**6. The microbiota interference with other autoimmune-mediated diseases**

Rheumatoid arthritis is characterized by a severe and chronic inflammatory condition of the joints. The clinical course of the disease underlines the potential role of dysbiosis in triggering an inflammatory process that involves autoimmune components [87]. Germ-free animals are protected from rheumatoid arthritis in experimental settings. However, the disease is induced in mice exposed to *Clostridium* SFB, which may act as pathobiont or symbiont, depending on conditions that are hostdependent or independent. Clostridial antigens stimulate Th17 (proinflammatory) lymphocytes that contribute to the progressive evolution of rheumatoid arthritis. Conversely, neutralization of Th17 lymphocytes halts the evolution of the disease. The microbiome of patients with rheumatoid arthritis is altered, with the abundance of *Prevotella copri*. Citrullinated peptides and specific anti-citrullinated proteins antibodies (ACPA) have been identified in patients suffering from rheumatoid arthritis. Citrullinated peptides result from the peptidyl-Arg-deiminase (PAD)-catalyzed deamination reaction. The enzyme is mainly released after the lysis of granulocytes, monocytes, and macrophages that accumulate in the inflammatory spreads. However, it is also produced by *Porphyromonas gingivalis* and *Aggregatibacter actinomycetemcomitans*, which citrulinate human fibrinogen, synovial fluid proteins [88]. Citrullination

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

is a common physiological process, especially associated with inflammatory processes. Citrullinated proteins, identified in the inflamed synovial membrane of the arthritic joint, exhibit new epitopes and induce the synthesis of ACPA. Circulating ACPAs incorporate into immune complexes aside from citrullinated peptides originating in the joints.

Periodontitis that is caused by oral microbiota bacteria progresses similarly to rheumatoid arthritis—leukocyte infiltration and the progressive destruction of alveolar bone. Leukocytes release the set of proinflammatory interleukins (such as TNF, Il-1, IL-6, IL-12, IL-17, IL-18, and IL-33), growth factors (such as colony-stimulating factors—i.e., GM-CSF, monocyte-CSF), activator receptor of nuclear factor kappa-β ligand (RANKL), metalloproteases, nitric oxide, and PG E2 [89].

In 2013, Rinaldi identified auto-antibodies against the cellular wall of *Saccharomyces cerevisiae* in rheumatoid arthritis, lupus erythematosus, and antiphospholipid syndrome. These antibodies are also observed in the sera of 32% of patients with celiac disease before its clinical occurrence, and they are considered as a specific serological marker of the disease [90].

Behcet's disease is a chronic, multisystemic inflammation that is characterized by uveitis, which is a major cause of blindness, and recurrent ulcerative lesions involving the mouth and genital mucosa. There have been reported changes in Th-1, Th-17, and T-reg lymphocytes, whose activity is regulated by the microbiome [91], as well as the diversification of potentially pathogenic bacteria and the decrease of those that produce butyrate (*Clostridium*).

The pathological change in ulcerative colitis consists of diffuse inflammation, with limited ulcers in the chorion of the colonic mucosa. The pathological process is extended over the entire mucosa of the intestinal epithelium [92].

In Crohn's disease, the inflammatory infiltrates often generate extensive granulomas in the submucosa and even in the muscular layer of the colon and small intestine. The pathological process of Crohn's disease is localized, with the damaged areas of the intestine alternating with the healthy ones [93].

Crohn's disease and ulcerative colitis are not AIDS in the strict sense, because triggering antigens appear to be components of the intestinal microbiota translocated into the chorion, but are the consequence of a large immune response in non-pathogenic antigens, which occurs in people with a genetic predisposition. The inflammatory condition increases the permeability of the colonic epithelium, and the microbiome is modified—the method of 16S rDNA sequencing has shown a decrease in bacterial diversity, especially of the non-pathogenic population, in favor of potentially pathogenic ones [94].

Lupus erythematosus is the prototype of systemic autoimmune disease—an autoimmune response characterized by hyper-reactivity of B lymphocytes and the presence of a large spectrum of serum antibodies [95]. As its name, the disease involves many organs and systems and has various clinical manifestations. Lupus erythematosus affects especially women (female/male ratio = 9/1), with the highest risk during pregnancy [96]. The intestinal microbiota is altered—depletion of lactobacilli, increased *Lachnospiraceae* density and general diversity, compared to healthy individuals. A large proportion (over 65%) of patients have periodontitis [97], which is always associated with extensive changes in the oral microbiota, in which species with potential pathogens predominate—*Fusobacterium nucleatum*, *Actinomyces naeslundii*, *Ps. anaerobius*, *Bacteroides intermedius*, and *Porphyromonas gingivalis* [98].

Multiple sclerosis is a chronic demyelinating inflammatory disease of the central nervous system, characterized by destruction of the integrity of the

haemato-encephalic barrier, T lymphocyte infiltrates, and autoimmune reaction against myelin proteins [99]. The immune response in experimental autoimmune encephalitis is mediated by Th-1 and Th-17 cells. The causative agent is not known, but the modification of the microbiota may be important in the onset and/or progression of autoimmune disease. The autoimmune encephalitis diminishes to extinction in *germ-free* mice, and colonization with *Clostridium* SFB restores the severity of the disease, as it stimulates the growth of the population of Th-17 (proinflammatory) lymphocytes [100]. Conversely, the administration of *Bacteroides* protects against demyelination and expansion of tissue-specific inflammation induced by Treg Foxp3 + [55].

The liver autoimmune disease appears to have a direct connection to the microbial load (cells, lipopolysaccharides, peptidoglycans, flagellin, DNA, RNA, toxins, and metabolites) that reaches the Kupffer cells and sinusoidal capillaries by passaging the portal vein. The immune response to these antigens can initiate liver damage and fibrosis [55, 101].

Vitiligo is a systemic autoimmune disease, which is characterized by areas of skin depigmentation, as a result of melanocyte lysis under the action of TCD8 lymphocytes. Melanocytes are located at the border between the epidermis and the dermis, but the disease is systemic because melanocytes are also found in other tissues. The number of melanocytes is the same in different individuals, but differences in pigmentation result from the number, distribution, and size of melanosomes in keratinocytes. The intestinal microbiota in patients with vitiligo is altered and is characterized by decreased taxonomic diversity [18, 102].

Atopic dermatitis is an inflammatory skin disease, clinically characterized by pruritus and xerosis (dry skin). The underlying cause is delayed hypersensitivity mediated by T lymphocytes. The local trigger is the colonization of the skin with *Staphylococcus aureus*. The toxins released by *S. aureus* exert a cytotoxic effect [103, 104].
