The arthritogenic adjuvant squalene does not accumulate in joints, but gives rise to pathogenic cells in both draining and non-draining lymph nodes.
A single intradermal injection of the adjuvant-oil squalene induces T cell-mediated arthritis in DA rats. The chain of events leading from non-specific provocation of the immune system to arthritis, with clinical similarities to rheumatoid arthritis, is largely undetermined. Here, we combined in vivo tracking of tritium-labelled squalene with lymph node (LN) cell transfer experiments to determine where critical activation events may take place. The majority of squalene remained at the injection site (79%). The amounts recovered in peripheral joints (<1%) were equal to that recovered in other organs that can be targets in autoimmune diseases. This argues that arthritis does not develop as a consequence of adjuvant accumulation in joints. In contrast, substantial amounts of squalene were recovered in hyperplastic LN draining the injection site (1-13%). The adjuvant was deposited to a larger extent in cells than in extracellular matrix. The draining LN cells could transfer arthritis to naïve irradiated DA rats following in vitro stimulation with conA. Interestingly, non-draining LN were also hyperplastic and harboured arthritogenic cells, although they contained low amounts of squalene (<1%). Consequently, the amount of arthritogenic adjuvant in a particular LN is not closely linked to the development of pathogenic cells. The distribution pattern of squalene was similar in MHC-identical but arthritis-resistant PVG.1AV1 and LEW.1AV1 rats, and it was unaffected by T cell depletion with a monoclonal antibody (R73). Thus, T cells and non-MHC genes do not regulate dissemination of squalene, but rather determine arthritis development at the level of adjuvant response.
Holm
B C
BC
Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Stockholm, Sweden. Barbro.Holm@cmm.ki.se
Svelander
L
L
Bucht
A
A
Lorentzen
J C
JC
D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D006965:Hyperplasia; D007596:Joints / Q000378:metabolism; D007700:Kinetics; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology*; D008212:Lymphocyte Depletion; D051381:Rats; D011917:Rats, Inbred Lew; D013045:Species Specificity; D013185:Squalene / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D014018:Tissue Distribution
D000276:Adjuvants, Immunologic; D013185:Squalene