This result suggests that iNKT cell activation by microbes can lead to severe inflammation

in some cases. Recent studies have indicated that the iNKT cell response to Sphingomonas spp. is important in the pathogenesis of PBC, an autoimmune disease characterized by the destruction of small bile ducts in the liver. PBC patients express antibodies against mitochondrial PDC-E2 in serum (45). Interestingly, N. aromaticivorans, a member of the Sphingomonodaceae family found in human intestines, also expresses PDC-E2 (45). Serum from PBC patients reacts with N. aromaticivorans, but not with E. coli (45). Mice infected with N. aromaticivorans express antibodies against PDC-E2 and develop chronic inflammation in the small bile duct mediated by autoreactive T cells, iNKT cells being required in Selleck Antiinfection Compound Library this process (59). These

results indicate that iNKT cells play an important Selleck MLN8237 role in PBC pathogenesis. When iNKT cells are activated by αGalCer or its analogues, they stimulate many other cells, including APCs, NK cells, B cells and conventional T cells (1–4). Glycolipid mediated iNKT cell activation induces protective responses against various microbial pathogens including bacteria, fungi, parasites and viruses (1–4). For example, αGalCer treatment has a positive effect during certain microbial infections. In mouse pneumonia models with P. aeruginosa and S. pneumoniae,αGalCer treatment induces rapid clearance of bacteria from the lungs by activating alveolar macrophages and increasing neutrophil recruitment to the lungs, respectively (11, 60). In a urinary tract infection model with E. coli, P. aeruginosa, and methicillin resistant Staphylococcus aureus, αGalCer treatment enhances antibacterial effects (61). α−galactosylceramide treatment has also been shown to be protective in mice infected with intracellular fungi and bacteria. During C. neoformans infection, αGalCer treatment enhances clearance of fungi from the lungs and spleen through an enhanced Th1 response (62).

When mice infected with L. monocytogenes, an intracellular Gram-positive bacterium, are treated with αGalCer, bacterial numbers in the liver, before spleen and peritoneal cavity decrease compared to control mice (63). iNKT cells stimulated by αGalCer enhance the killing of L. monocytogenes in macrophages with an increased respiratory burst (63). Similarly, in M. tuberculosis infected mice, αGalCer treatment prolongs survival and decreases the bacterial burden and tissue injury in the lungs (64). Furthermore, a combination of αGalCer and isoniazid, a first line antibiotic for tuberculosis, reduces bacterial numbers in the spleen and lungs in mice significantly more than does isoniazid alone (65). Human iNKT cells have also been shown to have lytic activity involving granulysin (an antimicrobial peptide) against M. tuberculosis infected APCs, and this is greatly enhanced by αGalCer (22).