Anti-transglutaminase antibodies

AutoAbBox
Autoantigen = transglutaminase
SharedInfo = Yes
CommentShared - Answer "Yes" only if true
SI_Gene =
SI_Organ =
SI_Tissue =
SI_Cell =
SI_Also =
SI_Disease =
SI_Class = IgA, IgG
SI_IgGSubclass =
SI_HLA1 = DQ2.5
SI_HLA2 = DQ8
SI_HLA3 = DQ2.2/DQ7.5
SI_TCellRestr = DQ/gliadin, DQ/deamidated-gliadin
SI_Trigger = Triticeae glutens(Prolamins and Glutelins)
Isoform1 = Tissue transglutaminase
I1_Gene = TGM2
I1_Organ = Intestine (small)
I1_Tissue = Villi
I1_Cell = Epithelial Cells
I1_Also = Epithelial matrix
I1_Disease = Coeliac disease
I1_Class =
I1_IgGSubclass =
I1_HLA1 =
I1_HLA2 =
I1_HLA3 =
I1_Trigger = & Gastrointestinal viruses
Isoform2 = Epidermal transglutaminase
I2_Gene = TGM3
I2_Organ = Skin
I2_Tissue =
I2_Cell =
I2_Also =
I2_Disease = Dermatitis herpetiformis
I2_Class =
I2_IgGSubclass =
I2_HLA1 =
I2_HLA2 =
I2_HLA3 =

Anti-transglutaminase antibodies (ATA) are antibodies found more frequently in certain autoimmune diseases. High levels (titers) of ATA are found in almost all instances of coeliac disease.cite journal | author = Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken E, Schuppan D | title = Identification of tissue transglutaminase as the autoantigen of celiac disease | journal = Nat Med | volume = 3 | issue = 7 | pages = 797–801 | year = 1997 | pmid = 9212111 | doi = 10.1038/nm0797-797] Given the association of ATA with coeliac disease, and the prevalence of the latter it is estimated that ~1% of the population have potentially pathogenic levels of ATA.

ATA can be classified according to 2 different schemes. Transglutaminase isoform and the reactivity of immunoglobulin subclass (IgA, IgG) toward transglutaminases.

Transglutaminase isoform reactivity

Anti-tissue transglutaminase

Antibodies to tissue transglutaminase (ATA or anti-tTG) are found in patients with coeliac disease. ATA are sometimes found in other autoimmune diseases, such as juvenile diabetes. ATA are involved in the destruction of the villous extracellular matrix and target the destruction of intestinal villous epithelial cellsby killer cells. Deposits of anti-tTG in the intestinal epithelium predict coeliac disease.cite journal | author = Kaukinen K, Peraaho M, Collin P, Partanen J, Woolley N, Kaartinen T, Nuuntinen T, Halttunen T, Maki M, Korponay-Szabo I | title = Small-bowel mucosal tranglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: A Prospective and radmonized clinical study | journal = Scand J Gastroenterology | volume = 40 | pages = 564–572 | year = 2005 | pmid = 16036509 | doi = 10.1080/00365520510023422]

Anti-endomysial reactivity

The major pathogenic component of anti-endomysial antibodies (EMA) are ATA, and EMA compose most of ATA. EMA may represent antibodies that bind with higher affinity to cell-surface tTG.cite journal |author=Salmi T, Collin P, Korponay-Szabó I, Laurila K, Partanen J, Huhtala H, Király R, Lorand L, Reunala T, Mäki M, Kaukinen K |title=Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits |journal=Gut |volume=55 |issue=12 |pages=1746–53 |year=2006 |pmid=16571636 |doi=10.1136/gut.2005.071514] therefore targeting those cells for apoptosis.The antiendomysial antibody test is a histological assay for patient serum binding to esophageal tissue from primate.

Anti-epidermal transglutaminase

Antibodies to epidermal transglutaminase (eGT, also Keratinocyte transglutaminase) are the autoantibodies believed to cause dermatitis herpetiformis.cite journal |author=Hull CM, Liddle M, Hansen N, "et al" |title=Elevation of IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis |journal=Br. J. Dermatol. |volume= |issue= |pages= |year=2008 |month=May |pmid=18503599 |doi=10.1111/j.1365-2133.2008.08629.x |url=]

Immunoglobin subclass

ATA IgA are more frequently found in CD; however, ATA IgG are found in CD and at higher levels when affected individual had the IgA-less phenotype. The IgA-less phenotype is more common in CD than the normal population; however, one haplotype, DQ2.5 is found in most CD, has genetic linkage to the IgA-less gene location.

Associated Conditions

Viral associations. Frequent rotavirus infections in children with DR3-DQ2 serological haplotype create higher risk of coeliac disease (CD).cite journal | author = Stene LC, Honeyman MC, Hoffenberg EJ, "et al" | title = Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study | journal = Am. J. Gastroenterol. | volume = 101 | issue = 10 | pages = 2333–40 | year = 2006 | pmid = 17032199 | doi = 10.1111/j.1572-0241.2006.00741.x] A large fraction of CD patients have anti-tTG antibodies that also recognize arotavirus protein called VP7. These "crossreactive" antibodies stimulate monocyte proliferation. Rotavirus infection might explain some early steps in the autoimmune progression in CD.cite journal |author=Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S, Beri R, Dolcino M, Valletta E, Corrocher R, Puccetti A |title=In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes |journal=PLoS Med |volume=3 |issue=9 |pages=e358 |year=2006 |pmid=16984219 |doi=10.1371/journal.pmed.0030358] Rotavirus damage in the gut showed a type villous atrophy similar to advanced grades of CD. [cite journal | author = Salim A, Phillips A, Farthing M | title = Pathogenesis of gut virus infection | journal = Baillieres Clin Gastroenterol | volume = 4 | issue = 3 | pages = 593–607 | year = 1990 | pmid = 1962725 | doi = 10.1016/0950-3528(90)90051-H] This suggests that viral proteins may take part in the initial flattening and could stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a continuous source of autoantibodies.

Juvenile diabetes and anti-tTG. Childhood (male) Type 1 diabetes (T1D) increases the risk for CD and vice versacite journal | author = Lampasona V, Bonfanti R, Bazzigaluppi E, Venerando A, Chiumello G, Bosi E, Bonifacio E. | title = Antibodies to tissue transglutaminase C in type I diabetes. | journal = Diabetologia. | volume = 42 | issue = 10 | pages = 1195–1198 | year = 1999 | pmid = 10525659 | doi = 10.1007/s001250051291] and the early signs of CD may precede T1D in many cases. [cite journal | author = Ludvigsson J, Ludvigsson J, Ekbom A, Montgomery S | title = Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents. | journal = Diabetes Care | volume = 29 | issue = 11 | pages = 2483–8 | year = 2006 | pmid = 17065689 | doi = 10.2337/dc06-0794] A search for CD in juvenile diabates patients revealed that GF diet resulted in some improvements. [cite journal | author = Hansen D, Brock-Jacobsen B, Lund E, Bjørn C, Hansen L, Nielsen C, Fenger C, Lillevang S, Husby S | title = 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. | journal = Diabetes Care | volume = 29 | issue = 11 | pages = 2452–6 | year = 2006 | pmid = 17065683 | doi = 10.2337/dc06-0990] A elevated number of diabetes patients have ATAcite journal | author = Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, and Eisenbarth GS. | title = One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. | journal = J Autoimmun. | volume = 13 | issue = 1 | pages = 143–148 | year = 1999 | pmid = 10441179 | doi = 10.1006/jaut.1999.0303] along with increased numbers of gluten-specific T-cells.

Rheumatoid arthritis. Studies of patients with rheumatoid arthritis showed highly increased frequencies of antibodies against guinea pig transglutaminase, human recombinant transglutaminase and peptidylarginine deiminase type 4 (PAD4). This suggests a potential for crossreactive antibodies between anti-tTG and anti-PAD4.cite journal | author = Roth EB, Stenberg P, Book C, Sjöberg K | title = Antibodies against transglutaminases, peptidylarginine deiminase and citrulline in rheumatoid arthritis--new pathways to epitope spreading | journal = Clin. Exp. Rheumatol. | volume = 24 | issue = 1 | pages = 12–8 | year = 2006 | pmid = 16539813 | doi = ]

Asymptomatic ATA+. A recent screeningcite journal | author = West J, Logan RF, Hill PG, Khaw KT | title = The iceberg of celiac disease: what is below the waterline? | journal = Clin. Gastroenterol. Hepatol. | volume = 5 | issue = 1 | pages = 59–62 | year = 2007 | pmid = 17234556 | doi = 10.1016/j.cgh.2006.10.020] 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 glucoseSimilar studies
* increased mortality, particularly to cancercite journal | author = Metzger MH, Heier M, Mäki M, "et al" | title = Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989-1998 | journal = Eur. J. Epidemiol. | volume = 21 | issue = 5 | pages = 359–65 | year = 2006 | pmid = 16649072 | doi = 10.1007/s10654-006-9002-4]

Symptomatic ATA+
* greater impairment of neurophysiology (peripheral neuropathies and motor neuron disease.cite journal | author = Matà S, Renzi D, Pinto F, Calabrò A | title = Anti-tissue transglutaminase IgA antibodies in peripheral neuropathy and motor neuronopathy | journal = Acta Neurol. Scand. | volume = 114 | issue = 1 | pages = 54–8 | year = 2006 | pmid = 16774628 | doi = 10.1111/j.1600-0404.2006.00602.x]
* increased inflammatory bowel symptoms(not celiac or EMA).cite journal | author = Di Tola M, Sabbatella L, Anania MC, "et al" | title = Anti-tissue transglutaminase antibodies in inflammatory bowel disease: new evidence | journal = Clin. Chem. Lab. Med. | volume = 42 | issue = 10 | pages = 1092–7 | year = 2004 | pmid = 15552265 | doi = ]

Alcohol consumption. ATA correlated with biomarkers of alcohol consumption, proinflammatory cytokines and markers of fibrogenesis.cite journal | author = Koivisto H, Hietala J, Anttila P, Niemelä O | title = Co-Occurrence of IgA Antibodies Against Ethanol Metabolites and Tissue Transglutaminase in Alcohol Consumers: Correlation with Proinflammatory Cytokines and Markers of Fibrogenesis | year = 2007 | pmid = 17597408 | doi = 10.1007/s10620-007-9874-5 | journal = Digestive Diseases and Sciences | volume = 53 | pages = 500]

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 autoimmunityautoreactive T-cells are not suppressed or antigens escape the protective process. T-cells are stimulated by antigen, presented by MHC molecules (HLA in humans) and surface IgM on antigen reactive B-cells. These T-helper cells then stimulate B-cells to multiply and mature into plasma cells that make IgG to that protein.

For tTG autoimmunity (CD), T-cells are generated against wheat gliadin and similar gluten proteins of the trib "Triticeae". The T-cells are defined by the ability to react to HLA-DQ8 and DQ2.5 restricted antigens and gliadin is one of the antigens. Gliadin is a favored dietary substrate for transglutaminase because of many enzyme reaction sites on gliadin. In disease, transglutaminase reacts with gliadin forming a linkagecite journal | author = Fleckenstein B, Qiao SW, Larsen MR, Jung G, Roepstorff P, Sollid LM | title = Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides | journal = J. Biol. Chem. | volume = 279 | issue = 17 | pages = 17607–16 | year = 2004 | pmid = 14747475 | doi = 10.1074/jbc.M310198200] . In forming this bond transglutaminase becomes linked to T-cell epitopes on gliadin. B-cells with surface IgM that react to transglutaminase can present it with bound gliadin peptides to T-cells which stimulate B-cell maturation and proliferation to plasma cells making IgA or IgM.

ATA correlates with severity of CD. A recent study of children demonstratesthat the level of ATA in correlates with the scalar Marsh score for the disease in the same patient.cite journal | author = Donaldson MR, Firth SD, Wimpee H, "et al" | title = Correlation of duodenal histology with tissue transglutaminase and endomysial antibody levels in pediatric celiac disease | journal = Clin. Gastroenterol. Hepatol. | volume = 5 | issue = 5 | pages = 567–73 | year = 2007 | pmid = 17428743 | doi = 10.1016/j.cgh.2007.01.003]

ATA changes the behavior of tTG. Some studies have revealed that antibodiesincrease 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 apparently interacting with cell-surface transglutaminase.cite journal | author = Barone MV, Caputo I, Ribecco MT, "et al" | title = Humoral immune response to tissue transglutaminase is related to epithelial cell proliferation in celiac disease | journal = Gastroenterology | volume = 132 | issue = 4 | pages = 1245–53 | year = 2007 | pmid = 17408665 | doi = 10.1053/j.gastro.2007.01.030]

Genetics

Genetics of coeliac disease is the common genetic factor for ATA. However studies of children with coeliac disease reveals that patients with DR7 have higher titers to ATA [pmid:17364503] . The DR7 is commonly found with HLA-DR5-DQ7/DR7-DQ2 phenotype in celiac disease. DR7-DQ2 homozygotes are also found.

=Links= [http://www.celiac.com/st_prod.html?p_prodid=1091 Anti-Tissue Transglutaminase (tTG) Antibodies Also Found in Inflammatory Bowel Disease]
[http://www.celiac.com/articles/21637/1/Tg6-Antibody-Plays-a-Key-Role-in-Celiac-Disease-Related-Neurological-Disorders/Page1.html Tg6 Antibody Plays a Key Role in Celiac-Related Neurological Disorders Celiac.com 09/02/2008 ]

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