New gout test: enhanced ex vivo cytokine production from PBMCS in common gout patients and a gout patient with Kearns-Sayre syndrome.
Monosodium urate (MSU) monohydrate crystals synergize with various toll-like receptor (TLR) ligands to induce interleukin-(IL)-1β production. Data are shown from a young male with mitochondriopathy in Kearns-Sayre syndrome (KSS) who developed gout and underwent urate-lowering therapy (ULT) versus a group of common gout patients. Peripheral blood mononuclear cells (PBMCs) are exposed in vitro to MSU crystals in the presence/absence of TLR2 ligands palmitic acid (C16:0) or palmitoyl-3-cysteine (Pam3Cys); proinflammatory cytokine production (IL-1β, IL-6, IL-8) is assessed by specific ELISA's. MSU crystals alone failed to induce IL-1beta, IL-6, or IL-8 in both the KSS patient and gout controls. A strong synergy between MSU crystals and C16:0 or Pam3Cys for induction of IL-1 beta/IL-6 is found in gout patients, but in gout with KSS, we found even more response than in control gout patients. Pam3Cys exposure reveals an enhanced response in cells originating from the KSS patient, indicating a high producer phenotype in response to TLR2 stimulation. During ULT, serum urate levels dropped in the KSS case. The hyperresponse of TLR2 may be secondary to the high serum urate concentration of 0.92 mmol/l that was initially found in circulation in vivo. Within a 6-month period, the serum urate concentration dropped, and the in vitro stimulation tests improved but did not fully normalize yet. The ex vivo cytokine production in gout patients is promising a novel gout test; PBMCs' responses in the mitochondriopathic gout patient is enhanced when compared with common gout patients, indicating a supersensitive gout patient profile. The non-inflammatory presentation in the KSS case with bulky gout is due to less inflammatory MSU crystals, i.e., specific crystal stereochemical/conformational properties. For developing gout attacks, the serum urate level and specific crystal properties both are of importance. Key Messages 1. Ex vivo cell tests are promising to serve as a novel gout lab test for screening purposes. 2. Ex vivo cellular responses are reduced following intraarticular glucocorticoid injection and/or urate-lowering therapy. 3. Crystal conformation properties play a role in the inflammatory in vivo and ex vivo response in gout. 4. A young male with Kearns-Sayre syndrome is described with less pronounced inflammatory PMBC responses to his own MSU crystals which explains the advanced stage of urate accumulation in this individual.
Department of Rheumatology, Radboud University Medical Centre, Geert Grooteplein Noord 8, 6525 GA, Nijmegen, The Netherlands, Tim.Jansen@radboudumc.nl.
Tim L
TL
Jansen
Dianne
D
Berendsen
Tania O
TO
Crisan
Maartje C P
MC
Cleophas
Mirian C H
MC
Janssen
Leo A B
LA
Joosten
D000328:Adult; D016207:Cytokines / Q000096:biosynthesis*; D006073:Gout / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism; D006801:Humans; D007625:Kearns-Sayre Syndrome / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D014527:Uric Acid / Q000378:metabolism
D016207:Cytokines; D014527:Uric Acid