New Insights into Innate Defense Mechanisms: Implications for Oral Health

HIV-1 can induce the expression of oral epithelial cell derived antimicrobial peptides (AMPs) called human beta defensins (hBDs). These innate defense molecules, in turn, can inhibit HIV-1 infection of immunocompetent cells. By studying the mechanism of protection, we discovered that hBDs can “cross-talk” with the adaptive immune system and possibly orchestrate outcomes that are important for defense of the oral mucosae. HBDs interact with chemokines and toll-like receptors (TLRs) to (1) promote T cell and immature dendritic cell chemoattraction (via CCR6), (2) promote monocyte/macrophage chemoattraction (possibly via CCR2), (3) induce antagonism of T cells (via CXCR4), (4) induce maturation of antigen presenting cells (via TLR1/2 heterodimerization) and (5) may participate in the coordination of inflammation (via melanocortin receptor 1; MC1r). The specificity of these interactions, and related outcomes, appears to be concentration dependent. At nanomolar concentrations, hBDs act as chemokines (1, 2 above), while at low micromolar concentrations they cause T cells to stop moving (antagonism) and APCs to mature and promote T cell activation (3, 4 above). Interestingly, hBD gene copy number variation, may be associated with interpersonal variability in levels of innate protection. Our recent proteomic studies have uncovered that chronic HIV infection and/or highly active antiretroviral therapy (HAART) predisposes the oral mucosae to both cellular and innate immune impairment. Moreover, supportive information that hBDs are expressed less in oral epithelium of HIV subjects, may clue us into understanding why subjects chronically infected with HIV appear to be more susceptible to oral complications. The role innate response elements, such as hBDs, whether alone or in concert with other AMPs; (i.e., SLPI, LL37, calprotectin, etc), play in protecting against microbial challenges, may lie in deciphering the network of the epithelial cell proteome and how it is affected by chronic microbial infection.

Supported by NIH/NIDCR RO1DE015510 and PO1DE019089