Cortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and natural killer cells are relevant for intracortical type 2 but dispensable for subpial type 3 lesions, whereas CCR2+ monocytes are required for both. Depleting CCR2+ monocytes in marmoset monkeys with experimental autoimmune encephalomyelitis using a novel humanized CCR2 targeting antibody translates into significantly less cortical demyelination and disease severity. We conclude that biologics depleting CCR2+ monocytes might be attractive candidates for preventing cortical lesion formation and ameliorating disease progression in MS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1706-x) contains supplementary material, which is available to authorized users.

Antigen-specific antibodies (Abs) to the 19-kDa carboxy-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP1 19 ) play an important role in protective immunity to malaria. Mouse monoclonal Abs (MAbs) 12.10 and 12.8 recognizing MSP1 19 can inhibit red cell invasion by interfering with MSP1 processing on the merozoite surface. We show here that this ability is dependent on the intact Ab since Fab and F(ab) 2 fragments derived from MAb 12.10, although capable of binding MSP1 with high affinity and competing with the intact antibody for binding to MSP1, were unable to inhibit erythrocyte invasion or MSP1 processing. The DNA sequences of the variable (V) regions of both MAbs 12.8 and 12.10 were obtained, and partial amino acid sequences of the same regions were confirmed by mass spectrometry. Human chimeric Abs constructed by using these sequences, which combine the original mouse V regions with human ␥1 and ␥3 constant regions, retain the ability to bind to both parasites and recombinant MSP1 19 , and both chimeric human immunoglobulin G1s (IgG1s) were at least as good at inhibiting erythrocyte invasion as the parental murine MAbs 12.8 and 12.10. Furthermore, the human chimeric Abs of the IgG1 class (but not the corresponding human IgG3), induced significant NADPHmediated oxidative bursts and degranulation from human neutrophils. These chimeric human Abs will enable investigators to examine the role of human Fc␥ receptors in immunity to malaria using a transgenic parasite and mouse model and may prove useful in humans for neutralizing parasites as an adjunct to antimalarial drug therapy.

Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been proposed as a ligand for the co-receptor CD4. The secreted active form of IL-16 has been detected at sites of T H 1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI), and tissue transplant rejection. Neutralization of IL-16 recruitment to its receptor, using an anti-IL16 antibody, has been shown to significantly attenuate inflammation and disease pathology in IRI, as well as in some autoimmune diseases. Interleukin-16 (also known as lymphocyte chemoattractant factor) was first described in 1982 as a T-cell chemoattractant factor produced by antigen and mitogen-stimulated lymphocytes (1). An array of immune and non-immune cells are now known to express IL-16 as one aspect of an inflammatory response, including CD4 ϩ and CD8 ϩ T cells, eosinophils, monocytes, mast cells, and dendritic cells (2-5). In addition, IL-16 has been reported to promote the entry of resting CD4 ϩ T cells into the cell cycle, and the up-regulation of IL-2 receptor and major histocompatibility (MHC) class II proteins on cell surfaces (6, 7).Human 4 is expressed as a 631-amino acid precursor protein and contains three PDZ domains, along with an N-terminal CcN motif, encompassing both CK2 and cdc2 kinase phosphorylation sites, a nuclear localization signal, and an Src homology 3 binding motif (Fig. 1A) (8, 9). Following cytosolic proteolysis of hIL-16 by caspase-3, a 121-amino acid fragment encompassing the C-terminal PDZ domain (residues 527-619) is secreted as the mature form of IL-16 (10). Secreted IL-16 has been reported to bind to CD4 with relatively high affinity (6,11,12), which is consistent with IL-16 functioning as a pro-inflammatory cytokine. The protein is reported to have two major effects on CD4 ϩ cells: chemoattraction, preferentially of T H 1 cells, and inhibition of CD3/T-cell mediated activation, preferentially of T H 2 cells (13). Co-incubation of CD4 ϩ cells with an anti-CD4 antibody (OKT4) is reported to lead to a reduction in the magnitude of IL-16-induced cell migration by monocytes (11). The protein CD4 contains four immunoglobulin (Ig)-like domains (D1-D4), and CD4-derived peptide inhibition studies of IL-16-mediated chemotaxis suggested that IL-16 binds to CD4 D4 (6). There is also evidence to suggest that chemokine receptor 5, which is expressed on the surface of T H 1 cells, enhances the binding of IL-16 to the co-receptor (14).Interestingly, the chemotactic activity of hIL-16 is not associated with a characteristic chemokine structural motif (15, 16). The solution structure of mature hIL-16 has been reported and showed the chemokine to contain a classical PDZ domain, consisting of a central up and down ␤-sandwich, adjacent to an ␣-helix (17). PDZ domains typically assist in the assembly of multiprotein signaling complexes, by binding peptides in a groove between the ␣1-helix and ␤2-strand, in a process known

No abstract