The Danger Within
http://www.100md.com
《新英格兰医药杂志》
But I must go and meet with danger there,
Or it will seek me in another place,
And find me worse provided.
— William Shakespeare, Henry IV
We come into contact with a vast assortment of external agents every day, and our immune system needs to deal with them. How does the immune system distinguish dangerous from nonthreatening situations? Many pathogens contain chemical signatures, such as lipopolysaccharide, that are not present in human cells. These exogenous danger signals interact with a variety of cellular receptors to trigger the maturation of antigen-presenting cells, especially tissue- and lymphoid-based dendritic cells. The mature dendritic cells can then induce the adaptive immune response by presenting antigen and costimulatory molecules to naive T cells.1
But what about pathogens that are predominantly intracellular or that lack the molecular patterns that signal danger? The immune system should be able to detect damaged cells directly, and indeed, several reports have shown that dying cells can induce the maturation of dendritic cells and prime the T-cell response. Shi and colleagues2 have now identified a molecule that acts as a danger signal (Figure 1). They obtained cytosol from apoptotic cells and isolated a low-molecular-weight fraction that induced specific cytotoxic T-cell activity when injected into mice along with the gp120 protein of the human immunodeficiency virus (HIV). Purification of this fraction identified the active compound as uric acid.
Figure 1. Recognition of Danger Signals by Dendritic Cells and T-Cell Priming.
Whereas the activation of dendritic cells by exogenous, pathogen-associated molecular patterns is well characterized, the activation of dendritic cells by endogenous signals, such as those from dying cells, is not. A recent study by Shi et al.2 shows that one such endogenous danger signal is crystalline uric acid. The study shows that crystalline uric acid drives the maturation of dendritic cells, leading to an increase in both antigen presentation and the expression of costimulatory molecules such as CD80 and CD86. The mature dendritic cells can then effectively prime the T-cell response.
Uric acid is the end product of purine catabolism and is released as dying cells degrade their DNA and RNA. Surprisingly, it is the crystalline form, monosodium urate, that was found to be active, whereas soluble uric acid and other crystals had no adjuvant effect. Suppression of uric acid with allopurinol and uricase greatly reduced the adjuvant effect.
These elegant experiments raise both opportunities and questions. Does this endogenous signaling pathway operate in humans? Can crystalline uric acid or a congener be developed as a safe and potent vaccine adjuvant? Tophaceous gout provides ample evidence of the potential of crystalline uric acid to unleash inflammation, yet gouty infiltrates are characterized by neutrophils, not lymphocytes. Can such responses be safely adapted and exploited? Most important, if uric acid is effective in humans, what is the risk that this treatment will induce autoimmunity?
That said, the results of Shi et al. may provide a means by which to prime the immune system against a wide variety of infectious agents. The design and development of new vaccines against agents such as HIV and those that cause tuberculosis, malaria, and hepatitis C require an improved knowledge of antigens and adjuvants that can induce vigorous immune responses. Safe adjuvants, especially those that promote the presentation of antigens by class I major-histocompatibility-complex molecules, have been difficult to develop. For therapeutic vaccines, including cancer vaccines, overcoming immune tolerance and activating T-cell immunity have proved difficult. The new approach to developing adjuvants described by Shi et al. is therefore of interest to all those who develop vaccines.
Source Information
From the Department of Laboratory Medicine, University of Washington; and the Program in Infectious Diseases, Fred Hutchinson Cancer Research Center — both in Seattle.
References
Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-252.
Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003;425:516-521.
Related Letters:
The Danger Within
Gu Y., Hershfield M. S., Cohen A., Jerome K. R., Corey L.(Keith R. Jerome, M.D., Ph)
Or it will seek me in another place,
And find me worse provided.
— William Shakespeare, Henry IV
We come into contact with a vast assortment of external agents every day, and our immune system needs to deal with them. How does the immune system distinguish dangerous from nonthreatening situations? Many pathogens contain chemical signatures, such as lipopolysaccharide, that are not present in human cells. These exogenous danger signals interact with a variety of cellular receptors to trigger the maturation of antigen-presenting cells, especially tissue- and lymphoid-based dendritic cells. The mature dendritic cells can then induce the adaptive immune response by presenting antigen and costimulatory molecules to naive T cells.1
But what about pathogens that are predominantly intracellular or that lack the molecular patterns that signal danger? The immune system should be able to detect damaged cells directly, and indeed, several reports have shown that dying cells can induce the maturation of dendritic cells and prime the T-cell response. Shi and colleagues2 have now identified a molecule that acts as a danger signal (Figure 1). They obtained cytosol from apoptotic cells and isolated a low-molecular-weight fraction that induced specific cytotoxic T-cell activity when injected into mice along with the gp120 protein of the human immunodeficiency virus (HIV). Purification of this fraction identified the active compound as uric acid.
Figure 1. Recognition of Danger Signals by Dendritic Cells and T-Cell Priming.
Whereas the activation of dendritic cells by exogenous, pathogen-associated molecular patterns is well characterized, the activation of dendritic cells by endogenous signals, such as those from dying cells, is not. A recent study by Shi et al.2 shows that one such endogenous danger signal is crystalline uric acid. The study shows that crystalline uric acid drives the maturation of dendritic cells, leading to an increase in both antigen presentation and the expression of costimulatory molecules such as CD80 and CD86. The mature dendritic cells can then effectively prime the T-cell response.
Uric acid is the end product of purine catabolism and is released as dying cells degrade their DNA and RNA. Surprisingly, it is the crystalline form, monosodium urate, that was found to be active, whereas soluble uric acid and other crystals had no adjuvant effect. Suppression of uric acid with allopurinol and uricase greatly reduced the adjuvant effect.
These elegant experiments raise both opportunities and questions. Does this endogenous signaling pathway operate in humans? Can crystalline uric acid or a congener be developed as a safe and potent vaccine adjuvant? Tophaceous gout provides ample evidence of the potential of crystalline uric acid to unleash inflammation, yet gouty infiltrates are characterized by neutrophils, not lymphocytes. Can such responses be safely adapted and exploited? Most important, if uric acid is effective in humans, what is the risk that this treatment will induce autoimmunity?
That said, the results of Shi et al. may provide a means by which to prime the immune system against a wide variety of infectious agents. The design and development of new vaccines against agents such as HIV and those that cause tuberculosis, malaria, and hepatitis C require an improved knowledge of antigens and adjuvants that can induce vigorous immune responses. Safe adjuvants, especially those that promote the presentation of antigens by class I major-histocompatibility-complex molecules, have been difficult to develop. For therapeutic vaccines, including cancer vaccines, overcoming immune tolerance and activating T-cell immunity have proved difficult. The new approach to developing adjuvants described by Shi et al. is therefore of interest to all those who develop vaccines.
Source Information
From the Department of Laboratory Medicine, University of Washington; and the Program in Infectious Diseases, Fred Hutchinson Cancer Research Center — both in Seattle.
References
Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-252.
Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003;425:516-521.
Related Letters:
The Danger Within
Gu Y., Hershfield M. S., Cohen A., Jerome K. R., Corey L.(Keith R. Jerome, M.D., Ph)