Toll-like Receptors Discriminate Self from Non-self

As was discussed in the introductory article of this issue, macrophages circulate through the body, protecting it from foreign invaders. As part of this job, the macrophages must be able to tell the difference between an invader and cells that belong in the body. Part of this discrimination, it has been discovered, comes from Toll-like receptors (TLRs) and their ability to differentiate between molecular patterns found on bacteria, viruses or fungi and molecular patterns found on the body’s own cells. It is the specificity of TLR binding that ensures inflammatory responses are limited to those aimed against foreign pathogens but not self tissues.

What Problem Was Studied?
Macrophages harbor several different TLRs, and different TLRs recognize molecular patterns from different pathogens. Furthermore, certain TLRs are found on the surface of macrophages and others are found within the cells. The significance of these different locals is what Arthritis Foundation-funded researcher Jonathan C. Kagan, PhD, and his colleagues have been investigating at the Yale University School of Medicine in New Haven, CT.

What Was Done in the Study?
Toll-like receptor 9 was the focus of this particular study. TLR9 recognizes nucleic acid patterns specific to viruses and bacteria. This particular TLR is normally located within the macrophage, not on its surface. To determine the significance of its location to its function, the scientists were able to construct a version of TLR9 that resided on the macrophage membrane rather than inside the cell. These cells were then exposed to viral and mammalian DNA (composed of nucleic acids) to see what would happen.

What Were the Study Results?
When TLR9 was on the surface, its ability to recognize nucleic acid patterns from viruses was “severely impaired.” The scientists were able to determine that when on the surface, TLR9 could not recognize viral nucleic acids most likely because the viral DNA was locked within the viral capsid. It is the act of phagocytosis and degradation of the capsid that releases the viral DNA and allows for the recognition of the nucleic acid patterns by TLR9. This is why TLR9 is located within the macrophage.

At the same time, the surface-located TLR9 gained the ability to recognize and react to DNA that does not normally activate TLR9. Because nucleic acids can be either self or non-self, the immune system must be able to discriminate between different sources of nucleic acids. The result that the relocated TLR9s could not discriminate between self and non-self indicated to the research team that something in the location of TLR9 must be the answer. The team determined that the most likely explanation is that self DNA is degraded by enzymes within the body’s circulation before it ever reaches the inside of the macrophage, where TLR9 normally resides.

What Does This Mean for People With Autoimmune Disease?
Systemic lupus erythematosus is an autoimmune disorder in which the immune system generates a response to self nucleic acid. Understanding how Toll-like receptors prevent reactions to self nucleic acids can help unravel the mysteries that happen within the body affected by lupus. Once the secrets of the immune system are known, treatments (or even cures) can be developed.

Barton GM, Kagan JC, Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nature Immunology 2006;7:49-56.

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