Tharwat Haj

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.

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.

B Cell-Activating Factor Enhances Interleukin-6 and Interleukin-10 Production by ODN-Activated Human B Cells

We aim to investigate the additive value of B cell‐activating factor (BAFF) when added to oligodeoxynucleotides (ODN)‐activated B cells with respect to TLR‐9, CD69, MHC‐II expression, IL‐6 and IL‐10 secretion and B cell cycling. Therefore, B cells from healthy individuals were incubated under the following conditions: (1) B cells with medium, (2) B cells with ODN 0.5 μm, (3) B cells with BAFF 20 μm and (4) B cells with both ODN 0.5 μm and BAFF 20 μm. We found that addition of BAFF did not enhance the expression of TLR‐9, CD69 and MHC‐II in ODN‐activated B cells. Incubation of B cells with BAFF and ODN together leads to a marked elevation of IL‐6 and IL‐10 levels compared to ODN alone. Synthesis and mitosis were higher in B cells stimulated by BAFF than in B cells stimulated by ODN. These findings suggest that both BAFF and TLR‐9 contribute independently to B cell function.

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 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.

AB0141 Lysyl oxidase is correlated with fibrosis in systemic sclerosis

Background Fibrosis is a major concern in patients with systemic sclerosis (SSc), the pathogenesis of which is not clear. Lysyl oxidase (LOX) is an extracellular copper enzyme that cross-links collagen and elastin, thus stabilizing collagen fibrils [1]. LOX was found to be overexpressed in patients with primary myelofibrosis (PMF), a disease with severe fibrosis [2]. In SSc, LOX was found to be elevated in the skin but has not been evaluated in the serum [3] in correlation with clinical parameters. Objectives To evaluate LOX serum level of patients with SSc compared to normal controls and to patients with PMF. To correlate this serum level to clinical parameters. Methods We prospectively evaluated patients with SSc for demographics, clinical manifestations and laboratory results including blood count, chemistry, urine examination, autoantibodies and serum LOX concentration determined by ELISA. We further evaluated lung function tests, echocardiography, lung high resolution CT scans, as needed, and determined lung involvement, modifies Rodnan skin score (mRSS), Medsger disease severity scale and Valentini activity index [4]. Results Twenty four women and 2 men with SSc at a mean age of 48±12.6 were evaluated and compared with 25, age and gender matched healthy controls and 9 patients with PMF. Of the SSc patients, 10 had diffuse disease- 8 of them with lung fibrosis, and 17 had limited disease. LOX concentration in SSc was higher than healthy controls and similar to PMF, 58.4±4.8 ng/ml vs. 28.4±2.5 ng/ml vs. 44.6±9.4 ng/ml (p< 0.001), respectively. LOX was higher in patients with diffuse SSc compared with limited disease 73±6.6 ng/ml vs. 49.3±5.5 ng/ml (p<0.01) and in those with lung fibrosis compared to patients with limited SSc without lung involvement 69.4±7.2 ng/ml vs. 49.3±5.5 ng/ml (p=0.04). LOX concentration was found to be correlated in linear regression with mRSS in limited disease and to severity score in all patients with SSc, correlation coefficients 0.64 (p=0.004) and 0.54 (p=0.004), respectively. Activity score, DLCO, capillaroscopy pattern and pulmonary hypertension, did not correlate with LOX concentration. Conclusions This is the first study to demonstrate high serum levels of LOX in SSc patients. These levels specifically correlate with skin fibrosis, lung fibrosis and disease severity - which reflects organ damage including fibrosis. We suggest that LOX has an important role in the pathophysiology of SSc and may serve as an objective assay for evaluation of disease severity. Our results suggest that LOX may be a promising future target of therapy in SSc. Future studies are warranted in order to determine the precise effects of such therapy. References Csiszar K et al. “Lysyl oxidases: a novel multifunctional amine oxidase family”. Prog. Nucleic Acid Res. Mol. Biol. 2001;70: 1–322. Papadantonakis N, Matsuura S, Ravid K. Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection. Blood 2012;120(9):1774-81 Chanoki M, et al. Increased expression of lysyl oxidase in skin with scleroderma. Br J Dermatol 1995;133(5):710-5. Hudson M, et al. Update on indices of disease activity in systemic sclerosis. Semin Arthritis Rheum 2007;37(2):93-8. Disclosure of Interest None Declared