Monocytes and Neutrophils in Juvenile Idiopathic Arthritis

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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Sammanfattning

Juvenile idiopathic arthritis (JIA) is a heterogenous inflammatory joint disease and the most common
rheumatic disease in children. Oligoarticular JIA (oJIA) is the major subgroup, which mainly affects few
and large joints, such as the knee. The immunological processes and key players driving inflammation
within the affected joints are not well characterised. Research has primarily focused on adaptive
immunity, and little is known of the contribution of the innate immune system. Neutrophils and monocytes
are central members, with crucial roles as phagocytes, cytokine producers and regulators of
inflammation. Given the limited knowledge of the role of innate immunity in oJIA, we aimed to
characterize the phenotype and function of monocytes and neutrophils in the arthritic joint.
We found that synovial monocytes had both regulatory and pro-inflammatory features. For example, at
the surface level, they expressed markers of clearance and antigen presentation. This was
correspondingly reflected at the mRNA level. Functionally, the synovial monocytes showed resistance to
cytokine production upon further activation and had an increased efferocytosis. Additionally, they also
promoted activation of healthy T-cells. Interestingly, we found that healthy monocytes acquired the
regulatory features of synovial monocytes (both phenotypical- and fucntional features) through exposure
to patient synovial fluid. This was primarily through the IL-6/JAK/STAT pathway. Furthermore, we showed
that the monocytes obtained the inflammatory features through cell-cell interactions, such as the ability
to promote T-cell activation. Specifically, we found that synovial fibroblasts induced this activation in
healthy monocytes in co-cultures in a contact-dependent manner, especially if the synovial fibroblasts
were priorly exposed to synovial fluid. Indeed, this exposure to synovial fluid resulted in cytokine
production and an enhanced ability to induce immune cell chemotaxis by the fibroblasts.
Furthermore, we found that synovial neutrophils displayed signs of activation at the surface level, and
they had acquired a monocyte-like phenotype. This phenotype correlated with impaired effector
functions, primarily decreased phagocytosis ability and reactive oxygen species production. Interestingly,
their phenotype could not be induced by stimulation of healthy neutrophils with synovial fluid, nor in cocultures
with synovial fibroblasts, suggesting that different mechanisms drive the neutrophil phenotype.
Taken together, the results of this thesis describe the phenotype and role of synovial monocytes and
neutrophils in the pathogenesis of oJIA, and emphasize potential underlying mechanisms driving their
phenotypes that could be utilized to develop therapies.
Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
  • Institutionen för kliniska vetenskaper, Lund
Handledare
  • Kahn, Robin, handledare
  • Bengtsson, Anders, Biträdande handledare
Tilldelningsdatum2023 okt. 6
UtgivningsortLund
Förlag
ISBN (tryckt)978-91-8021-453-7
StatusPublished - 2023

Bibliografisk information

Defence details
Date: 2023-10-06
Time: 09:00
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/69028754246
External reviewer(s)
Name: Croft, Adam P.
Title:professor
Affiliation: University of Birmingham, UK

Ämnesklassifikation (UKÄ)

  • Pediatrik
  • Immunologi inom det medicinska området

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