Impaired toll like receptor-7 and 9 induced immune activation in chronic spinal cord injured patients contributes to immune dysfunction

PLOS ONE, 2017 · DOI: 10.1371/journal.pone.0171003 · Published: February 7, 2017

Simple Explanation

Patients with spinal cord injuries (SCI) often experience reduced immune activation or immunosuppression. This can lead to complications such as urinary and respiratory infections, which are major causes of death in these patients. The research investigates whether this susceptibility to infections is due to impaired recognition of pathogens by the immune system. The study focuses on how the immune cells of chronic SCI patients respond to stimulation via toll-like receptors (TLR7 and TLR9), which are important for recognizing pathogens. The researchers compared the responses of immune cells from SCI patients with those from healthy individuals. The researchers found that in SCI patients, the TLR7 and TLR9 mediated APC function reduced substantially compared to healthy subjects. This suggests that chronic SCI patients have impaired innate immune activation via TLR7 and TLR9, which may contribute to their increased susceptibility to infections.

Study Duration

Not specified

Participants

17 SCI patients and 13 healthy controls

Evidence Level

Not specified

Key Findings

1
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 compared to healthy controls.
2
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.
3
IP10 producing monocytes were significantly fewer compared to healthy subjects in response to TLR7 and TLR9 stimulation of SCI PBMCs, indicating a defect in monocyte activation.

Research Summary

This study aimed to define the role of nucleic acid sensors triggering innate immune response from SCI PBMC. The researchers found that SCI patients with level of injury above T-6 displayed impaired TLR7 and TLR9 mediated immune activation. The results revealed that there is a TLR7 and TLR9 mediated innate immune dysfunction in chronic phase of spinal cord injury. The diminished T-cell response is not due to the increase in CD4+ regulatory T-cells mediated IL10, but due to impaired Th1-biased IFNγ response. The findings suggested that although there is no significant reduction in response to TLR7 and 9 ligands by B-cells and pDCs, the ability of monocytes to get activated is defective (as evidenced by reduced IP10) in response to the existing innate cytokine milieu. These defects could contribute to persistent complications due to increased susceptibility to infections.

Practical Implications

Therapeutic targets

The results might explain the underlying cause for infection susceptibility in the chronic phase of spinal cord injury, especially concerning the innate immune mediated immune activations. More detailed analyses should be planned to explore potential therapeutic targets, thereby helping chronic SCI patients to alleviate susceptibility to infection.

Monocyte Activation

Since the study identifies that monocytes are defective in IP10 production in response to D35 stimulation, future research can focus on developing strategies to enhance monocyte activation in SCI patients.

Infection Susceptibility

The findings provide insights into why chronic SCI patients are more susceptible to infections, particularly concerning innate immune responses. This knowledge can inform the development of targeted interventions to improve immune function.

Study Limitations

1
The sample size of each experiment was different and in some experiments, sample size of patient and healthy subjects was relatively limited.
2
The study intentionally included only complete SCI patients above level of T-6 to exclude the potential impact of the autonomic nerve system on the immune system.
3
The study included only chronic SCI patients in order to exclude the effects of both infections of the acute and sub-acute stages and the obscuring contributions of medication such as steroids.

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