Systemic Immune Deviation in the Brain That Does Not Depend on the Integrity of the Blood-Brain Barrier

Wenkel, Hartmut; Streilein, J. Wayne; Young, Michael J.

doi:10.4049/jimmunol.164.10.5125

Cited by 75 publications

(42 citation statements)

References 16 publications

(19 reference statements)

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“…Interestingly, Ags injected into the CNS evoke a deviant systemic immune response that is deficient in Ag-specific delayed-type hypersensitivity (59,60). Recently, it was shown that this deviated immune response could be transferred to naive animals by cervical LN cells from donors that received an injection of Ag in the brain 8 days earlier (60).…”

Section: Discussionmentioning

confidence: 99%

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Transfer of Central Nervous System Autoantigens and Presentation in Secondary Lymphoid Organs

Vos¹,

Meurs²,

Brok

et al. 2002

The Journal of Immunology

250

181

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Dendritic cells are thought to regulate tolerance induction vs immunization by transferring Ags and peripheral signals to draining lymph nodes (LN). However, whether myelin Ag transfer and presentation in LN occurs during demyelinating brain disease is unknown. In this study, we demonstrate redistribution of autoantigens from brain lesions to cervical LN in monkey experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). Immunohistochemical analysis revealed significantly more cells containing myelin Ags in cervical LN of monkeys with EAE compared with those of healthy control monkeys. Myelin Ags were observed in cells expressing dendritic cell/macrophage-specific markers, MHC class II, and costimulatory molecules. Moreover, these cells were directly juxtaposed to T cells, suggesting that cognate interactions between myelin-containing APC and T cells are taking place in brain-draining LN. Indeed, myelin Ag-reactive T cells were observed in cervical LN from marmosets and rhesus monkeys. Importantly, these findings were paralleled by our findings in human tissue. We observed significantly more myelin Ag-containing cells in LN of individuals with MS compared with those of control individuals. These cells expressed APC markers, as observed in marmosets and rhesus monkeys. These findings suggest that during MS and EAE, modulation of T cell reactivity against brain-derived Ags also takes place in cervical LN and not necessarily inside the brain. A major implication is that novel therapeutic strategies may be targeted to peripheral events, thereby circumventing the blood-brain barrier.

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Section: Discussionmentioning

confidence: 99%

“…Recently, it was shown that this deviated immune response could be transferred to naive animals by cervical LN cells from donors that received an injection of Ag in the brain 8 days earlier (60). We hypothesize that, during EAE, inflammatory signals from the CNS environment prevent the induction of a deviant immune response (2,3).…”

Section: Discussionmentioning

confidence: 99%

Transfer of Central Nervous System Autoantigens and Presentation in Secondary Lymphoid Organs

Vos¹,

Meurs²,

Brok

et al. 2002

The Journal of Immunology

250

181

View full text Add to dashboard Cite

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“…Several lines of evidence support that the lymphatic drainage of the CNS might contribute to shut down neuroinflammatory responses after brain injury, in view of the findings showing that lymphocytes isolated from the CLN emphasized anti-inflammatory responses and suppressed proinflammatory signals (11,21). Nonetheless, it is unknown whether the reactivity of lymphocytes to brain-derived Ags is nonspecific, or it is directed against specific brain Ags (22).…”

mentioning

confidence: 99%

Brain-Derived Antigens in Lymphoid Tissue of Patients with Acute Stroke

Planas

Gómez-Choco

Urra

et al. 2012

The Journal of Immunology

146

134

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In experimental animals, the presence of brain-derived constituents in cervical lymph nodes has been associated with the activation of local lymphocytes poised to minimize the inflammatory response after acute brain injury. In this study, we assessed whether this immune crosstalk also existed in stroke patients. We studied the clinical course, neuroimaging, and immunoreactivity to neuronal derived Ags (microtubule-associated protein-2 and N-methyl d-aspartate receptor subunit NR-2A), and myelin-derived Ags (myelin basic protein and myelin oligodendrocyte glycoprotein) in palatine tonsils and cervical lymph nodes of 28 acute stroke patients and 17 individuals free of neurologic disease. Stroke patients showed greater immunoreactivity to all brain Ags assessed compared with controls, predominantly in T cell zones. Most brain immunoreactive cells were CD68+ macrophages expressing MHC class II receptors. Increased reactivity to neuronal-derived Ags was correlated with smaller infarctions and better long-term outcome, whereas greater reactivity to myelin basic protein was correlated with stroke severity on admission, larger infarctions, and worse outcome at follow-up. Patients also had more CD69+ T cells than controls, indicative of T cell activation. Overall, the study showed in patients with acute stroke the presence of myelin and neuronal Ags associated with lymph node macrophages located near activated T cells. Whether the outcome of acute stroke is influenced by Ag-specific activation of immune responses mediated by CD69 lymphocytes deserves further investigation.

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“…Although the drainage of CNS-derived antigens into the cervical lymph nodes generates local production of antigen-specific antibodies, it does not provoke a rapid destruction of the CNS [127]. Moreover, intracranially injected antigens in normal mice rather evoked a systemic immune deviation that suppresses normal T-cell effector activity [133]. Cervical lymph node cells from the protected mice were able to transfer such suppression to naïve recipients.…”

Section: Cns-associated Cells Sentinels At the Gateway To The Cnsmentioning

confidence: 85%

Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain

2006

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The central nervous system (CNS) is traditionally viewed as an immune privileged site in which overzealous immune cells are prevented from doing irreparable damage. It was believed that immune responses occurring within the CNS could potentially do more damage than the initial pathogenic insult itself. However, virtually every aspect of CNS tissue damage, including degeneration, tumors, infection, and of course autoimmunity, involves a significant cellular inflammatory component. While the blood-brain barrier (BBB) inhibits diffusion of hydrophilic (immune) molecules across brain capillaries, activated lymphocytes readily pass the endothelial layer of postcapillary venules without difficulty. In classic neuro-immune diseases such as multiple sclerosis or acute disseminated encephalomyelitis, it is thought that neuroantigen-reactive lymphocytes, which have escaped immune tolerance, now invade the CNS and are responsible for tissue damage, demyelination, and axonal degeneration. The developed animal model for these disorders, experimental autoimmune encephalomyelitis (EAE), reflects many aspects of the human conditions. Studies in EAE proved that auto-reactive encephalitogenic T helper (Th) cells are responsible for the onset of the disease. Th cells recognize their cognate antigen (Ag) only when presented by professional Ag-presenting cells in the context of major histocompatibility complex class II molecules. The apparent target structures of EAE immunity are myelinating oligodendrocytes, which are not capable of presenting Ag to invading encephalitogenic T cells. A compulsory third party is thus required to mediate between the attacking T cells and the myelin-expressing target. This review will discuss the recent advances in this field of research and we will discuss the journey of an auto-reactive T cell from its site of activation into perivascular spaces and further into the target tissue.

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Systemic Immune Deviation in the Brain That Does Not Depend on the Integrity of the Blood-Brain Barrier

Cited by 75 publications

References 16 publications

Transfer of Central Nervous System Autoantigens and Presentation in Secondary Lymphoid Organs

Transfer of Central Nervous System Autoantigens and Presentation in Secondary Lymphoid Organs

Brain-Derived Antigens in Lymphoid Tissue of Patients with Acute Stroke

Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain

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