Autoantibodies and neurodegeneration in multiple sclerosis

Abstract

Neurodegeneration develops in association with inflammation and demyelination in multiple sclerosis. Available data suggest that the progressive neuroaxonal loss begins in the earliest stages of the disease and underlies the accumulation of clinical disability. The loss of neurons and their processes is driven by a complex molecular mechanism involving cellular and humoral immune histotoxicity, demyelination, reduced neurotrophic support, metabolic impairment, and altered intracellular processes. Here we survey available data concerning the role of autoreactive immunoglobulins in neurotoxicity. A better understanding of molecular pathways leading to immune-mediated neurodegeneration may have key importance in the successful treatment of the disease. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS).1 Many studies explored as to how the ignition of autoimmunity occurs, why an immunologically privileged site becomes targeted, what the efferent components of immune attacks are, and how the destruction of myelin and oligodendrocytes leads to the clinical presentation of the disease. A generally accepted view of MS pathogenesis has linked the disease process to myelinspecific, CD4 þ T lymphocytes which, upon activation by unknown factors, migrate through the blood-brain barrier (BBB), engage CNS-related antigenic peptides presented by antigen presenting cells, clonally expand, and exert cytotoxic attacks on oligodendrocytes and myelin. This hypothesis has been largely driven by observations from the experimental autoimmune encephalomyelitis (EAE) model that represents a demyelinating CNS disorder mediated by myelin-specific CD4 þ T cells. 2,3However, recent histological analyses 4 and in vivo studies by magnetic resonance imaging (MRI) and spectroscopy (MRS) 5,6 emphasize that neurodegeneration develops along with inflammatory demyelination. The pathology affects the entire brain, but with different distributions of inflammation, demyelination, and neurodegeneration in the white and gray matter. 7 The neuroaxonal loss is likely to be secondary to inflammation and demyelination, but it begins in the earliest stages of the disease and progresses even after the decline of inflammation. Most importantly, neuroaxonal loss represents the major pathological correlate of clinical disability. 5Further evidence to support the importance of neurodegeneration in MS is obtained from clinical data showing only a partial success of the available disease-modifying drugs (interferons, glatiramer acetate, monoclonal antibodies to antigenic determinants expressed on T lymphocytes), which impede activation and migration of inflammatory cells via the BBB, but have no direct effect on the degenerative processes in CNS. 8 The exploration of neurodegeneration in MS received high priority in the last few years. The data establish that this is a multifactorial process involving loss of myelin protection, immune-mediated histotoxicity, decreased trophic support, mitochondrial damage, metabol...

A Novel Unbiased Proteomic Approach to Detect the Reactivity of Cerebrospinal Fluid in Neurological Diseases

“…The finding that both CRMP-2 and cofilin were reactive to MS-CSF is important in view of some similarity existing between Leber hereditary optic neuropathy and MS (87). Increased anti-tubulin antibody levels with inflammatory demyelination similar to MS were also seen in Leber hereditary optic neuropathy patients, suggesting a role for these antibodies in inducing demyelination (42,87). Besides the regulation of actin and tubulin dynamics by cofilin and CRMP-2, we also found as reported by others (88,89), that the 14 -3-3 protein reacted to MS-CSF.…”

“…These include CRMP-2, ␥ enolase, cofilin, ␣␤-crystallin, cyclophilin A, creatine kinase B, and Ubiquitin carboxyterminal hydrolase L1 (UCH-L1/PGP 9.5). CRMP-2, a molecule that regulates neuronal polarity by way of axonal microtubule assembly, is found associated with degenerating neurons in its phosphorylated form (41)(42)(43)(44). Together with Rho-GTP, CRMP2 is an intracellular effector of neurite retraction, primary involving myelin-associated inhibitory factors (39,41).…”

“…Notably, we detected ␣␤-crystallin, a molecule present at enhanced levels in oligodendrocytes and astrocytes in MS lesions. Interestingly, the concentration of anti-␣␤-crystallin antibodies in sera and CSF of MS patients correlates with activity as well as severity of the disease (42). Among the other molecules known to be up-regulated in inflammatory conditions and autoimmune diseases are Peptidylprolyl cis-trans isomerase A (Cyclophilin A), an immunophilin with a variety of intracellular function, including protein trafficking, intracellular signaling, and apoptosis, (46); creatine kinase B, a molecule involved in cellular energy homeostasis and Ubiquitin carboxyterminal hydrolase L1 (UCH-L1) also known as PGP 9.5 (47,48).…”

“…In this context it is interesting to note that antibody responses to tubulin were seen in Leber's hereditary optic neuropathy, a mitochondrially inherited degeneration of retinal ganglion cells and their axons that lead to an acute or subacute loss of central vision, a clinical feature often seen in MS patients (42).…”

Development of a simple in vitro mature mixed glial model to investigate differential expression of cell markers on glial cells and their potential as targets in multiple sclerosis

“…Despite the presence of these OCB in MS patients, the specificity and functional relevance of these OCB, and of other autoantibodies found in MS patients, remain obscure. The original consensus was that these antibodies would be likely to attack components of CNS myelin (since demyelination is the predominant feature of MS), or the myelin-producing cells (oligodendrocytes); however, it has more recently become clear that autoantibodies may also target other CNS cells, such as neurons and astrocytes (de Bock et al, 2014;Schirmer et al, 2014;Vyshkina and Kalman, 2008). In addition, there does not appear to be a single specific antigen that is targeted in all patients.…”