The Involvement of LAG-3positive Plasma Cells in the Development of Multiple Myeloma.

The Lymphocyte-Activation Protein 3 (LAG-3) inhibitory receptor is expressed on regulatory plasma cells (PCs). Micro-environmental cells that express LAG-3 were found to be increased during the progression of smoldering multiple myeloma (SMM). To assess the possible role of LAG-3 expression on regulatory PCs in patients with plasma cell dyscrasia. Purified Cluster of Differentiation 138 (CD138+) PCs from patients with premalignant conditions, active multiple myeloma (MM), and controls were analyzed for the expression of LAG-3 by flow cytometry. Autologous CD8+T cells were incubated with sorted LAG-3pos or LAG-3neg PCs for 24 h. The expression of granzyme (Grz) in CD8+T cells was assessed by flow cytometry. LAG-3 expression on PCs in active MM (newly diagnosed and relapse refractory MM) was significantly increased compared to monoclonal gammopathy of undetermined significance (MGUS)/ SMM. Grz expression was significantly decreased in CD8+T cells incubated with CD138+LAG-3pos PCs, compared to CD138+LAG-3neg PCs in patients with plasma cell dyscrasia, n = 31, p = 0.0041. LAG-3 expression on malignant PCs can be involved in the development of MM from MGUS by decreasing the expression of Grz in CD8+T cells.

Highlights in Autoimmunity: 2020.

BACKGROUND: Innate and adaptive immune response dysregulations are equally involved in the induction of autoimmunity. Toll-like receptors play a leading role in the activation of innate immune cells, thus priming auto-reactive T cells. Th17 cells and related cytokines are widely involved in many immune-mediated diseases such as rheumatoid arthritis. Thus, the recent introduction of anti-IL-17 therapies should be further evaluated. Janus kinase inhibitors and Fc receptor-targeting drugs are some of the new therapeutic strategies that are being implemented when old classical therapies lack sufficient beneficial outcomes.

Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: Results of the PURIST Study.

BACKGROUND: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU. METHODS: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). RESULTS: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non-aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti-TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively. CONCLUSIONS: aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management.

Hemostasis in Allergy.

The involvement of the hemostatic system in immune-mediated inflammation is widely reported. Many coagulation factors play a role in the pathogenesis of autoimmune diseases, such as systemic vasculitis and systemic lupus erythematosus. Hemostatic disorders are also involved in asthma and chronic spontaneous urticaria (CSU). Factor XIIa (FXIIa) was one of the first coagulation factors implicated in inducing both humoral and cellular responses and is therefore considered a prime new therapeutic target in immune-mediated inflammation. The involvement of coagulation factors, such as tissue factor and fibrinogen, in the pathogenesis of asthma has been reported. The finding of platelet activation in asthma also indicates a link between bronchial inflammation and hemostasis. The pathogenesis of mast cell degranulation and CSU was also shown to be associated with the activation of hemostatic factors such as fibrinogen and FXIIa. Increased plasma levels of D-dimer have been widely reported as a biological marker for the duration and severity of CSU. In addition, endothelial-induced cell activation by the kallikrein-high molecular weight complex and the release of heat shock protein 90 was shown to be involved in mast cell degranulation disorders. In this narrative review, the authors aim to summarize the role of hemostasis in inflammation, asthma, and CSU by focusing on the increasing information linking hemostatic factors and immune-mediated disorders.

Icatibant Outcome Survey in Patients with Hereditary Angioedema: Experience in Israel Compared with Other Countries.

BACKGROUND: Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights. OBJECTIVES: To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries. METHODS: The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes. RESULTS: By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH. CONCLUSIONS: Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

Semaphorins 4A and 4D in chronic inflammatory diseases.

Long-term inflammatory processes directed at a particular endogenous or exogenous antigen, or sometimes of unknown etiology, form the pathogenetic basis for many debilitating conditions, such as cardiovascular, pulmonary, autoimmune, neurologic diseases, and cancer. Recent discoveries of neuroimmune semaphorins 4A and 4D (Sema4A and Sema4D, respectively) expression and function in the immune system and their key regulatory roles in fine tuning of inflammatory processes made them the molecules of interest for a potential immunotherapy. In this short review, we discuss the current knowledge in the Sema4A and Sema4D actions in chronic inflammation underlying the outlined above diseases.

Autoimmunity in the Elderly: Insights from Basic Science and Clinics - A Mini-Review.

Advancements in the field of biomedicine, including the control of infectious diseases through antibiotics and vaccination practices and the prevention of chronic disorders, have led to reduced mortality, increased life expectancy and, as such, growth of the older population. Ageing is accompanied by profound morphological and physiological alterations. In particular, the immune system undergoes a complex series of remodeling/restructuring events, involving almost all compartments - both the innate and the adaptive system. This process is termed immunosenescence or immune dysregulation and, basically, includes 3 events: a reduction in immune response, an increase in the inflammatory and oxidation background (inflammaging and oxi-inflammaging), and a production of autoantibodies. While there is an increase in autoimmunity in the elderly, this does not always translate into an increase in autoimmune diseases, which represent an important cause of morbidity and mortality and affect 5-10% of the world population. Each disease involves a specific age group. Generally speaking, most autoimmune diseases have a decreased peak age of onset, except for very few diseases such as giant cell arteritis and primary biliary cirrhosis, which are more prevalent among the elderly, or inflammatory bowel disease, which has 2 peaks of onset, the first one in young subjects and the other in those older than 60 years. Autoimmune disorders in the elderly have unique clinical presentations, and insidious and atypical symptoms may constitute a challenge for the physician. They are generally milder than in adults and can be controlled by a proper therapeutic treatment. However, despite advancements both in basic and clinical sciences, further studies and investigations are warranted and should be carried out in order to dissect the molecular framework induced by ageing.

Anti-BLyS Treatment of 36 Israeli Systemic Lupus Erythematosus Patients.

BACKGROUND: Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment. OBJECTIVES: To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers. METHODS: We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response. RESULTS: The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%). CONCLUSIONS: Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

Increased soluble CD72 in systemic lupus erythematosus is in association with disease activity and lupus nephritis.

INTRODUCTION: B cell receptor (BCR) -mediated signals are enhanced when CD72 expression is deficient on B cells in autoimmune diseases. The significance of soluble CD72 (sCD72) has not been elucidated. METHODS: Soluble CD72 was analyzed in the serum of 159 SLE patients, 40 rheumatoid arthritis (RA) patients, and 100 healthy individuals. Correlations between sCD72 and SLE disease activity (SLEDAI) were assessed. RESULTS: Soluble CD72 was found increased in SLE patients, when compared to both RA patients and healthy individuals (20.2 ± 1.2 ng/ml; 10.6 ± 4.6 ng/ml and 7.2 ± 3.3 ng/ml; p < 0.001). Soluble CD72 level was significantly higher in SLE patients with renal involvement than in patients without (31.8 ± 2.3 ng/ml vs 13.9 ± 0.9 ng/ml; p < 0.001) and also with the presence of auto-antibodies. CONCLUSION: Soluble CD72 is significantly increased in SLE patients mainly in those with renal involvement. Increased sCD72 may become a potential biomarker for renal involvement in SLE.

Seasonal Exacerbation of Asthma Is Frequently Associated with Recurrent Episodes of Acute Urticaria.

BACKGROUND: Asthma and urticaria are both partially mediated by an increased release of histamine from highly activated mast cells. They are pathophysiologically different, as mast cell degranulation in these 2 disorders results from different mechanisms. OBJECTIVE: To assess the incidence of urticaria in patients with asthma, and of asthma in patients with chronic spontaneous urticaria (CSU). PATIENTS AND METHODS: Over 1 year of follow-up, asthma patients (n = 110) were assessed for the incidence and characteristics of urticaria, and a link, if it existed, to seasonal exacerbations and the severity of asthma was traced. We also prospectively assessed CSU patients (n = 95) during the same period of time for the incidence of asthma. Healthy individuals (n = 100), serving as a control group, were also assessed. RESULTS: Episodes of urticaria occurred in 26/110 asthma patients (23.6%), but in only 2/100 healthy control subjects (2%) (p < 0.0001). During the 1-year observation period, episodes of urticaria were significantly more frequent in asthma patients with positive skin-prick test reactions (mainly seasonal pollens), and consequently occurred mostly during seasonal asthma exacerbation, i.e. during acute episodes of urticaria. The incidence of asthma in CSU patients was recorded in 10.5% of the group, similar to that in the healthy control population. DISCUSSION: Our study demonstrates, for the first time, that asthma patients frequently develop acute urticaria, mainly during seasonal exacerbations. In contrast, CSU patients do not show an increased incidence of asthma.

Adaptation and Validation of the Israeli Version of the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL).

BACKGROUND: Chronic urticaria (CU) is a common disabling disorder. The CU-Q2oL (Chronic Urticaria Quality of Life Questionnaire) is a specific questionnaire for evaluating quality of life in CU patients. It consists of 23 items divided into six quality-of-life dimensions. It was initially developed in Italy and later validated in other countries. OBJECTIVES: To validate and adapt the CU-Q2oL to the Hebrew language in order to make it suitable for use in Israel. METHODS: The CU-Q2oL questionnaire was translated to Hebrew. A group of 119 CU patients were asked to complete this version, in addition to the Dermatology Life Quality Index (DLQI) and Urticaria Activity Score (UAS) questionnaires. A factorial analysis was performed to identify CU-Q2oL subscales, internal consistency and convergent validity assessment, as well as factors determining quality-of-life scores. RESULTS: The factor analysis identified six scales of the Israeli CU-Q2oL: (i) sleep and concentration, (ii) function and mental status, (iii) embarrassment and clothing limitations, (iv) itching, (v) eating behavior and medication side effects, and (vi) swelling, which accounted for 77% of the data variance. Five scales showed good internal consistency over 0.81. The mean ± SD score of CU-Q2oL in our patients with CIU was 41 ± 21.7. We found a strong positive correlation between the overall scores of CU-Q2oL and DLQI questionnaires (r = 0.8, P < 0.01). Additionally, we found a positive correlation between UAS and both CU-Q2oL and DLQI (r = 0.62, P < 0.01, and r = 0.53, P < 0.01, respectively). CONCLUSIONS: This study demonstrates that the Israeli CU-Q2oL questionnaire is suitable for both clinical use and research in Israel.

[REGULATORY B CELLS].

B lymphocytes represent a major component of the immune system. In addition to their best understood functions, B cells have also been demonstrated to downregulate inflammatory reactions and induce tolerance. The general concept that B cells might have the ability to induce tolerance was already introduced in the 1970s. In mice subpopulations, regulatory B cells and their precursors seem to be able to arise from different subpopulations of Br1 and Br2 cells. In contrast to the murine studies, there is a paucity of data regarding regulatory B cells in healthy people or in patients with autoimmune disease, but such data exists. The composition of regulatory B cells is similar to that of regulatory T cells. In analogy to regulatory T cells, which can be subdivided into Treg, Tr1 and Th3 according to their expression of FoxP3, IL-10 and transforming growth factor TGF-ß, respectively, it is proposed to classify human regulatory B cells into Breg, Br1(10) and Br3. Regulatory T and B cells function at different time points. Br1 may be involved in the initiation of pathological responses and Tregs in their maintenance and progression. The main functions of regulatory B cells are mediated by releasing immunosuppressive cytokines and inducing target cell apoptosis. IL-10 is the hallmark cytokine of regulatory B cells. Impaired regulatory capacity of these cells might play a role in the development of inflammatory diseases. Their released cytokines have a broad range of target cells. Therefore, they downregulate the proinflammatory functions of both innate and adaptive immune cells. Targeting B regulatory cells for therapeutic applications holds great promise for the future treatment of autoimmune and allergic inflammatory conditions.

[KIDNEY DISEASES IN NORTH ISRAEL ACCORDING TO KIDNEY BIOPSIES - BNAI-ZION MEDICAL CENTER 14 YEARS' EXPERIENCE].

INTRODUCTION: Little is known about the prevalence of kidney diseases according to renal biopsy in Israel. Since updated literature worldwide emphasizes changing etiologies of chronic kidney disease, it is crucial to research and define the epidemiology and pathology of kidney disease in Israel. Hereby, we introduce an original review of the prevalence of kidney diseases in our study population, which we believe reflects the prevalence of kidney diseases in the population of Israel. AIMS: To investigate the prevalence of kidney diseases diagnosed by renal biopsy, according to age, gender, race and clinical symptoms. METHODS: A total of 155 kidney biopsies were conducted in the years 2000-2014 in Bnai-Zion Medical Center in Haifa, according to formal accepted indications. Most of the biopsies (65%) were needle aspirations in a retroperitoneal approach, in which 90% were ultrasound guided and the rest computed tomography guided, while the other 35% of biopsies involved laparoscopic approaches. RESULTS: The most common indications for kidney biopsy were nephrotic syndrome, nephritic syndrome and proteinuria (37.4%, 25.8% and 24.5%, respectively). Average glomeruli number per biopsy was 17.5 vs. 82.2 for needle aspiration and laparoscopic approach, respectively (statistically significant). The most common diagnosis was focal segmental glomerulosclerosis (FSGS), followed by chronic glomerulonephritis, IgA nephropathy, lupus nephritis, minimal change disease (MCD), membranous nephropathy and tubulointerstitial disease (20%, 11.5%, 11.5%, 10.1%, 9.5%, 8.1% and 6.1%, respectively). CONCLUSIONS: FSGS was the most common diagnosis in patients presented with nephrotic syndrome or proteinuria, men, and patients above 60 years of age. Patients below 30 years of age were mainly diagnosed with IgA nephropathy. DISCUSSION: In recent years, FSGS is becoming more prevalent compared with other chronic kidney disease especially in the older population. IgA nephropathy is still the most common diagnosis in young patients and in patients presented with hematuria. To the best of our knowledge, no data exists on the prevalence of kidney diseases in Israel, and our study is an important contribution to the epidemiological and clinical knowledge on the subject.

Icatibant for Multiple Hereditary Angioedema Attacks across the Controlled and Open-Label Extension Phases of FAST-3.

BACKGROUND: In randomized, controlled, double-blind, multicenter phase 3 studies, one icatibant injection was efficacious and generally well tolerated in patients with a single hereditary angioedema (HAE) attack. Here, the efficacy and safety of icatibant for multiple HAE attacks was evaluated across the controlled and open-label extension phases of the For Angioedema Subcutaneous Treatment (FAST)-3 study (NCT00912093). METHODS: In the controlled phase, adults with HAE type I or II were randomized (1:1) to receive a single subcutaneous injection of icatibant 30 mg or placebo within 6 h of an attack becoming mild (laryngeal) or moderate (cutaneous/abdominal). Open-label icatibant was administered for severe laryngeal symptoms. In the open-label extension phase, patients could receive up to three icatibant injections per attack. Efficacy and safety were analyzed for the first five icatibant-treated attacks at any location (prospective analysis) and laryngeal attacks (post hoc analysis) across both phases. Efficacy outcomes were based on patient-reported symptom severity (visual analog scale). RESULTS: In groups of patients with one to five icatibant-treated attacks at any location (n = 88), the median times to onset of symptom relief, onset of primary symptom relief and almost complete symptom relief were 1.9-2.1, 1.5-2.0 and 3.5-19.7 h, respectively. The same outcomes for laryngeal attacks (n = 25) were 1.0-2.0, 1.0-2.0 and 1.5-8.1 h, respectively. The most frequently reported adverse events were a worsening or recurrence of HAE attack, headache and nasopharyngitis. Two serious adverse events (arrhythmia and noncardiac chest pain) were considered to be related to icatibant. CONCLUSIONS: Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.

Interferon-gamma-release assay prevents unnecessary tuberculosis therapy.

BACKGROUND: The mass influx of immigrants from tuberculosis-endemic countries into Israel was followed by a considerable increase in the incidence of tuberculosis (TB). All contacts of active TB patients are obliged to be screened by tuberculin skin tests (TST) and, if found positive, prophylactic treatment is considered. OBJECTIVES: To assess the utility of interferon-gamma (IFNγ)-release assay with a prolonged follow-up in preventing unnecessary anti-TB therapy in individuals with suspected false positive results. METHODS: Between 2008 and 2012 the QuantiFERON TB gold-in-tube test (QFT-G) was performed in 278 sequential individuals who were mostly TST-positive and/or were in contact with an active TB patient. In all, whole blood was examined by the IFNγ-release assay. We correlated the TST diameter with the QFT-G assay and followed those patients with a negative assay. RESULTS: The QFT-G test was positive in only 72 (42%) of all 171 TST-positive individuals. There was no correlation between the diameter of TST and QFT-G positivity. Follow-up over 5 years was available in 128 (62%) of all QFT-G-negative individuals. All remained well and none developed active TB. CONCLUSIONS: A negative QFT-G test may obviate the need for anti-TB therapy in more than half of those with a positive TST.

The role of B regulatory cells and Semaphorin3A in atopic diseases.

When the pathogenesis of allergic inflammatory diseases such as asthma, allergic rhinitis and atopic dermatitis is discussed, one should take into consideration the involvement of regulatory cells/molecules whose role is to prevent the induction and/or deterioration of such diseases. The involvement of T regulatory cells and FoxPp3 is well established in asthma, but only little is known about the involvement of B regulatory cells (Bregs) and the soluble regulatory molecule semaphorin3A (sema3A) in atopic diseases. During the last decade, research has sought to better define the various subtypes of Breg cells and how similar they are to their parallel subtypes of Tregs. In this review, we focus on the newly reported role of Bregs in both experimental and human models of asthma. Bregs are also involved in the pathophysiology of food allergy. We also show how sema3A plays a role in the pathogenesis of allergic rhinitis and atopic dermatitis. Determining the above processes could facilitate the use of regulatory molecules as therapeutic tools in treating these diseases.