**2.3 Anti-transglutaminase (TGA)**

Anti-transglutaminase (TGA) are autoantibodies targeting tissue transglutaminase (tTG) or transglutaminase 2, which is a 76-kD calcium-dependent ubiquitous enzyme released during inflammation that catalyzes the post-translational modification of proteins [21]. This ubiquitously expressed enzyme also plays a role as a GTPase, ATPase, and protein kinase [22]. This enzyme has been considered a specific marker for celiac disease (CD). Dieterich et al. were one of the first scientists to determine the role of tTG in CD [23]. Sabatino et al., further explain that tTG has at least two roles in CD one is being a deamidating enzyme to enhance the immunostimulatory effect of gluten, and the other as a target autoantigen in the immune response [21]. In a systematic review done by Ghatti et al., 11 studies detected intestinal transglutaminase 2 Immunoglobin A (IgA) deposits in 100% of adults with overt CD, while the prevalence in children ranged between 73.2 and 100% [24]. Similarly, in a study examining children, Borrelli et al. detected anti-TG2 IgA deposits in all 53 patients with confirmed CD and three out of three potential patients with CD. As a result, Borrelli et al. concluded that intestinal deposits of anti-TG2 appear early in the course of the disease and are of constant presence in patients with CD [25]. Furthermore, other studies detected TGA presence in serum of patients with CD. For example, Miller et al. detected TGA presence in 46 patients with untreated CD (sensitivity 100%) [26]. Moreover, in a study testing 37 patients with biopsyconfirmed CD, Damoiseaux et al. found that 86.5% have IgA antirecombinant human tissue transglutaminase antibodies (rh-tTGA) [27]. In addition, Tola et al. found significantly high levels of TGA in patients with CD [28]. TGA can be even found in the serum of asymptomatic individuals who later in life develop CD [29], which further emphasizes its importance in detecting CD. In fact, Rubio-Tapia et al. have found that elevated IgA anti-TGA has been associated with an increased mortality rate among men aged 50 years old. They also concluded that IgA anti-TGA could be used as a nonspecific marker of serious disease in older men [30]. There are few studies documenting IgA anti-TGA in Crohn's disease; however, there are other conflicting reports about anti-TGA IgG presence [31, 32]. Tola et al. have found significantly low positive values in IBD (Crohn's disease and ulcerative colitis (UC)). In addition, Tursi et al. also detected antitransglutaminase (anti-tTG) in 5 out of 27 (18.52%) patients with Crohn's disease [33]. While Shor et al. also detected positive IgG tTG in 4 out of 26 patients with UC, and 2 out of 194 in healthy controls (11.1% versus 1%; P = 0.018) [28]. As a result, TGA was not found to be useful in IBD; therefore, serological screening testing was only recommended if there is a relevant clinical suspicion of Crohn's [34]. While in IBD, Watanabe et al. detected significantly higher levels of antibodies against tissue transglutaminase in patients, which also correlated with disease severity [35]. IgA against the autoantigen tissue transglutaminase (tTG) is frequently associated with untreated Crohn's disease but disappears with gluten exclusion [23]. TGA has also been associated with Crohn's disease and its severity.

Moreover, Fevre et al. also detected anti-tissue transglutaminase antibodies (TTG Ab) in 23% of patients diagnosed with eosinophilic esophagitis (EoE) during the study. Shor et al. also detected positive IgG tTG in 4 out of 26 patients with ulcerative colitis, and 2 out of 194 in healthy controls (11.1% vs. 1%; P = 0.018) [28].
