Viability of autoantibody-targets: how to tackle pathogenetic heterogeneity as an obstacle for treatment of multiple sclerosis.

The growing complexity number of multiple sclerosis (MS) therapy emphasizes the need for an individualized approach, tailoring therapy to the needs of the individual patient. There is evidence supporting the immunopathological heterogeneity of MS, based on the analysis of biopsy and autopsy tissues. In clinical practice it is impossible to differentiate between the pathological subtypes of MS, because blood or CSF markers of pathological heterogeneity are lacking. Identification of such markers would be important, because "tailored therapy" and "biomarkers for patient stratification" may be considered as two sides of the same coin. In this article, we discuss the emerging role of autoantibodies as potential biomarkers, focusing on myelin oligodendrocyte glycoprotein (MOG) as one of the best characterized autoantigens in MS. In addition, we discuss several strategies for the identification of novel candidate autoantigens.

Glycoproteins as targets of autoantibodies in CNS inflammation: MOG and more.

B cells and antibodies constitute an important element in different inflammatory diseases of the central nervous system (CNS). Autoantibodies can serve as a biomarker to identify disease subgroups and may in addition contribute to the pathogenic process. One candidate autoantigen for multiple sclerosis (MS) is myelin oligodendrocyte glycoprotein (MOG). MOG is localized at the outermost surface of myelin in the CNS and has been the focus of extensive research for more than 30 years. Its role as an important autoantigen for T cells and as a target of demyelinating autoantibodies has been established in several variants of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The literature regarding antibodies to MOG in MS patients is confusing and contradictory. Recent studies, however, have described high levels of antibodies to conformationally correct MOG in pediatric acquired demyelination, both acute disseminated encephalomyelitis (ADEM) and MS. In adult MS, such antibodies are rarely found and then only at low levels. In this review, we summarize key findings from animal models and patient studies, discuss challenges in detecting anti-MOG antibodies in patients and present recent approaches to identifying new autoantigens in MS.

Structure of the discoidin domain receptor 1 extracellular region bound to an inhibitory Fab fragment reveals features important for signaling.

The discoidin domain receptors, DDR1 and DDR2, are constitutively dimeric receptor tyrosine kinases that are activated by triple-helical collagen. Aberrant DDR signaling contributes to several human pathologies, including many cancers. We have generated monoclonal antibodies (mAbs) that inhibit DDR1 signaling without interfering with collagen binding. The crystal structure of the monomeric DDR1 extracellular region bound to the Fab fragment of mAb 3E3 reveals that the collagen-binding discoidin (DS) domain is tightly associated with the following DS-like domain, which contains the epitopes of all mAbs. A conserved surface patch in the DS domain outside the collagen-binding site is shown to be required for signaling. Thus, the active conformation of the DDR1 dimer involves collagen-induced contacts between the DS domains, in addition to the previously identified association of transmembrane helices. The mAbs likely inhibit signaling by sterically blocking the extracellular association of DDR1 subunits.