Anti-transglutaminase antibodies#Anti-endomysial reactivity

Image:Tissue transglutaminase.png]]

Antibodies to tissue transglutaminase (abbreviated as anti-tTG or anti-TG2) are found in patients with several conditions, including celiac disease, juvenile diabetes,{{cite journal|pmid=19758209|year=2009|last1=Krause|first1=I|last2=Anaya|first2=JM|last3=Fraser|first3=A|last4=Barzilai|first4=O|last5=Ram|first5=M|last6=Abad|first6=V|last7=Arango|first7=A|last8=García|first8=J|last9=Shoenfeld|first9=Y|title=Anti-infectious antibodies and autoimmune-associated autoantibodies in patients with type I diabetes mellitus and their close family members|volume=1173|pages=633–9|doi=10.1111/j.1749-6632.2009.04619.x|journal=Annals of the New York Academy of Sciences|issue=1|bibcode=2009NYASA1173..633K|s2cid=11261222 }} inflammatory bowel disease,{{cite journal|last=Farrace|first=MG|author2=Picarelli, A|author3=Di Tola, M|author4=Sabbatella, L|author5=Marchione, OP|author6=Ippolito, G|author7= Piacentini, M|title=Presence of anti-"tissue" transglutaminase antibodies in inflammatory intestinal diseases: an apoptosis-associated event?|journal=Cell Death & Differentiation|date=Jul 2001|volume=8|issue=7|pages=767–70|pmid=11464221|doi=10.1038/sj.cdd.4400880|doi-access=free}} and various forms of arthritis.{{cite journal|last=Teichmann|first=Joachim|author2=Voglau, Marcus J.|author3= Lange, Uwe|s2cid=28299599|title=Antibodies to human tissue transglutaminase and alterations of vitamin D metabolism in ankylosing spondylitis and psoriatic arthritis|journal=Rheumatology International|date=13 October 2009|volume=30|issue=12|pages=1559–1563|doi=10.1007/s00296-009-1186-y|pmid=19823832|url=https://hal.archives-ouvertes.fr/hal-00568308/file/PEER_stage2_10.1007%252Fs00296-009-1186-y.pdf}}{{cite journal|last=Picarelli|first=A|author2=Di Tola, M|author3=Sabbatella, L|author4=Vetrano, S|author5=Anania, MC|author6=Spadaro, A|author7=Sorgi, ML|author8= Taccari, E|title=Anti-tissue transglutaminase antibodies in arthritic patients: a disease-specific finding?|journal=Clinical Chemistry|date=Dec 2003|volume=49|issue=12|pages=2091–4|pmid=14633886|doi=10.1373/clinchem.2003.023234|doi-access=free}}

In celiac disease, ATA are involved in the destruction of the villous extracellular matrix and target the destruction of intestinal villous epithelial cells

by killer cells. Deposits of anti-tTG in the intestinal epithelium predict celiac disease.{{cite journal |vauthors=Kaukinen K, Peraaho M, Collin P, Partanen J, Woolley N, Kaartinen T, Nuuntinen T, Halttunen T, Maki M, Korponay-Szabo I | s2cid = 27068601 | title = Small-bowel mucosal tranglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: A Prospective and radmonized clinical study | journal = Scand J Gastroenterol | volume = 40 | pages = 564–572 | year = 2005 | pmid = 16036509 | doi = 10.1080/00365520510023422 | issue = 5}}

The endomysium is a layer of connective tissue that ensheaths a muscle fiber. The endomysium contains a form of transglutaminase called "tissue transglutaminase" or "tTG" for short, and antibodies that bind to this form of transglutaminase are called endomysial autoantibodies (EmA).{{cite journal |vauthors=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 |pmc=1856451}}

The antiendomysial antibody test is a histological assay for patient serum binding to esophageal tissue from primate. EmA are present in celiac disease. They do not cause any direct symptoms to muscles, but detection of EmA is useful in the diagnosis of the disease.{{cite journal |author=Pruessner HT |title=Detecting celiac disease in your patients |journal=Am Fam Physician |volume=57 |issue=5 |pages=1023–34, 1039–41 |date=March 1998 |pmid=9518950 |url=http://www.aafp.org/afp/980301ap/pruessn.html |access-date=2010-08-03 |archive-date=2011-10-20 |archive-url=https://web.archive.org/web/20111020013848/http://www.aafp.org/afp/980301ap/pruessn.html |url-status=dead }}

Antibodies to epidermal transglutaminase (eTG, also keratinocyte transglutaminase) are the autoantibodies believed to cause dermatitis herpetiformis.{{cite journal |author=Hull CM |title=Elevation of IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis |journal=Br. J. Dermatol. |volume= 159|issue= 1|pages= 120–4|date=May 2008 |pmid=18503599 |doi=10.1111/j.1365-2133.2008.08629.x |author2=Liddle M |author3=Hansen N |last4=Meyer |first4=L.J. |last5=Schmidt |first5=L. |last6=Taylor |first6=T. |last7=Jaskowski |first7=T.D. |last8=Hill |first8=H.R. |last9=Zone |first9=J.J.|s2cid=21374261 }}

ATA IgA are more frequently found in Celiac Disease (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.

Most attention to anti-transglutaminase antibodies is given with respect to celiac disease. A recent study of children published in 2007 demonstrated that the level of ATA in correlates with the scalar Marsh score for the disease in the same patient.{{cite journal | author = Donaldson MR | 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 | author2 = Firth SD | author3 = Wimpee H | last4 = Leiferman | first4 = Kristin M. | last5 = Zone | first5 = John J. | last6 = Horsley | first6 = Wyatt | last7 = o'Gorman | first7 = Molly A. | last8 = Jackson | first8 = W. Daniel | last9 = Neuhausen | first9 = Susan L.}}

High levels (titers) of ATA are found in almost all instances of celiac disease.{{cite journal |vauthors=Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken E, Schuppan D | s2cid = 20033968 | 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 celiac disease, and the prevalence of the latter, it is estimated that ~1% of the population have potentially pathogenic levels of ATA.

A study published in Nature in 2001 found high levels of anti-transglutaminase antibodies in inflammatory bowel disease, specifically in Crohn's disease and ulcerative colitis.

Studies of patients with various forms of 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 |vauthors=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 }}

Childhood (male) type 1 diabetes (T1D) increases the risk for CD and vice versa{{cite journal |vauthors=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| doi-access = free }} and the early signs of celiac disease may precede T1D in many cases.{{cite journal |vauthors=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| doi-access = free }} A search for CD in juvenile diabetes patients revealed that a gluten-free diet resulted in some improvements.{{cite journal |vauthors=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| doi-access = free }} An elevated number of diabetes patients have ATA{{cite journal |vauthors=Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, 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.

A recent screening{{cite journal |vauthors=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 Britons 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{{cite journal | author = Metzger MH | 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 | author2 = Heier M | author3 = Mäki M | last4 = Bravi | first4 = Enzo | last5 = Schneider | first5 = Andrea | last6 = Löwel | first6 = Hannelore | last7 = Illig | first7 = Thomas | last8 = Schuppan | first8 = Detlef | last9 = Wichmann | first9 = Heinz-Erich| s2cid = 31438746 }}

• greater impairment of neurophysiology (peripheral neuropathies and motor neuron disease.{{cite journal |vauthors=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| s2cid = 32691295 }}
• increased inflammatory bowel symptoms (not celiac or EMA).{{cite journal | author = Di Tola M | 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 =10.1515/CCLM.2004.225 | author2 = Sabbatella L | author3 = Anania MC | last4 = Viscido | first4 = Angelo | last5 = Caprilli | first5 = Renzo | last6 = Pica | first6 = Roberta | last7 = Paoluzi | first7 = Paolo | last8 = Picarelli | first8 = Antonio | s2cid = 46066640 }}

ATA correlated with biomarkers of alcohol consumption, proinflammatory cytokines and markers of fibrogenesis.{{cite journal |vauthors=Koivisto H, Hietala J, Anttila P, Niemelä O | s2cid = 27382605 | 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 = 500–5 | issue = 2}}

The antibodies to tissue transglutaminase follow a complex pathway of generation. For most antigens, T-cells specific to those antigens develop; for autoimmunity, either autoreactive T-cells are not suppressed, or antigens escape the protective process. T-cells are stimulated by antigen, presented by MHC molecules (HLA in humans) on antigen-reactive B-cells. These T-helper cells then stimulate B-cells to multiply and mature into plasma cells that make IgA and IgG to that protein.

In the case of celiac disease, the current understanding is that tTG autoimmunity arises when T-cells are generated against wheat gliadin and similar gluten proteins made by a class of grasses called Triticeae, which includes wheat (See Wheat taxonomy), barley, and rye. 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 linkage.{{cite journal |vauthors=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| doi-access = free }} 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 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-altering antibodies. A recent study has shown that ATA also modify and increase replication in intestinal epithelial Cells, by apparently interacting with cell-surface transglutaminase.{{cite journal | author = Barone MV | 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 | author2 = Caputo I | author3 = Ribecco MT | last4 = Maglio | first4 = Maria | last5 = Marzari | first5 = Roberto | last6 = Sblattero | first6 = Daniele | last7 = Troncone | first7 = Riccardo | last8 = Auricchio | first8 = Salvatore | last9 = Esposito | first9 = Carla| doi-access = free }}

{{reflist}}

{{gluten sensitivity}}

{{Autoantibodies}}

{{DEFAULTSORT:Anti-Transglutaminase Antibodies}}

T

Category:Gluten sensitivity