen only. Of these patients, 23 received preseasonal immunotherapy with an olive pollen allergoid. The olive pollen-specific basophil activation, the titrated nasal provocation test, the nasal symptom score, and olive pollen-specific IgE, IgG1 and IgG4 levels were evaluated before immunotherapy and 8 months after the end of immunotherapy in the follow-up visit. RESULTS: In comparison to baseline evaluation, 7 preseasonal injections of an allergoid resulted in a significant decrease in the percentage of basophils expressing CD63 (29 vs. 7%, respectively, p < 0.0001) and a significant increase in the titrated nasal provocative dose (1/10 vs. 1/1, respectively, p < 0.01). SPT induration diameters caused by an olive pollen extract decreased (12 mm at baseline vs. 5.5 mm at follow-up, p < 0.005), as did nasal symptom score (7 at baseline vs. 3 at follow-up, p < 0.01). Olive pollen-specific IgE (17.5 vs. 50 kU/l, p < 0.012), IgG1 (0.16 vs. 2.9 µg/ml, p < 0.0001) and IgG4 (0.07 vs. 1.92 µg/ml, p < 0.0001) levels significantly increased. CONCLUSIONS: Immunotherapy with 7 preseasonal injections of an olive pollen allergoid decreases olive pollen-specific basophil activation over 8 months, an effect observed in vitro and in vivo.

The Turkish Hereditary Angioedema Pilot Study (TURHAPS): the first Turkish series of hereditary angioedema.

BACKGROUND: No published data presently exist concerning hereditary angioedema (HAE) in Turkey. The aim of the study was to initiate a preliminary multicentric evaluation about HAE and to determine the genetic properties of Turkish patients. METHODS: Based on records drawn from four medical centers we identified a total of 70 subjects, belonging to 60 unrelated families, fulfilling clinical and laboratory criteria for diagnosis of HAE with C1 inhibitor deficiency. Ten type I patients, and their first-degree relatives, underwent genetic analysis for HAE. RESULTS: The majority of patients were female (60%), the mean age was 37.7 ± 14.1 years. The mean age at the time of first angioedema symptom was 12.5 ± 9.2 years. Mean time lag between first symptom and diagnosis was 26 ± 14.4 years. All but 3 subjects had HAE type I. Family history of angioedema was present in 75.7% of the cases. Cutaneous swelling was reported by 87.1% of the patients, facial edema by 65%, abdominal symptoms by 74.3% and approximately one half (55.7%) had experienced one or more laryngeal attack. Genetic analysis of 10 families demonstrated that 5 carried a mutation that had never been previously described. CONCLUSION: We found that the clinical features of Turkish HAE patients were consistent with previously described patterns of this rare disease. The most noteworthy feature identified in the study was a significantly long duration between the first symptom appearance and final diagnosis. Our detection of different mutations in 10 patients confirms the allelic heterogeneity of the disease.

Angioedema without wheals: a clinical update.

Angioedema without wheals (urticaria) represents a heterogeneous group of clinically indistinguishable diseases of hereditary or acquired etiology. Hereditary angioedema is a rare inherited condition leading to recurrent, sometimes life-threatening angioedema attacks in subcutaneous tissues and gastrointestinal and oropharyngeal mucosa dating back to childhood or adolescence. Most of these patients have mutations in the SERPING1 gene, causing either low C1 inhibitor production (hereditary angioedema with C1 inhibitor deficiency type I) or the production of dysfunctional C1 inhibitor (hereditary angioedema with C1 inhibitor deficiency type II). Hereditary angioedema with normal C1 inhibitor has been defined later. Although C1 inhibitor concentration and function are in the normal range, it leads to typical hereditary angioedema symptoms owing to mutations in FXII, PLG, ANGPT1, KNG1, and MYOF genes. Patients who exhibit none of these genetic mutations despite having a similar clinical presentation are classified as having unknown hereditary angioedema. Fewer than 1 in 10 patients with C1 inhibitor deficiency have acquired angioedema with C1 inhibitor deficiency. The clinical presentation is very similar to that of hereditary angioedema, making it difficult to distinguish these 2 conditions clinically. Unlike hereditary angioedema, there are no genetic mutations, and family history and symptoms tend to appear later in life. Acquired angioedema with C1 inhibitor deficiency is commonly associated with lymphoproliferative and autoimmune diseases. Angioedema attacks might start 1 year before the underlying disease in acquired angioedema with C1 inhibitor deficiency. Approximately half of the patients admitted to the hospital for acute angioedema are patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema typically occurs on the lips, tongue, mouth, pharynx, and subglottic regions. Patients may require hospitalization and intensive care monitoring owing to airway involvement. Idiopathic histaminergic acquired angioedema may be diagnosed only when any possible causes of histaminergic angioedema are excluded (foods, drugs, animal dander, aeroallergens, insect stings, latex, and others), and the symptoms respond well to antihistamine treatment. Idiopathic nonhistaminergic acquired angioedema should be considered when all other types of recurrent angioedema have been ruled out and patients do not respond to high-dose antihistamines. The lack of a standard biochemical laboratory test for patients with idiopathic histaminergic acquired angioedema, idiopathic nonhistaminergic acquired angioedema, angiotensin-converting enzyme inhibitor-induced acquired angioedema, and hereditary angioedema with normal C1 inhibitor makes the diagnosis more challenging. Future efforts should focus on increasing awareness of all the rare types of angioedema among physicians and developing more straightforward and more accessible diagnostic methods.

Determination of potential allergenic fungal flora and its clinical reflection in suburban elementary schools in Izmir.

In this research, in order to determine mean fungus counts, indoor and outdoor air samples were taken in five elementary school buildings located in the city center of Seferihisar, Izmir (45 km from Izmir) within a 1-year period between March and April 2004, and between January and February 2005 representing similar climatic characteristics. Five samples, three from three classes where 5-8, 10-12, and 12-15 age group students attended, one from the corridors, and one from outside the buildings in all the schools, were taken for each period. Within the period of the study, in indoor and outdoor air samples, 7,122 microfungus colonies were counted. Sixty-four species were identified that belong to 17 genera as a result of the identification of isolates obtained. Skin prick tests were applied to 55 out of a total of 117 teachers by the clinicians. According to these test results, 24 teachers were sensitive to at least one agent. Results revealed that, in terms of mold counts, the difference between the schools and the difference between the times (periods) were statistically significant (p < 0.05).

Vitamin D deficiency in the absence of enteropathy in three cases with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and a defect in antibody production. Herein we describe 3 patients diagnosed with CVID in whom vitamin D deficiency was detected in the absence of enteropathy. METHODS: Biochemical and immunological analysis, serum osteocalcin, parathyroid hormone, 25-OH vitamin D, 1,25(OH)(2) vitamin D, vitamin A, vitamin E, urinary calcium, and deoxypyridinoline measurements were carried out. Vitamin D receptor (VDR) expression was examined in the peripheral blood mononuclear cells and hair follicles by reverse transcriptase polymerase chain reaction. VDR gene polymorphism was evaluated by high-performance liquid chromatography. RESULTS: None of the patients presented nutrient deficiencies other than vitamin D. Two of them were free of osteomalacia-related symptoms. VDR expression was found to be lower in the peripheral blood mononuclear cells and hair follicles when compared to the control group. CONCLUSIONS: Patients with CVID may present asymptomatic vitamin D deficiency. Vitamin D and VDRs play an important role in the innate immune system and modulate Toll-like receptor-related responses. Delay in diagnosis may predispose these patients not only to irreparable bone loss but also to infections, and autoimmune and malignant disorders, thus emphasizing the importance of prompt intervention.

Latex allergy and associated risk factors in a group of Turkish patients with spina bifida.

Allergic reactions to latex are common in patients with spina bifida. Its incidence varies between 28% and 67%. The aim of this study was to investigate the incidence of latex allergy and its risk factors in patients with spina bifida in Izmir, Turkey. Forty-six patients (24 male, mean age 10 years) were included in the study. A questionnaire was completed and skin prick tests with latex solution and cross-reacting foods were performed. Total IgE levels, specific IgE to common aeroallergens (Phadiotop), and latex specific IgE levels were measured. Patients with positive skin test reaction and/or who had specific IgE to latex without clinical symptoms were considered as sensitive to latex. The patients who also had clinical symptoms with latex exposure were diagnosed as allergic to latex. Latex sensitivity was found in 5/46 patients (10.8%). Only two patients had latex allergy (4.3%). Total IgE levels were higher (median 157 vs. 40 kU/L, p=0.012) and the duration of clean intermittent catheterization was longer insensitized patients when compared to non-sensitized patients (median 8 vs. 3 years, p=0.015). Specific IgE to common aeroallergens and positive skin prick test to cross-reacting foods were more prevalent in sensitized than in non-sensitized patients (p=0.02 and 0.015, respectively). The incidence of latex allergy in our group was lower than reported in the literature. This result may be due to the low number of surgical interventions. High levels of total IgE, positive Phadiotop, positive skin prick test to cross-reacting foods and the duration of clean intermittent catheterization are the risk factors for latex sensitivity in patients with spina bifida.

Chlamydia pneumoniae arthritis in a patient with common variable immunodeficiency.

BACKGROUND: Arthritis is an important and sometimes life-threatening complication in patients with common variable immunodeficiency (CVID). OBJECTIVE: To describe a patient with CVID and arthritis due to Chlamydia pneumoniae, which is usually regarded as a respiratory tract pathogen and has not previously been detected in the synovial fluid by cell culture technique. METHODS: Routine bacteriologic, virologic, mycologic, and tuberculosis cultures were performed. The patient's synovial fluid was examined for fastidious organisms that might be causative pathogens of arthritis, such as chlamydiae, and special cell culture methods were used. Serologic tests were performed to determine viral and bacteriologic etiology. RESULTS: The patient had a history of recurrent respiratory tract infections, and the latest exacerbation was followed by arthritis. Cytologic examination of the fluid yielded abundant lymphocytes. Chlamydia pneumoniae was detected in synovial fluid specimens by cell culture technique. Her nasopharyngeal swab and sputum culture specimens were also positive for this pathogen. She was diagnosed as having arthritis caused by C pneumoniae and was given antibiotherapy. CONCLUSION: Chlamydia pneumoniae should be kept in mind as a causative pathogen in patients with CVID and arthritis, especially when effusion fluid is full of lymphocytes rather than polymorphonuclear cells and no organism is grown on routine cultures.

Psoriasiform contact dermatitis due to propolis in a beekeeper.

BACKGROUND: More than 250 cases of allergic contact dermatitis due to propolis have been described. A few of these occurred in beekeepers. OBJECTIVE: To describe a case of psoriasiform dermatitis caused by propolis in a beekeeper who thought that his lesions were related to honeybee stings. METHODS: A 45-year-old beekeeper experienced hand dermatitis for the past 5 years. He believed that the lesions occurred and worsened when he was stung by honeybees. He was prescribed topical corticosteroids several times, but because he was stung frequently, the drugs never helped control the lesions. In the past few years, he frequently had contact with propolis during honey collection, but he denied the role of propolis because he was wearing gloves while handling the beehives. For diagnostic evaluation, skin biopsy, skin prick tests (SPTs), identification of specific IgE antibodies, and atopic patch tests were performed. RESULTS: Skin biopsy showed psoriasiform contact dermatitis. Results of SPTs to honeybee and serum specific IgE for Apis mellifera remained negative. Results of the atopic patch test performed using A mellifera SPT material were also negative in the first 20 minutes and on the second and third days. However, propolis showed a positive erythematopapular reaction on day 2. The patient never again worked as a beekeeper, and neither did he, as far as he knew, use any medical or cosmetic products that contained propolis. His hand lesions improved almost completely. CONCLUSION: Dermatitis due to propolis should never be disregarded in beekeepers, and every effort should be put forth to make a correct diagnosis and to convince the patients of the cause.

The determinants of bronchial hyperresponsiveness in patients with allergic rhinitis.

BACKGROUND: Patients with allergic rhinitis and bronchial hyperresponsiveness (BHR) may be at higher risk of developing asthma. OBJECTIVE: To investigate whether reactivity to aeroallergens in skin prick testing (SPT) and serum eosinophil cationic protein levels can be used to predict BHR in allergic rhinitis patients. METHODS: Fifty-nine consecutive patients with allergic rhinitis underwent SPTs using grass, tree, weed, parietaria, Alternaria, Aspergillus, mites, and cat and dog dander extracts. Methacholine challenge tests were performed using spirometry. RESULTS: Methacholine-induced BHR was detected in 23 patients (39%). Of 59 patients, 14 had 1 positive SPT response, 35 had 2 to 4 positive responses, and 10 had more than 4 positive responses. There was a significant inverse correlation between methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20) and the number of positive SPT responses (r = -0.28; P = .03). The BHR-positive patients had a mean of 4 positive SPT responses, whereas BHR-negative patients had a mean of 2.6 (P = .04). Nine BHR-positive patients (39%) and only 1 BHR-negative patient (3%) had more than 4 positive SPT responses (P < .001). There was no correlation between serum eosinophil cationic protein levels and methacholine PC20 doses. There was a strong association between hyperresponsiveness to methacholine and both cat and dog dander sensitivity (P < .001 and P = .001, respectively). CONCLUSIONS: Allergic rhinitis patients with SPT responses to a higher number of allergens are more likely to have BHR. Whether the number of positive SPT responses correlates with the risk of developing asthma in allergic rhinitis patients remains to be determined.

Sensitization to cat allergens in non-cat owner patients with respiratory allergy.

BACKGROUND: Cats represent one of the most important sources of indoor allergens. The sensitization rate can reach up to 60% in western countries. Keeping cats indoors is uncommon in big cities in Turkey, but cats living in the streets are common. OBJECTIVE: To investigate the prevalence of sensitization to cats in patients with respiratory allergy from Izmir, Turkey, and its relationship to home cat allergen levels. METHODS: A total of 387 patients (70.8% female; mean age, 34.3 years) with respiratory allergic diseases (rhinitis and/or asthma) were included in this study. Skin prick test to cat was performed. House dust samples were collected from the living room of 25 patients and 14 healthy subjects. The major cat allergen (Fel d 1) levels were measured by Dustscreen. Fel d 1 levels given by the manufacturer were as follows: 0.05, 0.13, 0.40, 1.1, and 6.2 mU/mL. RESULTS: The prevalence of cat sensitivity was 44.7% (n = 173). Only 6 patients (1.6%) had a history of feeding a cat in their houses. Thirty-six (92%) of 39 houses had detectable levels of cat allergen (mean Fel d 1 level, 2.24 +/- 2.69 mU/mL). The mean Fel d 1 levels were 1.58 +/- 2.51 mU/mL in the healthy group, 1.91 +/- 2.61 mU/mL in the asthmatic group, and 3.26 +/- 2.85 mU/mL in the group with allergic rhinitis (P = 0.12). The prevalence of cat sensitivity in patients who had 1.1 mU/mL of Fel d 1 in their homes was 57.1%. This rate was five times lower (11.1%) in patients who had the highest Fel d 1 level (6.2 mU/mL) in their homes. CONCLUSIONS: The prevalence of cat sensitivity in Izmir, where cats are generally not kept within homes, is as high as in western countries. The sampled houses have measurable levels of Fel d 1 even in the absence of indoor cats. High prevalence of cat sensitivity in Izmir is probably due to indirect exposure.