Radiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

DOI: 10.1148/radiol.2463070338
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pirko, I.
Right arrow Articles by Johnson, A. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pirko, I.
Right arrow Articles by Johnson, A. J.
Related Collections
Right arrowRelated Article
(Radiology 2008;246:790-795.)
© RSNA, 2008

Experimental Studies

Multiple Sclerosis: Pathogenesis and MR Imaging Features of T1 Hypointensities in Murine Model1

Istvan Pirko, MD, Tifany K. Nolan, Scott K. Holland, PhD, and Aaron J. Johnson, PhD

1 From the Department of Neurology, University of Cincinnati, 260 Stetson St. Suite 2300, PO Box 670525, Cincinnati, OH 45267-0525 (I.P., A.J.J.); University of Cincinnati Medical School, College of Medicine, Cincinnati, Ohio (T.K.N.); and Imaging Research Center, Children's Hospital Research Foundation, Children's Hospital Medical Center, Cincinnati, Ohio (S.K.H.). Received February 18, 2007; revision requested May 2; revision received June 8; accepted June 27; final version accepted August 1. Supported by a research fund by the Neuroscience Institute at the University of Cincinnati and by intramural funds. Address correspondence to I.P. (e-mail: Istvan.Pirko{at}uc.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Purpose: To prospectively determine how T1 hypointensities (T1 black holes) on brain magnetic resonance (MR) images are generated by the immune system by using a Theiler murine encephalitis virus–induced model of multiple sclerosis and high-field-strength MR imaging.

Materials and Methods: All animal protocols and experiments were approved by the institutional animal care and use committee. Volumetric MR imaging studies were conducted at 7 T in six C57BL/6 mice and in immune differentiation marker (recombination activation gene [RAG]-1)–, immune cell (CD4, CD8)–, and immune effector molecule (Fas ligand, perforin)–deficient mice (six mice in each group) to determine which immune cell types and effector molecules lead to T1 hypointensities. The main outcome measure was the total T1 black hole volume per animal, as determined with volumetric analysis, and was analyzed statistically by using software.

Results: Compared with C57BL/6 mice, RAG-1–deficient mice showed a significant (P = .003) decrease in total T1 black hole volume, suggesting a clear role for the adaptive immune system. While CD4-deficient mice did not show a significant decrease in T1 black hole volume (P = .33), CD8-deficient mice did (P = .003). Perforin-deficient mice showed a significant reduction of T1 black hole volume (P = .002), whereas Fas ligand–deficient mice did not (P = .77).

Conclusion: The data suggest that CD8 T cells utilizing perforin effector molecules are responsible for T1 black hole formation.

© RSNA, 2008


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (1). Magnetic resonance (MR) imaging is a critical tool in diagnosing and monitoring MS disease activity (2,3). Despite the widespread use of conventional MR imaging in clinical practice, conventional MR imaging findings do not show a strong correlation with disability (4). A subset of T2-weighted lesions is identifiable on T1-weighted images as T1 hypointensities, or T1 black holes. These may be observed as a transient stage in the formation of a new MS lesion (5); however, approximately 30% of patients with MS also develop persistent T1 black holes. These lesions are thought to represent severe tissue loss, including axonal damage (6,7). The total volume of persistent T1-weighted hypointense lesions on short repetition time, short echo time spin-echo MR images correlates well with chronic disability (8–11). Therefore, understanding the pathogenesis of T1 black hole formation may allow us to gain new insight into the substrate of disability in MS. The mechanism leading to the formation of T1 hypointensities is currently not known.

We hypothesized that the presence of specific immune cells and specific effector molecules is required for T1 black hole formation to occur. Thus, the aim of our study was to prospectively determine how T1 hypointensities (T1 black holes) on brain MR images are generated by the immune system, by using a Theiler murine encephalitis virus (TMEV)–induced model of MS and high-field-strength MR imaging.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Mice
Our study was conducted with full approval by the Institutional Animal Care and Use Committee of the University of Cincinnati. C57BL/6 mice show T1 black hole formation when intracerebrally infected with TMEV. We studied six groups of mice (Table 1). Each group included six animals. Our control group was the C57BL/6 group; their T1 black hole formation was considered standard. The other groups were deficient in adaptive immune system (recombination activation gene [RAG]-1–deficient mice), specific immune cells (CD4- or CD8-deficient mice), or immune effector molecules, including perforin and Fas ligand. These effector molecules are known to be utilized by CD8+ T cells. By choosing these groups, we were able to study the role of specific immune cells in the pathogenesis of T1 black holes. The deficient mice otherwise had the same genetic background as the C57BL/6 mice. The mice were sex and age matched among the groups.


View this table:
[in this window]
[in a new window]

  		Table 1. Studied Groups of Mice

 
TMEV Infection
All mice were injected intracerebrally as described previously with 106 plaque-forming units of TMEV (12,13). The animals were anesthetized by using 1.5% inhalational isoflurane (Forane; Abbott Laboratories, North Chicago, Ill) prior to this procedure.

MR Image Acquisition
In vivo MR imaging was performed 7 days after TMEV infection. MR images were acquired with horizontal-bore 7-T equipment (Biospec; Bruker, Billerica, Mass) by using a 12-cm gradient insert designed for small rodent imaging. We also used a custom-built 2.5-cm-diameter birdcage radiofrequency coil for excitation and three-dimensional acquisition. Isometric or near-isometric high-spatial-resolution three-dimensional acquisition (on the order of 200 µm) is recommended in most cases of small rodent brain imaging (14). Imaging parameters included a standard spin-echo sequence with the following parameters: repetition time msec/echo time msec, 200/10; voxel dimensions, 135 x 200 x 200 µm; and two acquisitions. During the imaging session, inhalational anesthesia (1.5% isoflurane) was used. Electrocardiographic data, respiratory rate, and core temperature of the animals were monitored by using a commercially available system. The core temperature of the animals was maintained by using a custom-built water-heated MR imaging bed. We experienced no animal loss; the animals recovered without any sequelae after anesthesia and image acquisition.

MR Image Analysis and Volumetry
MR imaging data sets were analyzed by using a commercially available biomedical image-processing software package (Analyze, version 6.2; Biomedical Imaging Resource, Mayo Clinic, Rochester, Minn [15,16]). With the use of three-dimensional region-of-interest analysis tools, a semiautomated seed-growing algorithm was used to identify all areas of T1 hypointensity. The data set was analyzed by studying transverse sections extracted from the three-dimensional data set; all areas were also cross checked on coronal and sagittal images extracted from the same data set. The identified subvolumes were represented in three dimensions and analyzed by using the three-dimensional scan tool. The three-dimensional scan tool provides a numeric output that represents the total T1 black hole lesion volume per animal.

Because the analysis is semiautomated, there clearly is a possibility for human error in the procedure. To minimize this, the two analyzers (I.P., with 5 years of experience in small animal MR imaging, image acquisition, and image processing; T.K.N., with 1 year of experience in image processing) were trained on 23 standard data sets analyzed for previous projects utilizing the same volumetric method. They were blinded to the data set being analyzed. They were allowed to discuss the training data sets with each other after a volume set was analyzed. The interrater comparison of the volumetric analysis did not show any statistically significant difference between the raters after this training (P = .94), as determined with a Student t test to compare the resulting volumetric data of the two analyzers. The statistical analysis to compare the two analyzers was conducted by an author (A.J.J.) of this study.

Statistical Analysis
Statistical analysis of the volumetric data of the experimental groups was performed to determine intergroup differences in total T1-weighted hypointense lesion load. We compared the mean T1 black hole volumes by using a t test for independent samples with a software package (JMP IN, version 4.0.4 Academic, 2001; SAS Institute, Cary, NC). Because of the inequality of variances between the groups in our pilot study, a two-sided Satterthwaite t test was utilized in generating P values. A P value of .05 or less was considered to indicate a significant difference in these comparisons.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Volumetric MR Imaging Findings in Immune Cell–Deficient Animals
In six mice lacking adaptive immune cells (RAG-1–deficient mice), an 86% (666.4 divided by 777.4 [units are 0.01 mm3]) decrease in T1 lesion load was seen compared with data obtained in six C57BL/6 mice (P = .003) (Tables 2, 3). In CD8-deficient mice, a 75% decrease (585.1 divided by 777.4) in total T1 black hole volume was detected compared with that in C57BL/6 mice (P = .003). The extent of T1 lesion burden reduction in CD8-deficient mice was not significantly different (P = .51) than that in RAG-1–deficient mice. In contrast to this, the data in six CD4-deficient mice showed a reduction of only 21% (167.3 divided by 777.4), which was not statistically significant when compared with data in C57BL/6 mice (P = .33).


View this table:
[in this window]
[in a new window]

  		Table 2. Numeric Results of T1 Black Hole Volumetry at MR Imaging

 

View this table:
[in this window]
[in a new window]

  		Table 3. P Values for Intergroup Comparison

 
Volumetric MR Imaging Findings in Immune Effector Molecule–Deficient Animals
We found significantly decreased T1 black hole volumes in six perforin-deficient mice (80% reduction [620.2 divided by 777.4], P = .002) compared with volumes in C57BL/6 mice. The data in Fas ligand–deficient and wild-type mice were not significantly different (P = .77) (Figure; Tables 2, 3).


Figure 1
View larger version (73K):
[in this window]
[in a new window]
[Download PPT slide]
  		Representative transverse (left and middle) and coronal (right) sections extracted from T1-weighted volume acquisition MR imaging data set (200/10) in wild-type C57BL/6 mice infected with TMEV and imaged 7 days after infection. Frames surround areas of T1 hypointensity. Most T1 hypointensities are located around ventricles and near the hippocampus.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCE IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Our results strongly suggest that in the studied model, the formation of T1 hypointensities is linked to CD8+ T cells. CD8-deficient mice showed a prominent reduction in T1 black hole formation, to the same extent as RAG-1–deficient mice (mice lacking adaptive immunity). When analyzing effector molecules typically used by CD8+ T cells, we concluded that the perforin pathway is the most likely mediator of the process that leads to T1 black hole formation. The volumetric MR imaging data in the perforin-deficient mice was essentially the same as in the CD8-deficient mice, whereas data in the Fas ligand knock-out mice were identical to those in wild-type mice, which suggests that Fas ligand is not involved in this process.

To our knowledge, there are only a few autopsy-based MR imaging–histologic finding comparative studies published to date on the analysis of the relationship between T1 hypointensities on MR images and histologic findings. In an MR imaging–histologic finding comparative study of unfixed postmortem brains of patients with MS, MR images of the extracted brains were acquired prior to tissue processing (6). The degree of hypointensity correlated best with axonal density (R = –0.71, P = .01). The observation that T1 hypointensities likely represent severe tissue damage, including axonal and neuronal loss, was also replicated by Bitsch et al (7). In results of another study (17), T1 black holes were found to have a low magnetization transfer ratio on MR images, which is also indicative of structural loss.

The importance of a chronic T1 black hole in human MS is related to its correlation with disability (9–11). This is partially explained by the fact that T2 hyperintensities represent several different pathologic changes, including gliosis, demyelination, inflammation, focal edema, and so forth (18), whereas T1 hypointensities seem to indicate a more restrictive and more destructive set of processes at the tissue level. T1 hypointense lesion load shows a good correlation with disability: In cross-sectional studies, the correlation is 0.46–0.74, and in longitudinal studies, it is 0.46–0.52 (4). From this standpoint, it would be important to identify what mechanism leads to T1 black hole formation, so that future therapeutic efforts can be focused on this process. By identifying future therapeutic interventions that target T1 black hole formation, the same interventions will also have a potentially larger impact on prevention or reversal of disability.

We observed reduced T1 black hole formation at volumetric small-animal MR imaging in CD8-deficient and perforin-deficient mice, which suggests a strong role for the adaptive immune system in the disease process. One could suspect that the T1 black holes in these mice might be related directly to the viral infection and not to the function of the immune system. However, our observations in RAG-1–deficient mice suggest that the adaptive immune system plays a major role in the pathogenesis of T1 black holes. RAG-1–deficient mice do not have an adaptive immune system but otherwise have high virus loads. These mice had the most prominent reduction in T1 black hole formation. It is therefore unlikely that direct viral damage of central nervous system cells plays a role in the process of T1 black hole formation.

Contrary to what may have been expected, we did not see a substantial contribution by CD4+ T cells. Traditionally, CD4+ T cells (or T helper cells) have been thought to be responsible for the immunopathogenesis in MS, mainly for two reasons: Certain major histocompatibility complex class II alleles recognized by CD4+ T cells predispose for the development of MS, and CD4 T cells play a critical role in inducing experimental autoimmune encephalomyelitis (EAE), the most commonly studied animal model for MS. However, several therapeutic strategies that target CD4+ T cells in EAE have failed to show efficacy in human MS, and some have led to substantial worsening of the disease. In addition, many known features of human MS cannot be explained by using the EAE model (19–21).

Recently, the importance of CD8+ T cells has begun to emerge. CD8+ T cells have a sophisticated set of effector molecules that makes them uniquely suited to destroy somatic cells that display various kinds of pathology, including infections and neoplasia. CD8+ T cells damage only cells that display major histocompatibility complex I class surface antigens, which somatic cells do. In human MS, genetic associations with major histocompatibility complex class I alleles have now been established. In EAE, CD8+ T cells are mainly suspected to play a role in suppressing the inflammation, although some EAE models are induced by CD8+ T cells. Interestingly, such models display more brain lesions and a more severe disease course, whereas classic EAE is almost always confined to the spinal cord only (22,23).

With the advent of more sophisticated histopathologic techniques, there are increasing reports that CD8+ T cells are the most prevalent immune cell type observed in newly forming MS lesions (24,25). Furthermore, CD8+ T cells outnumber T cells of the CD4+ subtype by almost 10-fold in human MS lesions (24,26) and are directly enriched at the site of actively demyelinating lesions (24,27). CD8+ cells are also the most numerous in normal-appearing gray and white matter of the brain (21). CD8+ T cell infiltrates also correlate well with axonal damage in human MS (27,28).

Besides their role in MS, CD8+ lymphocytes are also important in the pathogenesis of other inflammatory central nervous system diseases, including paraneoplastic diseases, where they have been shown to recognize and kill neurons (29–32). They are also considered key mediators in the pathogenesis of X-linked adrenoleukodystrophy (33) and human T-cell lymphoma virus–associated myelopathy (34). CD8+ T cells are known to play key roles in the TMEV-induced model of MS (35–37). Furthermore, it has been described in MS lesions, as well as in other immune-mediated diseases of the brain, that clonal expansion and clonal restriction is commonly observed among the central nervous system–infiltrating CD8+ T cells, which suggests that they are targeting a focused, but as yet unidentified, antigen (24,31,34).

There were possible limitations to our study. These included the lack of correlative histologic and immunohistochemical data. Another limitation was that while CD8 T cells clearly seem to contribute to the described process, it is not yet clear whether these represent classic major histocompatibility complex I–restricted cytotoxic T cells or regulatory T cells. Our study was a pilot study to pave the way for a larger-scale project, which is currently in its planning stages and will investigate these important aspects of our model.

Practical applications: We suspect that, from the standpoint of T1 black hole formation, the main role of CD8+ T cells and perforin is that they directly contribute to axonal and neuronal damage. As discussed earlier, T1 black hole formation in human MS is known to be linked with disability. Our study results could therefore aid in the development of therapeutic approaches that more directly target the processes that lead to disability in patients with MS. Our study results also emphasize the emerging role of high-field-strength experimental MR imaging systems in translational projects aimed at understanding the pathogenesis of human MR imaging findings.


   ADVANCE IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
References
 


   ACKNOWLEDGMENTS
 
We acknowledge Moses Rodriguez, MD, Professor of Neurology and Immunology at Mayo Clinic, Rochester, Minnesota, for the critical review of this manuscript and R. Scott Dunn, RT, Imaging Research Center, Cincinnati Children's Hospital Medical Center, for his expert help in image acquisition.


   FOOTNOTES
 

Abbreviations: EAE = experimental autoimmune encephalomyelitis • MS = multiple sclerosis • RAG = recombination activation gene • TMEV = Theiler murine encephalitis virus

Author contributions: Guarantor of integrity of entire study, I.P.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, I.P., T.K.N.; experimental studies, all authors; statistical analysis, all authors; and manuscript editing, I.P., S.K.H., A.J.J.

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 

  1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343:938–952.[Free Full Text]
  2. Zivadinov R, Bakshi R. Role of MRI in multiple sclerosis. I. Inflammation and lesions. Front Biosci 2004;9:665–683.
  3. Zivadinov R, Bakshi R. Role of MRI in multiple sclerosis. II. Brain and spinal cord atrophy. Front Biosci 2004;9:647–664.
  4. Zivadinov R, Leist TP. Clinical–magnetic resonance imaging correlations in multiple sclerosis. J Neuroimaging 2005;15(4 suppl):10S–21S.[CrossRef][Medline]
  5. Levesque I, Sled JG, Narayanan S, et al. The role of edema and demyelination in chronic T1 black holes: a quantitative magnetization transfer study. J Magn Reson Imaging 2005;21:103–110.[CrossRef][Medline]
  6. van Walderveen MA, Kamphorst W, Scheltens P, et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 1998;50:1282–1288.[Abstract/Free Full Text]
  7. Bitsch A, Kuhlmann T, Stadelmann C, Lassmann H, Lucchinetti C, Bruck W. A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol 2001;49:793–796.[CrossRef][Medline]
  8. Uhlenbrock D, Sehlen S. The value of T1-weighted images in the differentiation between MS, white matter lesions, and subcortical arteriosclerotic encephalopathy (SAE). Neuroradiology 1989;31:203–212.[CrossRef][Medline]
  9. Truyen L, van Waesberghe JH, van Walderveen MA, et al. Accumulation of hypointense lesions ("black holes") on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996;47:1469–1476.[Abstract/Free Full Text]
  10. van Walderveen MA, Barkhof F, Hommes OR, et al. Correlating MRI and clinical disease activity in multiple sclerosis: relevance of hypointense lesions on short-TR/short-TE (T1-weighted) spin-echo images. Neurology 1995;45:1684–1690.[Abstract/Free Full Text]
  11. van Walderveen MA, Lycklama AN, Ader HJ, et al. Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis. Arch Neurol 2001;58:76–81.[Abstract/Free Full Text]
  12. Pirko I, Ciric B, Gamez J, et al. A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB J 2004;18:1577–1579.[Abstract/Free Full Text]
  13. Pirko I, Gamez J, Johnson AJ, Macura SI, Rodriguez M. Dynamics of MRI lesion development in an animal model of viral-induced acute progressive CNS demyelination. Neuroimage 2004;21:576–582.[CrossRef][Medline]
  14. Pirko I, Fricke ST, Johnson AJ, Rodriguez M, Macura SI. Magnetic resonance imaging, microscopy, and spectroscopy of the central nervous system in experimental animals. NeuroRx 2005;2:250–264.[Abstract/Free Full Text]
  15. Hanson DP, Robb RA, Aharon S, et al. New software toolkits for comprehensive visualization and analysis of three-dimensional multimodal biomedical images. J Digit Imaging 1997;10:229–230.[Medline]
  16. Robb RA. The biomedical imaging resource at Mayo Clinic. IEEE Trans Med Imaging 2001;20:854–867.[CrossRef][Medline]
  17. Hiehle JF Jr, Grossman RI, Ramer KN, Gonzalez-Scarano F, Cohen JA. Magnetization transfer effects in MR-detected multiple sclerosis lesions: comparison with gadolinium-enhanced spin-echo images and nonenhanced T1-weighted images. AJNR Am J Neuroradiol 1995;16:69–77.[Abstract]
  18. Bakshi R, Minagar A, Jaisani Z, Wolinsky JS. Imaging of multiple sclerosis: role in neurotherapeutics. NeuroRx 2005;2:277–303.[Abstract/Free Full Text]
  19. Nelson AL, Bieber AJ, Rodriguez M. Contrasting murine models of MS. Int MS J 2004;11:95–99.[Medline]
  20. Sriram S, Steiner I. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol 2005;58:939–945.[CrossRef][Medline]
  21. Lassmann H, Ransohoff RM. The CD4-Th1 model for multiple sclerosis: a critical [correction of crucial] re-appraisal. Trends Immunol 2004;25:132–137. [Published correction appears in Trends Immunol 2004;25:275.][CrossRef][Medline]
  22. Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med 2001;194:669–676.[Abstract/Free Full Text]
  23. Sun D, Whitaker JN, Huang Z, et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol 2001;166:7579–7587.[Abstract/Free Full Text]
  24. Babbe H, Roers A, Waisman A, et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 2000;192:393–404.[Abstract/Free Full Text]
  25. Skulina C, Schmidt S, Dornmair K, et al. Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc Natl Acad Sci U S A 2004;101:2428–2433.[Abstract/Free Full Text]
  26. Gay FW, Drye TJ, Dick GW, Esiri MM. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis: identification and characterization of the primary demyelinating lesion. Brain 1997;120(pt 8):1461–1483.[Abstract/Free Full Text]
  27. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W. Acute axonal injury in multiple sclerosis: correlation with demyelination and inflammation. Brain 2000;123(pt 6):1174–1183.[Abstract/Free Full Text]
  28. Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002;125:2202–2212.[Abstract/Free Full Text]
  29. Tanaka M, Maruyama Y, Sugie M, Motizuki H, Kamakura K, Tanaka K. Cytotoxic T cell activity against peptides of Hu protein in anti-Hu syndrome. J Neurol Sci 2002;201:9–12.[CrossRef][Medline]
  30. Tanaka K, Tanaka M, Inuzuka T, Nakano R, Tsuji S. Cytotoxic T lymphocyte-mediated cell death in paraneoplastic sensory neuronopathy with anti-Hu antibody. J Neurol Sci 1999;163:159–162.[CrossRef][Medline]
  31. Tanaka M, Tanaka K, Shinozawa K, Idezuka J, Tsuji S. Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody. J Neurol Sci 1998;161:88–90.[CrossRef][Medline]
  32. Tanaka M, Tanaka K, Tokiguchi S, Shinozawa K, Tsuji S. Cytotoxic T cells against a peptide of Yo protein in patients with paraneoplastic cerebellar degeneration and anti-Yo antibody. J Neurol Sci 1999;168:28–31.[CrossRef][Medline]
  33. McGuinness MC, Powers JM, Bias WB, et al. Human leukocyte antigens and cytokine expression in cerebral inflammatory demyelinative lesions of X-linked adrenoleukodystrophy and multiple sclerosis. J Neuroimmunol 1997;75:174–182.[CrossRef][Medline]
  34. Nakamura T. Immunopathogenesis of HTLV-I-associated myelopathy/tropical spastic paraparesis. Ann Med 2000;32:600–607.[Medline]
  35. Johnson AJ, Mendez-Fernandez Y, Moyer AM, et al. Antigen-specific CD8+ T cells mediate a peptide-induced fatal syndrome. J Immunol 2005;174:6854–6862.[Abstract/Free Full Text]
  36. Suidan GL, Pirko I, Johnson AJ. A potential role for CD8+ T-cells as regulators of CNS vascular permeability. Neurol Res 2006;28:250–255.[CrossRef][Medline]
  37. McDole J, Johnson AJ, Pirko I. The role of CD8+ T-cells in lesion formation and axonal dysfunction in multiple sclerosis. Neurol Res 2006;28:256–261.[CrossRef][Medline]

Related Article

Erratum
Radiology 2008 248: 322. [Full Text] [PDF]




This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pirko, I.
Right arrow Articles by Johnson, A. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pirko, I.
Right arrow Articles by Johnson, A. J.
Related Collections
Right arrowRelated Article

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
RADIOLOGY RADIOGRAPHICS RSNA JOURNALS ONLINE