Alphab-crystallin is a target for adaptive immune responses and a trigger of innate responses in preactive multiple sclerosis lesions.
We present the first comparative analysis of serum immunoglobulin G reactivity profiles against the full spectrum of human myelin-associated proteins in multiple sclerosis patients and healthy control subjects. In both groups, serum antibodies display a consistent and prominent reaction to alphaB-crystallin (CRYAB) versus other myelin proteins. As an apparently major target for the adaptive immune system in humans, CRYAB selectively accumulates in oligodendrocytes, but not in astrocytes, or axons in so-called preactive multiple sclerosis lesions. These are clusters of activated HLA-DR-expressing microglia in myelinated normal-appearing white matter with no obvious leukocyte infiltration. They are found in most multiple sclerosis patients at all stages of disease. In these lesion areas, CRYAB in oligodendrocytes may come directly in contact with activated HLA-DR+ microglia. We demonstrate that CRYAB activates innate responses by microglia by stimulating the secretion of leukocyte-recruiting factors, including tumor necrosis factor, interleukin 17, CCL5, and CCL1, and immune-regulatory cytokines such as interleukin 10, transforming growth factor-beta, and interleukin 13. Together, these data suggest that CRYAB accumulation in preactive lesions may be part of a reversible reparative local response that involves both oligodendrocytes and microglia. At the same time, however, accumulated CRYAB may represent a major target for adaptive immune responses that could contribute to progression of preactive lesions to a stage of demyelination.
van Noort
Johannes M
JM
TNO Quality of Life, Leiden, The Netherlands. hans@deltacrystallon.com
Bsibsi
Malika
M
Gerritsen
Wouter H
WH
van der Valk
Paul
P
Bajramovic
Jeffrey J
JJ
Steinman
Lawrence
L
Amor
Sandra
S
D056704:Adaptive Immunity / Q000502:physiology*; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000378:metabolism; D038201:alpha-Crystallins / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D006684:HLA-DR Antigens; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D038201:alpha-Crystallins; C405708:OLIG2 protein, human; C044882:neurofilament protein L