Possible Critical Role of Latent Chronic Toxoplasma Gondii Infection in Triggering, Development and Persistence of Autoimmune Diseases

T. gondii is globally distributed with a high proportion of the world population estimated to be seropositive, and in the U.S. the parasite is responsible for approximately million infections each year. T. gondii tachyzoites infect almost all nucleated cells and their intracellular multiplication and lifelong persistence in the host cells play an important role in triggering and development of autoimmune diseases (ADs). Latent chronic T. gondii infection may be associated with iron, iodine, and folic acid  deficiencies that facilitate development and/or progression of ADs. The oral route is the natural portal of entry for the parasite and gastrointestinal manifestations are frequently reported in patients with ADs. Prolactin was found to bind to tachyzoites and this process impairs their adhesion and penetration into the host cells. Hyperprolactinemia (HPRL) demonstrated in patients with different ADs may therefore reflect host defense against T. gondii infection, and several antipsychotic drugs that induce HPRL also have antitoxoplasmatic activity. Leptin and obesity play an important role of in triggering and maintenance of inflammation and autoimmunity. T. gondii infection causes a significant increase in leptin levels and there is a significant positive association between the parasite seropositivity and obesity. Nitric oxide (NO) acts as a proapoptotic as well as an antiapoptotic biomodulator, and have a variety effects on autophagy. Overproduction of NO during T. gondii infection causes dysfunction of both  these processes and therefore hinders cleaning service of the apoptotic/autophagic cell-derived antigenic remnants, finally leading to triggering and development of ADs. Damage of the olfactory system associated with chronic latent T. gondii infection may affect olfactory bulb volume and various olfactory functions, being therefore at least in part responsible for the smell impairment in ADs. The potent proinflammatory response of macrophages to infection with T. gondii type II may explain the ability of the strain to cause pathology after oral infection. The parasite also triggers the secretion of antiinflammatory cytokines, such as IL-10, TGF-b, and generation of reactive nitrogen intermediates, thus suppressing the development of the T H 1 immune responses and deactivating macrophages. Toxoplasma chronic infection-induced cytotoxic T lymphocyte exhaustion leads to development of ADs because of decreased polyfunctionality, cytotoxic capability,  cytokine production, proliferative capacity, and metabolic deficiency. The process of CD4 + and CD8 + T-cell immune exhaustion inhibits the immune response, thus facilitating pathogen persistence. Systemic T. gondii infection triggers a rapid and persistent decrease in the size of naive CD4 + T lymphocyte pool, and a long-term thymic atrophy and output due to destruction of the thymic epithelium. Chronic parasite infections characterized by lower pathogen burden usually restricted to tissues, suggest alternative driving forces in the induction of T cell exhaustion, such as parasite encystations. A significantly lower occurrence of antibodies to persistent viral infections reported in patients with some ADs compared with controls may be due to suppressed (exhausted) function of host B cells. Both T. gondii- and viral-associated inflammatory processes may be mutually overlapping which lead to worsening or improving clinical course of ADs depending on final temporary or stable proinflammatory/antiinflammatory cytokine constellations. Dual-affinity T cell receptors may at least in part be responsible for frequently observed coinfections of T.gondii with some viruses and bacteria. Commonly reported comorbidities in ADs may at least in part be explained by liver damage caused by the pathogen. Vitamin D deficiency is often found in patients with ADs and there is vast evidence that the vitamin has an important  beneficial impact on both innate and acquired immunity. Moreover, vitamin D exerts toxoplasmacidal effects and therefore should find a firm place in treatment regimens used in ADs.