Sabrina Boscolo

Gluten sensitivity: from gut to brain

Gluten sensitivity is a systemic autoimmune disease with diverse manifestations. This disorder is characterised by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Coeliac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. Although neurological manifestations in patients with established coeliac disease have been reported since 1966, it was not until 30 years later that, in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction. Furthermore, the concept of extraintestinal presentations without enteropathy has only recently become accepted. In this Personal View, we review the range of neurological manifestations of gluten sensitivity and discuss recent advances in the diagnosis and understanding of the pathophysiological mechanisms underlying neurological dysfunction related to gluten sensitivity.

The humoral response in the pathogenesis of gluten ataxia

Objective: To characterize humoral response to cerebellum in patients with gluten ataxia. Background: Gluten ataxia is a common neurologic manifestation of gluten sensitivity. Methods: The authors assessed the reactivity of sera from patients with gluten ataxia (13), newly diagnosed patients with celiac disease without neurologic dysfunction (24), patients with other causes of cerebellar degeneration (11), and healthy control subjects (17) using indirect immunocytochemistry on human cerebellar and rat CNS tissue. Cross-reactivity of a commercial IgG antigliadin antibody with human cerebellar tissue also was studied. Results: Sera from 12 of 13 patients with gluten ataxia stained Purkinje cells strongly. Less intense staining was seen in some but not all sera from patients with newly diagnosed celiac disease without neurologic dysfunction. At high dilutions (1:800) staining was seen only with sera from patients with gluten ataxia but not in control subjects. Sera from patients with gluten ataxia also stained some brainstem and cortical neurons in rat CNS tissue. Commercial anti-gliadin antibody stained human Purkinje cells in a similar manner. Adsorption of the antigliadin antibodies using crude gliadin abolished the staining in patients with celiac disease without neurologic dysfunction, but not in those with gluten ataxia. Conclusions: Patients with gluten ataxia have antibodies against Purkinje cells. Antigliadin antibodies cross-react with epitopes on Purkinje cells.

Anti transglutaminase antibodies cause ataxia in mice

Background Celiac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies. Amongst the neurological dysfunctions associated with CD, ataxia represents the most common one. Methods We analyzed by immunohistochemistry, the anti-neural reactivity of the serum from 20 CD patients. To determine the role of anti-TG2 antibodies in ataxia, two anti-TG2 single chain variable fragments (scFv), isolated from a phage-display IgA antibody library, were characterized by immunohistochemistry and ELISA, and injected in mice to study their effects on motor coordination. We found that 75% of the CD patient population without evidence of neurological involvement, has circulating anti-neural IgA and/or IgG antibodies. Two anti-TG2 scFvs, cloned from one CD patient, stained blood vessels but only one reacted with neurons. This anti-TG2 antibody showed cross reactivity with the transglutaminase isozymes TG3 and TG6. Intraventricular injection of the anti-TG2 or the anti-TG2/3/6 cross-reactive scFv provoked transient, equally intensive ataxia in mice. Conclusion The serum from CD patients contains anti-TG2, TG3 and TG6 antibodies that may potentially cause ataxia.

Cerebellar ataxia as a possible organ-specific autoimmune disease.

The purpose of this study was to investigate the possibility that autoimmunity is responsible for some cases of sporadic idiopathic ataxia. We prospectively investigated 400 patients with progressive ataxia and identified a group of patients with idiopathic sporadic ataxia. A comparison of the prevalence of autoimmune diseases, the autoimmunity linked HLA DQ2, and serum anticerebellar antibodies was made between patients with idiopathic sporadic and those with genetically characterized ataxia. Ninety‐one of 400 (23%) patients with progressive ataxia had idiopathic sporadic ataxia. The prevalence of autoimmune diseases in this group was 47% as compared with 6% in the group of patients with genetic ataxias (P < 0.0001). The HLA DQ2 was found in 71% of patients with sporadic ataxia, in 34% in patients with genetic ataxia, and in 36% of healthy local population (P = 0.0005 by Chi squared test). Anticerebellar antibodies were detected in 12 out of 20 patients with idiopathic sporadic as opposed to one of 20 patients with genetic ataxia. The significantly higher prevalence of autoimmune diseases, HLA DQ2 and anti‐cerebellar antibodies in patients with idiopathic sporadic ataxia compared to genetic ataxia supports the notion that autoimmunity may account for some cases of idiopathic sporadic cerebellar ataxia.

Gluten ataxia : Passive transfer in a mouse model

Abstract:  Gluten sensitivity is an autoimmune disease that usually causes intestinal atrophy resulting in a malabsorption syndrome known as celiac disease. However, gluten sensitivity may involve several organs and is often associated with extraintestinal manifestations. Typically, patients with celiac disease have circulating anti‐tissue transglutaminase and anti‐gliadin antibodies. When patients with gluten sensitivity are affected by other autoimmune diseases, other autoantibodies may arise like anti‐epidermal transglutaminase in dermatitis herpetiformis, anti‐thyroid peroxidase antibodies in thyroiditis, and anti‐islet cells antibodies in type 1 diabetes. The most common neurological manifestation of gluten sensitivity is ataxia, the so‐called gluten ataxia (GA). In patients with GA we have demonstrated that anti‐gliadin and anti‐tissue transglutaminase antibodies cross‐react with neurons but that additional anti‐neural antibodies are present. The aim of the present article is to review the knowledge on animal models of gluten sensitivity, as well as reviewing the role of anti‐neural antibodies in GA.

Simple scale-up of recombinant antibody production using an UCOE containing vector

Recombinant proteins, in particular antibodies, have become fundamental in biomedical research where they are used in numerous therapeutic and diagnostic applications. For this reason there is an increasing demand for quick and economical production systems for recombinant proteins in mammalian cells.

Anti-brain but not celiac disease antibodies in Landau-Kleffner Syndrome and related epilepsies

The Landau-Kleffner syndrome, the continuous spikes-waves during slow sleep syndrome and the benign epilepsy of childhood with rolandic spikes are rare childhood epilepsies with unknown etiology. Improvement in patients treated with immunoglobulin suggests an involvement of the immune system. We provide immunohistochemical evidence of autoantibodies against rat brain auditory cortex, brainstem and cerebellum, in children suffering with one or more of these syndromes. Only 1/14 patient was celiac.

B7h Triggering Inhibits Umbilical Vascular Endothelial Cell Adhesiveness to Tumor Cell Lines and Polymorphonuclear Cells

Vascular endothelial cells (ECs) are key players in leukocyte recruitment into tissues and metastatic dissemination of tumor cells. ECs express B7h, which is the ligand of the ICOS T cell costimulatory molecule. The aim of this work was to assess the effect of B7h triggering by a soluble form of ICOS (ICOS-Fc) on the adhesion of colon carcinoma cell lines to HUVECs. We found that B7h triggering inhibited HUVEC adhesiveness to HT29 and DLD1 cells (by 50 and 35%, respectively) but not to HCT116 cells. The effect was dependent on the ICOS-Fc dose and was detectable as early as 30 min after treatment and was still present after 24 h. It was inhibited by soluble anti-ICOS reagents (mAb and B7h-Fc) and silencing of B7h on HUVECs, and it was not displayed by an F119S mutated form of ICOS-Fc that does not bind B7h. HUVEC treatment with ICOS-Fc did not modulate expression of adhesion molecules and cytokines, but it substantially downmodulated ERK phosphorylation induced by E-selectin triggering or osteopontin, which may influence HUVEC adhesiveness. Moreover, HUVEC treatment with ICOS-Fc also inhibited adhesion of polymorphonuclear cells and several tumor cell lines from different origins. Therefore, the B7h–ICOS interaction may modulate spreading of cancer metastases and recruitment of polymorphonuclear cells in inflammatory sites, which opens a view on the use of ICOS-Fc as an immunomodulatory drug.

Quantification of antineural antibodies in autoimmune neurological disorders.

More than 50 different neurological pathologies have a confirmed or suspected autoimmune etiology affecting an estimated number of 75 million people worldwide. Autoantibodies are a useful diagnostic marker for most autoimmune diseases even though their pathological role is not evident, and several tests for their detection are commercially available. However, for autoimmune diseases involving the nervous system, lack of clear information on the identity of antineural antibody targets and the presence of many rare diseases have hampered the development of specific diagnostic assays. This review focuses on the actual knowledge on confirmed and suspected autoimmune diseases that target the CNS and the diagnostic relevance of corresponding antineural autoantibodies.