**4.1 Achalasia**

Achalasia is a rare autoimmune motility disorder that is caused by the degeneration of the myenteric neuronal esophageal plexus that consequently results in an aperistalsis and impaired incomplete relaxation of the lower esophageal sphincter (LES) and ineffective contractions in the esophageal body [53]. In the distal esophagus and the lower esophageal sphincter, achalasia is characterized by a functional loss of myenteric plexus ganglion cells or chronic ganglionitis [54]. Since there is no known cause for the initial loss of inhibitory neurons in individuals suffering from achalasia, it could be considered an idiopathic disorder [55]. Nevertheless, the onset of neuronal degeneration may be caused by an indolent viral infection such as herpes simplex virus 1 (HSV-1), measles, and human papillomavirus have been proposed as potential antigens. Evidence indicates that HSV-1 DNA has been detected in esophageal tissue, and that isolated T cells from achalasia are monoclonal in nature and that they proliferate and release cytokines upon exposure to HSV-1 antigens [56, 57]. It is possible that this is since HSV-1 is a neurotropic virus with a predilection for squamous epithelium, which causes selection loss of enteric neurons in the esophagus. Nevertheless, this theory is not entirely accurate, as HSV-1 DNA was also frequently detected in control individuals' esophagus [58]. Thus, it might be argued that HSV-1 only triggers persistent immune activation and subsequent loss of enteric neurons in individuals with genetically suspected hosts [59]. In patients who have an immunogenetic variation, viral infection may trigger a disordered immune reaction. Achalasia

*Autoimmune Diseases of the GI Tract Part I: Etiology and Pathophysiology DOI: http://dx.doi.org/10.5772/intechopen.106184*

may also be caused by muscular eosinophilia in some cases. It has been demonstrated that such inflammatory processes decrease, gradually destroy, or eventually eliminate the esophageal myenteric plexus (MP) [60]. It has been found that achalasia is associated with several genes and immunological markers including Interleukin-10 promoter polymorphism [61] and Interleukin 23 receptor [62], HLA class II gene polymorphisms [63], KIT (KIT proto-oncogene, receptor tyrosine kinase) [64, 65], and vasoactive intestinal peptide receptor 1 [66, 67], among others.

Achalasia is reported to have an annual incidence of 1 per 100,000 individuals worldwide [68]. There is an equal frequency of achalasia in men and women when they are adults [69] and among different ethnicities [70]. Other autoimmune diseases are prevalent in achalasia patients such as diabetes. Progressive dysphagia to both solids and liquids is the hallmark symptom associated with a diagnosis of achalasia [71]. In addition, regurgitation of undigested food, respiratory symptoms such as nocturnal coughs, recurrent respiratory infections, pneumonia, chest pains, and loss of weight may occur [58, 72, 73]. According to conventional manometry, the characteristics of achalasia are as follows: (1) absence of peristalsis, sometimes with increased intra-esophageal pressure associated with the stasis of food and saliva, (2) The LOS remains partially relaxed on deglutition (residual pressure > 10 mm Hg), and (3) the LOS often exhibits a raised resting tone.

### **4.2 Atrophic autoimmune gastritis (AAG)**

Atrophic autoimmune gastritis (AAG) is an immune-mediated disorder characterized by nonspecific symptoms [74–76]. A diagnosis of AAG is confirmed by the presence of circulating antibodies against the adenosine triphosphate enzyme H/K (parietal cell antibodies, PCA); the same antibodies are also found against anti intrinsic factor (anti-IF) [77]. In AAG, the native gastric glands within the mucosa gradually disappear or shrink over time [78]. Consequently, mucosal atrophy occurs sparing the antrum and extensive pseudopyloric or intestinal metaplasia occurs [79]. There may be involvement of both the antrum and corpus, but the corpus only has apparent functional and clinical consequences [80]. Multiple modifications may precede atrophy, including focal atrophy, lymphoplasmacytic infiltrate in the lamina propria, parietal cells pseudohypertrophy, and enterochromaffin-like (ECL) cell hyperplasia. It has long been recognized that AAG, as well as other autoimmune disorders, tend to cluster in families, which could reinforce the genetic component of disease. Through using mouse models, it has been possible to discover AAG susceptibility genes (Gasa 1, 2, 3, and 4) on chromosomes 4 and 6 and H2 region, three of which are located on the same locus as non-obese diabetic mouse diabetes mellitus susceptibility genes [12, 13]. The prevalence of autoimmune atrophic gastritis is relatively low. It may be attributed at least in part to the underdiagnosis of *Helicobacter pylori*-induced gastritis in many cases, and the absence of clinical manifestations in the early stages of the disease [81]. The incidence of AAG is three times higher in women than in men [82]. There is an age-dependent increase in the prevalence of AAG of 2% [83]. AAG occurs in 25 out of every 100,000 people each year. Patients with AAG have 3−5 higher risks of developing other autoimmune diseases, such as oral erosive lichen [84], myasthenia gravis [85], vitiligo [86], diabetes mellitus (DM) [87], autoimmune thyroid disease [88], and Addison's disease [89]. Patients are usually diagnosed in advanced stages when the disease is irreversible or threatening symptoms have occurred, including abnormalities such as pernicious anemia, and neurological or gastric oncological complications [90–92]. The symptoms of AAG appear slowly and may

remain asymptomatic for a long period of time. Symptoms of the disease range from mild weakness to severe psychological manifestations such as paranoia (megaloblastic madness). Pernicious anemia is the main clinical manifestation of AAG. A common symptom of iron deficiency is fatigue, restless legs, brittle nails, hair loss, impaired immune function, and poor wound healing. Iron deficiency is independent of and precedes anemia. Shortness of breath, dizziness, tachycardia, and lightheadedness are some of the symptoms of anemia (regardless of the cause) [93]. The presence of AAG can be asymptomatic or cause symptoms, depending on the level of atrophy that affects the absorption of vitamin B12 or other substances, such as folate and iron. Deficiency in vitamin D can develop over a long period of time, and patients may not show symptoms until reserves are exhausted. The diagnosis of AAG can be done through serological tests, endoscopy, and histopathology biopsy. Antibodies that are used for serological tests such as APCA, anti-ID antibodies, and anti-*H. pylori* antibodies (anti-HP-IgM and anti-HP-IgG). AAG patients who have oxyntic gland atrophy often have elevated levels of gastrin (including Gastrin-17) and it is measured in many cases to confirm the diagnosis. Endoscopy has been often used in the diagnosis, although it has many limitations such as low sensitivity and specificity. There is, however, a golden rule when it comes to diagnosing AAG through endoscopy, which is the absence of normal capillaries resembling honeycombs and collecting venules in regular shape and appearance. Biopsy histology is the most reliable method. Before oxyntic mucosa is lost completely, AAG appears as a series of features: (1) infiltrated lymphocytes and plasma cells in lamina propria, (2) focal atrophy of oxyntic mucosa along with SPEM or IM, (3) pseudohypertrophy of parietal cells and (4) hyperplasia of the ECL [93].

## **4.3 Celiac disease**

Celiac disease (CD) is a multisystem disorder characterized by enteropathy [94]. Genetically predisposed individuals develop CD when the immune system reacts inappropriately to a T cell-mediated immune response [95]. Almost any organ system can be affected by celiac disease, approximately half to two-thirds of patients suffer from extra-intestinal symptoms; some studies claim that they may be more common than gastrointestinal symptoms [96]. CD patients can be classified into two categories symptomatic and asymptomatic. Asymptomatic CD patients are those who at the time of their initial diagnosis of CD do not exhibit any symptoms even if they are directly questioned about their condition. The term symptomatic CD refers to those individuals who demonstrate clinically visible gastrointestinal and/or extraintestinal symptoms related to gluten consumption [97, 98]. Symptomatic celiac disease can be further divided into classical and nonclassical celiac disease. Some genes have been involved in CD. It is often considered that CD can be viewed as a polygenic disorder that involves both major histocompatibility complex MHC (human leukocyte antigen [HLA]) and non-MHC genes [99]. Currently, it is well-established that six MHC and 39 non-MHC loci, as well as several independent genetic variants, contribute to disease risk. The genetic variants are responsible for roughly 31% of CD heritability, and the MHC is responsible for 25% [100]. In CD, HLA-DQ2 and -DQ8 are key genetic markers, and an autoantigen is involved (tissue transglutaminase 2: tTG2). Approximately 25–35% of the general population has HLA-DQ2/DQ8 with only 3% of these individuals developing CD [101]. Globally, CD affects between 0.6% and 1% of the population [102]. CD affects both children and adults. The mean age at the diagnosis is 38, but 20% of the patients are diagnosed over the age of 60 [103]. Women however are diagnosed
