Autoantibodies against IgLON5: Two new cases

Objective: To dissect the relative pathogenic relevance of myelinspecific antibodies (ab) from myelin-specific B cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE). Background: B cells and B cell-derived ab may both play a pathogenic role in CNS autoimmune disease. Transgenic mice in which a majority of B cells recognize myelin oligodendrocyte glycoprotein (MOG) and plasma cells secrete high titres of MOG-specific ab (Th mice) experience a fulminant course of actively-induced EAE. Double-transgenic mice which further contain myelin-reactive T cells (Th mice x 2D2) spontaneously develop EAE. We utilized Th x 2D2 mice in combination with B cell-depleting anti (a)-CD20 ab and adoptive transfer of serum or ab preparations into 2D2 recipients to dissect the relative pathogenic contribution of myelin-reactive B cells from myelin-reactive ab. Methods: Th x 2D2 mice were injected with 0.2 mg a-CD20/week starting at the age of 4 weeks. Serum from Th mice immunized with rMOG 1–117 or myelin-reactive 8.18C5 ab was transferred i.v. into naive 2D2 recipients. Serum from WT mice immunized with MOG p35-55, or an isotype control ab served as control, respectively. In-vivo proliferation of CD4 T cells was determined by BrdU assay. In-vitro, bone-marrow derived monocytes were co-cultured with CFSE-labelled T cells in the presence of 8.18C5 or an isotype control ab. T cell proliferation was determined by flow cytometry. Results: In Th x 2D2 mice, a-CD20 treatment did not interfere with development of encephalitogenic T cells or incidence/severity of spontaneous EAE. While all peripheral compartments were efficiently depleted of B cells, a-CD20 did not affect constitutive secretion of a-MOG ab. Serum from Th mice containing high titres of pathogenic a-MOG ab triggered spontaneous EAE when transferred into naive 2D2 recipients. Further dissecting the role of pathogenic ab, transfer of purified 8.18C5 ab to naive 2D2 recipients led to in-vivo proliferation of T cells and similarly triggered spontaneous EAE. In co-culture with monocytes, myelin-reactive ab enhanced T cell proliferation at low antigen concentrations of rMOG 1–117. Conclusion: Our data indicate that a-MOG ab contribute to CNS autoimmune disease independent of myelin-reactive B cells. Besides promoting CNS demyelination a-MOG ab may enhance myelinrecognition of antigen-presenting cells by opsonisation resulting in accentuated activation of myelin-reactive T cells.