**2.4 Anti-gliadin antibodies (AGA)**

Anti-gliadin antibodies are antibodies that are targeted toward Gliadin, a protein found in Bread wheat, rye, and barley [36]. AGA IgA antibodies have been shown to be one of the hallmarks of CD. For instance, Jassim et al. tested AGA-IgA and AGA-IgG in 58 patients with celiac disease and 27 healthy control and found that both antibodies were significantly higher in the CD patients than in control [3]. In addition, Damoiseaux et al. found that 73% of 37 patients with biopsy-confirmed CD have IgA AGA in their serum [27]. Moreover, Lindqvist et al. have found that patients with psoriatic arthritis have an increased prevalence of high serum IgA AGA and of CD [37]. In fact, CD was commonly found in patients with isolated positive AGA; therefore, Taylor et al. recommended that all those patients should be referred to gastroscopy (OGD) and D2 biopsy to undergo further investigation [38]. Both AGA and anti-tTG antibodies are considered good serologic indicators of CD, and they can be even found in the serum of asymptomatic individuals who later in life develop CD [29, 39]. The sensitivities detected for tTG, AGA IgA, and AGA IgG are 90 to 98%, 80 to 90%, and 75 to 85%, respectively. While the specificities were found to be 95 to 97%, 85 to 95%, and 75 to 90%, respectively [40, 41]. Moving to Crohn's disease, Tursi et al. detected AGA in 8 out of the 27 patients with Crohn's disease (29.63%) [33]. Furthermore, Shor et al. detected high levels of AGA IgG in 17 out of 83 patients with Crohn's disease, and 20 out of 194 in healthy controls (20.5% vs. 10.3%; P = 0.023) [28].

## **2.5 Anti-endomysial antibodies (EMA)**

The endomysium is a perivascular connective tissue that separates smooth muscle fibers from each other [42]. Dieterich et al. stated that tissue transglutaminase is the target antigen in endomysium in CD [23]. Detection of anti-endomysial antibodies (EMA) in blood has been used as the most specific test to diagnose CD. However, EMA lacks sensitivity, particularly in the earlier stages of disease exhibiting mild villous atrophy [38, 43]. On the other hand, Farrell et al. state that sensitivity of EMA *Autoimmune Diseases of the GI Tract Part II: Emergence of Diagnostic Tools and Treatments DOI: http://dx.doi.org/10.5772/intechopen.106185*

IgA is equal to or exceeds 90%, while the specificity approaches 100% in untreated patients with CD. Kanthi et al., similarly, mention that the sensitivity and specificity of IgA EMAs are found to be 85–98% and 97–100%, respectively. As a result of that, blood EMA testing is estimated to have a high positive predictive value [44]. Another characteristic of EMA includes that the antibodies' levels fall after following a glutenfree diet [45]. Similar to IgA AGA, IgA EMA antibody will also not be detected in IgA deficient CD patients [46]. As for using it, Keren et al. recommended testing for EMA to help select patients who would be qualified for a biopsy [47]. While others used it for screening and estimating the prevalence of CD [48]. Kanthi et al. stated that EMA IgG1 have been used for diagnosing celiac disease, especially in IgA-deficient patients [44]. EMA has also been detected in other diseases. For example, Damoiseaux et al. detected IgA EMA presence in 86.5% of 37 patients with biopsy-confirmed CD [27]. Moving on to Crohn's disease, Tursi et al. only found anti-endomysial antibody (EMA) in 4 out of 27 patients with Crohn's disease (14.81%) [33].

### **2.6 Anti-Saccharomyces cerevisiae antibodies (ASCA)**

Anti-S. cerevisiae antibodies (ASCA) are autoantibodies targeted toward the mannose residues on unicellular fungus *S. cerevisiae* (S. cerevisiae) [49]. Several studies associated those antibodies with GI autoimmune diseases. For instance, Shor et al. detected high levels of IgA ASCA in 16 out 83 patients with Crohn's disease patients, while only 2 of the 198 healthy controls had positive ASCA titers (19.3% vs. 1%; P = 0.000). In addition to IgA ASCA, the high titers of IgG ASCA were detected in 23 out of 83 patients with Crohn's disease, while only one healthy control of the 194 had a positive IgG ASCA titers (27.7% versus 0.5%; P = 0.000) [28]. Even in a pediatric population, El-Matary et al. detected a correlation between both ASCA IgA and IgG titers and clinical Crohn's disease activity [50]. Furthermore, Smids et al. detected IgA ASCA in 23% of Crohn's disease patients and only 3% of UC patients [51]. However, ASCA is not a specific marker for Crohn's disease, since it was also detected in patients with CD. Kotze et al. tested patients with Crohn's disease, and 3 groups of CD patients, including those at time of diagnosis, patients that follow gluten-free diet, and lastly, others who admit transgression in their gluten-free diet. Kotze et al. found statistically significant levels of ASCA IgA in patients with Crohn's disease, in addition to patients with CD at diagnosis and others that admit transgression in their gluten-free diet. Furthermore, ASCA IgG was also positive in Crohn's disease and in all groups of CD. They concluded in their study that ASCA detection is associated with the inflammation of small intestine [52]. Moreover, it was also detected in CD. For example, Damoiseaux et al. detected ASCA presence in 16 of 37 patients with biopsy-confirmed CD [27]. Also, Granito et al. detected IgA and/ or IgG ASCA in 59% of 105 subjects with CD at the time of diagnosis. In their study, they did not find any significant correlation between ASCA positivity and severity of small intestinal mucosal damage. Furthermore, they tested 93% of revaluated coeliac patients again after they had followed a gluten-free diet and did not detect IgA ASCA. Instead, 83% of the subjects maintained their IgG ASCA reactivity [53]. ASCA can even help in predicting the development of CD in patients before they present with symptoms [53, 54]. Granito et al. called them the "potential/ silent" CD and suggested diagnosing them with CD in case of positive serological markers (EmA and tTG) and typical HLA predisposing genotype (DQ8 or DQ2) [55]. In a study involving a Korean cohort, Choi et al. detected a positive rate of ASCA in 44.35% of patients with intestinal Behcet disease, compared to 8.8% in

healthy control subjects [56]. Furthermore, Cheng et al. concluded in a metanalysis of 9 studies, that there is a strong correlation between ASCA and gastrointestinal Behcet disease, specially ASCA-IgG (OR = 5.50 (95% CI 2.58 to 11.55), p = 0.000) and ASCA-IgG + IgA (OR = 5.36 (95% CI 1.40 to 20.45), p = 0.014). The study also found that in gastrointestinal Behcet disease the positivity rate of ASCA was higher significantly than that in UC: IgA (OR = 2.13 (95% CI 1.30 to 3.50), p = 0.003); IgG + IgA (OR = 2.19 (95% CI 1.03 to 4.66), p = 0.042); IgG/IgA ((=2.03 (95% CI 1.30 to 3.17), p = 0.002). Moreover, the frequency of ASCA-IgG was found to be significantly higher in patients with Crohn's disease than in those with gastrointestinal Behcet disease (OR = 0.48 (95% CI 0.28 to 0.83), p = 0.009, [57]. This shows that ASCA plays a significant role in pathogenesis of autoimmune gastrointestinal diseases. ASCA have also been detected in other diseases. Shor et al. also detected IgG ASCA in Crohn's disease, Graves' disease, SLE, vasculitis, and cryoglobulinemia patients [28].
