The thrombophilic network of autoantibodies in celiac disease

BACKGROUND: Celiac disease is a life-long autoimmune condition, affecting genetically susceptible individuals that may present with thromboembolic phenomena. This thrombophilia represents a puzzle with multiple constituents: hyperhomocysteinemia, B12 and\or folate deficiency, methylenetetrahydrofolate reductase mutations, and protein C and S deficiency due to vitamin K deficiency. However, the well known thrombogenic factors, antiphosphatidylserine/prothrombin and antiprothrombin have never been explored in celiac disease. METHODS: The serum autoantibody levels were determined in 248 individuals, classified into three groups. Group 1 comprised 70 children with definitive celiac disease (age: 7.04 ±4.3 years, male to female ratio 1.06) and group 2 comprised 88 normal children (age: 6.7 ±4.17 years, male to female ratio 0.87), representing controls. The pediatric populations were compared to group 3, which included 90 adults who were family members (parents) of group 1 (age: 34.6 ±11.35 years, male to female ratio 1.2). Antibodies were checked by enzyme-linked immunosorbent assay. RESULTS: Mean optical density levels of serum antiphosphatidylserine/prothrombin immunoglobulin G antibodies were 32.4 ±19.4, 3.6 ±2.5 and 16.1 ±15.8 absorbance units in groups 1, 2 and 3 respectively (P <0.0001), with 45.7%, 0% and 7.8% of groups 1, 2 and 3 respectively positive for the antibody (P <0.01). Mean optical density levels of serum antiphosphatidylserine/prothrombin immunoglobulin M antibodies were 14.2 ±8.7, 6.7 ±6.4 and 12.4 ±15.5 absorbance units in groups 1, 2 and 3 respectively (P <0.0001), with 7.1%, 3.4% and 9.9% of groups 1, 2 and 3 positive for the antibody. Mean optical density levels of serum antiprothrombin and antiphospholipid immunoglobulin G antibodies were higher in groups 1 and 3 compared with 2 (P <0.005) and in groups 1 and 2 compared with 3 (P <0.01), respectively. Groups 1, 2 and 3 were positive for antiphospholipid immunoglobulin G antibodies (groups 1 and 2 compared with 3) . Celiac disease sera harbor a higher antiprothrombin immunoglobulin G level compared with controls. CONCLUSIONS: It is suggested that the intestinal injury, endothelial dysfunction, platelet abnormality and enhanced apoptosis recently described in celiac disease are at the origin of the increased exposure of phospholipids or new epitopes representing autoantigens. Those autoantibodies might play a pathogenic role in the thrombophilia associated with celiac disease and represent markers for potential anticoagulant preventive therapy

Local Allergic Rhinitis: An Old Story but a New Entity

Local allergic rhinitis (LAR) is a novel concept defining clinical allergic rhinitis with no evidence of systemic sensitization to aeroallergens. In this unique condition, the allergic response is confined to the nasal mucosa and can be demonstrated using different methods such as the immunoglobulin-E (IgE) level in the nasal secretions, nasal provocation test (NPT), or basophil activation test (BAT) with specific allergens or more sophisticated molecular diagnostic techniques. Furthermore, local allergic rhinitis can be relieved by interventions used to treat systemic allergic conditions such as antihistamines or anti-IgE monoclonal antibodies. Last but not least, several small studies demonstrated the efficacy of allergen immunotherapy for ameliorating LAR symptoms. In this chapter we reviewed old data and new concepts regarding clinical manifestation, plausible mechanisms, and treatments of LAR. The long-standing question whether LAR is an integral part of the “atopic spectrum” or it is a single-organ immune-mediated disease, is yet to be determined

Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins

The L1 adhesion molecule plays an important role in axon guidance and cell migration in the nervous system. L1 is also expressed by many human carcinomas. In addition to cell surface expression, the L1 ectodomain can be released by a metalloproteinase, but the biological function of this process is unknown. Here we demonstrate that membrane-proximal cleavage of L1 can be detected in tumors and in the developing mouse brain. The shedding of L1 involved a disintegrin and metalloproteinase (ADAM)10, as transfection with dominant-negative ADAM10 completely abolishes L1 release. L1-transfected CHO cells (L1-CHO) showed enhanced haptotactic migration on fibronectin and laminin, which was blocked by antibodies to αvβ5 and L1. Migration of L1-CHO cells, but not the basal migration of CHO cells, was blocked by a metalloproteinase inhibitor, indicating a role for L1 shedding in the migration process. CHO and metalloproteinase-inhibited L1-CHO cells were stimulated to migrate by soluble L1-Fc protein. The induction of migration was blocked by αvβ5-specific antibodies and required Arg-Gly-Asp sites in L1. A 150-kD L1 fragment released by plasmin could also stimulate CHO cell migration. We propose that ectodomain-released L1 promotes migration by autocrine/paracrine stimulation via αvβ5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions

Helicobacter pylori serology in autoimmune diseases - Fact or fiction?

Background: The pathogenesis of autoimmunity is presumed to be a complex process including genetic predisposition, hormonal balance and environmental factors such as infectious agents . Helicobacter pylori , a common bacterial infectious agent has been associated with a variety of autoimmune disorders. However, this bacteria is also thought to play a protective role in the development of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). We tested various links between anti- H. pylori (anti-HP) antibodies and a wide profile of autoimmune diseases and autoantibodies. Methods: A total of 1290 patients diagnosed with 14 different autoimmune diseases from two geographical areas (Europe and Latin America) and two groups of healthy matching controls (n = 385) were screened for the presence of H. pylori IgG antibodies by ' pylori detect ' kit. In parallel, a large profile belonging to three groups of autoantibodies was tested in all sera (anti-nuclear antibodies, autoantibodies associated with thrombophilia and gastrointestinal diseases). Results: Our data demonstrate associations between anti-HP antibodies and anti-phospholipid syndrome, giant cell arteritis, systemic sclerosis and primary biliary cirrhosis. Our data also support a previously known negative association between the prevalence of anti-HP antibodies and IBD. Additionally, links were made between seropositivity to H. pylori and the presence of anti-nuclear antibodies, dsDNA, anti-Ro and some thrombophiliaassociated antibodies, as well as negative associations with gastrointestinal-associated antibodies. Conclusions: Whether these links are epiphenomenal or H. pylori does play a causative role in the autoimmune diseases remains uncertain. The negative associations could possibly support the notion that in susceptible individuals infections may protect from the development of autoimmune diseases

16/6-idiotype expressing antibodies induce brain inflammation and cognitive impairment in mice: the mosaic of central nervous system involvement in lupus

Background: The 16/6-idiotype (16/6-Id) of the human anti-DNA antibody was found to induce experimental lupus in naive mice, manifested by production of autoantibodies, leukopenia and elevated inflammatory markers, as well as kidney and brain involvement. We assessed behavior and brain pathology of naive mice injected intracerebra-ventricularly (ICV) with the 16/6-Id antibody. Methods: C3H female mice were injected ICV to the right hemisphere with the human 16/6-Id antibody or commercial human IgG antibodies (control). The mice were tested for depression by the forced swimming test (FST), locomotor and explorative activity by the staircase test, and cognitive functions were examined by the novel object recognition and Y-maze tests. Brain slices were stained for inflammatory processes. Results: 16/6-Id injected mice were cognitively impaired as shown by significant differences in the preference for a new object in the novel object recognition test compared to controls (P = 0.012). Similarly, the preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-Id-injected mice (42% vs. 9%, respectively, P = 0.065). Depression-like behavior and locomotor activity were not significantly different between the16/6-Id-injected and the control mice. Immunohistochemistry analysis revealed an increase in astrocytes and microglial activation in the hippocampus and amygdala, in the 16/6-Id injected group compared to the control. Conclusions: Passive transfer of 16/6-Id antibodies directly into mice brain resulted in cognitive impairments and histological evidence for brain inflammation. These findings shed additional light on the diverse mosaic pathophysiology of neuropsychiatric lupus

EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome.

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus

Genetic Factors of Autoimmune Diseases

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