**4. Intestinal microbial antigens as inductors of central and peripheral tolerance**

Despite its much-diversified antigen panel, the microbiota is tolerated by the immune system. Central tolerance is induced during fetal life, as immature lymphocytes are exposed to various antigenic peptides, and is essentially dependent on the specific process of antigenic peptide selection and presentation in association with the Human Leucocytes Antigen/ Major Histocompatibility Complex (HLA/MHC) molecules [30]. The occurrence of peripheral tolerance breaks results from a functional adaptation of the immune system to specific antigenic peptides that have not (sufficiently) been exposed to lymphocytes in the bone marrow or thymus during embryonic development. It is now considered that the T lymphocyte antigen receptor (TCR) is the major mediator of immune tolerance. That is why, from an evolutionary perspective, TCR recognizes both the genetic and microbial self [31].

The immune tolerance to commensal intestinal microbiota is peripheral and results from both an immediate neonate colonization of the digestive tract and a progressive co-evolution in which the interactions of gut-associated lymphoid tissue (i.e., GALT) with bacterial antigens have been modulating innate and adaptive primarily local immune reactivity. Commensal antigens, on contact with the intestinal mucosa, induce the state of tolerance, in which dendritic cells play an essential role, while the effectors are the epithelial cells with their covering molecular complex (i.e., antimicrobial peptides, mucin layer, surface immunoglobulin A—sIgA) [32]. Bacterial cells or their components (i.e., lipopolysaccharides, polysaccharides, peptidoglycans, teichoic acids, and DNA) that cross the intestinal barrier and reach the internal environment, activate the immune response [33].

## **4.1 Causes of losing immune tolerance to microbiota antigens**

Interruption of immune tolerance to microbiota antigens is determined by several factors—genetic factors, the host's immune system, disturbance of the diversity, and physiology of the microbiota—as triggering events [34].

Mechanisms that modulate immune tolerance loss to the intestinal microbiota include: (i) abnormal translocation of bacteria in the internal environment due to permeability of the intestinal barrier, (ii) antigenic similarity of some bacterial peptides with epithelial molecules. Immune cells are activated by bacterial peptides and become autoreactive; and (iii) disorder of local and systemic immunity under the stimulating action of some bacterial derivatives (nucleic acids, polysaccharides, metabolites, and toxins). Aberrant activation of the immune system leads to the excessive synthesis of proinflammatory IL (IFN type I, IL-12, IL-23) and a decreased rate of synthesis of anti-inflammatory cytokines (IL-10, TGF-β—transforming growth factor) (**Figure 1**) [35].

### **4.2 Consequences of losing immune tolerance**

Although the autoimmune conflict occurs most of the time without clinical manifestations, it can generate under certain conditions, such as AIDS, that are characterized by the appearance of tissue lesions or disruption of physiological processes. AIDS have a multifactorial etiology involving genetic, epigenetic, and environmental factors. It is estimated that 70% of AIDS are due to environmental factors [36]. Among the multiple cellular and molecular mechanisms, yet not well

### **Figure 1.**

*The role of microbiota in mucosal homeostasis and immunological tolerance in healthy gut and activated inflammatory cascades in endocrine autoimmune disease. In germ-free animals, GALT structures are less developed and the microbiota has a major influence on the development of T lymphocyte subpopulations and in maintaining the numerical balance of Th-2/Th-1 lymphocyte populations in lymphoid organs. The healthy gut environment is characterized by high levels of antimicrobial peptides and metabolites (SCFAs), and the commensal-specific IgA is produced by plasma cells in the lamina propria, mediated by DCs in a T cellindependent mechanism. During homeostasis, gut microorganisms induce an immune tolerance phenotype in the host, whilst in inflammatory conditions, antigens from dysbiotic microorganisms activate Th1 and Th17 cells leading to decreased mucus layer, tissue injury, and microbial penetration and persistence in the intestinal tissues. This mucosal injury results in further uptake of microbial antigens that further perpetuate detrimental immune responses. Figure created with https://biorender.com/.*

established, by which the state of immune self-tolerance is disturbed, we can mention—(i) the genetic predisposition that may explain the familial character of AIDS, which, in general, have a polygenic determinism. The risk of a certain autoimmune disease for monozygotic twins is about 12 to 60%, and for dizygotic twins is 5%. The most important are certain specific polymorphisms generated by the change of a nucleotide, that is, SNP (single nucleotide polymorphism) in MHC genes [9]. For example, over 90% of Caucasians with ankylosing spondylitis express an allele of the HLA-B27 family, differing from that of normal individuals by two amino acids located in the peptide binding groove [37]; (ii) release of sequestered antigens after trauma, surgery, infectious processes, etc., become accessible to lymphocytes, triggering the autoimmune conflict and tissue damage (e.g., basic myelin protein in the central nervous system becomes the antigenic target in multiple sclerosis; crystalline proteins induce autoimmune ophthalmopathy; sperm proteins, in cases of sperm stasis, induce the synthesis of immobilizing or binder autoantibodies of sperm, leading to autoimmune infertility) [38, 39]; (iii) modification of the chemical structure of autoantigens (so-called altered self-theory), which occurs under the influence of some physical factors (such as burns or radiation), biological (i.e., bacteria, viruses, fungi), or chemical (i.e., drugs, alcohol) factors, with the exposure of some new antigenic determinants

### *Dysbiosis, Tolerance, and Development of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.104221*

[40]; (iv) infectious agents, which may have an important role in triggering AIDS by various mechanisms, such as the antigenic resemblance of non-self to self-molecules and their cross-reactivity (e.g., protein M from *Streptococcus pyogenes* is antigenically similar to cardiomyocyte's membrane proteins); (v) stimulation of the proinflammatory cytokines production that cause nonspecific activation of self-reactive immune cells; superantigens of infectious agents (i.e., Epstein-Barr virus, mycoplasmas, *Staphylococcus aureus*, *Streptococcus pyogenes*) that induce polyclonal activation of lymphocytes [41]; (vi) loss of peripheral immune tolerance, due to either mutation that generates the appearance of immunocompetent, self-reactive T or B lymphoid cell clones, or T-reg cell deficiency, or Th cell activation; (vii) disruption of the equilibrium state of the idiotypic network by the synthesis of anti-idiotypic antibodies, which may be autoantibodies [42]; and (viii) hormonal imbalances that may be involved in triggering AIDS, therefore explaining their increased frequency in women (8: 1 ratio) except for ankylosing spondylitis, or in men with higher levels of estrogen hormones. Moreover, pregnancy is associated with an improvement in the severity of AIDS, especially in rheumatoid arthritis cases.

AIDS resemble some general features—the pathological process has an individual intensity, dynamics, and evolution, may overlap with the same patient, and are rare in childhood, except for type 1 diabetes mellitus.

Regardless of the triggering mechanism, AIDS is characterized by the synthesis of autoantibodies (that are antibodies specific to self-tissue components) or by the generation of autoreactive T lymphocytes. Tissue injuries following the action of immune effectors occur in one of the above-mentioned scenarios—(i) autoantibodies recognize the tissue antigens and form immune complexes, the complement is activated, and the result is the cell lysis, or (ii) indirect action, in which case, the antigen-antibody—complement immune complexes are deposited in small vessels (arterioles, capillaries) from various organs and produces inflammatory reactions, with the consequence of tissue destruction; the AIDS that are mediated by various antibodies have a common feature, that is the target tissue is damaged by a chronic inflammatory reaction without a known infectious cause; and (iii) the lesions in the target tissue occur under the action of infiltrated Tc lymphocytes [43, 44].

Some AIDS are characterized by strictly localized pathological processes, that is, effectors (especially antibodies) have specific action against antigens specific to the target tissue (such is the case for autoantibodies specific only to B cells from Langerhans islands in type 1 diabetes mellitus, or autoantibodies specific to thyroid epithelial cell in Hashimoto's thyroiditis) [45], sometimes the lesions are localized in a single organ, but autoantibodies do not have organ specificity (for instance, anti-mitochondrial antibodies in primary cirrhosis, or type IV anticollagen autoantibodies in Goodpasture syndrome) [46, 47] while some AIDS are disseminated, characterized by the synthesis of autoantibodies to antigens with wide tissue distribution (e.g., antinuclear antibodies in systemic/disseminated lupus erythematosus) [48].

Often, in pathological cases, the body synthesizes auto-antibodies specific for components of the endocrine system, especially antibodies specific for a certain hormone receptor. The pathophysiological effects of these antibodies generated against hormone receptors are varied—they can stimulate the activity of the receptor, and the effect is to intensify the secretory activity of the gland (hormonal mimetic effect) or block the receptor, and the effect is to inhibit the secretory activity. Both antibodies can coexist in the same patient.
