The role of peripheral immunity in ALS: a population-based study

Abstract

Background Systemic inflammation has been proposed as a relevant mechanism in Amyotrophic Lateral Sclerosis (ALS). Recent evidence shows that an increased inflammatory status correlates with survival in ALS. Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate the role and characteristics of systemic immunity in a population-based ALS cohort using readily available hematological indexes that reflect changes in innate and adaptive immunity. Methods We collected the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d' Aosta Register for ALS (PARALS) from 2007 to 2019. Demographic and clinical data were collected using registry data. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. Logistic, linear and Cox regression models were used as appropriate. Results After adjustment for relevant covariates, neutrophils (p=0.001) and markers of increased innate immunity (NLR, p=0.008 and SII, p=0.006) were associated with a faster disease progression. Similarly, elevated innate immunity markers correlated with worse pulmonary function and shorter survival. Sex-based differences emerged, as the prognosis in women also correlated with a low lymphocyte (p=0.045) and a decreased LMR (p=0.013). ALS patients with cognitive impairment exhibited lower levels of monocytes (p=0.0415) and, although only in later-onset ALS (age at onset > 70 years), lower lymphocytes (p=0.006) and increased NLR (p=0.021) and SII (p=0.030). Conclusions and Relevance Our results confirm that a dysregulated systemic immune system participates in ALS progression. More specifically, an elevated innate immune response is associated with faster 2 progression and reduced survival. The immune response varied according to sex and age, thus prompting the speculation that involved immune pathways are patient-specific. Finally, we observed that ALS patients with greater cognitive impairment showed a reduction in monocytes count. Those data revealed that systemic inflammation plays a multifaceted role in ALS: further studies will help translate those findings into clinical practice or targeted treatments.

Competing Interest Statement

Maurizio Grassano, Umberto Manera, Fabiola De Marchi, Paolo Cugnasco, Enrico Matteoni, Margherita Daviddi, Luca Solero, Alessandro Bombaci, Francesca Palumbo, Rosario Vasta, Antonio Canosa, Paolina Salamone, Giuseppe Fuda, Federico Casale, Letizia Mazzini, Cristina Moglia: no disclosures. Andrea Calvo has received a research grant from Cytokinetics. Adriano Chio serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Denali Pharma, Cytokinetics, and Amylyx.

Funding Statement

Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, grant RF-2016- 02362405); Ministry of Education, University and Research (Progetti di Rilevante Interesse Nazionale programme, grant 2017SNW5MB); European Commissions Health Seventh Framework Programme (FP7/20072013 under grant agreement 259867).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study design was approved by the institutional ethical committees of Azienda Ospedale Universita, Citta della Salute e della Scienza, and Azienda Ospedale Universita Maggiore di Novara. All patients provided written informed consent.

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Yes

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Data Availability

Data are available upon reasonable request to the corresponding author by interested researchers.

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