Th17 cells induce a distinct graft rejection response that does not require IL-17A.

IL-17A-producing helper T (Th17) cells have been implicated in the pathogenesis of autoimmune disease, inflammatory bowel disease and graft rejection, however the mechanisms by which they cause tissue damage remain ill-defined. We examined what damage Th17 cell lines could inflict on allogeneic skin grafts in the absence of other adaptive lymphocytes. CD4(+) Th17 cell lines were generated from two TCR transgenic mouse strains, A1(M).RAG1(-/-) and Marilyn, each monospecific for the male antigen Dby. After prolonged in vitro culture in polarizing conditions, Th17 lines produced high levels of IL-17A with inherently variable levels of interferon gamma (IFNγ) and these cells were able to maintain IL-17A expression following adoptive transfer into lymphopenic mice. When transferred into lymphopenic recipients of male skin grafts, Th17 lines elicited a damaging reaction within the graft associated with pathological findings of epidermal hyperplasia and neutrophil infiltration. Th17 cells could be found in the grafted skins and spleens of recipients and maintained their polarized phenotype both in vivo and after ex vivo restimulation. Antibody-mediated neutralization of IL-17A or IFNγ did not interfere with Th17-induced pathology, nor did it prevent neutrophil infiltration. In conclusion, tissue damage by Th17 cells does not require IL-17A.

Protein misfolding in neurodegenerative diseases.

A common pathogenic mechanism shared by diverse neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease and transmissible spongiform encephalopathies, may be altered protein homeostasis leading to protein misfolding and aggregation of a wide variety of different proteins in the form of insoluble fibrils. Mutations in the genes encoding protein constituents of these aggregates have been linked to the corresponding diseases, thus a reasonable scenario of pathogenesis was based on misfolding of a neurone-specific protein that forms insoluble fibrils that subsequently kill neuronal cells. However, during the past 5 years accumulating evidence has revealed the neurotoxic role of prefibrillar intermediate forms (soluble oligomers and protofibrils) produced during fibril formation. Many think these may be the predominant neurotoxic species, whereas microscopically visible fibrillar aggregates may not be toxic. Large protein aggregates may rather be simply inactive, or even represent a protective state that sequesters and inactivates toxic oligomers and protofibrils. Further understanding of the biochemical mechanisms involved in protein misfolding and fibrillization may optimize the planning of common therapeutic approaches for neurodegenerative diseases, directed towards reversal of protein misfolding, blockade of protein oligomerization and interference with the action of toxic proteins.