Daniel Aeschlimann

• MSc, PhD
• Professor at Cardiff University

Gluten ataxia (GA) is the primary neurological manifestation of gluten sensitivity, characterised by loss of Purkinje cells throughout the cerebellar cortex and rooted in autoimmunity to transglutaminase 6 (TG6). Previous studies have shown the contribution of serum anti-TG6 antibodies to disease progression; however, it remains unclear where these...

Gluten sensitivity has long been recognised exclusively for its gastrointestinal involvement, however more recent research provides evidence for the existence of neurological manifestations that can appear in combination with, or independent of the small bowel manifestations. Amongst all neurological manifestations of gluten sensitivity, Gluten ata...

A wound healing model was developed to elucidate the role of mesenchymal-matrix-associated transglutaminase 2 (TG2) in keratinocyte re-epithelialisation. TG2 drives keratinocyte migratory responses by activation of disintegrin and metalloproteinase 17 (ADAM17). We demonstrate that epidermal growth factor (EGF) receptor ligand shedding leads to EGFR...

ZED1227 is a small molecule tissue transglutaminase (TG2) inhibitor. The compound selectively binds to the active state of TG2, forming a stable covalent bond with the cysteine in its catalytic center. The molecule was designed for the treatment of celiac disease. Celiac disease is an autoimmune-mediated chronic inflammatory condition of the small...

G protein-coupled receptor 56 (GPR56/ADGRG1) is an adhesion GPCR with an essential role in brain development and cancer. Elevated expression of GPR56 was observed in the clinical specimens of Glioblastoma (GBM), a highly invasive primary brain tumor. However, we found the expression to be variable across the specimens, presumably due to the intratu...

Mammalian transglutaminases (TGs) catalyze calcium-dependent irreversible posttranslational modifications of proteins and their enzymatic activities contribute to the pathogenesis of several human neurodegenerative diseases. Although different transglutaminases are found in many different tissues, the TG6 isoform is mostly expressed in the CNS. The...

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of gluten sensitivity, in which an autoimmune response is directed against transglutaminase 3 (TG3), an epidermal transglutaminase. TG2 is the autoantigen in celiac disease (CD), defined by the presence of enteropathy, and TG6 is the autoantigen in neurological manifestations of glut...

Background & aims: Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk...

Background Mammalian transglutaminases (TGs) catalyze calcium-dependent irreversible post-translational modifications of proteins. In the nervous system, at least four different transglutaminase isoforms are found with TG6 representing the neuronal isoform. Their enzymatic activities contribute to the pathogenesis of several human neurodegenerative...

Purpose: Phenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is toxic to Purkinje cells in vitro; the clinical and radiological phenotype and mechanism of cerebellar degeneration in vivo remain unclear. We describe the prevalence, clinic...

Background: TG6 antibodies have been shown to be a marker of gluten ataxia but their presence in the context of other neurological manifestations of gluten sensitivity has not been explored. We investigated the presence of TG6 antibodies in gluten neuropathy (GN), defined as as an otherwise idiopathic peripheral neuropathy associated with serologi...

Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis o...

Objectives: Antibodies against transglutaminase 6 (anti-TG6) have been implicated in neurological manifestations in adult patients with genetic-gluten intolerance and it is unclear whether autoimmunity to TG6 develops following prolonged gluten exposure. We measured the anti-TG6 in children with celiac disease (CD) at the diagnosis time to establi...

Transglutaminases have important roles in stabilizing extracellular protein assemblies in tissue repair processes but some reaction products can stimulate immune activation, leading to chronic inflammatory conditions or autoimmunity. Exacerbated disease in models of inflammatory arthritis has been ascribed to sustained extracellular enzyme activity...

Background Alcohol-related cerebellar degeneration is one of the commonest acquired forms of cerebellar ataxia. The exact pathogenic mechanisms by which alcohol leads to cerebellar damage remain unknown. Possible autoreactive immune mediated mechanisms have not been explored previously. In this study, we aim to investigate the potential role of alc...

The term gluten-related disorders (GRD) denotes a spectrum of diverse immune-mediated diseases triggered by the ingestion of gluten (protein found in wheat, barley and rye). Coeliac disease (CD) or gluten-sensitive enteropathy is the most recognised and studied entity within GRD. Extraintestinal manifestations are gaining recognition and are increa...

Supplementary material

Objectives: Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms without enteropathy that symptomatically benefit from gluten-free diet (GFD). Little is known about its pathophysiology, propensity to neurological manifestations, and if these differ from patients with coeliac disease (CD). We investigate...

The term gluten-related disorders (GRD) denotes a spectrum of diverse immune-mediated diseases triggered by the ingestion of gluten (protein found in wheat, barley and rye). Coeliac disease (CD) or gluten-sensitive enteropathy is the most recognised and studied entity within GRD. Extraintestinal manifestations are gaining recognition and are increa...

Degenerative joint diseases such as osteoarthritis are characterised by aberrant region-specific bone formation and abnormal bone mineral content. A recent study suggested a role for the complement membrane attack complex in experimental models of osteoarthritis. Since CD59a is the principal regulator of the membrane attack complex in mice, we eval...

Transglutaminases (TG) are externalized from cells via an unknown unconventional secretory pathway. We show for the first time that purinergic signaling regulates active secretion of TG2, an enzyme with a pivotal role in stabilizing extracellular matrices and modulating cell-matrix interactions in tissue repair. Extracellular ATP promotes TG2 secre...

The term gluten-related disorders (GRD) refers to a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. They include both intestinal and extraintestinal manifestations. Gluten ataxia (GA) is one of the commonest neurological manifestations of GRD. It was originally defined as othe...

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ata...

Cortical myoclonus with ataxia has only rarely been reported in association with Coeliac Disease (CD). Such reports also suggested that it is unresponsive to gluten-free diet. We present detailed electro-clinical characteristics of a new syndrome of progressive cortical hyperexcitability with ataxia and refractory CD. At our gluten/neurology clinic...

Objectives. We have previously reported a high prevalence of gluten-related serological markers (GRSM) in children and young adults with cerebral palsy (CP). The majority had no enteropathy to suggest coeliac disease (CD). Antibodies against transglutaminase 6 (anti-TG6) represent a new marker associated with gluten-related neurological dysfunction...

Osteoarthritis affects 40% of people aged 65 and over. In susceptible individuals, osteoarthritis can affect the TMJ or develop secondarily to injury, causing facial pain, headaches and limitation of joint motion. Diagnosis is confirmed by x-ray, yet this process detects gross structural changes, which occur late in the disease process. Objective...

Transglutaminase 2 (TG2) catalyzes various posttranslational protein modifications including transamidation, esterification and deamidation.TG2 has a predominant role in the cells stress response and in tissue repair, regulating extracellular matrix remodelling, cell-matrix interactions and cell activation. TG2-mediated stabilization of protein ass...

Objective: Squamous cell carcinoma is the most common type of esophageal tumours in humans. The overall prognosis for esophageal cancer is poor, with most patients dying within one year of diagnosis. G protein coupled receptors (GPCRs) like GPR56 are involved in diverse diseases like cancer and serve as targets for almost 50% of commercially availa...

Gluten related disorders (GRD) affect around 1% of the Western population. The most common is celiac disease (CD) that presents with gastrointestinal symptoms. However, GRD can present with symptoms other than those related to bowel inflammation, such as recurrent aphthous stomatitis in the oral cavity and neurological deficits including ataxia and...

Objectives: The previous finding of an immunologic response primarily directed against transglutaminase (TG)6 in patients with gluten ataxia (GA) led us to investigate the role of TG6 antibodies in diagnosing GA. Methods: This was a prospective cohort study. We recruited patients from the ataxia, gluten/neurology, celiac disease (CD), and moveme...

Transglutaminases (TG) form a family of enzymes that catalyse various post-translational modifications of glutamine residues in proteins and peptides including intra- and intermolecular isopeptide bond formation, esterification and deamidation. We have characterized a novel member of the mammalian TG family, TG6, which is expressed in a human carci...

A 4-year-old boy presented with occipital seizures but normal initial neuroimaging and proved refractory to antiepileptic medications. On repeat neuroimaging after 1 year, he had developed bi-occipital calcification and was then found to have positive coeliac serology. He was diagnosed with coeliac disease, epilepsy, and cerebral calcifications (CE...

Transglutaminases (TG) form a family of enzymes that catalyse various post-translational modifications of glutamine residues in proteins and peptides including intra- and intermolecular isopeptide bond formation, esterification and deamidation. We have characterized a novel member of the mammalian TG family, TG6, which is expressed in a human carci...

Decorin and oxidized low-density lipoprotein (Ox-LDL) independently induce osteogenic differentiation of vascular smooth muscle cells (VSMCs). We aimed to determine whether decorin glycosaminoglycan (GAG) chain synthesis contributes to Ox-LDL-induced differentiation and calcification of human VSMCs in vitro. Human VSMCs treated with Ox-LDL to induc...

The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases. We used ELISA assays for anti-GAD and for serological markers of gluten sensitivity. Patients were recruited from clinics based at the Royal Hallamshire hospi...

This figure represents the most frequent staining pattern of sera from various CD patients characterized by a weak cytoplasmic and a strong perinuclear labeling (CD1 and CD2). Sera from two patients stained only the cytoplasm when detecting IgG (CD3). (6.16 MB TIF)

Reactivity of monoclonals anti-TG2 on TG2 from various species. Class1 scFv and the commercial CUB7402 recognize human, mouse and guinea pig TG2 whereas class2 scFv reacts only with human-TG2. (1.86 MB TIF)

Immunohistochemistry on TG2−/− mouse brain sections with patient's serum, class1 or class2 scFv anti-TG2. Immunohistochemistry confirmed the absence of reactivity with class1 scFv (in blood vessels) while class2 scFv showed a similar anti-neural staining pattern to that seen in wildtype brain. (4.38 MB TIF)

Motor coordination test on the rotarod after intraventricular delivery of anti-TG2 scFvs. Mice treated with monoclonal antibodies were subjected to three rotarod trials (9 rpm) before the intraventricular injection (Pre in.), and were tested at 1 h, 3 h, 6 h, 24 h after antibody injection. The mean latency to fall (maximum trial duration = 120 sec)...

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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. We analyzed by immunohistochemistry, the anti-neural reactivity of the serum from 20 CD patients....

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...

Transglutaminase 2 (TG2) is well characterized as the main autoantigen of celiac disease. The ability of TG2 to deamidate and crosslink gluten peptides is essential for the gluten-dependent production of TG2 specific autoantibodies. In patients with primarily extraintestinal manifestation of gluten sensitivity the repertoire of autoantibodies may b...

Some patients with celiac disease (CD) may be seronegative with the commonly used test for IgA anti-tissue transglutaminase (anti-tTG) antibodies. Our aim was to explore whether newer assays incorporating synthetic deamidated gliadin-related peptides (DGPs) or other TG isoenzymes as antigen are useful for detecting gluten sensitivity in IgA anti-tT...

Bacterial infections can lead to a state of uncontrolled inflammation and also trigger autoimmune disease. At the centre of this are CD4(+) T cell responses in inflammatory tissues or local lymph nodes which are orchestrated by dendritic cells. IL-18 is a pro-inflammatory cytokine that drives dendritic cell maturation and mediates IFNgamma producti...

Transglutaminase 2 (TG2), a protein cross-linking enzyme with many additional biological functions, acts as coreceptor for integrin beta(3). We have previously shown that TG2(-/-) mice develop an age-dependent autoimmunity due to defective in vivo clearance of apoptotic cells. Here we report that TG2 on the cell surface and in guanine nucleotide-bo...

The cover image depicts multi-nucleated osteoclasts stained for tartrate-resistant alkaline phosphatase (maroon colour) after in vitro differentiation from bone marrow myeloid cells. The image was taken from the article of Chen et al. (pp. 2845–2854), in which the authors demonstrate that the proinflammatory IL-12 family cytokine, IL-23, up-regulat...

Gluten sensitivity typically presents as celiac disease, a chronic, autoimmune-mediated, small-intestinal disorder. Neurological disorders occur with a frequency of up to 10% in these patients. However, neurological dysfunction can also be the sole presenting feature of gluten sensitivity. Development of autoimmunity directed toward different membe...

The proteoglycan decorin is expressed by sprouting but not quiescent endothelial cells, and angiogenesis is dysregulated in its absence. Previously, we have shown that decorin core protein can bind to and activate insulin-like growth factor-I receptor (IGF-IR) in endothelial cells. In this study, we show that decorin promotes α2β1 integrin-dependen...

Small-angle X-ray scattering can be used to determine the molecular shape of macromolecules in solution which are otherwise refractory to conventional high-resolution studies. DAMMIN and GASBOR are applications that utilize ab initio methods to build models of proteins using simulated annealing; both DAMMIN and GASBOR have to be run numerous times...

This study is devoted to the development of a non-linear anisotropic model for the human periodontal ligament (PDL). A thorough knowledge of the behaviour of the PDL is vital in understanding the mechanics of orthodontic tooth mobility, soft tissue response and proposed treatment plans. There is considerable evidence that the deformation of the PDL...

Bone is a rigid but dynamic organ. Once formed, it is continually broken down and reformed by the co-ordinated actions of osteoclasts (that mediate resorption) and osteoblasts (that mediate formation) on trabecular bone surfaces and in the Haversian systems of cortical bone. Any net change in bone mass therefore reflects a change in the balance bet...

Tissue transglutaminase (TG2) affects cell-matrix interactions in cell spreading, migration and extracellular matrix (ECM) reorganisation. Using fibroblasts deficient in TG2 or overexpressing normal or crosslinking-deficient enzyme, we show that the extracellular crosslinking activity and intracellular G-protein function in signal transduction cont...

Introduction A major aspect of the normal ageing process is the loss of suppleness of tissues; skin becomes wrinkled and there is a decline in joint flexibility. These gradual changes predominantly result due to long‐term alterations in the extracellular matrices (ECMs) of structures including skin, tendons/ligaments, bones, cartilage and blood ves...

Tissue transglutaminase (TGase2) is a protein-crosslinking enzyme known to be associated with the in vivo apoptosis program. Here we report that apoptosis could be induced in TGase2-/- mice; however, the clearance of apoptotic cells was defective during the involution of thymus elicited by dexamethasone, anti-CD3 antibody, or gamma-irradiation, and...

We have isolated and characterized the gene encoding mouse matrilin-4 (Matn4), an extracellular matrix protein present in a broad spectrum of tissues. The gene spanned 16 kb, consisted of 12 exons, and localized to chromosome 2. As in all known matrilin genes, the last intron, separating the exons coding for the coiled-coil domain, did not follow t...

We isolated and characterized the gene encoding human transglutaminase (TG)(X) (TGM5) and mapped it to the 15q15.2 region of chromosome 15 by fluorescence in situ hybridization. The gene consists of 13 exons separated by 12 introns and spans about 35 kilobases. Further sequence analysis and mapping showed that this locus contained three transglutam...

Changes in expression of type III αl-collagen and myosin II heavy chains were characterized in rabbit skeletal muscle following single stretch injury using quantitative reverse transcription-polymerase chain reaction. Collagen III expression was highly elevated in the injured leg compared with the control limb both at the myotendinous junction and...

Transglutaminases form a family of proteins that have evolved for specialized functions such as protein crosslinking in haemostasis, semen coagulation, or keratinocyte cornified envelope formation. In contrast to the other members of this protein family, tissue transglutaminase is a multifunctional enzyme apparently involved in very disparate biolo...

Treatment of defects in articular cartilage is complicated by its limited spontaneous repair capacity. New approaches to treatment involve inducing healing with cells or growth factors. The effectiveness of these strategies requires delivery, spatial and temporal stability, as well as local biochemical and biologic effects. The authors have develop...

To assess the distribution of transglutaminase (TGase) activity in ocular tissues and the target structures for cross-linking. Cryosections from human and cynomolgus monkey eyes were incubated with the biotinylated amine donor substrate cadaverine (biotC), which was subsequently visualized with streptavidin-peroxidase. Confocal laser scanning was u...

Biodegradable materials for spatially and temporally controlled delivery of bioactive agents such as drugs, growth factors, or cytokines are key to facilitating tissue repair. We have developed a versatile method for chemical crosslinking high-molecular-weight hyaluronic acid under physiological conditions yielding biocompatible and biodegradable h...

On or before Jun 29, 2011 this sequence version replaced gi:7595352, gi:7595353, gi:7595351.

Increasing evidence indicates that tissue transglutaminase (tTG) plays a role in the assembly and remodeling of extracellular matrices and promotes cell adhesion. Using an inducible system we have previously shown that tTG associates with the extracellular matrix deposited by stably transfected 3T3 fibroblasts overexpressing the enzyme. We now show...

A large protein was purified from bovine kidney, using selective extraction with EDTA to solubilize proteins anchored by divalent cation-dependent interactions. An antiserum raised against the purified protein labeled the apical cell surface of the epithelial cells in proximal tubules and the luminal surface of small intestine. Ten peptide sequence...

Thrombospondin-1 and -2 (TSP1 and TSP2) are multifunctional, multimodular extracellular matrix proteins encoded by separate genes. We compared the distributions of TSP1 and TSP2 in mouse embryos (day 10 and later) by immunohistochemistry. TSP1 was detected on day 10 in the heart and intestinal epithelium, on day 11 in megakaryocytes, and on day 14...

We developed a method using a single set of degenerate oligonucleotide primers for amplification of the conserved active site of transglutaminases by reverse transcription-polymerase chain reaction (RT-PCR) and identification of the PCR products by cleavage with diagnostic restriction enzymes. We demonstrate amplification of tissue transglutaminase...

Autosomal recessive congenital ichthyoses are a heterogeneous group of disfiguring skin diseases. They are generally characterized by variable scaling and erythroderma, and patients are frequently collodion babies at birth. Autosomal recessive congenital ichthyoses are represented in 25 of our 50 families by a defective keratinocyte transglutaminas...

At birth, the mammalian lung is still immature. The alveoli are not yet formed and the interairspace walls contain two capillary layers which are separated by an interstitial core. After alveolarization (first 2 postnatal weeks in rats) the alveolar septa mature: their capillary layers merge, the amount of connective tissue decreases, and the matur...

The extracellular matrix (ECM) and basement membranes (BM, a specialized form of ECM) greatly influence proliferation, differentiation, and function of cells and the structure of tissues. While a considerable amount of information is available on thyroid cellular proliferation, differentiation and function, much less is known about thyroid ECM and...

In this study, we used an in vitro model to test the capacity of tissue transglutaminase to increase the adhesive strength at a cartilage-cartilage interface. Full-thickness cartilage-bone cylinders were prepared from fresh adult bovine shoulder joints, and the superficial half of the hyaline cartilage was then removed to provide a plane surface. T...

Since transglutaminases create covalent gamma-glutamyl-epsilon-lysine cross-links between extracellular matrix proteins they are prime candidates for stabilizing tissue during wound healing. Therefore, we studied the temporo-spatial expression of transglutaminase activity in skin regenerating from cultured epithelial autografts in severely burned c...