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Due to its stimulatory potential for immunomodulatory CD4+regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) immunotherapy has recently gained considerable attention for treatment of various autoimmune diseases. Although early-stage clinical trials have correlated expansion of circulating Treg cells with clinical response to IL-2 treatment, detailed mechanistic data on responding Treg cell subsets are lacking. In this investigator-initiated phase-2 clinical trial of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE) patients, we performed an in-depth study of circulating and cutaneous Treg cell subsets by imaging mass cytometry, high-parameter spectral flow cytometry, bulk and single-cell RNA sequencing with cellular indexing, and targeted serum proteomics. Low-dose IL-2 stimulated circulating Treg cells with skin-homing properties that appeared in the skin of SLE patients in close interaction with endothelial cells, suggestive of a gatekeeper function. Analysis of surface proteins and transcriptomes detected different IL-2-driven Treg cell programs, including highly proliferative CD38+HLA-DR+, activated gut-homing CD38+, and skin-homing HLA-DR+Treg cells. These data identify distinct and functionally characteristic Treg cell subsets in human blood and skin, including the Treg cell subsets most responsive to IL-2 immunotherapy, thus providing unprecedented insight into Treg cell biology during IL-2 treatment.

Introduction: Few studies assess biologicals such as, omalizumab, mepolizumab, benralizumab, and dupilumab in patients suffering from chronic rhinosinusitis with nasal polyposis (CRSwNP). The reported success rate in these studies differ, and it remains uncertain if there are any biomarkers to predict successful therapy. Our aim was to analyze the therapeutic outcome in a real life setting and to identify predictive biomarkers for successful treatment. Methods: Data from patients with CRSwNP treated with a monoclonal antibody between November 2014 and January 2020 were analyzed retrospectively. Improvement in the polyp score and clinical symptoms like nasal obstruction, sense of smell, nasal discharge, and facial pain were evaluated. Other characteristics, including use of nasal or systemic steroids, comorbidities, previous history of sinus surgery, eosinophilia tissue, blood values (eosinophils, total immunoglobulin E, eosinophilic cationic protein, and interleukin 5), and allergic sensitization in serum were also investigated to identify possible predictive biomarkers. Results: Forty-eight treatments in 29 patients (m/f = 15/14) aged 27–70 years were reviewed. Treatments with mepolizumab showed the best success rates (78.9%), followed by omalizumab (50%) and benralizumab treatments (50%). However, a correlation between biomarkers and treatment success could not be found. Discussion/Conclusion: Treatment of CRSwNP with biologicals is a promising option for severe cases not responding to conventional therapy, including difficult-to-treat patients. Predictive biomarkers for a successful treatment could not be identified, but the reduction of eosinophilic cationic protein was linked with the response.

Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. Methods: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. Results: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. Conclusions: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. Trial registration: The study is registered with ClinicalTrials.gov (NCT03472040).

Background: Young patients with Crohn’s disease (CD) show a high prevalence of human papillomavirus (HPV) which is the main cause of high-grade squamous intraepithelial lesions (HSIL). A major complication for patients undergoing immunocompromising therapy is the development of genital dysplasia. Methods: We report the case of a 32-year-old patient with recurrent genital dysplasia under long-term therapy for CD with a focus on different drug-related, immunosuppressive mechanisms. Results: Gynecological examination and biopsy revealed high-grade vulvar intraepithelial neoplasia (VIN) positive for HPV 16 treated with laser vaporization. Due to the combination of HPV positivity, intraoperative multilocularity, and CD, follow-up examinations were performed every 6 months. One year later, the patient showed a VIN at a new location and additionally, a cervical intraepithelial neoplasia (CIN), which were surgically treated. Catch-up HPV vaccination was applied accessorily. After the switch from a TNF-α blocker to vedolizumab, which acts as a gut-selective anti-integrin, the subsequent PAP smear, vulvoscopy, and colposcopy showed no more evidence of dysplasia. Conclusions: This case report highlights that gut-selective immunosuppression with vedolizumab might be favorable in young HPV-positive patients due to a good side effect profile. Regular screening and HPV vaccination are a mainstay of dysplasia prevention and control. The risk for HPV-associated dysplasia in immunosuppressed patients is highly dependent on the choice of immunosuppressive therapy.

Dieser Artikel geht naher auf die TH2-Immunantwort mit ihren klinischen Manifestationen ein und beleuchtet die aktuellen therapeutischen Moglichkeiten und Entwicklungen betreffend Biologika.

Cet article s’interesse de plus pres a la reponse immunitaire TH2 et a ses manifestations cliniques, et explique les possibilites therapeutiques et developpements actuels relatifs aux biomedicaments.

BackgroundImmune-checkpoint inhibitors (ICI) present a new treatment for malignancies by boosting the immune system. This has led to a variety of immune-related adverse events, including ICI-associated pneumonitis (ICIaP). Diagnosis thereof is often challenging, and its pathogenesis has not yet been fully understood. The aim of this parallel cohort study was to investigate cytokines in serum and bronchoalveolar lavage fluid (BALF) expressed in patients with ICI-associated pneumonitis compared to healthy individuals.MethodsFrom January 2018 until June 2019, 401 adult patients with various lung diseases were prospectively enrolled in a BALF- and serum biobank, called BALOTHEK. Of these, 12 patients were diagnosed with ICIaP (Pembrolizumab, Ipilimumab, or both, and Durvalumab) and included in this parallel cohort study. Additionally, 12 healthy subjects from the biobank served as matched control group. The following 11 cytokines were simultaneously analyzed in BALF and serum of each study participant: interferon gamma, tumor necrosis factor alpha, interleukin (IL) 1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13 and IL-17A. This study was approved by the local ethic review committee (BASEC-ID 2017-02307 and 2018-01724).ResultsAbsolute number and percentage of lymphocytes in BALF of patients with ICIaP were significantly higher compared to control group. For the investigated cytokines in serum and BALF, a significant increase of IL-6 levels was shown for patients with ICIaP (p=0.044, adjusted for multiple comparisons). ConclusionCytokine profile assessed in BALF shows promising potential for facilitating diagnosis and understanding of pathophysiology of ICIaP. IL-6 may not only contribute to better understanding of pathophysiology but also herald therapeutic implications for Tocilizumab.

Introduction Lung cancer is the leading cause of death by cancer. In recent years, immunotherapy with checkpoint inhibitors (ICI) emerged as a promising new therapeutic approach. However, a deeper understanding of the immunologic responses adjacent to the tumor known as tumor microenvironment (TME) is needed. Our study investigated TME of lung cancer by analyzing cytokines in bronchoalveolar lavage fluid (BALF). Materials and methods Between January 2018 and June 2019, 119 patients were prospectively enrolled in this study. For each cancer patient, levels of 16 cytokines (fractalkine, granulocyte–macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukins (IL): IL-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, and IL-23) were measured in BALF and serum and compared to healthy individuals and patients with other lung diseases. Results There were several significant differences of cytokine levels of patients with lung cancer compared to healthy individuals. However, none of them remained in the multivariate analysis compared to other lung diseases in either BALF or serum. Furthermore, there were no significant differences between the groups in cell differentiation of either BALF or serum. Cytokine levels in BALF were generally near the lower detection limit and showed almost no correlation with their respective levels measured in serum of the same individual. Conclusions Cytokines in BALF and serum of lung cancer patients may indicate unspecific inflammation. BAL is not recommendable as a tool to investigate TME of lung cancer. Therefore, cytokines measured in BALF are probably not appropriate as predictors in patients treated with ICIs.

Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, often presenting with neuropsychiatric manifestations. Reports on the frequency and patterns of these manifestations vary substantially and remain incompletely understood. We examined neuropsychiatric manifestations in the prospective nationwide cohort of Swiss SLE (SSCS) patients and conducted a systematic literature review to contextualise our findings. Methods We reviewed all patients included in the SSCS from 2007–2019 and classified severe neuropsychiatric manifestations. Searches were performed in relevant electronic databases from 1.1999–1.2020 and by checking reference lists of the pertinent literature. Authors of important papers were contacted to obtain further (unpublished) studies. We included prospective or cross-sectional studies focussing on neuropsychiatric manifestations in SLE, defined according the ACR criteria of 1999. Study selection and data extraction was made in duplicate. We secured salient study characteristics, composition of cohorts, the definitions and the frequencies of neuropsychiatric manifestations. We assessed heterogeneity across reports and investigated sources of variation using meta-regression models. Results The frequencies of severe manifestations found in the SSLE were 7.1% (49/688) for cerebrovascular events, 5.3% (37/688) for seizures and 6.5% (45/688) for psychosis. The time-to-event analysis showed a linear relationship between duration of SLE and cumulative incidence of severe neuropsychiatric manifestations. Searches identified 530 studies and authors’ contact yielded another unpublished report. We included 28 studies. The mean rates of the most commonly reported severe neuropsychiatric manifestations ranged in the magnitude of 50 percent points. Study characteristics and composition of cohorts could not explain heterogeneity of reported manifestation rates. Conclusions The spectrum of neuropsychiatric manifestations in SLE is widely dispersed. The diagnostic work-up and the reporting of manifestations varied substantially across studies which may explain inconsistencies to some extent. We call for concerted efforts and a broad consensus regarding stringent definitions of neuropsychiatric SLE manifestations that allow targeted detection, particularly with view to timely intervention and patient outcomes.

Zusammenfassung. Wir präsentieren den Fall eines 49-jährigen Patienten mit linksseitiger Carotidynie. Als Ursache fand sich eine Lymphknotentuberkulose. Unter tuberkulostatischer Therapie zeigte sich eine rasche Besserung der Symptome.

Une patiente de 67 ans a ete admise pour des examens stationnaires en raison d’une fievre presente depuis 4 mois survenant surtout le soir et pouvant ­atteindre jusqu’a 40 °C, parfois accompagnee de frissons.

Eine 67-jahrige Patientin trat zur stationaren Abklarung ein bei seit vier Monaten bestehendem, vor allem abendlich auftretendem Fieber bis 40 °C, zeitweise einhergehend mit Schuttelfrost.

Background:Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, often presenting with neuropsychiatric manifestations. Reports on the frequency and patterns of these manifestations vary substantially and remain incompletely understood.Objectives:We examined neuropsychiatric manifestations in the prospective nationwide cohort of Swiss SLE (SSCS) patients and conducted a systematic literature review to contextualise our findings.Methods:We reviewed all patients included in the SSCS from 2007-2019 and classified severe neuropsychiatric manifestations. Searches were performed in relevant electronic databases from 1.1999-1.2020 and by checking reference lists of the pertinent literature. Authors of important papers were contacted to obtain further (unpublished) studies. We included prospective or cross-sectional studies focussing on neuropsychiatric manifestations in SLE, defined according the ACR criteria of 1999. Study selection and data extraction was made in duplicate. We secured salient study characteristics, composition of cohorts, the definitions and the frequencies of neuropsychiatric manifestations. We assessed heterogeneity across reports and investigated sources of variation using meta-regression models.Results:The frequencies of severe manifestations found in the SSLE were 7.1% (49/688) for cerebrovascular events, 5.3% (37/688) for seizures and 6.5% (45/688) for psychosis. The time-to-event analysis showed a linear relationship between duration of SLE and cumulative incidence of severe neuropsychiatric manifestations. Searches identified 530 studies and authors’ contact yielded another unpublished report. We included 28 studies. The mean rates of the most commonly reported severe neuropsychiatric manifestations ranged in the magnitude of 50 percent points. Study characteristics and composition of cohorts could not explain heterogeneity of reported manifestation rates.Conclusion:The spectrum of neuropsychiatric manifestations in SLE is widely dispersed. The diagnostic work-up and the reporting of manifestations varied substantially across studies which may explain inconsistencies to some extent. We call for concerted efforts and a broad consensus regarding stringent definitions of neuropsychiatric SLE manifestations that allow targeted detection, particularly with view to timely intervention and patient outcomes.Disclosure of Interests:None declared

International audience; BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks.METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life.RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P

Background Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease for which there are no available laboratory parameters to clearly define the disorder. Therapy is often difficult and various treatment options have been proposed. In this paper, we have evaluated the most effective therapies for InH-AAE on the basis of current literature and report the therapeutic effect of omalizumab in three patients with InH-AAE. Methods Literature was searched with a combination of MeSH/EMTREE terms and freetext search for angioedema and therapy/omalizumab in the databases Medline (Ovid), PubMed/Premedline, Embase, Cochrane library and Scopus with no time or language restrictions. In three patients affected by InH-AAE the therapeutic effect of omalizumab was demonstrated by clinical outcome. In one patient the FcεRI receptor density on basophils was monitored under therapy with omalizumab. Results From the review of the current literature, 25 out of 286 publications dealing with relevant therapeutic recommendations for InH-AAE were analyzed. Six publications with 98 patients referred to tranexamic acid, of which 27 had a complete, 70 a partial and 1 no response. In three case reports ecallantide showed 2 patients with a complete and 1 a partial response. In four case reports for Icatibant 2 had a complete and 3 a partial response. When evaluated in three reports, C1-INH found complete and partial responses in 2 patients each. One patient had a complete response to progestin. Omalizumab was described in 6 reports with 20 patients, all of whom showed a complete response. All three patients described in our study responded to omalizumab with a complete remission. Density of FcεRI receptors on basophils, monitored in patient 1 on a long-term course of 31 months, decreased from 74,051.61 to a minimal level of 1907 receptors per cell. Conclusions Omalizumab seems to be the most effective therapy in InH-AAE. The continuous decrease of FcεRI-receptor density on basophils under therapy with omalizumab along with clinical improvement observed in one patient, could serve as a new approach for further studies to evaluate FcεRI-receptor density as a surrogate marker for therapeutic efficacy and for dosing and determining injection intervals of omalizumab. Trial registration BASEC-Nr. Req-2016-00692. Retrospectively registered 24.11.2016. Electronic supplementary material The online version of this article (doi:10.1186/s13601-017-0164-9) contains supplementary material, which is available to authorized users.

Hereditary angioedema (HAE) is a rare, autosomal dominant disease due to functional deficiency of C1-esterase inhibitor (C1-INH). In this observational study anamnestic, clinical and treatment data from forty patients were retrospectively analysed. Thirty nine of the patients suffered from type I of HAE and one patient from type II. Between first manifestation of the disease and correct diagnosis a median time lag of 10 years was observed. Two C1-INH deficient individuals had no symptoms so far; 36 patients suffered from recurrent, self-limiting abdominal attacks (convulsion, vomiting and diarrhea); 32 patients presented with edema of the (sub-) cutis. Thirty percent of swelling attacks involved the upper respiratory tract and two larynx attacks needed intubation. Hormonal changes in 25% of the female patients were associated with an aggravation of the attacks. Long-term therapy was established in 19 patients; treatment of acute attacks was performed in 10 patients and 11 patients needed no therapy.

Background Rhinitis is a very common disease with allergies being the most frequent causative factor. It can co-occur together with asthma and eczema in atopic as well as in nonatopic patients. Objectives To assess the prevalence of allergic sensitization within patient groups with rhinitis in consideration of the co-occurring disorders of asthma and eczema. Methods Students of the third year of medical school completed an anonymous questionnaire on age, gender, and clinical symptoms, such as seasonal rhinitis, perennial rhinitis, asthma, and eczema, and underwent an ImmunoCAP Rapid test. We calculated the prevalence of sensitization within subgroups of patients reporting allergic disorders, such as rhinitis, asthma, and eczema. Results Questionnaires and ImmunoCAP Rapid tests of 1513 medical students were analyzed. The participants’ self-reported presence of seasonal/perennial rhinitis, asthma, and eczema was compared to the presence of sensitization. Data of 1467 subjects could be analyzed. Seasonal rhinitis was the most common symptom, followed by eczema, asthma, and perennial rhinitis. The participants were differentiated into 16 subgroups according to the combined clinical manifestations of the different symptoms and association to sensitization within subgroups. The prevalence of sensitization ranged from 18% in subjects reporting only eczema without any other symptom to 100% in those reporting to have asthma, seasonal/perennial rhinitis, and eczema together. In subjects reporting no sign or symptom at all, the prevalence of sensitization was 19%. Seasonal rhinitis was the strongest single predictor for sensitization with the highest proportion of sensitized participants in all symptom combinations (67%–100%), followed by perennial rhinitis (31%–100%), asthma (30%–100%), and eczema (18%–100%). Conclusion Rhinitis most often is associated with allergen sensitization, and the probability of sensitization is substantially enhanced by co-occurrence of asthma. A careful assessment of clinical signs and symptoms is important and enables the selection of patients in whom targeted diagnostic analysis and therapy is appropriate. Trial registration: retrospectively registered by the Cantonal Ethics Committee Zurich on 22.01.2016; Nr: 08-2016.

Extensive formation of nonfollicular sterile pustules on erythematous background combined with fever and peripheral blood leukocytosis are the characteristics of acute generalized exanthematous pustulosis. This uncommon eruption most often is an allergic reaction because of drugs such as aminopenicillins and sulfonamides inter alia. We recently demonstrated the important role of drug-specific T cells in the pathogenesis of this disease, showing that they produce high amounts of the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a special subgroup of T cells, differing from the usual Th1 and Th2 subsets. In this study we use immunohistochemistry as well as cytotoxicity assays (4- and 18-hour assays) and fluorescence-activated cell-sorting analysis of drug-specific circulating T cells and of cells eluted from the skin of five patients with acute generalized exanthematous pustulosis, to analyze whether cytotoxic T-cell functions are important in the pathogenesis of this disease, in particular for the formation of vesicles. The data reveal that drug-specific CD4+ as well as CD8+ T cells both are activated and cytotoxic; perforin/granzyme B and to a variable degree the Fas/FasL-killing mechanism is involved in tissue destruction. These features allow the formation of vesicles. Additional secretion of interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the vesicles and transform them into pustules.

Background According to the World Health Organization position paper, immunodeficiency such as human immunodeficiency virus (HIV) infection is a relative contraindication for specific immunotherapy (SIT). Since the introduction of highly active antiretroviral therapy, a significant reconstitution of immune competence in individuals with HIV is possible.Case Report In a 52-year-old man, HIV infection was diagnosed in 1987. Antiretroviral therapy was started in 1998. He presented himself in July 2001 because of an increasingly severe seasonal rhinoconjunctivitis. Symptoms were not sufficiently alleviated by various antiallergic drugs.Results The investigations showed a relevant sensitization to tree pollens. Specific immunotherapy with a tree pollen mix (hazel, birch, ash, and alder, 25% each) was started in November 2001. Viral load at this time was less than 50 copies/mL, the CD4+ cell count was 307/μL. Therapy was given in monthly intervals until mid-April 2005 without any side effects. Viral load and CD4+ cell counts did not change during SIT. Clinically, rhinoconjunctivitis was experienced only intermittently and symptom relief was almost 90%.Conclusions This report indicates that in patients with well-controlled HIV infection on highly active antiretroviral therapy, SIT with pollen extracts is a potential and successful therapeutic option. Keywords: human immunodeficiency virus, pollen allergy, respiratory allergy, allergy treatment, specific immunotherapy

Extensive formation of nonfollicular sterile pustules on erythematous background combined with fever and peripheral blood leukocytosis are the characteristics of acute generalized exanthematous pustulosis. This uncommon eruption most often is an allergic reaction because of drugs such as aminopenicillins and sulfonamides inter alia. We recently demonstrated the important role of drug-specific T cells in the pathogenesis of this disease, showing that they produce high amounts of the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a special subgroup of T cells, differing from the usual Th1 and Th2 subsets. In this study we use immunohistochemistry as well as cytotoxicity assays (4- and 18-hour assays) and fluorescence-activated cell-sorting analysis of drug-specific circulating T cells and of cells eluted from the skin of five patients with acute generalized exanthematous pustulosis, to analyze whether cytotoxic T-cell functions are important in the pathogenesis of this disease, in particular for the formation of vesicles. The data reveal that drug-specific CD4(+) as well as CD8(+) T cells both are activated and cytotoxic; perforin/granzyme B and to a variable degree the Fas/FasL-killing mechanism is involved in tissue destruction. These features allow the formation of vesicles. Additional secretion of interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the vesicles and transform them into pustules.

Patients with adult-onset Still’s disease (AOSD) are at increased risk for adverse outcomes of pregnancy. An increased rate of preterm birth, intrauterine growth retardation and a possible influence of disease activity on pregnancy outcome have been reported.1 Interleukin 1 (IL1) is thought to have a key role in the pathogenesis of AOSD. Interestingly, it has also been related to an increased risk of preterm birth in animal models.2 3 An increasing number of reports on treatment of refractory AOSD with IL1 receptor antagonist (anakinra) emphasise its dramatic therapeutic effect and the rarity of its adverse events.4 5 However, its effects in pregnancy are not well known. Here we report successful continuous treatment of AOSD during pregnancy and breastfeeding. A 33-year-old woman with …

BACKGROUND: H1 antihistamines increase safety during allergen-specific immunotherapy and might influence the outcome because of immunoregulatory effects. OBJECTIVE: We sought to analyze the influence of 5 mg of levocetirizine (LC) on the safety, efficacy, and immunologic effects of ultrarush honeybee venom immunotherapy (BVIT). METHOD: In a double-blind, placebo-controlled study 54 patients with honeybee venom allergy received LC or placebo from 2 days before BVIT to day 21. Side effects during dose increase and systemic allergic reactions (SARs) to a sting challenge after 120 days were analyzed. Allergen-specific immune response was investigated in skin, serum, and allergen-stimulated T-cell cultures. RESULTS: Side effects were significantly more frequent in patients receiving placebo. Four patients receiving placebo dropped out because of side effects. SARs to the sting challenge occurred in 8 patients (6 in the LC group and 2 in the placebo group). Seven SARs were only cutaneous, and 1 in the placebo group was also respiratory. Difference of SARs caused by the sting challenge was insignificant. Specific IgG levels increased significantly in both groups. Major allergen phospholipase A(2)-stimulated T cells from both groups showed a slightly decreased proliferation. The decrease in IFN-gamma and IL-13 levels with placebo was not prominent with LC, whereas IL-10 levels showed a significant increase in the LC group only. Decreased histamine receptor (HR)1/HR2 ratio in allergen-specific T cells on day 21 in the placebo group was prevented by LC. CONCLUSIONS: LC reduces side effects during dose increase without influencing the efficacy of BVIT. LC modulates the natural course of allergen-specific immune response and affects the expression of HRs and cytokine production by allergen-specific T cells.

It is unknown whether neutrophilic inflammations can be regulated by T cells. This question was analyzed by studying acute generalized exanthematous pustulosis (AGEP), which is a severe drug hypersensitivity resulting in intraepidermal or subcorneal sterile pustules. Recently, we found that drug-specific blood and skin T cells from AGEP patients secrete high levels of the potent neutrophil-attracting chemokine IL-8/CXCL8. In this study, we characterize the phenotype and function of CXCL8-producing T cells. Supernatants from CXCL8+ T cells were strongly chemotactic for neutrophils, CXCR1, and CXCR2 transfectants, but not for transfectants expressing CXCR4, CX3CR1, human chemokine receptor, and RDC1. Neutralization experiments indicated that chemotaxis was mainly mediated by CXCL8, but not by granulocyte chemotactic protein-2/CXCL6, epithelial cell-derived neutrophil attractant-78/CXCL5, or growth-related oncogene-α,β,γ/CXCL1,2,3. Interestingly, ∼2.5% of CD4+ T cells in normal peripheral blood also produced CXCL8. In addition to CXCL8, AGEP T cells produced large amounts of the monocyte/neutrophil-activating cytokine GM-CSF, and the majority released IFN-γ and the proinflammatory cytokine TNF-α. Furthermore, apoptosis in neutrophils treated with conditioned medium from CXCL8+ T cells could be reduced by 40%. In lesional skin, CXCL8+ T cells consistently expressed the chemokine receptor CCR6, suggesting a prominent role for CCR6 in early inflammatory T cell recruitment. Finally, our data suggest that CXCL8-producing T cells facilitate skin inflammation by orchestrating neutrophilic infiltration and ensuring neutrophil survival, which leads to sterile pustular eruptions found in AGEP patients. This mechanism may be relevant for other T cell-mediated diseases with a neutrophilic inflammation such as Behçet’s disease and pustular psoriasis.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption most often provoked by drugs, by acute infections with enteroviruses, or by mercury. It is characterized by acute, extensive formation of nonfollicular sterile pustules on erythematous background, fever, and peripheral blood leukocytosis. We present clinical and immunological data on four patients with this disease, which is caused by different drugs. An involvement of T cells could be implied by positive skin patch tests and lymphocyte transformation tests. Immunohistochemistry revealed a massive cell infiltrate consisting of neutrophils in pustules and T cells in the dermis and epidermis. Expression of the potent neutrophil-attracting chemokine IL-8 was elevated in keratinocytes and infiltrating mononuclear cells. Drug-specific T cells were generated from the blood and skin of three patients, and phenotypic characterization showed a heterogeneous distribution of CD4/CD8 phenotype and of T-cell receptor Vbeta-expression. Analysis of cytokine/chemokine profiles revealed that IL-8 is produced significantly more by drug-specific T cells from patients with AGEP compared with drug-specific T cells from patients that had non-AGEP exanthemas. In conclusion, our data demonstrate the involvement of drug-specific T cells in the pathomechanism of this rather rare and peculiar form of drug allergy. In addition, they indicate that even in some neutrophil-rich inflammatory responses specific T cells are engaged and might orchestrate the immune reaction.