**2. The autophagy process**

Eukaryotic cells digest their cytoplasmic content through different processes that come under the general term autophagy (from the Greek words *auto* meaning "self" and *paghein* meaning "to eat"). Autophagy includes different forms of digestive pathways such as macroautophagy, microautophagy, chaperone-mediated autophagy, and noncanonical autophagy. Generally, the term autophagy refers to macroautophagy, and this process depends on specialized autophagy-related proteins (ATGs) to digest different targets, such as organelles, large aggregates of proteins, and microorganisms. Autophagy also plays a key role in direct microorganisms and virus clearance, in the control of inflammation through the inhibition of inflammasome, in antigen presentation, in regulating T cell homeostasis, and the secretion of immune mediators [6]. It is worth nothing that autophagy impairment plays a crucial role in several diseases, in particular proteopathies, such as Parkinson's [7] and Huntington's disease [8].

As analytically described by Codogno et al. [9], there are four types of autophagy:


To date, several autophagy-related genes (*ATG*s) have been described and exert a finely coordinated function at different stages of the pathway. It is widely accepted that autophagy consists of six sequential steps: (1) initiation; (2) nucleation or phagophore formation; (3) ATG5-ATG12 conjugation, interaction with ATG16L, and multimerization at the phagophore; (4) LC3 processing and insertion into the nascent autophagosome; (5) capture of random/selective targets for degradation; and (6) fusion of the autophagosome with the lysosome.

**57**

disease complications.

**4. Non-dietary therapies**

*The Emerging Role of the Autophagy Process in Children with Celiac Disease: Current Status…*

Autophagy plays a crucial role in the pathogenesis of several autoimmune diseases. In particular, in Crohn's disease, an inflammatory bowel disease is caused by a combination of environmental, immune, and bacterial factors in genetically susceptible individuals. It has been demonstrated that genetic polymorphisms in the *ATG16L* and *IRGM* autophagy-related genes lead to a strong predisposition for the development of Crohn's disease [10]. Despite this significant association, the role played by the ATG16L protein in the disease pathogenesis is still under debate. In particular, the ATG16L protein is known to suppress the inflammatory process, as demonstrated in Atg16L-deficient mice, which were find to be highly susceptible to colitis induced by dextran sulfate sodium. Subsequently the symptoms developed by these mice were effectively treated with injections of anti-IL-1β and IL-18 antibodies [11]. Recently, nucleotide polymorphisms within the key regulatory autophagy gene *ULK1* have been shown to increase susceptibility to Crohn's disease, thus demonstrating that autophagy might contribute to the pathogenesis of this disease [12]. Similarly, the ATG5 protein, another essential component of the autophagic machinery, is implicated in the development of systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis (RA). SLE is an autoimmune disease in which the patient's immune system attacks healthy tissues. Different single nucleotide polymorphisms (SNPs), identified near and within the *ATG5* locus, are associated with SLE initiation and/or development, although the pathogenetic mechanisms involved are still unknown. In another study, it was demonstrated that T cells in SLE patients are autoreactive and autophagy promotes their survival and contributes to their persistence in autoimmune conditions [13]. MS is a demyelinating disease that affects the brain and the spinal cord. Changes in the expression of the ATG5 protein correlates also with immune-mediated myelin injury in MS-derived mice and in affected patients. Specifically, ATG5 is overexpressed in circulating T cells of relapsing–remitting MS patients compared with healthy controls. ATG5 altered expression seems to extend T cell survival and proliferation during active disease; moreover, ATG5 expression profiles correlate with the severity of the disease in mice models [14]. In RA, anti-citrullinated protein antibodies are the most powerful biomarkers in the diagnosis of this disease. During inflammation, the arginine residues of self-proteins are converted to citrulline (a nonessential alpha amino acid) by the peptidylarginine deiminase enzyme, in a process known as citrullination, thus leading to an altered immune response. Presentation of these peptides is blocked after treatment with 3-methyladenine, an autophagy modulator drug, or by reducing ATG5 protein expres-

*DOI: http://dx.doi.org/10.5772/intechopen.80692*

**3. Autophagy and autoimmune diseases**

sion, confirming a key role of autophagy in RA pathogenesis [15].

treatment (versus gluten-free diet) or GFD adjuvant.

is to offer a better quality of life to celiac patients.

The clinical spectrum of celiac disease is broad, and often it may be not so easy to discern between poor compliance, difficult acceptance of therapy, or presence of

It is important to emphasize experimental therapies, in terms of alternative

Recent advances in the "non-dietary" treatment of CD include engineering gluten-free grains, degrading immunodominant gliadin peptides, decreasing intestinal permeability, and inducing oral tolerance to gluten with a therapeutic vaccine.

As outlined above, there are many reasons behind the need to identify new therapeutic options for celiac disease, especially non-dietary therapies. The purpose *The Emerging Role of the Autophagy Process in Children with Celiac Disease: Current Status… DOI: http://dx.doi.org/10.5772/intechopen.80692*
