@article {3559, title = {A non-complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome.}, journal = {Blood}, volume = {123}, year = {2014}, month = {2014 May 29}, pages = {3478-87}, abstract = {

A single-chain fragment variable (scFv) recognizing β2-glycoprotein 1 (β2GPI) from humans and other species was isolated from a human phage display library and engineered to contain an IgG1 hinge-CH2-CH3 domain. The scFv-Fc directed against β2GPI domain I-induced thrombosis and fetal loss, thus mimicking the effect of antibodies from patients with antiphospholipid syndrome (APS). Complement is involved in the biological effect of anti-β2GPI scFv-Fc, as demonstrated by its ability to promote in vitro and in vivo complement deposition and the failure to induce vascular thrombosis in C6-deficient rats and fetal loss in C5-depleted mice. A critical role for complement was also supported by the inability of the CH2-deleted scFv-Fc to cause vessel occlusion and pregnancy failure. This antibody prevented the pathological effects of anti-β2GPI antibodies from APS patients and displaced β2GPI-bound patient antibodies. The CH2-deleted antibody represents an innovative approach potentially useful to treat APS patients refractory to standard therapy.

}, keywords = {Abortion, Spontaneous, Animals, Antibodies, Monoclonal, Antiphospholipid Syndrome, Autoantigens, beta 2-Glycoprotein I, Complement Activation, Complement System Proteins, Human Umbilical Vein Endothelial Cells, Humans, Immunoglobulin G, Male, Mice, Protein Binding, Rats, Recombinant Proteins, Single-Chain Antibodies, Thrombosis, Trophoblasts}, issn = {1528-0020}, doi = {10.1182/blood-2013-11-537704}, author = {Agostinis, Chiara and Durigutto, Paolo and Sblattero, Daniele and Borghi, Maria O and Grossi, Claudia and Guida, Filomena and Bulla, Roberta and Macor, Paolo and Pregnolato, Francesca and Meroni, Pier Luigi and Tedesco, Francesco} } @article {1741, title = {Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet.}, journal = {Gut}, volume = {60}, year = {2011}, month = {2011 Nov}, pages = {1487-93}, abstract = {

BACKGROUND AND OBJECTIVE: Antitransglutaminase (anti-TG2) antibodies are synthesised in the intestine and their presence seems predictive of future coeliac disease (CD). This study investigates whether mucosal antibodies represent an early stage of gluten intolerance even in the absence of intestinal damage and serum anti-TG2 antibodies.

METHODS: This study investigated 22 relatives of patients with CD genetically predisposed to gluten intolerance but negative for both serum anti-TG2 antibodies and intestinal abnormalities. Fifteen subjects were symptomatic and seven were asymptomatic. The presence of immunoglobulin A anti-TG2 antibodies in the intestine was studied by creating phage-antibody libraries against TG-2. The presence of intestinal anti-TG2 antibodies was compared with the serum concentration of the intestinal fatty acid-binding protein (I-FABP), a marker for early intestinal mucosal damage. The effects of a 12-month gluten-free diet on anti-TG2 antibody production and the subjects{\textquoteright} clinical condition was monitored. Twelve subjects entered the study as controls.

RESULTS: The intestinal mucosa appeared normal in 18/22; 4 had a slight increase in intraepithelial lymphocytes. Mucosal anti-TG2 antibodies were isolated in 15/22 subjects (68\%); in particular symptomatic subjects were positive in 13/15 cases and asymptomatic subjects in 2/7 cases (p=0.01). No mucosal antibodies were selected from the controls{\textquoteright} biopsies. There was significant correlation between the presence of intestinal anti-TG2 antibodies and positive concentrations of I-FABP (p=0.0008). After a gluten-free diet, 19/22 subjects underwent a second intestinal biopsy, which showed that anti-TG2 antibodies had disappeared in 12/15 (p=0.002), while I-FABP decreased significantly (p<0.0001). The diet resolved both extraintestinal and intestinal symptoms.

CONCLUSIONS: A new form of genetic-dependent gluten intolerance has been described in which none of the usual diagnostic markers is present. Symptoms and intestinal anti-TG2 antibodies respond to a gluten free-diet. The detection of intestinal anti-TG2 antibodies by the phage-antibody libraries has an important diagnostic and therapeutic impact for the subjects with gluten-dependent intestinal or extraintestinal symptoms. Clinical trial number NCT00677495.

}, keywords = {Adolescent, Adult, Antibodies, Anti-Idiotypic, Asymptomatic Diseases, Celiac Disease, Child, Child, Preschool, Diet, Gluten-Free, Fatty Acid-Binding Proteins, Female, Genetic Predisposition to Disease, GTP-Binding Proteins, Health Status, Humans, Intestinal Mucosa, Male, Middle Aged, Peptide Library, Transglutaminases, Young Adult}, issn = {1468-3288}, doi = {10.1136/gut.2010.232900}, author = {Not, Tarcisio and Ziberna, Fabiana and Vatta, Serena and Quaglia, Sara and Martelossi, Stefano and Villanacci, Vincenzo and Marzari, Roberto and Florian, Fiorella and Vecchiet, Monica and Sulic, Ana-Marija and Ferrara, Fortunato and Bradbury, Andrew and Sblattero, Daniele and Ventura, Alessandro} } @article {1626, title = {Anti transglutaminase antibodies cause ataxia in mice.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010}, pages = {e9698}, abstract = {

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.

}, keywords = {Adult, Animals, Antibodies, Ataxia, Autoimmune Diseases, Brain, Celiac Disease, Female, Gliadin, Humans, Isoenzymes, Male, Mice, Mice, Inbred C57BL, Middle Aged, Motor Skills, Rats, Rats, Sprague-Dawley, Transglutaminases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0009698}, author = {Boscolo, Sabrina and Lorenzon, Andrea and Sblattero, Daniele and Florian, Fiorella and Stebel, Marco and Marzari, Roberto and Not, Tarcisio and Aeschlimann, Daniel and Ventura, Alessandro and Hadjivassiliou, Marios and Tongiorgi, Enrico} }