Journal of Molecular Medicine

, 89:833 | Cite as

Danger signals activating innate immunity in graft-versus-host disease

  • Robert Zeiser
  • Olaf Penack
  • Ernst Holler
  • Marco Idzko


Extensive cell death with consecutive release of danger signals can cause immune-mediated tissue destruction. The abundance of cell death is likely to determine the relevance of the danger signals as physiological mechanisms that counteract immune activation may be overruled. Such constellation is conceivable in chemo-/radiotherapy-induced tissue damage, reperfusion injury, trauma, and severe infection. Studies on graft-versus-host disease (GvHD) development have to consider the effects of chemo-/radiotherapy-related tissue damage leading to the release of exogenous and endogenous danger signals. Our previous work has demonstrated a role for adenosine-5′-triphosphate (ATP) as an endogenous danger signal in GvHD. Besides ATP, uric acid or soluble extracellular matrix components are functional danger signals that activate the NLRP3 inflammasome when released from dying cells or from extracellular matrix. In contrast to sterile inflammation, GvHD is more complex since bacterial components that leak through damaged intestinal barriers and the skin can activate pattern recognition receptors and directly contribute to GvHD pathogenesis. These exogenous danger signals transmit immune activation via toll-like receptors and NOD-like receptors of the innate immune system. This review covers both the impact of endogenous and exogenous danger signals activating innate immunity in GvHD.


Graft-versus-host disease Danger signals Innate immunity Adenosine triphosphate Purinergic receptors Extracellular matrix Pathogen-associated molecular patterns Pattern recognition receptors Toll-like receptors NOD-like receptors 



Antigen-presenting cells


Apoptosis-associated speck-like protein containing caspase activation and recruitment domain




Caspase recruitment domain




Dendritic cells


Extracellular matrix


Graft-versus-host disease


Indoleamine 2,3-dioxygenase


Muramyl dipeptide


Mesenchymal stromal cells


NACHT, LRR, and PYD domains-containing protein 3


Nicotinamide adenine dinucleotide


NOD-like receptors


NACHT-, LRR-, and PYD-containing proteins


Nucleotide-binding oligomerization domain


Pathogen-associated molecular patterns


Plasmacytoid DC


Pattern recognition receptors


Reactive oxygen species


Toll-like receptors


Regulatory T-cells


Uric acid



We apologize to those whose work was not cited due to space limitations.

Grant support

This study was supported by the Deutsche Forschungsgemeinschaft, Germany (ID 7/4-2 to M.I., ZE 872/1-1 and Heisenberg Fellowship to R.Z. and PE 1450/1-1 to O.P.) and the Deutsche Krebshilfe, Germany (ID 108977 to O.P.).

Conflict of interests

The authors declare no competing financial interests.


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Robert Zeiser
    • 1
  • Olaf Penack
    • 2
  • Ernst Holler
    • 3
  • Marco Idzko
    • 4
  1. 1.Department of Hematology and OncologyFreiburg University Medical Center, Albert-Ludwigs-UniversityFreiburgGermany
  2. 2.Department of Hematology and OncologyCharité, Campus Benjamin FranklinBerlinGermany
  3. 3.Department of Hematology and OncologyUniversity of RegensburgRegensburgGermany
  4. 4.Department of PneumologyFreiburg University Medical Center, Albert-Ludwigs-UniversityFreiburgGermany

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