Polymorphonuclear Cell Functional Impairment in Relapsing Remitting Multiple Sclerosis Patients: Preliminary Data

Abstract

Multiple Sclerosis patients run an increased risk of microbial infections, which leads to high rates of hospitalization and infection-related mortality. Although immunotherapy may increase infection risk in some cases, data as to the relationship among microbial factors, immunotherapy and alterations in the innate immunity of these patients are still scanty. On these grounds, this interdisciplinary study aims at investigating the role the functional activity of polymorphonuclear cells (PMNs) play in relapsing remitting multiple sclerosis at different stages. The in vitro ability of PMNs from patients, either untreated or treated with immunosuppressant or immunomodulatory drugs to kill Klebsiella pneumonia or Candida albicans, were investigated and compared to PMNs from healthy subjects. The release of various cytokines was also assessed, as was the production of reactive oxygen species and their ability to regulate apoptosis after microbial stimulation. Our results indicate that although patients have a normal number of PMNs, they have a statistically significant (p<0.05) reduction in intracellular killing activity. Although variations are strongly related to the therapeutic management of patients, they are independent from their disease stage. As no statistically significant differences were observed between patients and controls in cytokine release values, reactive oxygen species production or apoptosis, we came to the conclusion that other factors may be involved. Supportive validation of these results from further studies might well help in identifying a subset of patients at high risk of infection who could benefit from a closer follow-up and/or antibiotic prophylaxis.

The Emerging Role of Neutrophil Granulocytes in Multiple Sclerosis

“…However, in this study, neutrophils from the treated group with normal oxidative burst demonstrated significantly reduced ability to kill bacteria (in vitro) [58]. Furthermore, in people with MS, with or without treatment, a slight reduction in neutrophil production of pro-inflammatory cytokines (IL-1β and IL-8) was found in response to bacterial stimulation (in vitro) [58].…”

“…Secondary studies evaluating neutrophil phenotype and function in MS are prevalent and heterogeneous, producing no consensus as to the effects of disease on neutrophils or vice versa. Neutrophil oxidative burst studies either describe neutrophils as primed, exhibiting enhanced ROS production [24], or as normal, with similar ROS production, in healthy controls and people with MS, irrespective of treatment [58]. However, in this study, neutrophils from the treated group with normal oxidative burst demonstrated significantly reduced ability to kill bacteria (in vitro) [58].…”

“…Neutrophil oxidative burst studies either describe neutrophils as primed, exhibiting enhanced ROS production [24], or as normal, with similar ROS production, in healthy controls and people with MS, irrespective of treatment [58]. However, in this study, neutrophils from the treated group with normal oxidative burst demonstrated significantly reduced ability to kill bacteria (in vitro) [58]. Furthermore, in people with MS, with or without treatment, a slight reduction in neutrophil production of pro-inflammatory cytokines (IL-1β and IL-8) was found in response to bacterial stimulation (in vitro) [58].…”

“…Collectively, phenotypic studies suggest that activated neutrophils may participate in MS immunopathology. While priming prolongs the lifespan of PMN by activating anti-apoptotic signal transduction pathways and transcription factors to decrease transcription of pro-apoptotic factors, no change in apoptosis of neutrophils from people with MS was reported under stimulated or unstimulated conditions [58].…”

Inhibition of Human Neutrophil Functions In Vitro by Multiple Sclerosis Disease-Modifying Therapies

“…Polymorphonuclear leukocytes (PMNs) play a key role in the elimination of pathogens from the body through a wide range of effector functions [15][16][17][18][19][20]. As we have previously shown that PMNs isolated from RRMS patients display reduced intracellular killing activity [20], here we sought to determine whether treatment with first-line (moderate-efficacy) DMTs, such as IFNβ-1b (Extavia ® ) and GA (Copaxone ® ), or second-line (high-efficacy) DMTs, such as FTY (Gilenya ® ) and NAT (Tysabri ® ), would affect neutrophil functions in vitro.…”