Interconnection and Communication between Bone Marrow - The Central Immune System - And the Central Nervous System

Bone marrow and the central nervous system are both protected by bone. The two systems are interconnected not only structurally but also functionally. In both systems specialized cells communicate through synapses. There exists a tridirectional communication within the neuroimmune network, including the hormonal system, the immune system, and the nervous system. Bone marrow is a priming site for T cell responses to blood-borne antigens including those from the central nervous system. In cases of auto (self) antigens, the responses lead to immune tolerance while in cases of neo (non-self) antigens, the responses lead to neoantigen-specific T cell activation, immune control, and finally to the generation of neoantigen-specific immunological memory. Bone marrow has an important function in the storage and maintenance of immunological memory. It is a multifunctional and very active cell-generating organ, constantly providing hematopoiesis and osteogenesis in finely-tuned homeostasis. Clinical perspectives include mesenchymal stem cell transplantation for tissue repair within the central nervous system.

In analogy to the Central Nervous System (CNS), Bone Marrow (BM) has recently been described as the Central Immune System (CIS) [1]. Both systems developed during vertebrate evolution, communicate through synapses and are able to learn.

The immune system has the capacity to learn and develop memory, similar to the brain. Unlike the brain with its mostly immobile network of neurons, the immune system is based on a network of mostly mobile cells. These two learning systems are interconnected. The development of immune cells is regulated by autonomic and somatosensory neurons. These nerves influence hematopoiesis as well as priming, migration, and cytokine production of immune cells. In reverse, homeostatic neural circuits that control metabolism, hypertension, and the inflammatory reflex are influenced by specific immune cell subsets [2]. Neuronal synapses transmit electrical impulses directly via gap junctions (about 3.5 nm distance) or indirectly via neurotransmitters (20 - 40 nm distance). Immunological synapses (about 13 nm distance) transmit biochemical signals. Nestin-GFPhi neuron-glial antigen-2 (NG2+) elongated cells run adjacent to arteries and arterioles [3]. These adrenergic nerves are surrounded by bundles of nonmyelinating Schwann cells [3]. Recently, it was suggested that lymphoid organs are innervated in a new way [2]. It could be visualized that the cytoplasm of a subset of dendritic cells is infiltrated by adrenergic nerve fiber terminals ending at microtubular and microfilament walls [2].

The central immune system and the neuroimmune network

In 2003, bone marrow was reported for the first time to function as a priming site for T-cell responses to blood-borne antigens [4]. This was corroborated and extended ten years later by two-photon dynamic imaging of mouse brain calvaria [5]. Naïve CD8+ T cells were observed to crawl rapidly at a steady state but arrested immediately upon sensing antigenic peptides. As shown in the cartoon of [1], antigen-specific T cells decelerated, clustered together with antigen-presenting cells, upregulated CD69, and divided in situ to yield effector cells [5].

The neuroimmune network is tridirectional. It consists of immune cells and immune-derived molecules, endocrine glands and hormones, the nervous system, and neuro-derived molecules [6]. This network plays a significant role in communication pathways. It is involved in homeostatic regulation at the level of the whole organism and at local levels [6]. Details of such neuronal–immune cell units have been studied in allergic inflammation of the nose [6]. The nervous system regulates the function of immune cells through neurotransmitters or neuropeptides. Conversely, immune cells play a key role in neuronal injury, repair, and differentiation [7].

CNS immunosurveillance

The CNS is lined by meninges - dura, arachnoid, and pia mater. Recently, a fourth meningeal layer has been described. This new Subarachnoid Lymphatic-Like Membrane (SLYM) encases blood vessels and immune cells [8]. SLYM is closely associated with the endothelial lining of the meningeal venous sinus. This permits the direct exchange of small solutes between cerebrospinal fluid and venous blood [9]. Recently, a calvarial hematopoietic niche was discovered in a distinct region of the skull. This acts as a myeloid cell reservoir to the underlying meninges [9]. The inner skull of the cortex contains vascular channels. These provide a passageway for cells and cerebrospinal fluid-derived antigens between the skull and the brain parenchyma [9].

Throughout the CNS parenchyma, a tightly controlled microglia network facilitates efficient immunosurveillance [10]. Each cell is constantly surveilling its microenvironment. During tissue surveillance, microglia screen for pathogens, remove cell debris and metabolites, groom neighboring cells, and facilitate cellular crosstalk [10]. This is an essential process for CNS homeostasis and development [11]. Also, microglia continuously monitor and sculpt synapses, thereby allowing for the remodeling of brain circuits [12]. Such glia-mediated neuroplasticity is driven by neuronal activity. It is controlled by various feedback signaling mechanisms and crucially involves extracellular matrix remodeling [12]. Molecular signatures of homeostatic microglia and disease-associated microglia have provided insights into how these cells are regulated in health and disease and how they contribute to the maintenance of the neuronal environment [13].

Astrocytes were recently demonstrated to communicate with neurons and to mediate glutamatergic gliotransmission in the CNS [14]. Nine molecularly distinct clusters of hippocampal astrocytes were identified by single-cell RNA-sequencing and patch-seq data analysis [14]. A specialized subpopulation selectively expressed a synaptic-like glutamate-release machinery and was localized to a discrete hippocampal site [14].

Neuropathologies and interventions

i. In primary CNS lymphoma, recent studies have highlighted the excellent disease control afforded by high-dose chemotherapy and stem cell transplantation [15]. Also, chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) achieved impressive increases in complete remission rates [16].

ii. For Glioblastoma Multiforme (GBM), an orphan disease, an immune landscape has been described as a double-edged sword for treatment [17]. On one hand, there are the immunosuppressive effects of tumor cells and myeloid immune cells on the tumor microenvironment, while on the other, there are the immune-stimulatory effects of lymphocyte responses against the glioma cells [17]. Clinical and translational advances in malignant glioma immunotherapy have been summarized recently [18,19]. The reviews include vaccine-based therapies, adoptive cell therapies, oncolytic virus therapy, and technical innovation [18,19]. The overall survival of IDH1 wild-type MGMT promoter-unmethylated GBM could be improved by a synergy between temozolomide chemotherapy and individualized multimodal immunotherapy [20]. The concept of randomized controlled immunotherapy clinical trials for orphan diseases like GBM has been challenged [21] and compared to the evidence obtained by real-world patient data from individualized medicine [22].

iii. Neuro-degenerative and neuro-autoimmune diseases are influenced and affected by the immune system. The immune system is involved in neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and amyotrophic lateral sclerosis (ALS) [23]. CD4+ T cells, CD8+ T cells, and regulatory T cells (Tregs) play an important role in cerebral infarction and autoimmune diseases of the CNS, such as Multiple Sclerosis (MS), N-Methyl-D-Aspartate (NMDA) receptor encephalitis, and narcolepsy (23). An important auto (self)-antigen of the CNS is Myelin Oligodendrocyte Glycoprotein (MOG) [24].

iv. Ischemic stroke involves complex interactions between neuronal, glial, and immune cell subsets across multiple immunological compartments. These include the blood-brain barrier, the meningeal lymphatic vessels, the choroid plexus, and the skull bone marrow [25].

v. From Alzheimer’s models, it was reported that neuronal expression of a single-chain antibody selective for Aß oligomers protects synapses and rescues memory [26].

vi. New diagnostic tools. Immuno-positron emission tomography (immunoPET) is a non-invasive in vivo imaging method based on tracking and quantifying radiolabeled monoclonal antibodies [27]. ImmunoPET could be a new approach to developing more specific PET probes directed to different brain targets [27].

vii. Extracellular vesicles. Neural-derived and immune-derived extracellular vesicles from blood appear to be good specific biomarkers in Multiple Sclerosis (MS) for reflecting the disease state [28].

viii. New interventional tools. To increase the brain bioavailability of certain drugs polymer- and lipid-based micro- and nanoparticles are being developed. For bypassing the blood-brain barrier, the intranasal route of drug administration offers numerous advantages. It provides a direct entrance to the brain through the olfactory and trigeminal neurons [29].

ix. Bone Marrow-derived Mesenchymal Stem Cells (BM MSCs) have a dampening effect on neurological diseases. One example is Intracerebral Hemorrhage (ICH). This is a common acute nervous system disease that causes severe disability and high mortality. Alleviation of brain injury after ICH was demonstrated following BM MSC transplantation in mice. This was affected by the Hippo signaling pathway [30]. It was also reported that polarized anti-inflammatory MSCs increase hippocampal neurogenesis and improve cognitive function in aged mice [31]. Another example is Alzheimer`s Disease (AD). In an AD mouse model, the transplantation of nasal olfactory mucosa MSCs resulted in benefits [32]. A dampening effect of BM MSCs has been ascribed to microRNA. An exosomal microRNA (miR-146a) secreted from BM-MSCs was reported to be taken up into astrocytes [33]. Intracerebral-ventricular injected BM-MSCs were shown to improve cognitive impairment by increasing the expression of miR-146a in the hippocampus [34]. This can be explained by an effect on astrocytes - key cells for the formation of synapses. Restoration of astrocyte function may lead to synaptogenesis and improvement of cognitive function [35]. In conclusion, MSC-based therapy is an important means of ameliorating neurological impairment [31-35].

The evolution of vertebrates went along with the co-evolution of the bones, the BM, and the CNS. BM is a central, multifunctional, and protective immune organ and should receive more attention in the future. Among all antigen-responsive immune organs (BM, spleen, lymph nodes), BM is the largest. It is also the most prominent source of de novo cellular generation within the body. Newly described functions of this central immune organ include i) capacity of antigen presentation by specialized Antigen-Presenting Cells (APCs), ii) T cell-APC interaction capacity, iii) memory cell storage capacity, iv) capacity of maintaining self-tolerance and immune homeostasis, v) capacity of tissue repair by mesenchymal stem cells, vi) ability to sense signals via adrenergic nerve fibers from the autonomous peripheral nervous system and vii) capacity of immunosurveillance of the CNS.

Because the BM is of great importance for general health, new drug approvals should minimize detrimental drug effects on the BM. Among the available immunotherapeutic drugs, the most important are immune checkpoint inhibitors, anti-cancer vaccines, oncolytic viruses, and adoptive T-cell therapies. All of these have to be assessed with regard to their side effects on the BM.

Examples are given for neuropathologies and immunological interventions. This area of research is considered in the future of great medical relevance.

1. Schirrmacher V. Bone marrow: The central immune system. Immuno. 2023; 3:289-329. Doi.org/10.3390/immuno3030019.
2. Wu K, Li R, Zhang Y, Liu Y, Wang M, Huang J, Zhu C, Zhang J, Yuan X, Liu Q. The discovery of a new type of innervation in lymphoid organs. Physiol Rep. 2023 Feb;11(4):e15604. doi: 10.14814/phy2.15604. PMID: 36823776; PMCID: PMC9950540.
3. Nombela-Arrieta C, Manz MG. Quantification and three-dimensional microanatomical organization of the bone marrow. Blood Adv. 2017 Feb 14;1(6):407-416. doi: 10.1182/bloodadvances.2016003194. PMID: 29296956; PMCID: PMC5738992.
4. Feuerer M, Beckhove P, Garbi N, Mahnke Y, Limmer A, Hommel M, Hämmerling GJ, Kyewski B, Hamann A, Umansky V, Schirrmacher V. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med. 2003 Sep;9(9):1151-7. doi: 10.1038/nm914. Epub 2003 Aug 10. PMID: 12910264.
5. Milo I, Sapoznikov A, Kalchenko V, Tal O, Krauthgamer R, van Rooijen N, Dudziak D, Jung S, Shakhar G. Dynamic imaging reveals promiscuous crosspresentation of blood-borne antigens to naive CD8+ T cells in the bone marrow. Blood. 2013 Jul 11;122(2):193-208. doi: 10.1182/blood-2012-01-401265. Epub 2013 May 1. PMID: 23637125.
6. Koni PA, Joshi SK, Temann UA, Olson D, Burkly L, Flavell RA. Conditional vascular cell adhesion molecule 1 deletion in mice: impaired lymphocyte migration to bone marrow. J Exp Med. 2001 Mar 19;193(6):741-54. doi: 10.1084/jem.193.6.741. PMID: 11257140; PMCID: PMC2193418.
7. Abbas A, Lichtman A, Pillai S. Cellular and Molecular Immunology. 10th ed. Elsevier: Philadelphia, PA, USA. 2022.
8. Møllgård K, Beinlich FRM, Kusk P, Miyakoshi LM, Delle C, Plá V, Hauglund NL, Esmail T, Rasmussen MK, Gomolka RS, Mori Y, Nedergaard M. A mesothelium divides the subarachnoid space into functional compartments. Science. 2023 Jan 6;379(6627):84-88. doi: 10.1126/science.adc8810. Epub 2023 Jan 5. PMID: 36603070.
9. Mills WA 3rd, Coburn MA, Eyo UB. The emergence of the calvarial hematopoietic niche in health and disease. Immunol Rev. 2022 Oct;311(1):26-38. doi: 10.1111/imr.13120. Epub 2022 Jul 26. PMID: 35880587; PMCID: PMC9489662.
10. Petry P, Oschwald A, Kierdorf K. Microglial tissue surveillance: The never-resting gardener in the developing and adult CNS. Eur J Immunol. 2023 Jul;53(7):e2250232. doi: 10.1002/eji.202250232. Epub 2023 May 5. PMID: 37042800.
11. Arutyunov A, Klein RS. Microglia at the scene of the crime: what their transcriptomics reveal about brain health. Curr Opin Neurol. 2023 Jun 1;36(3):207-213. doi: 10.1097/WCO.0000000000001151. Epub 2023 Apr 18. PMID: 37078646.
12. Dzyubenko E, Hermann DM. Role of glia and extracellular matrix in controlling neuroplasticity in the central nervous system. Semin Immunopathol. 2023 May;45(3):377-387. doi: 10.1007/s00281-023-00989-1. Epub 2023 Apr 13. PMID: 37052711; PMCID: PMC10279577.
13. Butovsky O, Weiner HL. Microglial signatures and their role in health and disease. Nat Rev Neurosci. 2018 Oct;19(10):622-635. doi: 10.1038/s41583-018-0057-5. PMID: 30206328; PMCID: PMC7255106.
14. de Ceglia R, Ledonne A, Litvin DG, Lind BL, Carriero G, Latagliata EC, Bindocci E, Di Castro MA, Savtchouk I, Vitali I, Ranjak A, Congiu M, Canonica T, Wisden W, Harris K, Mameli M, Mercuri N, Telley L, Volterra A. Specialized astrocytes mediate glutamatergic gliotransmission in the CNS. Nature. 2023 Sep 6. doi: 10.1038/s41586-023-06502-w. Epub ahead of print. PMID: 37674083.
15. Barden MM, Omuro AM. Top advances of the year: Neuro-oncology. Cancer. 2023 May 15;129(10):1467-1472. doi: 10.1002/cncr.34711. Epub 2023 Feb 24. PMID: 36825454.
16. Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group (IELSG). Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. doi: 10.1016/S2352-3026(16)00036-3. Epub 2016 Apr 6. PMID: 27132696.
17. Mahajan S, Schmidt MHH, Schumann U. The Glioma Immune Landscape: A Double-Edged Sword for Treatment Regimens. Cancers (Basel). 2023 Mar 28;15(7):2024. doi: 10.3390/cancers15072024. PMID: 37046685; PMCID: PMC10093409.
18. Bunse L, Bunse T, Krämer C, Chih YC, Platten M. Clinical and Translational Advances in Glioma Immunotherapy. Neurotherapeutics. 2022 Oct;19(6):1799-1817. doi: 10.1007/s13311-022-01313-9. Epub 2022 Oct 27. PMID: 36303101; PMCID: PMC9723056.
19. Schirrmacher V, van Gool S, Stuecker W. Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy. Int J Mol Sci. 2022 Oct 27;23(21):13050. doi: 10.3390/ijms232113050. PMID: 36361831; PMCID: PMC9655431.
20. Van Gool SW, Makalowski J, Bitar M, Van de Vliet P, Schirrmacher V, Stuecker W. Synergy between TMZ and individualized multimodal immunotherapy to improve overall survival of IDH1 wild-type MGMT promoter-unmethylated GBM patients. Genes Immun. 2022 Dec;23(8):255-259. doi: 10.1038/s41435-022-00162-y. Epub 2022 Feb 16. PMID: 35173295; PMCID: PMC9758045.
21. Van Gool SW, Makalowski J, Fiore S, Sprenger T, Prix L, Schirrmacher V, Stuecker W. Randomized Controlled Immunotherapy Clinical Trials for GBM Challenged. Cancers (Basel). 2020 Dec 24;13(1):32. doi: 10.3390/cancers13010032. PMID: 33374196; PMCID: PMC7796083.
22. Van de Vliet P, Sprenger T, Kampers LFC, Makalowski J, Schirrmacher V, Stücker W, Van Gool SW. The Application of Evidence-Based Medicine in Individualized Medicine. Biomedicines. 2023 Jun 23;11(7):1793. doi: 10.3390/biomedicines11071793. PMID: 37509433; PMCID: PMC10376974.
23. Yoshimura A, Ohyagi M, Ito M. T cells in the brain inflammation. Adv Immunol. 2023;157:29-58. doi: 10.1016/bs.ai.2022.10.001. Epub 2022 Nov 24. PMID: 37061287.
24. Eliseeva DD, Zakharova MN. Myelin Oligodendrocyte Glycoprotein as an Autoantigen in Inflammatory Demyelinating Diseases of the Central Nervous System. Biochemistry (Mosc). 2023 Apr;88(4):551-563. doi: 10.1134/S0006297923040107. PMID: 37080940.
25. Maïer B, Tsai AS, Einhaus JF, Desilles JP, Ho-Tin-Noé B, Gory B, Sirota M, Leigh R, Lemmens R, Albers G, Olivot JM, Mazighi M, Gaudillière B. Neuroimaging is the new "spatial omic": multi-omic approaches to neuro-inflammation and immuno-thrombosis in acute ischemic stroke. Semin Immunopathol. 2023 Jan;45(1):125-143. doi: 10.1007/s00281-023-00984-6. Epub 2023 Feb 14. PMID: 36786929; PMCID: PMC10026385.
26. Boyuklieva R, Pilicheva B. Micro- and Nanosized Carriers for Nose-to-Brain Drug Delivery in Neurodegenerative Disorders. Biomedicines. 2022 Jul 14;10(7):1706. doi: 10.3390/biomedicines10071706. PMID: 35885011; PMCID: PMC9313014.
27. Selles MC, Fortuna JTS, Cercato MC, Santos LE, Domett L, Bitencourt ALB, Carraro MF, Souza AS, Janickova H, Azevedo CV, Campos HC, de Souza JM, Alves-Leon S, Prado VF, Prado MAM, Epstein AL, Salvetti A, Longo BM, Arancio O, Klein WL, Sebollela A, De Felice FG, Jerusalinsky DA, Ferreira ST. AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models. Mol Ther. 2023 Feb 1;31(2):409-419. doi: 10.1016/j.ymthe.2022.11.002. Epub 2022 Nov 11. PMID: 36369741; PMCID: PMC9931599.
28. de Lucas ÁG, Lamminmäki U, López-Picón FR. ImmunoPET Directed to the Brain: A New Tool for Preclinical and Clinical Neuroscience. Biomolecules. 2023 Jan 13;13(1):164. doi: 10.3390/biom13010164. PMID: 36671549; PMCID: PMC9855881.
29. Torres Iglesias G, Fernández-Fournier M, Botella L, Piniella D, Laso-García F, Carmen Gómez-de Frutos M, Chamorro B, Puertas I, Tallón Barranco A, Fuentes B, Alonso de Leciñana M, Alonso-López E, Bravo SB, Eugenia Miranda-Carús M, Montero-Calle A, Barderas R, Díez-Tejedor E, Gutiérrez-Fernández M, Otero-Ortega L. Brain and immune system-derived extracellular vesicles mediate regulation of complement system, extracellular matrix remodeling, brain repair and antigen tolerance in Multiple sclerosis. Brain Behav Immun. 2023 Oct;113:44-55. doi: 10.1016/j.bbi.2023.06.025. Epub 2023 Jul 3. PMID: 37406976.
30. Chen X, Xu CX, Liang H, Xi Z, Pan J, Yang Y, Sun Q, Yang G, Sun Y, Bian L. Bone marrow mesenchymal stem cells transplantation alleviates brain injury after intracerebral hemorrhage in mice through the Hippo signaling pathway. Aging (Albany NY). 2020 Apr 9;12(7):6306-6323. doi: 10.18632/aging.103025. Epub 2020 Apr 9. PMID: 32271159; PMCID: PMC7185092.
31. Tfilin M, Gobshtis N, Fozailoff D, Fraifeld VE, Turgeman G. Polarized Anti-Inflammatory Mesenchymal Stem Cells Increase Hippocampal Neurogenesis and Improve Cognitive Function in Aged Mice. Int J Mol Sci. 2023 Feb 24;24(5):4490. doi: 10.3390/ijms24054490. PMID: 36901920; PMCID: PMC10003244.
32. Hong CG, Chen ML, Duan R, Wang X, Pang ZL, Ge LT, Lu M, Xie H, Liu ZZ. Transplantation of Nasal Olfactory Mucosa Mesenchymal Stem Cells Benefits Alzheimer's Disease. Mol Neurobiol. 2022 Dec;59(12):7323-7336. doi: 10.1007/s12035-022-03044-6. Epub 2022 Sep 29. PMID: 36173534.
33. Qu M, Xing F, Xing N. Mesenchymal stem cells for the treatment of cognitive impairment caused by neurological diseases. Biotechnol Lett. 2022 Aug;44(8):903-916. doi: 10.1007/s10529-022-03274-7. Epub 2022 Jul 9. PMID: 35809141.
34. Nakano M, Kubota K, Kobayashi E, Chikenji TS, Saito Y, Konari N, Fujimiya M. Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer's disease model by increasing the expression of microRNA-146a in hippocampus. Sci Rep. 2020 Jul 1;10(1):10772. doi: 10.1038/s41598-020-67460-1. PMID: 32612165; PMCID: PMC7330036.
35. Vigo T, Voulgari-Kokota A, Errede M, Girolamo F, Ortolan J, Mariani MC, Ferrara G, Virgintino D, Buffo A, Kerlero de Rosbo N, Uccelli A. Mesenchymal stem cells instruct a beneficial phenotype in reactive astrocytes. Glia. 2021 May;69(5):1204-1215. doi: 10.1002/glia.23958. Epub 2020 Dec 31. PMID: 33381863.