Dendritic cell presentation of type II collagen
Sammanfattning: Type II collagen (CII) is the main protein component of cartilage and immune recognition of CII plays a critical role for the development of collagen induced arthritis (CIA), a widely used animal model for rheumatoid arthritis (RA). Antigen presentation is an important requirement for the immune response, the more efficient presentation of the antigen the better tolerance will be induced and thereby protect against arthritis. Out of different professional antigen presenting cells (APCs), Langerhans cells (LCs), a subtype of dendritic cells, have been shown to poorly present CII compared to other antigens tested, but also compared to other APCs like B cells and macrophages. The inability to present CII is an exception from the rule that dendritic cells (DCs) are efficient in antigen presentation and subsequently in priming of naive T cells. This incompetence could however be overcome by treating with cysteine protease inhibitors, inhibiting certain cathepsins important for antigen degradation of the CII peptide in endosomes. Cystatin C, a natural occurring inhibitor of cathepsin S, is expressed in immature DCs. Cystatin C deficient mice were back-crossed into arthritis susceptible B10.Q mouse strain, surprisingly, with no difference in CII presentation between different genotypes and APCs in vitro. However, upon CII immunization, homozygous cystatin C deficient mice had a more severe arthritis ans disease incidence compared to wild-type littermates. The anti-CII antibody titers and delayed type hypersensitivity response (DTH) were also increased in the cystatin C deficient mice compared to the wild-type controls. The interpretation of our data favours antigen presentation being the targe cells for cystatin C activity. The present observation that the NOD.Q strain, which is resistant ti CIA in spite of expressing the arthritis susceptibel MHC class II H2-Aq allele, in fact have LCs which do present CII provide possibility to genetically dissect the phenomena. The major loci located on chromosome 2 and 13 were found to control LC presentation of CII. Of these two loci ine of them strongly correlated with CIA, an observation confirmed with the help of the Cia2 congenic mouse. Thus within this limited region there are one or several genes that affect LC CII presentaion and possibly these could be same as the genes controlling CIA.
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