title: Peripheral monocytes are functionally altered and invade the CNS in ALS patients.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease affecting primarily the upper and lower motor neurons. A common feature of all ALS cases is a well-characterized neuroinflammatory reaction within the central nervous system (CNS). However, much less is known about the role of the peripheral immune system and its interplay with CNS resident immune cells in motor neuron degeneration. Here, we characterized peripheral monocytes in both temporal and spatial dimensions of ALS pathogenesis. We found the circulating monocytes to be deregulated in ALS regarding subtype constitution, function and gene expression. Moreover, we show that CNS infiltration of peripheral monocytes correlates with improved motor neuron survival in a genetic ALS mouse model. Furthermore, application of human immunoglobulins or fusion proteins containing only the human Fc, but not the Fab antibody fragment, increased CNS invasion of peripheral monocytes and delayed the disease onset. Our results underline the importance of peripheral monocytes in ALS pathogenesis and are in agreement with a protective role of monocytes in the early phase of the disease. The possibility to boost this beneficial function of peripheral monocytes by application of human immunoglobulins should be evaluated in clinical trials.
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zondler
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Müller
authors.affiliation: Department of Experimental Physics, Ulm University, Ulm, Germany.
authors.forename: Samira
authors.initials: S
authors.lastname: Khalaji
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Bliederhäuser
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Wolfgang P
authors.initials: WP
authors.lastname: Ruf
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Veselin
authors.initials: V
authors.lastname: Grozdanov
authors.affiliation: Apogenix GmbH, Heidelberg, Germany.
authors.forename: Meinolf
authors.initials: M
authors.lastname: Thiemann
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fundel-Clemes
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Freischmidt
authors.affiliation: Core Facility Genomics, Ulm University, Ulm, Germany.
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Holzmann
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Strobel
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Weydt
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Anika M
authors.initials: AM
authors.lastname: Helferich
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
authors.affiliation: Department of Experimental Physics, Ulm University, Ulm, Germany.
authors.forename: Kay-Eberhard
authors.initials: KE
authors.lastname: Gottschalk
authors.affiliation: Apogenix GmbH, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hill
authors.affiliation: Apogenix GmbH, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kluge
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
authors.affiliation: Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany. jochen.weishaupt@uni-ulm.de.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D012157:Mononuclear Phagocyte System / Q000378:metabolism*; D009046:Motor Neurons / Q000473:pathology*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*
keywords: Amyotrophic lateral sclerosis; Fc receptor; Immunoglobulin; Innate immunity; Microglia; Monocyte