Innate and acquired immunity to commensal bacteria

Sammanfattning: The innate immune system recognises molecular patterns shared by large groups of micro-organisms. Monocytes and macrophages respond to microbes by production of substances which act in concert to promote effective clearance of bacteria. Additionally cells of the innate immune system enhance and modulate antigen specific responses by cells in the acquired immune system.Gram-positive and Gram-negative bacteria differ in cell wall architecture and composition. Gram-positive bacteria have a thick peptidoglycan layer, teichoic and lipotheichoic acids. Gram-negative bacteria have a much thinner peptidoglycan layer covered by an outer phospholipid membrane into which LPS is anchored.In this study, cytokine responses by human mononuclear cells or purified monocytes to various Gram-positive and Gram-negative bacterial species were compared. Bacteria represented species commonly found on the human mucosa. They were either culture collection strains or isolate from healthy adult or infants and represented both aerobic or anaerobic species, commensals and potential pathogens. Gram-positive and Gram-negative bacteria induced different cytokine patterns. In monocyte cultures Gram-positive bacteria induced more TFN-a than did Gram-negative bacteria which instead induced more IL-6 and IL-8. IL-1b was induced equally well by both groups of bacteria. Gram-positive bacteria induced much more of the T cell stimulating cytokine IL-12 than did Gram-negative bacteria, which preferentially stimulated secretion of IL-10, another immunoregulatory cytokine with largely opposing properties to IL-12. Isolated cell wall components from Gram-positive and Gram-negative bacteria induced pro-inflammatory cytokines and LPS induced IL-10, but none of the components tested mimicked the potent induction of IL-12 by Gram-positive bacteria.IL-12 stimulates production of IFN-g from T cells. Hence, stronger IFN-g responses were induced by Gram-positive than Gram-positive bacteria while lymphocyte proliferation was comparable. Both IFN-g production and proliferation was MHC class II dependent. IL-10 inhibits T cell functions. Accordingly, E. coli-induced proliferation and IFN-g production was dampened by IL-10 induced by its LPS. Gram-negative bacteria also downregulated IL-12 and IFN-g responses to S. aureus and IFN-g responses induced by C. albicans, partly through the induction of IL-10.We further investigated whether there was a difference in responsiveness to Bifidobacterium sp., Bacteroides sp. or E. coli carried by the individual compared with strains carried by other individuals. Both proliferation and cytokine production were equal whether bacteria derived from the person's own or other people's microfora. We could, thus, not detect a systemic tolerance towards autologous bacteria. Instead, T cell memory seems to exist in humans to commensal bacteria. However, since IL-10 and other factors produced by monocytes in response to bacteria strongly modulate T cell responses, evidence of memory may be masked. Thus, the innate immune responses must be taken into account when acquired responses to microbes are measured.We suggest that the sum effect of cytokines induced by Gram-positive bacteria; IL-12, IFN-g and TNF-a might increase the capacity of phagocytes to digest the sturdy Gram-positive cell wall. IL-6, IL-8 and IL-10 produced in response to Gram-negatives should lead to recruitment of PMNs and production of acute phase proteins which might be more important for their elimination.