Anti-transglutaminase antibodies

Autoantibody
Anti-transglutaminase
Common autoantibody characteristics
Autoantibody class IgA, IgG
DQ2.5
HLA associations DQ8
DQ2.2/DQ7.5
Associated T-Cell
restrictions 		DQ/gliadin, DQ/deamidated-gliadin
Triggering
agent(s) 		Triticeae glutens(Prolamins and Glutelins)
Isoform specific
autoantibody characteristics
Autoantigen
Isoform 		Tissue transglutaminase
Autoantigen Gene TGM2
Affected Organ(s) Intestine (small)
Affected Tissue(s) Villi
Affected Cells(s) Epithelial Cells
Also Affected Epithelial matrix
Associated
Disease(s) 		Coeliac disease
Triggering
agent 		& Gastrointestinal viruses
Autoantigen
Isoform 		Epidermal transglutaminase
Autoantigen Gene TGM3
Affected Organ(s) Skin
Associated
Disease(s) 		Dermatitis herpetiformis

Anti-transglutaminase antibodies (ATA) are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign (for example, viruses) and also can be produced by the body (for example, cancer cells). Antibodies against the body's own products are called autoantibodies. Autoantibodies can sometimes errantly be directed against healthy portions of the organism, causing autoimmune diseases.

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

Transglutaminase isoform reactivity

transglutaminase

Anti-tissue transglutaminase

Antibodies to tissue transglutaminase (abbreviated as anti-tTG or anti-TG2) are found in patients with several conditions, including coeliac disease, juvenile diabetes,[1] inflammatory bowel disease,[2] and various forms of arthritis.[3][4]

In coeliac 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 coeliac disease.[5]

Anti-endomysial reactivity

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).[6] The antiendomysial antibody test is a histological assay for patient serum binding to esophageal tissue from primate. EmA are present in coeliac disease. They do not cause any direct symptoms to muscles, but detection of EmA is useful in the diagnosis of the disease.[7]

Anti-epidermal transglutaminase

Antibodies to epidermal transglutaminase (eTG, also keratinocyte transglutaminase) are the autoantibodies believed to cause dermatitis herpetiformis.[8]

Immunoglobin subclass

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.

Associated Conditions

Coeliac Disease

Most attention to anti-transglutaminase antibodies is given with respect to coeliac 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.[9]

High levels (titers) of ATA are found in almost all instances of coeliac disease.[10] 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.

Inflammatory bowel disease

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.[2]

Arthritis

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.[11]

Juvenile diabetes and anti-tTG

Childhood (male) type 1 diabetes (T1D) increases the risk for CD and vice versa[12] and the early signs of coeliac disease may precede T1D in many cases.[13] A search for CD in juvenile diabates patients revealed that a gluten-free diet resulted in some improvements.[14] An elevated number of diabetes patients have ATA[15] along with increased numbers of gluten-specific T-cells.

Asymptomatic ATA+

A recent screening[16] of 7550 Briton's found 87 undetected ATA+. In this study a 50% increase of ATA was associated with:

Similar studies

Symptomatic ATA+

Alcohol consumption

ATA correlated with biomarkers of alcohol consumption, proinflammatory cytokines and markers of fibrogenesis.[20]

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, 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 IgG to that protein.

In the case of coeliac 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.[21] 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.[22]

Links

References

  1. ↑ Krause, I; Anaya, JM; Fraser, A; Barzilai, O; Ram, M; Abad, V; Arango, A; García, J; Shoenfeld, Y (2009). "Anti-infectious antibodies and autoimmune-associated autoantibodies in patients with type I diabetes mellitus and their close family members". Annals of the New York Academy of Sciences. 1173: 633–9. doi:10.1111/j.1749-6632.2009.04619.x. PMID 19758209.
  2. 1 2 Farrace, MG; Picarelli, A; Di Tola, M; Sabbatella, L; Marchione, OP; Ippolito, G; Piacentini, M (Jul 2001). "Presence of anti-"tissue" transglutaminase antibodies in inflammatory intestinal diseases: an apoptosis-associated event?". Cell death and differentiation. 8 (7): 767–70. doi:10.1038/sj.cdd.4400880. PMID 11464221. Retrieved 26 December 2012.
  3. ↑ Teichmann, Joachim; Voglau, Marcus J.; Lange, Uwe (13 October 2009). "Antibodies to human tissue transglutaminase and alterations of vitamin D metabolism in ankylosing spondylitis and psoriatic arthritis". Rheumatology International. 30 (12): 1559–1563. doi:10.1007/s00296-009-1186-y. PMID 19823832.
  4. ↑ Picarelli, A; Di Tola, M; Sabbatella, L; Vetrano, S; Anania, MC; Spadaro, A; Sorgi, ML; Taccari, E (Dec 2003). "Anti-tissue transglutaminase antibodies in arthritic patients: a disease-specific finding?". Clinical Chemistry. 49 (12): 2091–4. doi:10.1373/clinchem.2003.023234. PMID 14633886. Retrieved 26 December 2012.
  5. ↑ Kaukinen K, Peraaho M, Collin P, Partanen J, Woolley N, Kaartinen T, Nuuntinen T, Halttunen T, Maki M, Korponay-Szabo I (2005). "Small-bowel mucosal tranglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: A Prospective and radmonized clinical study". Scand J Gastroenterology. 40 (5): 564–572. doi:10.1080/00365520510023422. PMID 16036509.
  6. ↑ Salmi T, Collin P, Korponay-Szabó I, Laurila K, Partanen J, Huhtala H, Király R, Lorand L, Reunala T, Mäki M, Kaukinen K (2006). "Endomysial antibody‐negative coeliac disease: clinical characteristics and intestinal autoantibody deposits". Gut. 55 (12): 1746–53. doi:10.1136/gut.2005.071514. PMC 1856451Freely accessible. PMID 16571636.
  7. ↑ Pruessner HT (March 1998). "Detecting celiac disease in your patients". Am Fam Physician. 57 (5): 1023–34, 1039–41. PMID 9518950.
  8. ↑ Hull CM, Liddle M, Hansen N, et al. (May 2008). "Elevation of IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis". Br. J. Dermatol. 159 (1): 120–4. doi:10.1111/j.1365-2133.2008.08629.x. PMID 18503599.
  9. ↑ Donaldson MR, Firth SD, Wimpee H, et al. (2007). "Correlation of duodenal histology with tissue transglutaminase and endomysial antibody levels in pediatric celiac disease". Clin. Gastroenterol. Hepatol. 5 (5): 567–73. doi:10.1016/j.cgh.2007.01.003. PMID 17428743.
  10. ↑ Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken E, Schuppan D (1997). "Identification of tissue transglutaminase as the autoantigen of celiac disease". Nat Med. 3 (7): 797–801. doi:10.1038/nm0797-797. PMID 9212111.
  11. ↑ Roth EB, Stenberg P, Book C, Sjöberg K (2006). "Antibodies against transglutaminases, peptidylarginine deiminase and citrulline in rheumatoid arthritis--new pathways to epitope spreading". Clin. Exp. Rheumatol. 24 (1): 12–8. PMID 16539813.
  12. ↑ Lampasona V, Bonfanti R, Bazzigaluppi E, Venerando A, Chiumello G, Bosi E, Bonifacio E (1999). "Antibodies to tissue transglutaminase C in type I diabetes". Diabetologia. 42 (10): 1195–1198. doi:10.1007/s001250051291. PMID 10525659.
  13. ↑ Ludvigsson J, Ludvigsson J, Ekbom A, Montgomery S (2006). "Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents". Diabetes Care. 29 (11): 2483–8. doi:10.2337/dc06-0794. PMID 17065689.
  14. ↑ Hansen D, Brock-Jacobsen B, Lund E, Bjørn C, Hansen L, Nielsen C, Fenger C, Lillevang S, Husby S (2006). "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". Diabetes Care. 29 (11): 2452–6. doi:10.2337/dc06-0990. PMID 17065683.
  15. ↑ Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, Eisenbarth GS (1999). "One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies". J Autoimmun. 13 (1): 143–148. doi:10.1006/jaut.1999.0303. PMID 10441179.
  16. ↑ West J, Logan RF, Hill PG, Khaw KT (2007). "The iceberg of celiac disease: what is below the waterline?". Clin. Gastroenterol. Hepatol. 5 (1): 59–62. doi:10.1016/j.cgh.2006.10.020. PMID 17234556.
  17. ↑ Metzger MH, Heier M, Mäki M, et al. (2006). "Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989-1998". Eur. J. Epidemiol. 21 (5): 359–65. doi:10.1007/s10654-006-9002-4. PMID 16649072.
  18. ↑ Matà S, Renzi D, Pinto F, Calabrò A (2006). "Anti-tissue transglutaminase IgA antibodies in peripheral neuropathy and motor neuronopathy". Acta Neurol. Scand. 114 (1): 54–8. doi:10.1111/j.1600-0404.2006.00602.x. PMID 16774628.
  19. ↑ Di Tola M, Sabbatella L, Anania MC, et al. (2004). "Anti-tissue transglutaminase antibodies in inflammatory bowel disease: new evidence". Clin. Chem. Lab. Med. 42 (10): 1092–7. doi:10.1515/CCLM.2004.225. PMID 15552265.
  20. ↑ Koivisto H, Hietala J, Anttila P, Niemelä O (2007). "Co-Occurrence of IgA Antibodies Against Ethanol Metabolites and Tissue Transglutaminase in Alcohol Consumers: Correlation with Proinflammatory Cytokines and Markers of Fibrogenesis". Digestive Diseases and Sciences. 53 (2): 500–5. doi:10.1007/s10620-007-9874-5. PMID 17597408.
  21. ↑ Fleckenstein B, Qiao SW, Larsen MR, Jung G, Roepstorff P, Sollid LM (2004). "Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides". J. Biol. Chem. 279 (17): 17607–16. doi:10.1074/jbc.M310198200. PMID 14747475.
  22. ↑ Barone MV, Caputo I, Ribecco MT, et al. (2007). "Humoral immune response to tissue transglutaminase is related to epithelial cell proliferation in celiac disease". Gastroenterology. 132 (4): 1245–53. doi:10.1053/j.gastro.2007.01.030. PMID 17408665.
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