Are autoimmune diseases considered autoimmune epithelitis?

Epithelial tissues such as those in the skin and mucus or glands (endocrines and exocrines) are a frequent target of the immune response, which is responsible for the natural history and development of autoimmune diseases. Therefore, it is not surprising that autoimmune thyroiditis, type 1 diabetes, and Sjögren’s syndrome (3 of the most frequent autoimmune diseases) are organ specific diseases, and that those organs have a purely epithelial parenchyma (Table 1) (1). Moreover, a great number of autoimmune diseases have an epithelial component as is the case with psoriasis, pemphigus, autoimmune hepatitis, immune glomerulonephritis, autoimmune cholangitis, ulcerative colitis, and Crohn’s disease.

Table 1

Most relevant histological features of major autoimmune diseases.

If the fact that the epithelium is the tissue present on body surfaces is considered, and at the same time, that these tissues are the boundary between the exterior and the entrance for microorganisms, it will be obvious that epithelial tissue must play an important role in the discrimination between foreign and self molecules. Therefore, this tissue is essential for the initial immune response to what is foreign and the immune tolerance induction against self molecules. All these roles put the epithelium at risk as a target for autoimmune attack.

Hence, this chapter will describe some structural and functional characteristics of epithelial tissues which convert them into undeniable targets for autoimmune reactions with the subsequent development of autoimmune diseases.

Epithelium as the most representative of all tissues present within the animal kingdom

Evolutionarily speaking, once unicellular eukaryote microorganisms (protozoa) evolved to multicellular microorganisms (metazoan), a single cell evolved to generate one or more layers composed of various cells which make up the covering epithelial tissue. Since then, epithelium has been the only tissue component to serve as an interface between the inner (self organisms) and the exterior (foreign organisms). Consequently, when these organisms evolved to more complex ones, the epithelium started to generate other tissues and with them create different organs (parenchyma) and the systems-organs known in the most evolved superior animals (mammals).

Everything mentioned above takes place during human ontogeny when two purely epithelial cells - the oocyte and spermatozoon - fuse into one: the zygote. This cell will then generate a blastula, gastrula, embryoblast, and the trophoblast. All of these are strictly epithelial in nature.

The embryoblast, which will give rise to the new human being, will take the shape of a bilaminar germ disk and then a trilaminar one, thus generating from the ectoderm an endoderm and, finally, a mesoderm. All of the above supports the idea that the epithelial cell is the source of a new human being because it is the primary representative and participant in the development of all body tissues from the perspective of the structural composition (phenotype) (Figure 1).

Figure 1

Phylogeny and ontogeny of four basic tissues from epithelial tissue.

Epithelium as the entrance point for microorganisms

The majority of microorganisms that infect an organism gained access through body surfaces such as skin and mucus. All these surfaces are covered by cell layers of epithelial tissue called covering epithelial tissue or simple epithelium. Some, like the skin, are resistant to foreign attack because they consist of various cell layers which originate in the lowest layer (the stratum basal or germinativum or stem cell. These cells proliferate, differentiate, and migrate to the surface where they finally suffer apoptosis in which they become the stratum corneum and shed, thus relieving the skin of many noxious substances that adhere to the external surface. In terms of evolution, the high rate of cell change in these tissues is a mechanism of protection from toxic substances, but also explains the harmful conseuqences of epithelial neoplasias such as carcinomas and adenocarcinomas.

In contrast, other tissues such as distal respiratory mucus are more vulnerable to attacks of microorganisms because they only have a single layer of simple columnar epithelial cells or, as in the case of alveoli, a layer of simple squamous epithelium. These types of epithelium do not easily stop the invasion of microorganisms. That is why distal respiratory tract and mucus infections especially are more frequent than cutaneous ones.

On any of these biological surfaces where there actually are commensal microorganisms, self and foreign antigens live together, most of the time, in homeostatic conditions. There, rather than discerning between self and foreign, epithelial cells eliminate whatever is hazardous or dangerous through the expression of pathogen associated molecular pattern receptors/danger associated molecular pattern receptors (PAMP/DAMP) as TLRs (Toll like receptor), NLR (Nucleotide-binding and oligomerization domain-NOD-like receptors) receptors, and RLR (RIG-I-like receptors) (2) (Figure 2). These receptors recognize pathogen self molecules such as lipopolysaccharides (LPS), peptidoglycans, nucleic acids, etc. and initiate a biological process which, with the presence of microbial antigens, will stimulate dendritic cells (DC) to mature them and start the immune response.

Figure 2

Pathogen associated molecular pattern receptors/danger associated molecular pattern receptors (PAMP/DAMP) in epithelial cells.

The expression of the PAMP/DAMP receptors by the epithelial cells has evolved from invertebrate organisms because they lived and interacted with different classes of pathogens. The above suggests that in addition to being an entrance point for microorganisms, the epithelium has the ability to differentiate between self and foreign. Hence, just as the epithelium functions as an entrance for the various microorganisms, it is a target of attack. In response to the pathogens, it releases alarmins such as IL-18, IL-33, and IL-1 beta, which are members of IL-1 family. All of them are related to the induction of Th1, Th2, and Th17 response respectively. Other key cytokines in the epithelial response that coordinate the immune response are IL-25 and TSLP, which points it toward a Th2 pattern. Epithelium has anatomically kidnapped antigens

Epitheliums are in limbo between the exterior and the inner of the body. This means that although they are an integral part of the body:

• They are separated from it by a basal membrane - specialized structural-functional underlying connective tissue - which attaches it to these tissues. This membrane is also a selective physiochemical barrier in processes such as diffusion.
• A lot of epithelial cells have a rich, apical glycocalyx which is also a selective physiochemical barrier.
• A lot of epithelial cells produce biomolecular glycoprotein interfaces (e.g., mucins from mucociliary barrier) and/ or lipidics (fat, surfactant) which also behave as an efficient physiochemical barrier.
• They have a high tissue replacement rate in comparison to other tissues (apoptosis). As a result, this replacement functions as a barrier that prevents the perpetuation of potential toxins.
• Their waste products go directly (except for, obviously, endocrine epithelium) to a corporal surface, i.e., the exterior.
• There is a lack of blood and lymphatic vessels.
• They are fed by diffusion from connective tissues with vessels and its drainage is to the exterior of the organism. Therefore, a lot of antigens present within epithelial tissue do not usually go into lymphatic circulation unless trauma or inflammation has occurred. These antigens that are present within the tissue and to which the lymphocytes moving through the blood and lymphoid organs are usually not exposed are called anatomically kidnapped antigens. They abound within epithelium, and they are in greater quantities within barriers which hide them even more as is the case with the eye, testicles, etc.

Unlike other epithelial tissues, endocrine organs do not drain their products to the exterior but rather into the blood. Furthermore, once their cells die by physiological apoptosis, they must be cleaned out by neighboring cells or by macrophages and DC which are present within the surrounding connective tissue. Therefore, in the case of tissular damage, anatomically kidnapped antigens are released, are recognized by antigen presenting cells, and travel to secondary drainage lymphatic tissues (e.g., lymphatic tissue associated with skin and mucus - SALT, MALT-, and lymph nodes), where they initiate the immune response. This explains why autoimmune diseases are more frequent in endocrine organs (Table 1).

The majority of organs and tissues affected by autoimmune diseases have fenestrate capillaries

All the endocrine organs, e.g., renal nephron, skin, synovial joints, and the liver have capillaries characterized by the presence of fenestrate-pores, which allow large molecules to cross through to the tissue to a greater or lesser degree (Table 1). This crossing is dependent on pore size and hemodynamic factors (rheological ones) such as the flow and intravascular pressure. The presence of these fenestrae makes it easier for molecules and viral or microbial particles to cross from the blood to the tissue. Additionally, during all inflammatory processes cytokines, chemokines, and other inflammatory molecules travel by lymphatic and blood vessels toward arterial circulation and from there to different organs and systems (3,4).

These molecules reach target organs involved in acute phase response such as the hypothalamus, liver, adipose tissue, muscle, bone, and organs with fenestrated capillaries, which are necessarily involves the inflammatory process. It is well known that viral infections that cause significant viremia, are usually associated with joint inflammation (reactive arthritis) manifested as arthralgia. Likewise, all viral infection induces interferon (IFN) production, which will disseminate by blood towards distant organs where it can start the inflammatory process (5).

Epithelial tissues are the ones which suffer the most apoptosis

Apoptosis - a form of programed cell death - (See chapter 13) is a process in which cells are eliminated whether because they have accomplished their functions, because it is a part of the functional cycle of an organ, because they are part of a transitory structure or even because they are the target of stress or infection. That is how through apoptosis interdigital membranes are eliminated during embryo development, endometrium is released during the menstrual phase, ovarian follicles suffer atresia, spermatozoa get older within the sperm tract, injured hepatocytes are released by toxins or pharmaceutical drugs, the effector lymphocytes are eliminated once they have eliminated their antigens, and the non functional lymphocytes depleted within the thymus. In other words, cells entering the cell cycle are the ones with a higher chance of suffering apoptosis. Therefore, epithelial tissues and immune system organs suffer more apoptosis than others (6).

Apoptosis is a very important source of auto-antigens which under normal conditions do not unleash immune responses, but under stress conditions (inflammation, trauma, and oxidative-reductive imbalance) may be a source of PAMP/DAMP and modified auto-antigens (e.g., citrullination) which would induce an immune response. It has been convincingly proven that the most important immunogen in Systemic Lupus Erithematosus (SLE) is nucleosome (structure for chromatin storage) which is released by epithelial cells suffering physiological apoptosis as their life cycle ends. Under normal conditions, the nucleosome is not exposed to the immune system because apoptotic cells are easily phagocytised and cleaned out by macrophages and DC. A similar process happens in Sjögren’s syndrome and its known antigens (7,8).

However, in the genetic background of SLE, a defect in the physiological phagocytosis makes the macrophages insufficient under conditions of intense apoptosis. That being the case, the apoptotic molecules and their structures are exposed to the oxidative environment within the tissue and to a variety of post-traductional modifications. It is during this period that the nucleosomes are exposed to the immune system and thus produce anti-DNA-protein antibodies (e.g., histones) which will be deposited by electrochemical affinity within the tissue, particularly within the glomerular basal membrane of the kidney. All these together in addition to alteration within the signaling pathway (e.g., PTPN22) guarantee that this recognition will be pathologically effective and be perpetuated (9,10).

According to this, SLE is an autoimmune disease directed at first towards nucleosomes which are produced and released by epithelial cells in constant replacement and regeneration. Therefore, we should ask ourselves if SLE is a purely epithelial disease?

It is very likely that the explanation for the higher frequency of autoimmune diseases such as SLE is related to what was mentioned above since women have more epithelium tissue (breast glands and endometrium) which is highly sensitive during the menstrual cycle to the action of hormonal oscillations. Furthermore, the endometrium expresses Vitamin D receptors (VDR), which are deregulated by the presence of microbiota, and this mechanism is involved in the immunological deregulation associated with the autoimmune response (11).

Epithelium as a target of viral infection

Viruses as obligatory intracellular parasites require a host that frequently enters the cell cycle for replication and protein assembly. In other words, viruses have a trophism for highly cyclical cells.

Viruses have evolved to enter their targets and the best target for them is the surface epithelial cells. Therefore, epithelial cells have frequently become hosts for viral infection as is indicated by the expression of epithelial receptors for viruses and the high frequency of viral diseases compromising the epithelium. Moreover, the presence of viruses within epithelial cells is not innocuous and, in most cases, entails programed apoptotic death for the cell. In both situations, infected cells produce cytokines and chemokines, e.g., type I IFN which in addition to attracting inflammatory cells, activates them to initiate the immune response. Viral infection is an important stimulus for the recruitment of plasmocytoid dendritic cells (pDC) which are the main source of IFNα. The interferon produced within the infection sites and in the plasma by pCD generates systemic effects that cause tissular damage and the expression of anatomically kidnapped antigens. Naturally, the main targets of interferon action are the epithelial tissues and those with fenestrated capillaries. As a consequence, new therapeutic molecules involving cytokines such as IFN have been associated with an increase in the frequency of autoimmune diseases as was clearly demonstrated by the association between IFNα used to treat hepatitis C and the higher risk of autoimmune thyroiditis (12,13). pDC population is under strict regulatory control, and this control includes negative feedback mechanisms managed by self IFN type I (14).

Finally, considering what was mentioned above, the participation of pDCs as mediators between viral infection and autoimmune disease is now becoming recognized in the pathogenesis of various autoimmune diseases, e.g., Sjögren’s syndrome (12,13).

Viral infection associated with autoimmune disease

A lot of autoimmune diseases have been related to viral infections as is the case with rheumatic arthritis, the Epstain Barr virus (Herpes virus type 4), type 1 diabetes, the Coxsackie virus, Sjögren’s syndrome, Hepatitis C, and the association between this last virus and autoimmune thyroiditis (See chapter 19).

Viruses not only produce tissue damage and inflammation but they also induce the expression of extracellular antigens and raise the presentation of antigens on the surface of infected cells. This converts infected cells into targets for the IFN, lymphocytes T CD8, and natural killer (NK) cells. This cell lysis not only raises auto-antigen exposure but also the exposure of cryptic epitopes because of the use of the granzyme B enzyme, which is usually not used during the conventional processing of antigen, by the professional APC. That is why, viruses produce inflammation and the subsequent production of co-stimulators which expose and modify the conventional processing of intracellular auto-antigens with the subsequent production of cryptic epitopes (15,16).

Epithelial cells act as antigen presenting cells

Nucleated cells express molecular complexes within their membrane produced by peptides created by the proteolitic degradation of their intracellular proteins and histocompatibility type I molecules (HLA). These HLA-antigen complexes avoid attacks by NK cells and, at the same time, they allow CD8 T lymphocytes to review the intracellular component in search of possible intracellular microbial antigens. Strictly speaking, all cells act as antigen presenting cells, but the name, professional antigen presenting cell, is reserved for T lymphocyte accessory cells which in addition to presenting intracellular antigen in HLA I, phagocytose, process, and present extracellular antigens in HLA II as well as in HLA I (cross-presentation). These cells are capable of expressing co-stimulator molecules such as B7 family molecules (e.g., CD80, CD86) and the tumoral necrosis factor family and its receptors (TNF/TNFR: CD40/CD40L system and OX40/OX40L system) which ensure the activation of T lymphocytes. Therefore, the title of professional presenting cell is reserved for CD, macrophages, and B lymphocytes acting as professional APC during primary and secondary immune responses. Within this context, epithelial cells (including endothelial cells) acquire an important role because they not only express HLA I constitutively but also HLA II under cytokine action, and furthermore, the co-stimulator molecules of B7 family and TNF/TNFR family convert them into authentic antigen presenting cells (17-27).

In the majority of organs which are primary targets for autoimmune disease, molecules related to antigen presentation in parenchyma epithelial cells have been identified. With an APC behavior, these epithelial cells reinforce the stimulation of the immune system, but at the same time they collaborate with the perpetuation of the established autoimmune disease (17,19-25,27).

Epithelial cells select the repertoire of T lymphocytes within the thymus

The thymus is an organ which remains a major mystery. The epithelial nature of its stroma comes from its ectoderm and endoderm, embryo layers which are the origin of a major amount of diversity of diversity of epithelia (28-30). When the precursors? of T lymphocytes reach the thymus from the bone marrow (common lymphoid progenitor stem cells -CLP), they initiate the expression of antigen receptors (TCR). The TCR is a membrane heterodimer which enables the lymphocytes to recognize HLA-peptide complexes expressed on the antigen presenting cell surfaces (Figure 3). The genes codifying for both proteic chains of the receptor have evolved through the genetic duplication mechanism which has allowed them to diversify in mammals and reach approximately 1018 different specificities. This huge diversity within the TCR surpasses the accumulated polymorphisms within HLA molecules by a very wide margin. The HLA in human beings do not surpass 2,000 and, in each individual, they reach a maximum of 22 (2 HLA A, 2HLA B, 2HLA C, 4 HLA DQ, 4 HLA DP, and 8 HLA DR). If we add to this the fact that every HLA molecule has a limited ability to attach to antigenic peptides, that it will not surpass 2,000 per molecule, it is easy to calculate that the majority of lymphocytes generated within the thymus cortex will not have any functionality in every individual. This means there are many more lymphocytes with their respective TCR than HLA-peptide complexes expressed in presenting cells (31-34). This indicates a need for positive selection to choose from this huge potential repertoire only those lymphocytes that are capable of seeing peptides attach to HLA molecules on the surface of their own presenting cells (20,26). This job is done by epithelial cells from the cortex (cTEC) of the thymus, which process their own constitutive proteins and present them together with HLA I and II molecules on their surface. Once the intrathymic T lymphocyte expresses its receptor, it activates a programed cell death mechanism which will be carried out in 3 days unless the cell interrupts it. This will only occur if the lymphocyte presents a receptor that is able to interact with the peptide-HLA complexes expressed by the cTEC (Figure 4.). This process, which is called positive selection, rescues functional lymphocytes for every individual from death because it has the ability to recognize peptides derived from epithelial antigens. In other words, the entire selected repertoire is autoimmune in nature and directed against self antigens or against epithelial antigens, even when their avidity is moderate. Once the positively selected cells go to the medulla, they run into other presenting cells—medullar epithelial cells (mTEC) and DC. The peculiarity of the former is that they ectopically express specific extrathymic antigens of the tissue due to the expression of protein encoding by AIRE gen (autoimmune regulator). This protein produces complexes with other proteins (AIRE nuclear body) for diverse functions and, they interact with promoter regions of various genes which, under normal conditions, are only expressed in tissues or organs other than the thymus (promiscuous antigen expression) (36,37).

Figure 3

Peptide presentation to T cells through the interaction of HLA-peptide complex to the TCR.

Figure 4

Thymocyte selection in the thymic cortex. cTEC: epithelial cells from the cortex of the thymus.

Thymic processing also has its own particularities. Therefore, within epithelial reticular thymic cells from the cortex a large variety of immunoproteosomes (thymoproteosome). The immunoproteosome presents variations in its sub-unitary constitution in its quaternary structure (35). The proteosome presents 3 main catalytic activities: as a trypsine, chemotrypsine, and caspase. In the thymoproteosome, the structural variation for an alternative beta subunit (β5t) diminishes chemotrypsine activity and conditions the differential proteolytic catalysis of the antigenic epitopes

In addition, the DC reaches the thymus from the blood stream and peripheral tissues. They may or may not carry antigens captured from extrathymic tissues. Once they locate in the thymic medulla, they can phagocytose antigens reaching the thymus from peripheral tissues. These antigens are then processed and presented to the previously selected medullar thymocytes within the cortex. This second interaction between thymocytes and thymic APC seeks to eliminate auto-reactive T lymphocytes with high affinity directed against auto-antigens within the medulla (negative selection) or differentiate them from T regulatory lymphocytes (Tregs) which, once they leave the thymus and interact with self auto-antigens, suppress any chance of immune response against them (Figure 5.) (30-32,34).

Figure 5

Thymocyte selection in thymic medulla. mTEC: medullar epithelial cells.

Considering the fact that the most widely accepted thymic model selection is the avidity model. This model demonstrates

Note that the most widely accepted thymic model selection is the avidity model. This model demonstrates the average avidity of the different interactions between HLA-peptide complexes and the thousands of TCR (because one APC can present up to 100,000 HLA molecules with 200 different peptides). A positive selected lymphocyte in the cortex can recognize different epithelial peptides with different affinities (low, moderate, or high) due to the low or moderate avidity (Figure 4) (38). The low, moderate or high affinity auto-reactive thymocytes for epithelial cortical antigens go through the thymic medulla. Within the medulla, the affinity of the interaction between new HLA-peptide complexes and the TCR from medullar thymocytes is modified by changing the presentation of cortical peptides to medullar ones. Therefore, within the medulla there are auto-reactive lymphocytes of low, moderate, and high affinity for the new peptides brought to the thymus or expressed ectopically for mTEC (31-35).

DC cells from the thymus -particularly those interacting with thymic reticular epithelial cells from the Hassal corpuscles - convert some of these cells into Treg cells (CD4 and CD8) expressing the FOXP3 gen and the other cells are eliminated by negative selection (Figure 5): Thus, the autoimmunity risk is reduced (39-43).

In summary, all lymphocytes migrating from the thymus to the periphery are auto-reactive to epithelial antigens. Eventually, they may react to other self antigens or foreign ones that were not expressed within the thymus. Therefore, self is epithelial and foreign is extrathymic. Deregulation of high affinity auto-reactive lymphocytes on the periphery generates a risk of loss of tolerance to self antigens, which are primordially epithelial.

An indirect conclusion of all this is that it is not at all unusual for a specialized epithelial cell in the thymus to respond to the selection profile of T lymphocytes interacting with epithelial cells on the periphery. It appears that this process is not random!

The epithelium is frequently compromised by autoimmune polyglandular syndromes

Based on what was discussed above, it is easy to speculate that an disruption in the production of regulatory cells, for example, in IPEX (Immunodeficiency, Polyendocrinopathy, and Enteropathy, X-Linked Syndrome) (OMIM304790) or in the promiscuous thymic expression of antigens such as in APECED (Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy) (OMIM240300) due to mutation in the FOXP3 genes (forkhead box P3) and AIRE respectively will translate into an increase in the lifespan of high affinity auto-reactive T lymphocytes. These can interact with non expressed peptides in the thymus that were positively selected based on their interaction with cortical epithelial antigens. All of the above explains why the compromise of endocrine epithelial organs is frequently found in these syndromes (24,44,45).

Epigenetics and autoimmunity: Is the epithelial cell an epigenetic target? What are the implications of that?

There is more and more consistent evidence of how environmental modulation can alter gene expression patterns, thus altering the cell phenotype. This dynamic process is due to:

• Chemical modification of chromatine histones (acetylation, methylation, phosphorylation, ubiquitination, sumolyation, poliACP-ribosylation, biotylation, deamination, butylation, N-formylation, and prolinic isomerization).
• Methylation or demethylation of gene promoters, in cytosine nucleotide residue (in the context of CpG dinucleotides) or in adenine residue.

These chemical modifications are redundant in the differential inhibition or expression of genes, including in the filial progeny which is called transgenerational heritage (46). From the same genotype, due to epigenetic mechanisms, there will be an infinity of phenotypes which in the cell and tissue context is a way to guarantee the flexibility to adapt to noxious substances, physical and chemical stress agents, and endogenous or exogenous factors, e.g., infections, inflammation, nutrition-energetic alterations, metabolic-endocrine aberrations, etc.

In all honesty, which is the tissue which is ecologically exposed? What tissue is the border or limbo and, therefore, defenseless to an epigenetic regulation? The answer is: epithelial tissue. Therefore, the differential gene modulation caused by epigenetics in the epithelial cell (and not only in the immune cells) is, potentially, a key player in autoimmunity genesis (47). This epigenetic deregulation has been identified in such autoimmune diseases as psoriasis, autoimmune thyroiditis, and ulcerative colitis (See chapter 22) (48-50).

However, epigenetic alterations and their role in the autoimmunity process go beyond differential gene expression. Covalently modified histones exposed to the immune system on apoptotic cell surfaces and in the apoptosomes are better immunogens than native non modified histones as has been observed in SLE. Indeed, DNA-modified histone complexes are excellent innate response stimulators because they function as TLR9 ligands (51-54).

The impact radius of the epigenetic field in epithelial regulation continues to amaze. In fact it could participate in thymic selection since within the medullar thymic epithelium, AIRE generates complexes with various enzymatic factors associated with histone modifications (55).

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