Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL.
Correlation of Peripheral Immunity With Rapid Amyotrophic Lateral Sclerosis Progression.
JAMA Neurol. 2017 Dec 1;74(12):1446-1454.
PubMed.
Murdock and colleagues have conducted a detailed study of leukocyte populations in peripheral blood samples taken from ALS patients and controls. Serial samples were collected from a number of the ALS patients, allowing the authors to track changes in leukocyte subpopulations over time. They discovered that total leukocyte counts, and counts of a number of subpopulations, including neutrophils, natural killer (NK) cells, but not CD4+ or CD8+ T-cells, are increased in ALS patients compared to controls. They went on to test whether leukocyte counts correlated with disease progression as measured by change in ALS-FRS score.
Change over time in several of the cell populations correlated significantly with change in the ALS-FRS score. However, ALS is a relentless disease that will always progress over time, and therefore any marker that changes in a consistent manner over time might be expected to correlate with changes in the ALS-FRS score. This highlights the great unanswered question for study of the peripheral immune system in ALS—correlation or causation? We know that changes in the peripheral immune system correlate with changes in ALS: for example, work from our group has shown that gene expression in peripheral lymphocytes can be used to classify ALS patients as fast or slow progressors (Mar 2017 news on Cooper-Knock et al., 2017). What we do not know is whether these peripheral changes are causative and therefore a good therapeutic target, or whether they are a secondary downstream effect of changes in the CNS—a limitation acknowledged by the authors of this work. A recent study of CNS microglia has suggested that these cells are relatively long-lived, tend to remain in their local environment, and increase their numbers through cell division rather than recruitment from outside the CNS (Aug 2017 news on Réu et al., 2017, and Füger et al., 2017). This would suggest that the CNS immune system is relatively independent but there is much more work to be done.
A very interesting aspect of this study was the dissection of myeloid cell subgroups using cell surface markers. The authors discovered that, although changes in CD16+ and CD16- monocytes overall did not correlate with changes in the ALS-FRS, when the analysis was limited to monocytes expressing CX3CR1 there was a significant relationship. Increased numbers of CX3CR1+ cells associated with slower disease progression. CX3CR1 has been implicated in myeloid cell trafficking to the CNS and therefore this observation may be consistent with a protective effect of migrating peripheral monocytes. This is an exciting observation which may provide a peripherally accessible therapeutic target.
References:
Cooper-Knock J, Green C, Altschuler G, Wei W, Bury JJ, Heath PR, Wyles M, Gelsthorpe C, Highley JR, Lorente-Pons A, Beck T, Doyle K, Otero K, Traynor B, Kirby J, Shaw PJ, Hide W.
A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis.
Acta Neuropathol Commun. 2017 Mar 16;5(1):23.
PubMed.
Réu P, Khosravi A, Bernard S, Mold JE, Salehpour M, Alkass K, Perl S, Tisdale J, Possnert G, Druid H, Frisén J.
The Lifespan and Turnover of Microglia in the Human Brain.
Cell Rep. 2017 Jul 25;20(4):779-784.
PubMed.
Füger P, Hefendehl JK, Veeraraghavalu K, Wendeln AC, Schlosser C, Obermüller U, Wegenast-Braun BM, Neher JJ, Martus P, Kohsaka S, Thunemann M, Feil R, Sisodia SS, Skodras A, Jucker M.
Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging.
Nat Neurosci. 2017 Oct;20(10):1371-1376. Epub 2017 Aug 28
PubMed.
This study highlights the importance of the interaction between the immune system and ALS disease progression. The strengths of the study are the number of patients who participated and the fact that a part of the study analyzed blood cells longitudinally.
An important aspect is that different leukocyte populations show a difference in their number in ALS patients compared with controls. This could, therefore, be used as a marker of the disease if this happens to be specific for ALS (data would have to be compared with other related neurodegenerative diseases) and, importantly, if the results were confirmed in other ALS populations.
Interestingly, some variations with cell population numbers correlated with the ALSFRS-R score, which hints at the potential impact of the immune system in ALS. From these data, it is not possible to conclude whether ALS disease progression impacts the immune system leading to variations in the number of subpopulations of leukocytes or if those variations impact disease progression.
Some perspective comes from other new findings showing that the most common genetic cause of ALS (C9ORF72) has an important immune function, as determined in several studies analyzing the effect of C9ORF72 knockout in mice, and that some genes previously known for their implication in the immune system are mutated in ALS (TBK1). In addition, the results provided by this new study from Feldman and collaborators are important in regard to clinical trials currently testing the impact of compounds targeting immune cells. It would be interesting to analyze the impact of these compounds on the cell populations highlighted in this study.
Comments
University of Sheffield
Murdock and colleagues have conducted a detailed study of leukocyte populations in peripheral blood samples taken from ALS patients and controls. Serial samples were collected from a number of the ALS patients, allowing the authors to track changes in leukocyte subpopulations over time. They discovered that total leukocyte counts, and counts of a number of subpopulations, including neutrophils, natural killer (NK) cells, but not CD4+ or CD8+ T-cells, are increased in ALS patients compared to controls. They went on to test whether leukocyte counts correlated with disease progression as measured by change in ALS-FRS score.
Change over time in several of the cell populations correlated significantly with change in the ALS-FRS score. However, ALS is a relentless disease that will always progress over time, and therefore any marker that changes in a consistent manner over time might be expected to correlate with changes in the ALS-FRS score. This highlights the great unanswered question for study of the peripheral immune system in ALS—correlation or causation? We know that changes in the peripheral immune system correlate with changes in ALS: for example, work from our group has shown that gene expression in peripheral lymphocytes can be used to classify ALS patients as fast or slow progressors (Mar 2017 news on Cooper-Knock et al., 2017). What we do not know is whether these peripheral changes are causative and therefore a good therapeutic target, or whether they are a secondary downstream effect of changes in the CNS—a limitation acknowledged by the authors of this work. A recent study of CNS microglia has suggested that these cells are relatively long-lived, tend to remain in their local environment, and increase their numbers through cell division rather than recruitment from outside the CNS (Aug 2017 news on Réu et al., 2017, and Füger et al., 2017). This would suggest that the CNS immune system is relatively independent but there is much more work to be done.
A very interesting aspect of this study was the dissection of myeloid cell subgroups using cell surface markers. The authors discovered that, although changes in CD16+ and CD16- monocytes overall did not correlate with changes in the ALS-FRS, when the analysis was limited to monocytes expressing CX3CR1 there was a significant relationship. Increased numbers of CX3CR1+ cells associated with slower disease progression. CX3CR1 has been implicated in myeloid cell trafficking to the CNS and therefore this observation may be consistent with a protective effect of migrating peripheral monocytes. This is an exciting observation which may provide a peripherally accessible therapeutic target.
References:
Cooper-Knock J, Green C, Altschuler G, Wei W, Bury JJ, Heath PR, Wyles M, Gelsthorpe C, Highley JR, Lorente-Pons A, Beck T, Doyle K, Otero K, Traynor B, Kirby J, Shaw PJ, Hide W. A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2017 Mar 16;5(1):23. PubMed.
Réu P, Khosravi A, Bernard S, Mold JE, Salehpour M, Alkass K, Perl S, Tisdale J, Possnert G, Druid H, Frisén J. The Lifespan and Turnover of Microglia in the Human Brain. Cell Rep. 2017 Jul 25;20(4):779-784. PubMed.
Füger P, Hefendehl JK, Veeraraghavalu K, Wendeln AC, Schlosser C, Obermüller U, Wegenast-Braun BM, Neher JJ, Martus P, Kohsaka S, Thunemann M, Feil R, Sisodia SS, Skodras A, Jucker M. Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging. Nat Neurosci. 2017 Oct;20(10):1371-1376. Epub 2017 Aug 28 PubMed.
View all comments by Johnathan Cooper-KnockUniversity Pierre and Marie Curie
This study highlights the importance of the interaction between the immune system and ALS disease progression. The strengths of the study are the number of patients who participated and the fact that a part of the study analyzed blood cells longitudinally.
An important aspect is that different leukocyte populations show a difference in their number in ALS patients compared with controls. This could, therefore, be used as a marker of the disease if this happens to be specific for ALS (data would have to be compared with other related neurodegenerative diseases) and, importantly, if the results were confirmed in other ALS populations.
Interestingly, some variations with cell population numbers correlated with the ALSFRS-R score, which hints at the potential impact of the immune system in ALS. From these data, it is not possible to conclude whether ALS disease progression impacts the immune system leading to variations in the number of subpopulations of leukocytes or if those variations impact disease progression.
Some perspective comes from other new findings showing that the most common genetic cause of ALS (C9ORF72) has an important immune function, as determined in several studies analyzing the effect of C9ORF72 knockout in mice, and that some genes previously known for their implication in the immune system are mutated in ALS (TBK1). In addition, the results provided by this new study from Feldman and collaborators are important in regard to clinical trials currently testing the impact of compounds targeting immune cells. It would be interesting to analyze the impact of these compounds on the cell populations highlighted in this study.
View all comments by Severine BoilleeMake a Comment
To make a comment you must login or register.