Express Yourself Immune Evasion by Anthrax

HIGHLIGHTS MACROPHAGES Bacillus anthracis, the causative agent (LPS)-activated macrophages. First, of anthrax, kills macrophages and they showed that LT causes the apop- evades the host immune response by tosis of LPS-treated macrophages; secreting a protein that leads to the then, they investigated the signalling Immune evasion inhibition of p38 mitogen-activated pathways involved. At the concentra- LF protein kinase (p38 MAPK), accord- tion that is required to induce apopto- by anthrax PA ing to a report in Science.The activity sis, LT inhibits the activation of ERK, of this MAPK is required for the c-Jun NH2-terminal kinase 1 (JNK1) transcription of certain downstream and p38, but the activity of JNK2 and nuclear factor-κB (NF-κB) targets. inhibitor of NF-κB (IκB) kinase (IKK) LT Macrophage Three proteins secreted by B. anthr- is unaffected. The authors used spe- acis are important for its pathogenic- cific MAPK inhibitors to determine ity: protective antigen (PA), oedema the contribution of these MAPK cas- factor (EF) and lethal factor (LF). PA cades to LT-induced apoptosis. Only enables EF and LF to enter the cytosol the p38-specific inhibitor (SB202190) of host cells, where EF causes tissue induced apoptosis of LPS-activated oedema and LF acts as a metallopro- macrophages, which indicates that LT X tease, cleaving MAPK kinases (MKKs) might cause apoptosis by inhibiting P and thereby preventing MAPK activa- p38 signalling. MKKs p38 X tion. Lethal toxin (LT; a complex of Macrophages lacking IKK and activated PA and LF) has been shown NF-κB activity were shown to be sen- to be cytotoxic for macrophages, but it sitive to LPS-induced apoptosis also. was not known how the blockade of So, Park et al. investigated whether MAPK signalling tied in with these p38 synergizes with NF-κB to induce Nucleus P cytotoxic effects. the transcription of anti-apoptotic P Transcription of X anti-apoptotic Park and colleagues carried out a genes. They used real-time PCR to genes NF-κB X series of in vitro experiments to study study the effects of blocking p38 sig- the effects of LT on lipopolysaccharide nalling on the expression of known TOLERANCE report their findings in Science,generated several of which are known to be targets of their own Aire-knockout mice and made autoimmunity in patients with APS1, such as radiation chimeras to investigate this issue insulin and cytochrome P450. Express yourself further. This study provides the first insight into the They show that to prevent autoimmunity, molecular basis of the phenomenon of Accumulating evidence indicates that the Aire must be expressed by radio-resistant, promiscuous gene expression by MECs. ectopic expression of tissue-specific proteins non-haematopoietic cells. But, are these However, at present, only a correlation by rare thymic medullary epithelial cells cells in the thymus or in the periphery? Real- between reduced levels of messenger RNA (MECs) might be important for the deletion time reverse-transcriptase-PCR did not and autoimmunity has been observed — we of potentially harmful T cells during their detect expression of Aire in parenchymal do not know how the lower levels of mRNA development (see the Highlight ‘Random tissues. However, low levels of expression influence protein expression, antigen reflections’ in our December 2001 issue). were found in peripheral lymphoid tissues, presentation, T-cell repertoire selection and Now, clues from a human genetic disorder although at much lower levels than in immune responsiveness. There is also the have led Harvard researchers Mark Anderson the thymus. A thymic-graft experiment question of how AIRE might regulate the and colleagues to suggest a potential was used to settle the issue. Thymi from ectopic expression of such a large, but select, − − mechanism for this ectopic gene expression. Aire / or Aire+/+ mice were depleted of group of genes. These are important In autoimmune polyendocrine syndrome haematopoietic cells then transplanted into questions for future investigation. type 1 (APS1), loss-of-function mutations in athymic recipients. Only recipients of Aire- Jennifer Bell deficient thymi developed autoantibodies, a single gene, AIRE (autoimmune regulator), References and links which encodes a transcriptional activator, which indicates that Aire must be expressed ORIGINAL RESEARCH PAPER Anderson, M. S. et al. result in autoimmune responses to many by thymic stromal cells to prevent Projection of an immunological self-shadow within the autoimmunity. thymus by the Aire protein. Science 10 October 2002 tissues and organs. Intriguingly, AIRE is (DOI: 10.1126/science.1075958) expressed most highly in the thymus, So, is Aire involved in the ectopic FURTHER READING Derbinski, J., Schulte, A., Kyewski, B. specifically by MECs. So, does AIRE have a expression of organ-specific antigens by & Klein, L. Promiscuous gene expression in medullary thymic role in ectopic gene expression by MECs, MECs? Microarrays were used to compare epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001) | Klein, L. & Kyewski, B. ‘Promiscuous’ leading to tolerance induction? the expression of 12,000 mouse genes by expression of tissue antigens in the thymus: a key to T-cell −/− +/+ Aire-deficient mice have a similar Aire and Aire MECs. The absence of Aire tolerance and autoimmunity? J. Mol. Med. 78, 483–494 autoimmune syndrome to patients with resulted in the decreased expression of (2000) 100–300 genes. Strikingly, the 30 genes that WEB SITE APS1, but an earlier study concluded that Mathis and Benoist lab home page: this was the result of a defect in peripheral were downregulated to the greatest extent http://www.joslinresearch.org/PINET/InvestigatorDetail.asp? tolerance. Anderson and colleagues, who encode mainly tissue-specific proteins, InvestigatorID=11 810 | NOVEMBER 2002 | VOLUME 2 www.nature.com/reviews/immunol © 2002 Nature Publishing Group.

Load more