Zahava Vadasz

Age-related autoimmunity

Older persons have higher autoimmunity but a lower prevalence of autoimmune diseases. A possible explanation for this is the expansion of many protective regulatory mechanisms highly characteristic in the elderly. Of note is the higher production of peripheral T-regulatory cells.The frequent development of autoimmunity in the elderly was suggested to take place in part due to the selection of T cells with increased affinity to self-antigens or to latent viruses. These cells were shown to have a greater ability to be pro-inflammatory, thereby amplifying autoimmunity. During aging, thymic T-regulatory cell output decreases in association with the loss of thymic capacity to generate new T cells. However, to balance the above mentioned autoimmunity and prevent the development of autoimmune diseases, there is an age-related increase in peripheral CD4+ CD25highFoxP3+ T-regulatory cells. It remains unclear whether this is an age-related immune dysfunction or a defense response. Whatever the reason, the expansion of T-regulatory cells requires payment in terms of an increased incidence of cancer and higher susceptibility to infections.

Susac's syndrome--pathogenesis, clinical variants and treatment approaches.

Susacs syndrome is a rare disease that is characterised by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. It was first described as a distinctive syndrome by Susac in 1979. There have been 304 reported individual patients with Susacs syndrome. Etiopathogenesis is not clear, although it is now thought that it is an immune-mediated endotheliopathy that affects the microvasculature of the brain, retina, and inner ear. Antiendothelial cell antibodies (AECAs) play an important role in mediating the endothelial cell injury with consequent deposition of thrombotic material in the lumen of the small vessel. In biopsies of the brain, microinfarcts with atrophy of the white and grey matter could be detected. These microinfarcts are caused by a microangiopathic process with arteriolar wall proliferation, lymphocytic infiltration and basal lamina thickening. At clinical onset, the most common manifestation was central nervous system symptoms, followed by visual symptoms and hearing disturbances. Diagnosis is based on Magnetic Resonance Imaging (MRI), retinal fluorescein angiography, and audiometry; these are considered crucial tests to enable diagnosis. Antiendothelial cell antibodies (AECAs) are also of diagnostic relevance. Based on the hypothesis of being an autoimmune disease, treatment has to be immunosuppressive. In addition, anticoagulation measures, antiplatelet agents and antivasospastic agents should be considered. The majority of patients did not initially present with the complete triad of symptoms. An appropriate approach would be to perform a search for absent components of the triad if the clinical presentation is suggestive of Susacs syndrome. Improved understanding of the presentation of Susacs syndrome will prevent misdiagnosis and ensure that patients receive the best possible care.

B‐regulatory cells in autoimmunity and immune mediated inflammation

B cells are a source of inhibitory cytokines such as IL‐10 and TGF‐β. The ability of being B‐regulatory cells (B‐regs) was shown to be driven by many stimulatory factors such as toll‐like receptors, CD40‐ligand and others. However, the characterization of B‐regs is still underway. B‐regs express high levels of CD25, CD86, IL‐10 and TGF‐β. In addition, we propose that semaphorin3A is a regulatory molecule and therefore can serve as one of the additional markers for B‐regs. This subset of B cells was able to suppress Th1 proliferation, thus contributing to the maintenance of self‐tolerance. Finally, the potentiation of B‐reg function should become the aim of many immunomodulatory drugs, contributing to a better control of autoimmune diseases.

Brief Report: Lysyl Oxidase Is a Potential Biomarker of Fibrosis in Systemic Sclerosis

Fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc). Levels of lysyl oxidase (LOX), an extracellular enzyme that stabilizes collagen fibrils, have been found to be elevated in the skin of SSc patients, but have not been evaluated in the serum or correlated with the clinical parameters. We undertook this study to evaluate serum LOX levels in SSc patients and to correlate these levels with clinical parameters of SSc.

The expression of lysyl-oxidase gene family members in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are malignant disorders originating from clonal expansion of a single neoplastic stem cell and characteristically show an increase in bone marrow reticulin fibers. Lysyl oxidases (LOXs) are copper‐dependent amine oxidases that play a critical role in the biogenesis of connective tissue by crosslinking extracellular matrix proteins, collagen and elastin. Expression of LOX gene family members is increased in disorders associated with increased fibrosis. To evaluate involvement of LOX gene family in various MPNs. In‐situ hybridization was used to detect Lysyl‐Oxidase family members in bone marrow biopsies from patients with different MPNs. We compared normal bone marrows and those from patients with polycythemia vera, essential thrombocythemia, chronic myeloid leukemia, and primary myelofibrosis (PMF). Serum levels of lysyl‐oxidase from patients with PMF and healthy controls were also examined. LOX gene family was not detected in normal bone marrows. All members of the LOX gene family were over expressed in PMF. In other MPNs a differential pattern of expression was observed. Differences in gene expression were statistically significant (P < 0.010). The medianserum LOX levels in normal controls was 28.4 ± 2.5 ng\ml and 44.6 ± 9.44 ng\ml in PMF (P = 0.02). The varying pattern of expression of LOX genes may reflect differences in the pathophysiology of bone marrow fibrosis in these MPNs. These observations could be used as the basis for future targeted therapy directed against bone marrow fibrosis. Am. J. Hematol. 88:355–358, 2013.

Elevated serum B-cell activating factor in patients with chronic urticaria

The B and T cells abnormalities that have been described among CU patients, lend support to its regard as an autoimmune disease. In this study we compared serum B-cell activation factor (BAFF) levels in 46 CU patients to 24 healthy controls and evaluated a possible association between elevated serum BAFF in CU patients and the presence of autologous serum skin test, anti-thyroid antibodies, antinuclear antibodies, high total IGE levels, and urticaria disease severity. We found that serum BAFF levels is elevated statistically significant in CU patients compared to healthy control (1228±342 pg/ml vs. 758±313 pg/ml, P<0.0001). CU patients with severe disease activity had significantly higher serum BAFF levels compared to patients with mild CU (1394.6±299.6 vs. 1097.6±221.3, P=0.0008). No association was found between the presence of positive autologous serum skin test, anti-thyroid antibodies or antinuclear antibodies or high levels of total IgE and serum BAFF levels in CU Patients. We conclude that CU patients have higher levels of serum BAFF which associate with disease severity.

The Involvement of Immune Semaphorins in the Pathogenesis of Inflammatory Bowel Diseases (IBDs).

Background and Aims Immune semaphorins are a large family of proteins involved in the pathogenesis of inflammatory diseases through the regulation of immune homeostasis and tissue inflammation. We aim to assess the possible involvement of semaphorin3A (sema3A) and 4A (sema4A) in peripheral immune responses and bowel tissue inflammation of patients suffering from Crohn’s disease (CD) and ulcerative colitis (UC). Patients and Methods Twenty-seven CD patients and 10 UC patients were studied and compared to 10 patients followed for acute diverticulitis (disease control) and 12 healthy individuals. All were evaluated for sema3A expression on T regulatory cells (Tregs), serum levels of sema3A and sema4A, and tissue expression of sema3A and sema4A in bowel biopsies. Results The percentage (%) of T regulatory cells (Tregs) expressing sema3A in patients with active CD (64.5% ±14.49%) and active UC (49.8% ±16.45%) was significantly lower when compared to that of healthy controls (88.7% ±3.6%, p< 0.001 and p< 0.0001, respectively). This expression was seen to be in negative correlation with CD activity. Serum levels of Sema4A were significantly lower in patients with CD and UC when compared to that of controls (5.69±1.48ng\ml for CD, 5.26±1.23 ng/ml for UC patients vs 9.74±2.73ng/ml for normal controls, P<0.001). Sema4A was highly expressed in lymphocytes of the lamina propria of CD and UC patients but absent in patients with diverticulitis or in normal individuals. Conclusions Altered % of Tregs expressing sema3A in patients with inflammatory bowel diseases (IBD) is partially responsible for their failure in preventing CD4+ effector T cell induced inflammation in IBD in peripheral blood. The increased expression of sema4A in bowel biopsies from CD and UC patients is suggestive of its central role in regulating local tissue inflammation in the bowel.

The Expansion of CD25highIL-10highFoxP3high B Regulatory Cells Is in Association with SLE Disease Activity

B regulatory cells (Bregs) belong to a subgroup of activated B cells tasked with maintaining self-tolerance and preventing autoimmunity. While sharing similar regulatory mechanisms such as IL-10 dependency, they also defer in exhibiting their suppressive effects by expressing Fas-Ligand, TGF-beta, and PDL-1. In this study we show, for the first time, the expansion of CD25highFoxP3high Bregs in systemic lupus erythematosus (SLE) patients compared to healthy individuals (18.5 ± 3.052% versus 11.0 ± 1.654%, p < 0.001, resp.). This expansion was also shown to correlate with SLE disease activity (r = 0.75). In addition, CD25highFoxP3high Bregs were also IL-10high expressing and further expanded when stimulated with semaphorin 3A. In sum we show that CD25highFoxP3high are an additional subtype of Bregs, involved in regulating SLE disease activity. Being IL-10 expressing, we may assume that they are one of the sources of increased serum IL-10 in SLE patients. Further studies are required in order to assess the relation between high serum IL-10 and CD25highFoxP3high Breg cells.

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.

Omalizumab for severe chronic spontaneous urticaria: Real-life experiences of 280 patients

Omalizumab for severe chronic spontaneous urticaria: Real-life experiences of 280 patients Zahava Vadasz, MD, PhD, Yuval Tal, MD, Menachem Rotem, MD, Vered Shichter-Confino, MD, Keren Mahlab-Guri, MD, Yael Graif, MD, Aharon Kessel, MD, Nancy Agmon-Levin, MD, Ramit Maoz-Segal, MD, Shmuel Kivity, MD, Shira Benor, MD, Idit Lachover-Roth, MD, Yuri Zeldin, MD, Migel Stein, MD, Ori Toker, MD, Gamal Hassoun, MD, Shira Bezalel-Rosenberg, MD, Elias Toubi, MD, Ilan Asher, MD*, and Zev Sthoeger, MD*; for The Israeli Forum for investigating and treating Chronic Spontaneous Urticaria (CSU)