The hypereosinophilic syndromes: current concepts and treatments

The hypereosinophilic syndromes (HES) encompass a spectrum of diseases that have increased blood eosinophils and tissue damage in common. The clinical manifestations are protean and may involve any organ system, but especially the skin. Our understanding of these diseases has drastically changed over the past 15 years, along with new classifications that characterize patients with marked eosinophilia. One HES variant, myeloproliferative, is actually chronic eosinophilic leukaemia with a unique genetic marker, FIP1L1-PDGFRA . Such patients are well-controlled by administration of the kinase inhibitor, imatinib, and remissions appear durable with continued imatinib therapy. FIP1L1-PDGFRA is expressed in several cell lineages, thus explaining increases in neutrophils and mast cells in HES. The lymphocytic HES variant is associated with T-cell clones producing interleukin-5 (IL-5) and can evolve into lymphoma. While myeloproliferative and lymphocytic HES are well established and permit elimination of the term, idiopathic, to these varieties, most HES patients do not fall into these categories and are classified as complex (using the 2006 Workshop Report). A recent study showed that a monoclonal antibody to IL-5, mepolizumab, reduced glucocorticoid therapy in HES patients who did not possess the FIP1L1-PDGFRA mutation while controlling eosinophilia and preventing recurrence or progression of tissue damage. These advances augur well for continued progress in the understanding and treatment of HES.     

Exogenous IL-15 in Combination With IL-15Rα Rescues Natural Killer Cells From Apoptosis Induced by Chronic Alcohol Consumption

Background:  Chronic alcohol consumption reduces the percentage and number of peripheral natural killer (NK) cells in mice and in humans. The underlying mechanism for these changes is only partly known. We recently found that chronic alcohol consumption inhibits NK cell release from the bone marrow (BM) and that this is associated with a decrease in splenic NK cells. The number of peripheral NK cells is tightly controlled by homeostatic proliferation. It is not known whether this mechanism is initiated in response to the reduction in splenic NK cells, or if so, why the steady state levels of NK cells are not restored.
Methods:  To examine this mechanism, female C57BL/6 mice were given 20% w/v alcohol in the drinking water for 3 months. NK cell proliferation and apoptosis were determined before and after treatment with IL-15 alone or combined with its alpha receptor.
Results:  Chronic alcohol consumption invoked homeostatic proliferation of splenic NK cells in an attempt to return NK cells to normal levels; however, this did not happen due to enhanced apoptosis of NK cells relative to proliferation. Chronic alcohol consumption decreased IL-15 producing cells in the spleen but not in the BM. The numbers of NK cells in the alcohol-consuming mice returned to normal levels in the spleen and were higher than normal in the BM after 2 daily injections of IL-15; however, the enhanced rate of apoptosis due to alcohol consumption was not decreased in the spleen or BM. Combined IL-15 and IL-15Rα treatment decreased apoptosis of NK cells from alcohol-consuming mice to levels similar to untreated water-drinking mice and greatly increased the percentage and number of NK cells in both the spleen and BM.
Conclusion:  Chronic alcohol consumption causes a self-unrecoverable loss of NK cells in the spleen by compromising NK cell release from the BM and enhancing splenic NK cell apoptosis that can be reversed with IL-15/IL-15Rα treatment.     

Changes with ageing in several leukocyte functions of male and female rats

The impairment of the immune system with aging, or immunosenescence, appears to contribute to the increased morbidity and mortality of aged subjects. T cell functions and Natural Killer activity seem to be the immune responses most affected by ageing. Since the immune system works more efficiently in females than in males, we have studied the changes of several immune functions with age in rats of both sexes. In addition, we have investigated if ovariectomy, a model of menopause in rats, produces a loss of this gender-related advantage. In the present work, the changes with age (2, 6, 12, 14, 18, 22 and 24 months old) in lymphocyte chemotaxis, T lymphoproliferative response to the mitogen ConA, IL-2 release and Natural Killer activity of cells from axillary nodes and spleen of male and female rats as well as of females ovariectomized at 12 months of age have been studied. An age-related decrease was found in all investigated functions, with a slightly different evolution depending on the immune organ and gender considered. In general, the data obtained show that a certain degree of immunosenescence takes place with age in rats, with males being less immunocompetent than intact age-matched females, but showing an immune response similar to that of ovariectomized animals.     

熊去氧胆酸联合非诺贝特治疗PBC患者血清TGF-β、IFN-γ和IL-10水平变化*

目的 探讨熊去氧胆酸(UDCA)联合非诺贝特治疗原发性胆汁性胆管炎(PBC)患者血清转化生长因子-β(TGF-β)、γ-干扰素(IFN-γ)和白介素-10(IL-10)水平的变化。方法 2016年12月～2018年12月我科诊治PBC患者48例,随机将患者分为观察组(n=24)和对照组(n=24)。给予对照组患者UDCA治疗半年,给予观察组UDCA联合非诺贝特口服治疗半年。采用ELISA法检测血清TGF-β、IFN-γ和IL-10水平。使用FibroTouch行肝脏硬度测定(liver stiffness measurement, LSM)。结果 在治疗观察结束时,观察组血清谷丙转氨酶水平为(51.4±23.7)U/L,显著低于对照组【(74.9±21.2)U/L,P<0.05】,谷草转氨酶为(59.5±32.3)U/L,显著低于对照组【(81.3±35.8)U/L,P<0.05】,谷氨酰转肽酶水平为(95.7±31.8)U/L,显著低于对照组【(127.3±50.7)U/L,P<0.05】;观察组血清IFN-γ水平为(57.4±21.3)pg/mL,显著高于对照组【(39.7±23.7)pg/mL,P<0.05】,而血清TGF-β水平为(14.3±4.8)pg/mL,显著低于对照组【(23.6±3.5)pg/mL,P<0.05】;观察组血清免疫球蛋M(IgM)为(2.3±0.4)g/L,显著低于对照组【(3.1±0.9)g/L,P<0.05】, IgG水平为(11.3±1.8)g/L,显著低于对照组【(15.5±1.3)g/L,P<0.05】,IgA水平为(2.7±0.6)g/L,显著低于对照组【(3.5±0.2)g/L,P<0.05】;观察组患者LSM为(10.8±6.5)kPa,与对照组的(9.7±7.7)kPa比,无统计学差异(P>0.05)。结论 熊去氧胆酸联合非诺贝特联合治疗PBC患者可以明显改善血生化指标,可能与抑制了免疫球蛋白水平和提高了血清IFN-γ水平有关,其治疗的远期疗效还有待于观察。     

Risk factors for progression to acute respiratory failure after casirivimab and imdevimab administration: A retrospective study

BackgroundCasirivimab and imdevimab are effective in preventing hospitalization in outpatients with coronavirus disease 2019 (COVID-19); however, disease progression after casirivimab and imdevimab administration has been reported. This study aimed to elucidate the risk factors for disease progression after casirivimab and imdevimab administration.MethodsThis retrospective study included patients with COVID-19 who received casirivimab and imdevimab at Hiroshima City Funairi Citizens Hospital between August 6, 2021, and October 10, 2021. All patients had at least one risk factor for severe disease and were treated on admission. The patients’ background characteristics and test results at the first visit were analyzed. The patients were divided into two groups (progressed and improved) based on whether they progressed to acute respiratory failure during hospitalization.ResultsSixty-seven patients were included: 9 patients in the progressed group (median age, 56 years) and 58 patients in the improved group (median age, 51 years). Age, coexistence rate of diabetes, cycle threshold value of polymerase chain reaction test, rate of detectable pneumonia on chest radiographs or chest computed tomography images, lymphocyte count, and the levels of C-reactive protein, interleukin-6, glucose, and glycated hemoglobin were significantly different between the two groups. Multivariate logistic regression analysis revealed that the coexistence of diabetes and the presence of detectable pneumonia on chest radiographs were independent factors predicting the progression to acute respiratory failure.ConclusionAcute respiratory failure after antibody therapy with casirivimab and imdevimab may develop in patients with diabetes or detectable pneumonia on chest radiographs at the first visit.     

尘螨变应性鼻炎全血细胞IL-4、IL-13的表达及临床意义

目的探讨IL-4、IL-13在变应性鼻炎发病机制中的作用及IL-4、IL-13拮抗剂治疗变应性鼻炎的临床意义。方法取52例变应性鼻炎（实验组）及25例无过敏性疾病（对照组）患者的外周血，用PMA（phorbol 12-myristate 13-acetate佛波酯）＋inomycin（离子霉素）及标准化尘螨抗原刺激后经细胞内染色，流式细胞仪检测IL-4、IL-13、IFN-γ的表达细胞百分数，ELISA检测血清IL-4、IL-13含量。结果对照组经标准化尘螨变应原刺激后细胞内测出IFN-γ为0．3％-0．4％，但检测不到IL-4与IL-13，经PMA＋inomycin刺激后IFN-γ为5．0％-12．4％、IL-4为0．5％-0．8％、IL-13为0％-0．2％；实验组经标准化尘螨变应原刺激后IFN-γ为0．3％-0．5％、IL-4为0．9％-1．3％、IL-13为0．5％-0．9％，经PMA＋inomycin刺激后IFN-γ为17.3％-24．0％、IL-4为2．1％-3．5％、IL-13为0．8％-2．0％。实验组血清中IL-4含量为（1．768±0．485）pg／ml、IL-13为（5．427±1．263）pg／ml，对照组IL-4与IL-13含量均低于敏感度。结论IL-4、IL-13在变应性鼻炎患者中表达升高，参与了变态反应过程，为临床应用IL-4、IL-13拮抗剂治疗变应性鼻炎提供了依据。     

Copper addition prevents the inhibitory effects of interleukin 1-β on rat pancreatic islets

Summary Since copper [Cu(II)] is a necessary cofactor for both intra-mitochondrial enzymes involved in energy production and hydroxyl scavenger enzymes, two hypothesised mechanisms for action of interleukin-Iβ (IL-1β), we studied whether CU(II) addition could prevent the inhibitory effect of IL-1β on insulin release and glucose oxidation in rat pancreatic islets. Islets were incubated with or without 50 U/ml IL-1β, in the presence or absence of various concentrations of Cu(II)-GHL (Cu(II) complexed with glycyl-l-histidyl-l-lysine, a tripeptide known to enhance copper uptake into cultured cells). CuSO₄ (1–1000 ng/ml) was used as a control for Cu(II) effect when present as an inorganic salt. At the end of the incubation period, insulin secretion was evaluated in the presence of either 2.8 mmol/l (basal insulin secretion) or 16.7 mmol/l glucose (glucose-induced release). In control islets basal insulin secretion was 92.0±11.4 pg · islet⁻¹ h⁻¹ (mean ± SEM,n=7) and glucose-induced release was 2824.0±249.0 pg · islet⁻¹ h⁻¹. In islets pre-exposed to 50 U/ml IL-1β, basal insulin release was not significantly affected but glucose-induced insulin release was greatly reduced (841.2±76.9,n=7,p<0.005). In islets incubated with IL-1β and Cu-GHL (0.4 μmol/l, maximal effect) basal secretion was 119.0±13.1 pg · islet⁻¹ h⁻¹ and glucose-induced release was 2797.2±242.2, (n=7,p<0.01 in respect to islets exposed to IL-1β alone). In contrast to data obtained with Cu(II)-GHL, increasing concentrations of CuSO4 (up to 10 μmol/l) did not influence the inhibitory effect of IL-1β on glucose-stimulated insulin release. Glucose oxidation (in the presence of 16.7 mmol/l glucose) was 31.5±2.4 pmol · islet⁻¹·90min⁻¹ in control islets and 7.0±0.9 (p<0.01) in IL-1β-exposed islets. In islets exposed to IL-1β and Cu-GHL glucose oxidation was similar to control islets (31.9±1.9). In contrast, Cu-GHL did not prevent the IL-1β-induced increase in nitric oxide production. Nitrite levels were 5±1.7, 26±5 and to 29±4 pmol · islet⁻¹·48 h⁻¹ (mean ± SEM,n=5) in the culture medium from control IL-1β and IL-1β+Cu-GHL exposed islets, respectively. These data indicate that the Cu(II) complexed to GHL is able to prevent the inhibitory effects of IL-1β on insulin secretion and glucose oxidation, but not on NO production. The mechanism of action of Cu-GHL is still unclear, but it might restore the activity of the enzymatic systems inhibited by IL-1β. [Diabetologia (1995) 38∶39–45]