This production occurs physiologically at a low rate [83] as part of the immunotolerant mechanisms aimed at counterbalancing an unwanted
boost of immune responses. MHC-I and -II expression by enterocytes increases as a consequence of stress and infection. These molecules present antigens to antigen-experienced T cells resident in LP as part of the protective immune response [84]. MHC-II-associated peptides produced by enterocytes can be packed in the form of exosomes, detached from the basal pole. These types of exosomes, in this situation named tolerosomes, participate in the generation of a tolerogenic intestinal environment [85]. The exact structure Pirfenidone datasheet of tolerosomes is unknown, but it is supposed that they may contain other co-stimulatory molecules, which could induce tolerance to the MHC-associated peptide [86]. The tolerosomes were discovered less than 10 years ago. It has been known from 1983 that oral tolerance is transferrable through serum. Tolerosomes were identified by electron microscopy in 2001, in the serum of animals subjected to induction of oral tolerance, namely in the insoluble fraction resulted by ultracentrifugation.
The soluble fraction, containing serum without tolerosomes, could no longer mediate the transfer of oral tolerance [85]. This discovery has proved the existence of intercellular communication through exosomes during induction of oral tolerance. What exactly happens with tolerosomes after their production is yet not fully elucidated. A recent study suggested that they harbour the αvβ6 integrin and their targets are migratory DCs (CCR7+CD103+ DC), to whom they selleck kinase inhibitor convey the necessary information for mounting tolerance to luminal antigens. CD103+ DCs will prime Tregs after their arrival in MLN which are specific for the MHC-associated peptide contained in tolerosomes [87]. Another possibility, as an intact portal circulation is needed in order for oral tolerance to develop and tolerosomes
are retrievable in serum, could be that tolerosomes are also addressed to DCs in the liver, but this has yet to be proved. Enterocytes also favour the translocation of intact antigens from the gut lumen into LP. This is achieved Pregnenolone in a controlled manner through Ig receptors [88]. In newborn mice, and during the entire human life, neonatal Fc receptor (FcRn) enables internalization of the IgG–antigen complexes [89] as well as IgG externalization, allowing binding to the specific antigen [90]. Most interestingly, FcRn is also present in the mammary glands, where it contributes to exocytosis of IgG–antigen complexes in milk [91]. The excretion of these immune complexes in the human milk induces a state of profound and prolonged oral tolerance in the offspring, due to induction of antigen-specific Tregs[92]. FcRn is also found in the placenta, allowing materno–fetal transfer of IgG [93].
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