Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions.

Objective: Serum antibodies against the glial potassium channel KIR4.1 are found in a subpopulation of multiple sclerosis (MS) patients. Little is known about the expression of KIR4.1 in human normal brain tissue and in MS lesions. Methods: We analyzed the expression pattern of KIR4.1 in normal brain tissue and MS lesions of the subcortical white matter by immunohistochemistry. Markers of related glial proteins, myelin, and inflammatory cells were analyzed in parallel. Results: KIR4.1 is expressed in oligodendrocytes and astrocytes in the adult human brain. In oligodendrocytes, KIR4.1 appears as a homotetramer channel, in astrocytes as homo- and heterotetramer channels together with KIR5.1. In acute MS lesions, KIR4.1 immunoreactivity (IR) was differentially lost on periplaque oligodendrocytes and perivascular astrocytes. In part of acute lesions, complement activation, apoptotic KIR4.1(+) glial cells, and phagocytes containing KIR4.1(+) fragments accompanied loss of glial KIR4.1 IR. Periplaque reactive astrocytes showed enhanced IR for both KIR4.1 and KIR5.1. In chronic active MS lesions, apart from a general loss of oligodendrocytes in the demyelinated area, we observed a decrease of astroglial KIR4.1 but not glial fibrillary acidic protein IR. In chronic inactive and remyelinating MS lesions, KIR4.1 IR was restored on astrocytes and found in a subset of presumably new myelinating oligodendrocytes. Interpretation: The expression profile of KIR4.1 in glial cells and stage-dependent alterations of KIR4.1 IR in MS lesions are compatible with an immune response against KIR4.1 at least in a subset of MS patients

Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells

The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the TH17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirp[alpha] were essential for the generation of pathogenic TH17 cells. Using their IL-6 receptor [alpha]-chain (IL-6R[alpha]), Sirp[alpha]+ DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6R[alpha] (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-[gamma] (IFN-[gamma]) expression in T cells and to generate pathogenic TH17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of TH17-cell-mediated autoimmune diseases. E