Abstract
Reduced immune activation or immunosuppression is seen in patients withneurological diseases. Urinary and respiratory infections mainly manifested as septicemia and pneumonia are the most frequent complications following spinal cord injuries and they account for the majority of deaths. The underlying reason of these losses is believed to arise due to impaired immune responses to pathogens. Here, we hypothesized that susceptibility to infections of chronic spinal cord injured (SCI) patients might be due to impairment in recognition of pathogen associated molecular patterns and subsequently declining innate and adaptive immune responses that lead to immune dysfunction. We tested our hypothesis on healthy and chronic SCI patients with a level of injury above T-6. Donor PBMCs were isolated and stimulated with different toll like receptor ligands and T-cell inducers aiming to investigate whether chronic SCI patients display differential immune activation to multiple innate and adaptive immune cell stimulants. We demonstrate that SCI patients' B-cell and plasmacytoid dendritic cells retain their functionality in response to TLR7 and TLR9 ligand stimulation as they secreted similar levels of IL6 and IFNα. The immune dysfunction is not probably due to impaired T-cell function, since neither CD4+ T-cell dependent IFNγ producing cell number nor IL10 producing regulatory T-cells resulted different outcomes in response to PMA-Ionomycin and PHA-LPS stimulation, respectively. We showed that TLR7 dependent IFNγ and IP10 levels and TLR9 mediated APC function reduced substantially in SCI patients compared to healthy subjects. More importantly, IP10 producing monocytes were significantly fewer compared to healthy subjects in response to TLR7 and TLR9 stimulation of SCI PBMCs. When taken together this work implicated that these defects could contribute to persistent complications due to increased susceptibility to infections of chronic SCI patients.
Highlights
Infectious complications, predominantly septicemia and pneumonia are the most common causes of death in the years following spinal cord injury (SCI) [1,2]
We found that SCI patients with level of injury above T-6 displayed impaired TLR7 and TLR9 mediated immune activation
Cytokine ELISA results revealed that SCI patients‘B cells and pDCs compared to healthy control cells had no significant difference in response to R848 (TLR7 ligand, 5μg/ml) and D35 (TLR9 ligand, 3μM) stimulation, since they induced similar levels of IL6 and IFNα (Fig 1A and 1B, respectively)
Summary
Infectious complications, predominantly septicemia and pneumonia are the most common causes of death in the years following spinal cord injury (SCI) [1,2]. It is likely that there is an increased susceptibility to infections in patients with chronic SCI due to impaired sensing of pathogen associated molecular patterns (PAMPs) of the microbial world [3]. This increased susceptibility to infections following SCI has prompted the researchers to consider the reasons leading to reduced immune response in this patient group. Natural killer cell counts and cytotoxicity levels were found to be decreased [4], whereas there were contradictory reports about the relationship between the level of injury and immune dysfunction [5,6]
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