INJ Search

CLOSE


Int Neurourol J > Volume 20(Suppl 1); 2016 > Article
Park, Park, and Kwon: Central Nervous System-Peripheral Immune System Dialogue in Neurological Disorders: Possible Application of Neuroimmunology in Urology

ABSTRACT

Previous concepts of immune-privileged sites obscured the role of peripheral immune cells in neurological disorders and excluded the consideration of the potential benefits of immunotherapy. Recently, however, numerous studies have demonstrated that the blood–brain barrier in the central nervous system is an educational barrier rather than an absolute barrier to peripheral immune cells. Emerging knowledge of immune-privileged sites suggests that peripheral immune cells can infiltrate these sites via educative gates and that crosstalk can occur between infiltrating immune cells and the central nervous system parenchyma. This concept can be expanded to the testis, which has long been considered an immune-privileged site, and to neurogenic bladder dysfunction. Thus, we propose that the relationship between peripheral immune cells, the brain, and the urologic system should be considered as an additional possible mechanism in urologic diseases, and that immunotherapy might be an alternative therapeutic strategy in treating neurogenic bladder dysfunction.

left
    right

    THE BLOOD-BRAIN BARRIER AND THE CENTRAL NERVOUS SYSTEM AS AN IMMUNE-PRIVILEGED SITE

    Components of the immune system are widely distributed throughout the body and this system continually performs immune surveillance, the process of detecting and eliminating pathogens for maintenance of tissue homeostasis. Immune surveillance plays a critical role in individual survival. Peripheral immune cells such as leukocytes are recruited immediately by signaling from damaged sites, and subsequently, a series of fine-tuned and well-organized processes result in wound healing. However, the central nervous system (CNS) has a differentiated structure called the blood-brain barrier (BBB). The BBB is composed of endothelial basement membrane, pericytes, epithelial basement membrane, and glial basement membrane and blocks normal surveillance by peripheral immune cells. This anatomical BBB concept was confirmed by early experiments showing that foreign tissue grafted into the CNS elicits a delayed immune response [1]. These observations suggest that the CNS is an “immune-privileged site’’ and that the brain is free from normal immune surveillance. Indeed, in the healthy state, peripheral immune cells are not detected in the CNS parenchyma [2]. Instead, resident microglia, which are innate immune cells, are responsible for surveillance in the CNS, and various immune cells are found in the meningeal spaces [2]. Another reason the CNS is considered an immune-privileged site is the infiltration of peripheral immune cells in inflammatory autoimmune diseases such as multiple sclerosis (MS) [3]. For decades, peripheral immune cell infiltration into the brain’s territory has been considered a pathological process resulting from BBB breakdown in which immune cells attack the CNS. Peripheral immune cell infiltration has been targeted for blockade in patients with MS. Thus, the CNS is likely protected from peripheral immune cells in its healthy state.

    A NEW BLOOD-BRAIN BARRIER CONCEPT: ABSOLUTE VERSUS EDUCATIONAL BARRIER

    Despite this evidence, the concept of the CNS as an immuneprivileged site remains a subject of debate. Recent evidence of immune-privileged sites has been questioned in the neuroimmunology community, and compelling papers have been published on this topic indicating that the CNS may not be an immune-privileged site [4].
    To understand the crosstalk between the CNS and peripheral immune cells, the anatomical structures of the BBB should be reestablished as the combination of absolute barriers and educational barriers [2,4]. The first gate is the endothelial BBB localized in CNS microvessels, capillaries, and postcapillary venules, which we have already defined as an absolute barrier in the healthy state. The highly specialized endothelial cells establish a barrier by sealing the paracellular space with complex tight junctions, forming an endothelial basement membrane with many embedded pericytes. In addition, the parenchymal basement membrane containing astrocyte endfeet establishes the glia limitans perivascularis. At the vascular segment of CNS capillaries, two segments are merged and cannot be distinguished ultrastructurally. However, in postcapillary venules, these basement membranes are separated and provide a cerebrospinal fluid (CSF)-drained perivascular space between two segments. Antigen-presenting cells can be found in the perivascular space.
    The second gate is the epithelial blood-cerebrospinal fluid barrier (BCSFB) within the choroid plexus (CP). The CP is located in four brain ventricles and is composed of fenestrated blood capillaries (endothelium of the blood vessels) and CP parenchyma (monolayer of epithelial cells interconnected by tight junctions) [5]. The CP produces the CSF, which plays a role as a neuroimmunological interface in maintaining normal brain function in both healthy and pathological states by integrating signals between the brain and blood circulation. In contrast to the BBB, the BCSFB is not an absolute barrier and peripheral immune cells can enter into the CNS (perivascular space and CSF, but not parenchyma) via the CP in the healthy state [2,4]. Thus, the migration of circulating immune cells across the BCSFB allows them to perform immunosurveillance of the CNS in the absence of neuroinflammation because of the permeability of the BCSFB to cellular elements. For example, fenestrated CP microvessels constitutively express P-selectin, allowing T cells to enter CSF-filled ventricles by breaching the BCSFB, which was confirmed by intravenously injecting fluorescently labeled T cells [6]. In addition, the observation that T cells are present in the ventricular and lumbar CSF in healthy individuals further suggests real-time immune surveillance by circulating immune cells [7]. Interestingly, the T cells found in the CSF in healthy states are mainly central memory T cells (TCM cells), which are distinct from T-cell subpopulations in the periphery or in the CNS during neuroinflammation [7,8]. Thus, this suggests that in healthy individuals, TCM cells freely enter the CSF in a regulated manner via the BCSFB for immune surveillance of the CNS.

    THE EMERGING ROLE OF CIRCULATING IMMUNE CELLS IN NEUROLOGICAL DISORDERS

    The prevailing dogma of the absolute impermeability of the BBB to immune cells has been increasingly challenged over the past few years. It is now apparent that the general perception of the CNS as an immune-privileged site should be revised. Circulating leukocytes have been shown to play an indispensable role in maintenance and repair of the CNS. Emerging data suggest that circulating immune cells can participate in the maintenance of homeostatic brain functions as well as the progression of neurological disorders. In this section, we review recent immunological studies of aging, neurodegenerative diseases, and psychiatric disorders.

    Aging

    It has not yet been established how brain senescence is influenced by aging of other body tissues. However, recently, several studies have reported that circulating immune cells are involved in brain senescence. Aging mice and humans show increased type I interferon (IFN) response at the CP, and the neutralization of the aging-induced type I IFN response restores CP function in the brain, partially restoring cognitive function and hippocampal neurogenesis [9]. Although circulating immune cells from young blood did not directly affect brain function in aged CP (type I IFN response), this study suggests that targeting the CP, which is the major gate for circulating immune cells, might ameliorate cognitive decline in aging. In addition, a different study reported that young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice [10]. Supply of young blood using the heterochronic parabiosis model in aged mice stimulates adult neurogenic processes, oligodendrocyte activity, synaptic plasticity, and vascularization in the aged CNS [11]. Although the mechanism by which youthful blood-borne factors access the aged CNS is still unclear, it can be speculated that youth-associated leukocytes or youthful systemic factors seem to be associated with restoration of CNS functional decline with age.

    Alzheimer disease

    Alzheimer disease (AD) is characterized by the accumulation of amyloid beta (Aβ), and the impaired elimination of this neurotoxic peptide contributes to disease progression [12]. Cerebral amyloid angiopathy, a condition involving Aβ deposition within the cerebral vasculature, is also observed in most patients with AD. A clearance system exists within the CNS to prevent accumulation of toxic peptides, and this system is regulated by innate immune cells called microglia. Microglia modulate inflammatory reactions, phagocytize neuronal debris and foreign pathogens, and induce wound healing [13]. Thus, many studies have focused on the function of microglia in AD. Interestingly, however, it has been shown that circulating monocytes play a role in the elimination of Aβ in AD [14]. Live intravital two-photon microscopy showed that patrolling monocytes are attracted to and crawl onto the luminal walls of Aβ-positive veins, but not on Aβ-positive arteries or Aβ-free blood vessels [14]. Crawling monocytes carried Aβ in these veins and were able to circulate back into the bloodstream. These data clearly showed that enhancing the function of specific circulating monocytes by boosting the immune system constitutes a potential therapeutic target in AD.

    Parkinson disease

    Parkinson disease (PD) is a chronic progressive disorder that is characterized by tremor, rigidity, and bradykinesia. PD is caused by degeneration of the nigrostriatal pathway, which consists of both dopaminergic (DA) and nondopaminergic neurons [15]. The pathological hallmarks of PD are loss of nigrostriatal DA neurons and formation of Lewy bodies, which are aggregates of proteinaceous cytoplasmic inclusions [16]. Degeneration of DA neurons is accompanied by activation of microglia and infiltration of T lymphocytes into the CNS [17]. Mouse strains that lack T cells or mature T cells are relatively resistant to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced degeneration of DA neurons [18]. Notably, CD4+ T cells, but not CD8+ T cells, are involved in the MPTP resistance [19]. Collectively, these data indicate that the deleterious activity of MPTP is associated with infiltrating CD4+ T cells. Further, passive transfer of T cells obtained from mice immunized with the immunomodulatory drug glatiramer acetate is neuroprotective against MPTP neurotoxicity, possibly by increasing anti-inflammatory cytokines such as interleukin (IL)-4, IL-10, and transforming growth factor-beta [20,21].
    Regulatory T cells (Treg cells), a specialized T-cell subtype, can be neuroprotective [21]. In vitro, Treg cells suppress the inflammatory microglial phenotype, whereas CD4+ CD25 effector T cells (Teff cells) exacerbate the inflammatory microglial phenotype [22]. In an in vivo PD model, adoptive transfer of activated Treg cells, but not Teff cells provided neuroprotective effects in MPTP-induced DA cell loss [23]. These studies demonstrate that T cells are important participants in mediating cytotoxicity and neuroprotection in models of PD, depending on their subtype and microenvironment. Therefore, novel therapeutic approaches are needed to clarify the role of innate and adaptive immune responses in patients with PD.

    Amyotrophic lateral sclerosis

    Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is a neurodegenerative disorder characterized by fatal progressive motor neuron death, consequently resulting in death within 3–5 years [24]. There is no effective therapeutic regimen, and several clinical trials using various types of stem cells as well as new chemical drugs are ongoing [25,26]. Neuroinflammation similar to other neurodegenerative diseases is one of the most striking hallmarks of ALS [27], a heterogeneous disease with various genetic backgrounds [28,29]. Recent studies have demonstrated that innate and adaptive immune cells play interdependent roles in regulating the rate of disease progression in ALS [30]. T lymphocytes, a type of adaptive immune cell, are able to infiltrate into the spinal cord in patients with ALS, and in an ALS mouse model, CD4+ T lymphocytes slowed disease progression, shaped microglial phenotypes, and extended survival [31,32]. ALS patients with elevated peripheral Treg cell levels exhibited slow disease progression in a prospective cohort study, suggesting that Treg cells may be associated with the slowing of ALS progression [30,33]. Because neuroinflammation is a prominent pathological feature in ALS, up-regulating Treg cell activity or increasing the Treg cell ratio in the immune system of patients with ALS may represent a potential therapeutic strategy.

    Depression

    Major depression exhibits various disease courses with inconsistent response to antidepressant treatments [34]. Despite the availability of both pharmacological and psychotherapeutic treatments to a large number of patients, major depression has high rates of relapse and recurrence. A long course of treatment is required for complete recovery from symptoms and prevention of relapse, which is considered the major obstacle in the treatment of major depressive disorder [35].
    Most antidepressants were developed based on the “monoamine theory,” which postulates that persistent reduction in the levels of serotonin, norepinephrine, and dopamine in the synaptic cleft induces neuroplastic changes, inhibits neurogenesis, and affects cognitive function, finally leading to depression. Thus, current antidepressants are designed to elevate monoamines in CNS. However, more than 50%–70% of patients who recover from a first episode of depression are vulnerable to stress and are at risk of chronic depression [35,36]. In addition, more than 50% of patients are resistant to antidepressant treatment [35,36]. Thus, new approaches beyond the monoamine theory are needed to better treat depression.
    Systemic inflammation is associated with the lack of clinical therapeutic benefit of antidepressants in patients resistant to treatment [37,38]. In addition, recent studies have demonstrated that the peripheral immune system is involved in susceptibility or resilience to social stress [39]. In an animal study, mice receiving IL-6 knockout bone marrow transplantation after irradiation were resilient to social stress, suggesting that the peripheral immune system interacts actively with the CNS to shape synaptic circuits [39]. Nude mice, which are T cell depleted, exhibit stress vulnerability, showing depressive-like behaviors in a single foot shock session [40]. Peripheral IL-4/10, an anti-inflammatory cytokine, prevents stress vulnerability in depressed mice via restoration of alternatively activated microglia phenotype [40]. The kynurenine pathway has been demonstrated as a factor linking “cytokine theory” and “monoamine theory” in depression, since pro-inflammatory cytokines lead to tryptophan degradation by indoleamine 2,3-dioxygenase and its metabolites with downstream enzymes inducing neurotoxicity, eventually resulting in depression [41]. Regarding the role of the innate immune system in the CNS, recent studies have demonstrated the role of microglia in depression [42]. Several data suggest that microglia are involved in brain homeostasis processes, such as synaptic transmission and neural plasticity, as well as in pathological brain processes [43]. Microglia interact closely with the peripheral immune system in healthy and diseased states [44]. Peripheral immune cells such as Treg and Th2 cells and their releasing factors restore microglia functional phenotype in depressed mice, leading to reduced stress vulnerability [40]. Thus, targeting the circulating immune system could be an alternative therapeutic strategy, especially in recurrent and refractory forms of depression.

    Schizophrenia

    Schizophrenia is disabling neuropsychiatric disorder, characterized by positive symptoms (hallucinations and delusions), depression-like negative symptoms, cognitive dysfunction, and neurodegeneration [45,46]. Epidemiological and genetic studies strongly implicate neuroinflammation and peripheral immunity in the pathogenesis of schizophrenia [46-48]. Crosstalk between the peripheral immune system and the brain has been investigated extensively in the context of schizophrenia pathophysiology [49]. Recent population-based longitudinal studies and meta-analysis show an association between elevated levels of pro-inflammatory cytokines and the risk of psychosis [46-48]. In addition, malfunctions of both the innate and adaptive immune systems are observed in schizophrenia. As mentioned above, it is now well established that adaptive immunity in conjunction with innate immunity plays an active role in brain development and homeostasis. Recently, neurodegeneration has been demonstrated to be one of the predominant underlying mechanisms in schizophrenia progression, in which immunemodulatory processes play a crucial role [50]. For example, T-cell-related molecular changes in immune dysfunction have been demonstrated in patients with first-onset schizophrenia [51], and activated lymphocytes in the CSF and hippocampus of patients have been reported, suggesting BBB impairment [52]. Altogether, these studies indicate that T-cell-mediated immunity is involved in schizophrenia pathogenesis [53].

    LESSONS FROM NEUROIMMUNOLOGY: THE ROLE OF THE CIRCULATING IMMUNE SYSTEM IN UROLOGY

    The peripheral immune system appears to be actively involved in the development of neurologic disorders. The central concept of involvement of the circulating immune system in neurological disorders is a new insight concerning immune-privileged sites. Similarly, in urology, the testis is no longer considered an immune-privileged site. A layer of epithelial sertoli cells, which are interconnected by tight junctions, encloses the testis germinal compartment, and though leukocytes are strictly blocked from the lumen of the seminiferous tubules in normal tissue, they occasionally penetrate the blood-testis barrier (BTB) of tubuli recti [54,55]. In addition, the testis has a BTB gating system at the seminiferous tubule [2]. The interstitial space, like the perivascular space in the CNS, is a place where immunomodulatory mechanisms are evoked by circulating immune cells. In addition, testicular autoimmunity is primarily observed in “normal” tubuli recti and rete testes, indicating that these structures may be a site of lymphocyte entry.
    From a neurourology viewpoint, circulating immune cells may play various roles. Neurogenic lower urinary tract dysfunction can occur in patients with various neurological disorders. For example, PD is one of the most common neurological disorders causing lower urinary tract dysfunction, and DA brain lesions induced by 6-hydroxydopamine injections into the medial forebrain bundle cause bladder dysfunction [56]. Stroke may also cause voiding dysfunction. In an animal model, intracerebral hemorrhage (ICH) induced lower urinary tract dysfunction, showing that ICH significantly enhanced bladder contraction pressure and time, while simultaneously reducing voiding pressure and time [57]. The crosstalk between the CNS and circulating immune cells suggests that the immune system may affect urologic function indirectly via the CNS in patients with neurological disorders. In regard to drug treatment, immune-regulating drugs might be repositioned in neurogenic bladder dysfunction via both immune and brain system. Thus, the relationship between peripheral immune cells, the brain, and the urologic system can be considered an additional possible mechanism in urologic diseases, and immunotherapy might be an alternative therapeutic strategy in neurourological disorders.

    CONCLUSION

    Modulating peripheral immune cells to treat neurological disorder is no longer an “if” but a “how.” Over the past two decades, numerous studies have investigated the pivotal role of peripheral immune cells in the progression of neurological diseases. Proper balance between the CNS and circulating immune cells maintains homeostatic brain functions, but the breakdown of this balance may cause or aggravate aging, neurodegenerative disease, and psychiatric disorders. Peripheral immune cells show varying kinetics in terms of the molecular and cellular immune response in neurological diseases, acting as aggravating or resolving factors depending on the microenvironment and immune state. Thus, a deeper understanding of the crosstalk between the CNS and the immune system will shed light on the pathologies of aging, neurodegenerative diseases, and psychiatric disorders. In addition, effective immunotherapies for timely and beneficial modulation of the immune response might present alternatives for treatment of various intractable diseases.

    NOTES

    Grant Support
    This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2015R1D1A1A02062312).
    Conflict of Interest
    No potential conflict of interest relevant to this article was reported.

    REFERENCES

    1. Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 1948;29:58-69. PMID: 18865105
    pmid pmc
    2. Shechter R, London A, Schwartz M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol 2013;13:206-18. PMID: 23435332
    crossref pmid
    3. Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008;31:247-69. PMID: 18558855
    crossref pmid
    4. Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 2012;33:579-89. PMID: 22926201
    crossref pmid
    5. Mortazavi MM, Griessenauer CJ, Adeeb N, Deep A, Bavarsad Shahripour R, Loukas M, et al. The choroid plexus: a comprehensive review of its history, anatomy, function, histology, embryology, and surgical considerations. Childs Nerv Syst 2014;30:205-14. PMID: 24287511
    crossref pmid
    6. Carrithers MD, Visintin I, Kang SJ, Janeway CA Jr. Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment. Brain 2000;123(Pt 6):1092-101. PMID: 10825349
    crossref pmid
    7. Provencio JJ, Kivisakk P, Tucky BH, Luciano MG, Ransohoff RM. Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients. J Neuroimmunol 2005;163:179-84. PMID: 15885320
    crossref pmid
    8. Kivisäkk P, Trebst C, Liu Z, Tucky BH, Sorensen TL, Rudick RA, et al. T-cells in the cerebrospinal fluid express a similar repertoire of inflammatory chemokine receptors in the absence or presence of CNS inflammation: implications for CNS trafficking. Clin Exp Immunol 2002;129:510-8. PMID: 12197893
    crossref pmid pmc
    9. Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 2014;346:89-93. PMID: 25147279
    crossref pmid pmc
    10. Castellano JM, Kirby ED, Wyss-Coray T. Blood-borne revitalization of the aged brain. JAMA Neurol 2015;72:1191-4. PMID: 26237737
    crossref pmid pmc
    11. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014;20:659-63. PMID: 24793238
    crossref pmid pmc
    12. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 2010;330:1774. PMID: 21148344
    crossref pmid pmc
    13. Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 2009;27:119-45. PMID: 19302036
    crossref pmid
    14. Michaud JP, Bellavance MA, Prefontaine P, Rivest S. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep 2013;5:646-53. PMID: 24210819
    crossref pmid
    15. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 2003;39:889-909. PMID: 12971891
    crossref pmid
    16. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature 1997;388:839-40. PMID: 9278044
    crossref pmid
    17. Appel SH, Beers DR, Henkel JS. T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 2010;31:7-17. PMID: 19879804
    crossref pmid pmc
    18. Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, et al. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 2008;3:e1376.
    19. Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, BerayBerthat V, et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 2009;119:182-92. PMID: 19104149
    pmid
    20. Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 2004;101:9435-40. PMID: 15197276
    crossref pmid pmc
    21. Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M. Neuroprotective autoimmunity: naturally occurring CD4+ CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci U S A 2002;99:15620-5. PMID: 12429857
    crossref pmid pmc
    22. Reynolds AD, Stone DK, Mosley RL, Gendelman HE. Nitrated [31]-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 2009;182:4137-49. PMID: 19299711
    crossref pmid pmc
    23. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL. Neuroprotective activities of CD4+ CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 2007;82:1083-94. PMID: 17675560
    crossref pmid
    24. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet 2011;377:942-55. PMID: 21296405
    crossref pmid
    25. Gordon PH, Meininger V. How can we improve clinical trials in amyotrophic lateral sclerosis? Nat Rev Neurol 2011;7:650-4. PMID: 21947135
    crossref pmid
    26. Oh KW, Moon C, Kim HY, Oh SI, Park J, Lee JH, et al. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med 2015;4:590-7. PMID: 25934946
    crossref pmid pmc
    27. Philips T, Robberecht W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 2011;10:253-63. PMID: 21349440
    crossref pmid
    28. Paez-Colasante X, Figueroa-Romero C, Sakowski SA, Goutman SA, Feldman EL. Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era. Nat Rev Neurol 2015;11:266-79. PMID: 25896087
    crossref pmid
    29. Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 2013;14:248-64. PMID: 23463272
    crossref pmid
    30. Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, et al. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med 2013;5:64-79. PMID: 23143995
    crossref pmid pmc
    31. Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, et al. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 2011;134(Pt 5):1293-314. PMID: 21596768
    crossref pmid pmc
    32. Zhao W, Beers DR, Appel SH. Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J Neuroimmune Pharmacol 2013;8:888-99. PMID: 23881705
    crossref pmid pmc
    33. Kwon MS, Noh MY, Oh KW, Cho KA, Kang BY, Kim KS, et al. The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALS patients. J Neurochem 2014;131:206-18. PMID: 24995608
    crossref pmid
    34. Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008;358:55-68. PMID: 18172175
    crossref pmid
    35. Melfi CA, Chawla AJ, Croghan TW, Hanna MP, Kennedy S, Sredl K. The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression. Arch Gen Psychiatry 1998;55:1128-32. PMID: 9862557
    crossref pmid
    36. Teasdale JD, Segal ZV, Williams JM, Ridgeway VA, Soulsby JM, Lau MA, et al. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol 2000;68:615-23. PMID: 10965637
    crossref pmid
    37. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010;67:446-57. PMID: 20015486
    crossref pmid
    38. Carvalho LA, Torre JP, Papadopoulos AS, Poon L, Juruena MF, Markopoulou K, et al. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord 2013;148:136-40. PMID: 23200297
    crossref pmid
    39. Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci U S A 2014;111:16136-41. PMID: 25331895
    crossref pmid pmc
    40. Han A, Yeo H, Park MJ, Kim SH, Choi HJ, Hong CW, et al. IL-4/10 prevents stress vulnerability following imipramine discontinuation. J Neuroinflammation 2015;12:197. PMID: 26521132
    crossref pmid pmc
    41. Dantzer R, O’Connor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 2011;36:426-36. PMID: 21041030
    crossref pmid pmc
    42. Yirmiya R, Rimmerman N, Reshef R. Depression as a microglial disease. Trends Neurosci 2015;38:637-58. PMID: 26442697
    crossref pmid
    43. Wake H, Moorhouse AJ, Miyamoto A, Nabekura J. Microglia: actively surveying and shaping neuronal circuit structure and function. Trends Neurosci 2013;36:209-17. PMID: 23260014
    crossref pmid
    44. Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 2011;11:775-87. PMID: 22025055
    crossref pmid
    45. Mitchell KJ, Porteous DJ. Rethinking the genetic architecture of schizophrenia. Psychol Med 2011;41:19-32. PMID: 20380786
    crossref pmid
    46. Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr Res 2014;155:101-8. PMID: 24704219
    crossref pmid
    47. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011;70:663-71. PMID: 21641581
    crossref pmid pmc
    48. Watkins CC, Andrews SR. Clinical studies of neuroinflammatory mechanisms in schizophrenia. Schizophr Res; 2015 Jul 30 [Epub]. http://dx.doi.org/10.1016/j.schres.2015.07.018. crossref
    49. Khandaker GM, Dantzer R. Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology (Berl) 2016;233:1559-73. PMID: 26037944
    crossref pmid pmc pdf
    50. Durrenberger PF, Fernando FS, Kashefi SN, Bonnert TP, Seilhean D, Nait-Oumesmar B, et al. Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study. J Neural Transm (Vienna) 2015;122:1055-68. PMID: 25119539
    crossref pmid
    51. Herberth M, Rahmoune H, Schwarz E, Koethe D, Harris LW, Kranaster L, et al. Identification of a molecular profile associated with immune status in first-onset schizophrenia patients. Clin Schizophr Relat Psychoses 2014;7:207-15. PMID: 23395839
    crossref pmid
    52. Busse S, Busse M, Schiltz K, Bielau H, Gos T, Brisch R, et al. Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations? Brain Behav Immun 2012;26:1273-9. PMID: 22917959
    crossref pmid
    53. Debnath M. Adaptive Immunity in schizophrenia: functional implications of t cells in the etiology, course and treatment. J Neuroimmune Pharmacol 2015;10:610-9. PMID: 26162591
    crossref pmid
    54. Naito M, Terayama H, Hirai S, Qu N, Moriyama H, Itoh M. The presence of intra-tubular lymphocytes in normal testis of the mouse. Okajimas Folia Anat Jpn 2008;85:91-6. PMID: 19227199
    crossref pmid
    55. Goyal HO, Williams CS. The rete testis of the goat, a morphological study. Acta Anat (Basel) 1987;130:151-7. PMID: 3504080
    crossref pmid
    56. Soler R, Fullhase C, Santos C, Andersson KE. Development of bladder dysfunction in a rat model of dopaminergic brain lesion. Neurourol Urodyn 2011;30:188-93. PMID: 20589898
    crossref pmid
    57. Cho YS, Ko IG, Kim CJ, Kim KH. A novel intracerebral hemorrhage-induced rat model of neurogenic voiding dysfunction: Analysis of lower urinary tract function. Mol Med Rep 2015;12:2563-9. PMID: 25954993
    crossref pmid pmc
    TOOLS
    Share :
    Facebook Twitter Linked In Google+
    METRICS Graph View
    • 1 Crossref
    • 1 Scopus
    • 2,633 View
    • 44 Download


    ARTICLE & ORGAN
    Article Category

    Browse all articles >

    Organ

    Browse all articles >

    ISSUES
    DISEASES & TOPICS
    Diseases

    Browse all articles >

    Topics

    Browse all articles >

    AUTHOR
    INFORMATION

    Editorial Office
    Department of Urology, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine,
    29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea
    Tel: +82-2-2001-2237     Fax: +82-2-2001-2247    E-mail: choys1011@naver.com

    Copyright © 2017 by Korean Continence Society. All rights reserved.

    Powerd by M2community

    Close layer
    prev next