Innate Immunity in ALS: A Biobank to Provide Answers

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ALS – Pathology, Morbidity, Mortality Stats

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is adebilitating condition that affects voluntary muscle movements such as walking, talking and breathing. The disease destroys nerve cells in the brain and the spinal cord, causing severe disability. ALS typically affects those between the ages of forty and seventy with the average age at diagnosis being 55. However, in recent times, there are increasing reports of ALS diagnosis in people younger than 40 years old.

The ALS Association suggests that the incidence rate of Amyotrophic Lateral Sclerosis to be 1.8 to 2 per 100,000 people, indicating 5,760 to 6,400 new diagnoses per year. Most people with ALS die within 3 to 5 years of the first appearance of the symptoms, primarily due to respiratory failure. Such a rapid rate of disease progression makes it challenging to develop new treatments.

Current treatment options for ALS are focused on managing the symptoms associated with the disease and attempting to slow down the rate of disease progression. However, there is no cure for ALS. The molecular mechanisms underlying the disease are poorly understood, and need to be further elucidated to form the basis of novel therapeutic strategies¹.

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Innate Immunity and ALS

Innate immune responses are the first line of defense against any foreign infection, and are not specific to a particular pathogen. The complement system, which is a component of the innate immune response,  consists of about 20 interacting soluble proteins that circulate in the blood, and are mostly inactive until they are triggered by an infection. The complement system is a cascade of reactions that culminates in the assembly of  a ‘membrane attack complex’. This complex assembles in the pathogen membrane and form aqueous pores through the membrane, thus making the membrane leaky and causing the microbial cell to lyse².

In ALS, the immune system has been found to be altered. Studies have shown that the blood of ALS patients have increased levels of CD4+ cells, and reduced CD8+ T-lymphocytes compared to healthy controls³. Resident innate immune cells have also been found to be altered in the brains of ALS patients as well as in animal models of ALS. Indeed, staining for leukocyte common antigen (LCA), lymphocyte function associate molecule-1 (LFA-1), and complement receptors CR3 (CD11b) and CR4 (CD11c) are increased, supporting the idea that microglia and macrophages are activated in the areas of ALS degeneration⁴. Thus, the immunological aspect of ALS etiology deserves more investigation.

ALS Biobank to Study Innate Immunity Etiology

In this study published in the British Medical Journal, the study authors intend to develop a national ALS biobank in Denmark, that comprises samples from three groups of patients: patients with ALS, neurologically healthy patients (healthy controls) and patients with neurological diseases other than ALS (neurological controls). From all patients, venous blood and spinal fluid (CSF) from a lumbar puncture is collected and stored for follow-up studies. The following demographic information about the patients with ALS are collected: age, gender, subtype of disease, current stage of disease, T₀ (defined as the month and year of the first subjective symptoms that later led to the diagnosis of either probable ALS or definite ALS), treatment regimen, daily medication and observed cognitive changes.

At this point, a number of studies have been planned by the group that evaluate the presence and expression levels of the various components of the complement pathway in the CSF, plasma and muscle biopsies: ficolin-1, ficolin-2, ficolin-3, collectin-11, PTX3, MASP-3, MBL, MAP-1, C4c, C3bc, and sC5b-9⁵.

This manuscript describes the generation of a Danish ALS biobank that potentially provides a starting point for future national ALS research. The generation of this biobank was inspired by the hypothesis that the innate immune system plays a significant role in the pathogenesis of ALS. The interesting fact about this particular biobank is that all Danish citizens are registered in the National Patient Registry (DNPR), which is linkable on an individual level with other clinical and administrative registries⁶. Hence, there is a possibility to conduct registry-based research combined with data from this ALS biobank in future studies.

The authors believe the establishment of this biobank will be a major step in moving forward not just ALS research, but research in other rare disease as well “With the present project, a substantial amount of biological material from patients suffering from ALS will be obtained. We hope that the project will bring ALS research a significant step forward, will inspire other groups to start similar projects regarding this and other rare diseases, and hence will enable future basic biobank research within this challenging field.”

References:

1. ALS association: https://www.als.org/. Accessed 22^nd September 2020
2. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Innate Immunity. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26846/
3. Mantovani S., Garbelli S., Pasini A., Alimonti D., Perotti C., Melazzini M., Bendotti C., Mora G. (2009). Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J. Neuroimmunol. 210, 73–7910.1016
4. Papadimitriou D., Le Verche V., Jacquier A., Ikiz B., Przedborski S., Re D. B. (2010). Inflammation in ALS and SMA: sorting out the good from the evil. Neurobiol. Dis. 37, 493–50210.
5. Phani S, Re DB, Przedborski S. The Role of the Innate Immune System in ALS. Front Pharmacol. 2012;3:150. Published 2012 Aug 14. doi:10.3389/fphar.2012.00150
6. Kjældgaard AL, Pilely K, Olsen KS, Lauritsen AØ, Pedersen SW, Møller K, Garred P. Amyotrophic lateral sclerosis and the innate immune system: protocol for establishing a biobank and statistical analysis plan. BMJ Open. 2020 Aug 5;10(8):e037753.
7. Schmidt M, Schmidt SAJ, Sandegaard JL, et al. . The Danish national patient registry: a review of content, data quality, and research potential. Clin Epidemiol 2015;7:449–90.