The Inflammatory Myelinopathy of Adreno-Leukodystrophy: Cells, Effector Molecules, and Pathogenetic Implications
Abstract
Prominent inflammation in the demyelinative lesion of adreno-leukodystrophy (ALD) has suggested an immune-mediated pathogenetic component. Commercially available antibodies to T cells, B cells, macrophages, class I and II molecules, complement, IgG, IgM, IgA, interleukin-1 (IL-1), intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF) were applied to paraffin sections of formaldehyde-fixed postmortem samples. Twenty-five primary demyelinative lesions from five juvenile ALD, three adult ALD, and three adrenomyeloneuropathic patients were evaluated with appropriate positive and negative controls. Macrophages and astrocytes were the predominant cells detected at the active edge; T lymphocytes, including T4 and CD45R subsets, were nearly as numerous but usually located around vessels within the lesion. B cells and plasma cells, usually containing IgG, were uncommon. The expression of class II molecules, restricted to one adult, was problematic; class I expression was increased in microvascular and other cells. Degraded myelin was labeled with antibodies to C3d and IL-1; IL-1 and ICAM-1 immunoreactivity was seen on microvessels and astrocytes. Tumor necrosis factor-alpha immunoreactivity was detected in macrophages, but more prominently in astrocytes. These data support a natural immune response in the demyelinative lesion of ALD, consisting predominantly of reactive astrocytes, macrophages, T cells and cytokines. A two-stage pathogenetic theory is discussed. The postulated roles of TNF and reactive astrocytes, in concert with a fundamental myelinolytic biochemical defect, suggest a different pathogenetic mechanism and raise novel therapeutic possibilities.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
cALD brain histopathology shows marked regional disparity with contiguous white matter areas ranging from intact myelinated axons to chronic gliotic lesions.
“Histopathology of five brains showed marked disparity across regions [72] with contiguous white matter areas [73]: (i) intact zones showing densely packed myelinated axons and normal-looking oligodendrocytes (OLs); (ii) zones of limited demyelination showing occasional astrocytes and lipid-containing macrophages; (iii) zones of active demyelination with loss of axons and myelin, variable loss of O”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [72]
Gadolinium enhancement just behind the leading edge of the lesion indicates active cerebral ALD disease.
“Gadolinium enhancement just behind the leading edge of the lesion indicates active disease.25-27”
From International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy (2022) · cites this paper as [27]
Cited by
Sorted by citations
Moser, H. W., Mahmood, A., & Raymond, G. V. (2007) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0421 · Cited by 663 · see citing works
Self-citationHematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy
Eichler, F., Duncan, C., Musolino, P. L., Orchard, P. J., De Oliveira, S., Thrasher, A. J., Armant, M., Dansereau, C., Lund, T. C., Miller, W. P., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1700554 · Cited by 604 · see citing works
Kemp, S., Pujol, A., Waterham, H. R., van Geel, B. M., Boehm, C. D., Raymond, G. V., Cutting, G. R., Wanders, R. J. A., & Moser, H. W. (2001) · Human Mutation · doi:10.1002/humu.1227 · Cited by 332 · see citing works
Self-citationX-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects
Kemp, S., Berger, J., & Aubourg, P. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.03.012 · Cited by 283 · see citing works
Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy
Loes, D. J., Fatemi, A., Melhem, E. R., Gupte, N., Bezman, L., Moser, H. W., & Raymond, G. V. (2003) · Neurology · doi:10.1212/01.wnl.0000079050.91337.83 · Cited by 268 · see citing works
Self-citationPathophysiology of X-linked adrenoleukodystrophy
Berger, J., Forss-Petter, S., & Eichler, F. S. (2014) · Biochimie · doi:10.1016/j.biochi.2013.11.023 · Cited by 238 · see citing works
Peroxisomal Disorders: Genotype, Phenotype, Major Neuropathologic Lesions, and Pathogenesis
Powers, J. M., & Moser, H. W. (1998) · Brain Pathology · doi:10.1111/j.1750-3639.1998.tb00139.x · Cited by 208 · see citing works
Self-citationAdrenomyeloneuropathy: A Neuropathologic Review Featuring Its Noninflammatory Myelopathy
Powers, J. M., DeCiero, D. P., Ito, M., Moser, A. B., & Moser, H. W. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.2.89 · Cited by 204 · see citing works
Self-citationHo, J. K., Moser, H., Kishimoto, Y., & Hamilton, J. A. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118182 · Cited by 199 · see citing works
Self-citationVery long chain fatty acids in higher animals: a review
Poulos, A. (1995) · Lipids · doi:10.1007/bf02537036 · Cited by 192 · see citing works
Peroxisomes in brain development and function
Berger, J., Dorninger, F., Forss-Petter, S., & Kunze, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.12.005 · Cited by 194 · see citing works
Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?
Eichler, F. S., Ren, J., Cossoy, M., Rietsch, A. M., Nagpal, S., Moser, A. B., Frosch, M. P., & Ransohoff, R. M. (2008) · Annals of Neurology · doi:10.1002/ana.21391 · Cited by 178 · see citing works
Self-citationHein, S., Schonfeld, P., Kahlert, S., & Reiser, G. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn066 · Cited by 180 · see citing works
International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy
Engelen, M., van Ballegoij, W. J. C., Mallack, E. J., Van Haren, K. P., Köhler, W., Salsano, E., van Trotsenburg, A. S. P., Mochel, F., Sevin, C., Regelmann, M. O., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000201374 · Cited by 156 · see citing works
Self-citationIto, M., Blumberg, B. M., Mock, D. J., Goodman, A. D., Moser, A. B., Moser, H. W., Smith, K. D., & Powers, J. M. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.10.1004 · Cited by 125 · see citing works
Self-citationExpression of the adrenoleukodystrophy protein in the human and mouse central nervous system
Fouquet, F., Zhou, J. M., Ralston, E., Murray, K., Troalen, F., Magal, E., Robain, O., Dubois-Dalcq, M., & Aubourg, P. (1997) · Neurobiology of Disease · doi:10.1006/nbdi.1997.0127 · Cited by 115 · see citing works
Plasmalogens participate in very-long-chain fatty acid-induced pathology
Brites, P., Mooyer, P. A. W., el Mrabet, L., Waterham, H. R., & Wanders, R. J. A. (2008) · Brain · doi:10.1093/brain/awn295 · Cited by 112 · see citing works
McGuinness, M. C., Powers, J. M., Bias, W. B., Schmeckpeper, B. J., Segal, A. H., Gowda, V. C., Wesselingh, S. L., Berger, J., Griffin, D. E., & Smith, K. D. (1997) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(97)00020-9 · Cited by 89 · see citing works
Self-citationAsheuer, M., Bieche, I., Laurendeau, I., Moser, A., Hainque, B., Vidaud, M., & Aubourg, P. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi140 · Cited by 86 · see citing works
Self-citationNerve conduction studies in adrenomyeloneuropathy
Chaudhry, V, Moser, H. W., & Cornblath, D. R. (1996) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.61.2.181 · Cited by 73 · see citing works
Self-citationImpaired plasticity of macrophages in X-linked adrenoleukodystrophy
Weinhofer, I., Zierfuss, B., Hametner, S., Wagner, M., Popitsch, N., Machacek, C., Bartolini, B., Zlabinger, G., Ohradanova-Repic, A., Stockinger, H., et al. (2018) · Brain · doi:10.1093/brain/awy127 · Cited by 72 · see citing works
Gilg, A. G., Singh, A. K., & Singh, I. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.12.1063 · Cited by 66 · see citing works
Baarine, M., Ragot, K., Athias, A., Nury, T., Kattan, Z., Genin, E. C., Andreoletti, P., Ménétrier, F., Riedinger, J.-M., Bardou, M., et al. (2012) · NeuroToxicology · doi:10.1016/j.neuro.2011.10.007 · Cited by 43 · see citing works
Cerebral X‐linked adrenoleukodystrophy in a girl with Xq27‐Ter deletion
Hershkovitz, E., Narkis, G., Shorer, Z., Moser, A. B., Watkins, P. A., Moser, H. W., & Manor, E. (2002) · Annals of Neurology · doi:10.1002/ana.10248 · Cited by 30 · see citing works
Self-citationSingh, J., Khan, M., & Singh, I. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.01.004 · Cited by 21 · see citing works
Leukodystrophy imaging: Insights for diagnostic dilemmas.
Thakkar, R. N., Patel, D., Kioutchoukova, I. P., Al-Bahou, R., Reddy, P., Foster, D. T., & Lucke-Wold, B. (2024) · Medical Sciences · doi:10.3390/medsci12010007 · Cited by 17 · see citing works
Cerebral adrenoleukodystrophy: a demyelinating disease that leaves the door wide open: Figure 1
Aubourg, P. (2015) · Brain · doi:10.1093/brain/awv271 · Cited by 15 · see citing works
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- POWERS, J. M., LIU, Y., MOSER, A. B., & MOSER, H. W.
- Affiliations
- NewYork–Presbyterian Hospital (US)
- Kennedy Krieger Institute (US)
- Corresponding author
- POWERS, JAMES M.
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1992-11
- Volume
- 51
- Issue
- 6
- Pages
- 630-643
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W2078576948
- Cited by
- 265
- References
- 0
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 14 · 2023: 9 · 2022: 5 · 2021: 9 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 5 · 2016: 6 · 2015: 6 · 2014: 3 · 2013: 9 · 2012: 6
- FWCI
- 9.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- adrenoleukodystrophy, demyelination, astrocytes, macrophages, T cells, interleukin-1, TNF-α, ICAM-1, complement C3d, adrenomyeloneuropathy, immune-mediated demyelination, pathogenesis
- MeSH terms
- Adrenoleukodystrophy, Adult, B-Lymphocytes, Brain, Cell Adhesion, Child, Complement System Proteins, Demyelinating Diseases, HLA-D Antigens, Humans, Immunoglobulin A, Immunoglobulin M, Macrophages, Multiple Sclerosis, Retrospective Studies, T-Lymphocytes, Tumor Necrosis Factor-alpha, Histocompatibility Antigens Class I, Cell Adhesion Molecules, Intercellular Adhesion Molecule-1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
