ANTI-TRANSGLUTAMINASE ANTIBODIES

'Anti-transglutaminase antibodies' are antibodies found at higher prevelance in many autoimmune diseases, but are found at high levels in almost all instances of coeliac disease. Identification of tissue transglutaminase as the autoantigen of celiac disease, Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken E, Schuppan D, , , Nat Med, 1997
Given the association of ATA with celiac disease, and the prevelance of coeliac disease it is estimated that ~1% of the population have potentially pathogenic
levels of ATA.
ATA can be classified according to 2 different schemes.
1. 'Transglutaminase Isoform reactivity':

★ 'Anti-tissue transglutaminase' (tTG)- anti-tTG antibodies (ATA) are associated with coeliac disease at high frequency and other autoimmune diseases such as juvenile diabetes at lower frequencies. They are the autoantibodies believed to mediate the destruction of the villous extracellular matrix and target the destruction of intestinal villous epithelial cells.

★
★ deposits of anti-tTG in the intestinal epithelium predict coeliac disease. Small-bowel mucosal tranglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: A Prospective and radmonized clinical study, Kaukinen K, Peraaho M, Collin P, Partanen J, Woolley N, Kaartinen T, Nuuntinen T, Halttunen T, Maki M, Korponay-Szabo I, , , Scand J Gastroenterology, 2005

★
★ the major componet of anti-endomysial antibodies (EMA)

★
★
★ EMA may represent antibodies that bind with higher affinity to cell surface bound tTG. Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits, Salmi T, Collin P, Korponay-Szabó I, Laurila K, Partanen J, Huhtala H, Király R, Lorand L, Reunala T, Mäki M, Kaukinen K, , , Gut, 2006

★ 'Anti-epidermal transglutaminase' (eTG) - anti-eTG antibodies are the autoantiboides believed to cause dermatitis herpetiformis.
2. 'Immunoglobin subclass':

★ ATA IgA are more frequently found in CD

★ ATA IgG are found in CD and at higher levels when affected individual had the IgA-less phenotype.

Contents

Associated Conditions

Mechanism of Autoimmunity

Associated Conditions

'Viral associations'. A study of DR3-DQ2 positive children examining both rotavirus and gluten-sensitivity. Frequent rotavirus infections predicted a higher risk of disease.^[1]
In a large percentage of coeliac patients, the anti-tTG antibodies also recognize a rotavirus protein called VP7. These antibodies stimulate monocytes proliferation and rotavirus infection might explain some early steps in the cascade of immune cell proliferation. In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes, Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S, Beri R, Dolcino M, Valletta E, Corrocher R, Puccetti A, , , PLoS Med, 2006 Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy.^[2] This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin mediated tTG presentation provides a second source of crossreactive antibodies.
'Juvenile diabetes and anti-tTG'. Childhood (male) Type 1 diabetes increases the risk for GSE and vice versa Antibodies to tissue transglutaminase C in type I diabetes., Lampasona V, Bonfanti R, Bazzigaluppi E, Venerando A, Chiumello G, Bosi E, Bonifacio E., , , Diabetologia., 1999 and it now appears that GSE precedes T1D in many cases^[3] and an active search for coeliac disease in early juvenile diabetes patients revealed that GF diet resulted in some improvements.^[4] A high frequency of diabetes patients have antibodies to the GSE autoantigen, tTG One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies., Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, and Eisenbarth GS., , , J Autoimmun., 1999 along with increased levels of gluten specific T-cells in T1D patients.
'Rheumatoid arthritis'. Studies of patients with RA showed highly increased
frequencies of antibodies against guinea pig transglutaminase, human recombinant transglutaminase and peptidylarginine deiminase type 4. Suggesting the potential for crossreactive antibodies between anti-tTG and anti-PAD4.^[5]
'Asymptomatic ATA+'. A recent screening^[6] of 7550 Briton's found 87 undetected ATA+.
In this study a 50% increase of ATA was associated with:

★ lower bone mineral density of the hip.

★ lower hemoglobin levels

★ decreased weight.

★ lower cholesterol

★ higher blood glucose
Similar studies

★ increased mortality, particularly to cancer^[7]
'Symptomatic ATA+'

★ greater impairment of neurophysiology (peripheral neuropathies and motor neuron disease.^[8]

★ increased irritable bowel (not celiac or EMA).^[9]

Mechanism of Autoimmunity

The antibodies to tissue transglutaminase follow a complex pathway of generation.
For most antigens, T-cells specific to those antigens develop, for autoimmunity
autoreactive T-cells are not suppressed or the antigen escapes the protective process. T-cells are stimulated by antigen presented by antigen reactive B-cells, the present both in the context of MHC and sIgM receptor. This then stimulates B-cells to multiply and mature into plasma cells that make IgG.
For tTG, T-cells are generated against gliadin. The T-cells are clearly defined by the ability to react to DQ8 and DQ2.5 restricted antigens. Tissue transglutaminase can react with gliadin forming a covelant linkage^[10] that can also be presented by the same T-lymphocytes; however, the most reactive state of gliadin, deamidated gliadin, is no longer reactive to tTG, but is formed from the reaction with tTG. As a result tTG makes
gliadin more immuno-stimulatory and allows a less reactive form allows tTG reactive B-lymphocytes to present gliadin-tTG to gliadin reactive T-cells. The result is the stimulation of autoreactive B-cells to tTG.
'ATA correlates with severity of CD'. A recent study of children demonstrates
that the level of ATA in correlates with the scalar Marsh score for the disease in the same patient.^[11]
'ATA changes the behavior of tTG'. Some studies have revealed that antibodies
increase the activity of tTG, instead of inhibiting activity as is commonly encountered with function alterning antibodies. A recent study has shown that ATA also modify and increase replication in intestinal epithileal cells, by apparent interacting with cell-surface transglutaminase.^[12]
=Links=
Anti-Tissue Transglutaminase (tTG) Antibodies Also Found in Inflammatory Bowel Disease
=References=
1. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study, Stene LC, Honeyman MC, Hoffenberg EJ, ''et al'', , , Am. J. Gastroenterol., 2006
2. Pathogenesis of gut virus infection, Salim A, Phillips A, Farthing M, , , Baillieres Clin Gastroenterol, 1990
3. Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents., Ludvigsson J, Ludvigsson J, Ekbom A, Montgomery S, , , Diabetes Care, 2006
4. Clinical benefit of a gluten-free diet in type 1 diabetic children with screening-detected celiac disease: a population-based screening study with 2 years' follow-up., Hansen D, Brock-Jacobsen B, Lund E, Bjørn C, Hansen L, Nielsen C, Fenger C, Lillevang S, Husby S, , , Diabetes Care, 2006
5. Antibodies against transglutaminases, peptidylarginine deiminase and citrulline in rheumatoid arthritis--new pathways to epitope spreading, Roth EB, Stenberg P, Book C, Sjöberg K, , , Clin. Exp. Rheumatol., 2006
6. The iceberg of celiac disease: what is below the waterline?, West J, Logan RF, Hill PG, Khaw KT, , , Clin. Gastroenterol. Hepatol., 2007
7. Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989-1998, Metzger MH, Heier M, Mäki M, ''et al'', , , Eur. J. Epidemiol., 2006
8. Anti-tissue transglutaminase IgA antibodies in peripheral neuropathy and motor neuronopathy, Matà S, Renzi D, Pinto F, Calabrò A, , , Acta Neurol. Scand., 2006
9. Anti-tissue transglutaminase antibodies in inflammatory bowel disease: new evidence, Di Tola M, Sabbatella L, Anania MC, ''et al'', , , Clin. Chem. Lab. Med., 2004
10. Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides, Fleckenstein B, Qiao SW, Larsen MR, Jung G, Roepstorff P, Sollid LM, , , J. Biol. Chem., 2004
11. Correlation of duodenal histology with tissue transglutaminase and endomysial antibody levels in pediatric celiac disease, Donaldson MR, Firth SD, Wimpee H, ''et al'', , , Clin. Gastroenterol. Hepatol., 2007
12. Humoral immune response to tissue transglutaminase is related to epithelial cell proliferation in celiac disease, Barone MV, Caputo I, Ribecco MT, ''et al'', , , Gastroenterology, 2007