Localized elevation in Type I IFN has been uniquely linked to the severe Lyme arthritis that develops in C3H mice infected with the spirochete Borrelia burgdorferi. In this study, the dynamic interactions that result in generation of these responses were further examined in C3H mice carrying the Type I IFN receptor gene ablation, which effectively blocks all autocrine/paracrine signaling crucial to induction of downstream effectors. Reciprocal radiation chimeras between C3H and IFNAR1−/− mice implicated both radiation-sensitive and radiation-resistant cells of the joint tissue in the pro-arthritic induction of Type I IFN. Ex vivo analysis of cells from the naïve joint revealed CD45+ cells residing in the tissue to be uniquely capable of initiating the Type I IFN response to B. burgdorferi. Type I IFN responses were analyzed in real time by lineage sorting of cells from infected joint tissue. This demonstrated that myeloid cells, endothelial cells, and fibroblasts were responsible for propagating the robust IFN response, which peaked at Day 7 post infection and rapidly resolved. Endothelial cells and fibroblasts were the dominant sources of IFN signature transcripts in the joint tissue. Fibroblasts were also the major early source of chemokines associated with PMN and monocyte/macrophage infiltration, thus providing a focal point for arthritis development. These findings suggest joint-localized interactions among related and unrelated stromal, endothelial, and myeloid cell lineages that may be broadly applicable to understanding the pathogeneses of diseases associated with type I IFN signature, including systemic lupus erythematosus and some rheumatoid arthritides.

IL-10 is a non-redundant inflammatory modulator that suppresses arthritis development in Borrelia burgdorferi infected mice. Infected B6 IL-10−/− mice were previously found to have a prolonged interferon-inducible response in joint tissue. Infection of B6 IL-10 reporter mice identified macrophages and CD4+ T cells as the primary sources of IL-10 in the infected joint tissue, suggesting that early local production of IL-10 dampened the pro-arthritic interferon response. Treatment of B6 IL-10−/− mice with anti-IFN-γ reduced the increase in arthritis severity and suppressed interferon-inducible transcripts to wild type levels, thereby linking dysregulation of IFN-γ to disease in the B6 IL-10−/− mouse. Arthritis in B6 IL-10−/− mice was associated with elevated numbers of NK cell, NKT cell, α/β T cell, and macrophage infiltration of the infected joint. FACS lineage sorting revealed NK cells and CD4+ T cells as sources of IFN-γ in the joint tissue of B6 IL-10−/− mice. These findings suggest the presence of a positive feedback loop in the joint tissue of infected B6 IL-10−/− mice, where production of inflammatory chemokines, infiltration of IFN-γ producing cells, and additional production of inflammatory cytokines result in arthritis. This mechanism of arthritis is in contrast to that seen in C3H mice, where arthritis development is linked to transient production of Type I interferon, and develops independently of IFN-γ. Due to the sustained interferon response driven by NK cells and T cells, we propose the B6 IL-10−/− mouse as a potential model to study the persistent arthritis observed in some human Lyme disease patients.

Antegrade or retrograde nailing for femoral shaft fractures remains the gold standard, but long-term data on functional outcomes after intramedullary nailing are lacking. In a retrospective review of prospectively collected patient registry data, patients with an isolated femoral shaft fracture treated with antegrade or retrograde femoral nailing from 1997 to 2012 were interviewed and their medical records analyzed. Functional reported outcome data were obtained via the visual analog scale (VAS) for pain and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 5 to 17 years postoperatively. Antegrade and retrograde intramedullary nailing of diaphyseal femur shaft fractures demonstrated a mean WOMAC of 23.5%±23.6% (range, 0%–82.3%) and 29.7%±24.0% (range, 0%–88%), respectively ( P =.23). The mean VAS scores of the antegrade vs retrograde intramedullary nailing groups were 2.5±2.6 (range, 0–8) and 3.4±2.8 (range, 0–10), respectively ( P =.11). Location of pain differed between groups as well, with the antegrade group noting an increased rate of hip pain (25.6% vs 7.0%, P =.01), but a nonsignificant difference in the rate of thigh pain (27.9% vs 15.5%, P =.15) and knee pain (18.6% vs 26.7%, P =.49) as compared with the retrograde group. Diaphyseal femur fractures are successfully treated with either antegrade or retrograde intramedullary nails without significantly differing long-term functional outcomes, which correlates with other reported findings in the literature at short-term follow-up. [ Orthopedics . 2020;43(4):e278–e282.]

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