Synovial fluid from patients with rheumatoid arthritis modulates monocyte cell-surface phenotype.

OBJECTIVES: To investigate the ability of synovial fluid from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) to modulate cell-surface phenotype, function and viability of monocytes. METHODS: Monocytes from healthy donors were incubated with synovial fluid from patients with RA or OA. These were then cultured with autologous healthy CD4+ T-cells. Immunoglobulin-like transcript 4 (ILT4) and CD86 were evaluated on stimulated monocytes and CD4+ T-cells via fluorescence activated cell sorting. RESULTS: Monocytes incubated with synovial fluid from patients with RA (SF-RA; n = 12) had significantly lower ILT4 and higher CD86 levels than those incubated with synovial fluid from patients with OA (SF-OA; n = 12) or medium alone. In patients with RA, there was a significant negative correlation between ILT4 and disease activity score (DAS; r = -0.699), and a positive correlation between CD86 and DAS (r = 0.626). T-cells costimulated with monocytes cultured with SF-RA produced significantly more interferon-γ and tumour necrosis factor-α than those costimulated with monocytes cultured with SF-OA or controls. CONCLUSIONS: Soluble mediators in SF-RA could contribute to modulating inflammation and local effectiveness of the immune response.

Downregulation of immunoglobulin-like transcript-4 (ILT4) in patients with psoriatic arthritis.

OBJECTIVE: The immunoglobulin-like transcript-4 (ILT4) is an inhibitory receptor that modulates the activity of innate immune agents. We determined the expression of ILT4 and analysed the relationship with the expression of costimulatory proteins and tumor necrosis factor-α (TNF-α) production in monocytes from patients with psoriatic arthritis (PsA) starting anti-TNF treatment. METHODS: Peripheral blood monocytes from 15 healthy controls and from 16 patients with PsA were activated in vitro by CD40 ligand (CD40L) and analyzed for ILT4, CD40, CD80 and CD86 expression, and spontaneous lipopolysaccharide (LPS)-induced TNF-α production by flow cytometry, before and after treatment with adalimumab. RESULTS: The percentage of ILT4-negative monocytes was greater in PsA patients compared to controls and negatively correlated with DAS44. Normal monocytes treated with sera of PsA patients showed a reduced expression of ILT4 compared with monocytes exposed to sera from controls. CD40, CD80 and CD86 expression was higher in patients compared to controls. Both spontaneous and LPS-induced TNF-α production was restricted to ILT4-negative monocytes and was greater in PsA patients compared to controls. Finally, twelve weeks-treatment with adalimumab resulted in a significant increase of ILT4 expression and a decrease of costimulatory molecules expression in PsA patients, compared to pre-therapy levels. CONCLUSIONS: These data support the possibility that changes in the immunophenotype of monocytes play a role in the pathogenesis of PSA. Thus, modulation of the expression of ILT4 may represent an enticing new therapeutic target.

Upregulation of the inhibitory receptor ILT4 in monocytes from septic patients.

Sepsis-induced immune dysfunction is a complex phenomenon that involves both innate and adaptive responses. Upregulation of the inhibitor receptor named immunoglobulin like transcript 4 (ILT4) is crucial to the tolerogenic function of monocytes. Here, ILT4 expression, endotoxin-induced IL-12 and IL-10 production and CD86 expression were investigated in circulating monocytes from 16 patients with severe sepsis and 16 age and sex matched controls. We found that monocytes from patients with severe sepsis express significantly higher levels of ILT4 than monocytes from controls. Upregulation of ILT4 expression appeared to be induced by soluble factors present in the serum of septic patients and directly correlated with the degree of organ dysfunction. ILT4(+) monocytes from septic patients also displayed an alteration in the cytokine response to endotoxin stimulation characterized by reduced IL-12 production and increased IL-10 production, and a reduced expression of the costimulatory molecule CD86. In conclusion, the increased ILT4 expression and IL-10 production and the decreased CD86 expression and IL-12 production indicate that during sepsis monocytes undergo substantial modulation of the surface and cytokine phenotype. These phenotypic changes may interfere with the antigen presenting cell activity of monocytes, which may contribute to the impairment of adaptive immune responses that takes place during sepsis.

Proton magnetic resonance spectroscopy in the evaluation of patients with acute Charcot neuro-osteoarthropathy.

OBJECTIVE: To evaluate whether bone marrow proton magnetic resonance spectroscopy (MRS) might provide a quantitative parameter able to assess disease activity in acute Charcot neuro-osteoarthropathy (CN). METHODS: Ten diabetic patients with stage 0 CN were prospectively evaluated at clinical onset and during treatment follow-up. The MRS lipid spectrum was analysed and a lipid polyunsaturation index (PUI) was calculated. Disease recovery was defined as the disappearance of bone marrow oedema as demonstrated on MRI short-tau-inversion-recovery (STIR) images. A 3-T MRI was used. RESULTS: Inter- and intra-individual PUI measurements generated reproducible results with approximately 7 % and 6 % variation respectively. Baseline PUI values were significantly higher in patients with acute CN compared with controls. Also, a significant positive correlation was observed between baseline PUI values and serum levels of IL-6 and TNF-α. During follow-up a gradual decrease in PUI was observed. The percentage reduction of PUI values at 3 months' follow-up with respect to baseline values showed a negative correlation with recovery time. CONCLUSIONS: Bone marrow MRS may provide a measurable index that allows progressive evaluation of disease activity in acute CN. MRS may be a complementary tool that can be used to guide clinicians in the management of acute CN patients. KEY POINTS: • Bone marrow MRS demonstrates lipid alterations in acute Charcot neuro-osteoarthropathy (CN). • Bone marrow MRS allows disease activity in acute CN to be evaluated. • MRS could become a new tool in the management of CN.