αB-Crystallin Is a Target for Adaptive Immune Responses and a Trigger of Innate Responses in Preactive Multiple Sclerosis Lesions

Abstract

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.

High-Density Peptide Microarray Analysis of IgG Autoantibody Reactivities in Serum and Cerebrospinal Fluid of Multiple Sclerosis Patients

“…Indeed, CRYAB is expressed at elevated transcript and protein levels in active MS lesions (80,81). This up-regulation of CRYAB is assumed to be part of an early reparative innate response, but the acquired immune response against CRYAB abrogates these immunosuppressive effects and thus promotes the progression of demyelination (82).…”

Innate and adaptive immune responses in neurodegeneration and repair

“…This paper also reviews the evidence that stress and damage to oligodendrocytes triggers activation of the innate immune system through production of heat-shock proteins such as HSPB5. 9,19 While induction of HSPB5 protects cells from apoptosis, when released by oligodendrocytes in MS it leads to clustering of microglia to form what is termed pre-active MS lesions, 20 triggering a cascade of protective and regenerative responses in microglia. The paper discusses how oligodendrocytes may become stressed and the consequences of such microglial activation that triggers progression of disease.…”

Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis

“…The presence of T cells and antibodies directed to myelin and myelin-associated antigens (Iglesias et al, 2001;van Noort et al, 2010) has led to the widely accepted view that MS is an autoimmune disease targeting myelin and oligodendrocytes. Antibodies from patients with MS bind to myelin, facilitating phagocytosis of myelin in vitro (Breij et al, 2006;van der Goes et al, 1999) indicating a role in vivo.…”