A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4+ T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4+ T cell hybridomas were generated from inflamed tissue–derived CD4+ T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0–specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3–5 wk of age. This abrupt disease was associated with the production of interferon γ by P0-specific T cells and a lack of CD4+ Foxp3+ regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy

HIV genome coverage is uniform and complete but varies in sequence depth.

<p>Three representative specimens sequenced by NGS with a wide range in percentage of HIV reads were selected and aligned to the A1-AF004885 reference genome to demonstrate the uniformity of genome coverage regardless of read depth. Coverage is expressed as number of reads at each nucleotide position along the length of the HIV genome. Strain/mean read number: 833-62/1085, green; 886-24/223, orange; B4043-15/7939, blue.</p

Phylogenetic trees of HPgV indicate Cameroon sequences group with genotype 1.

<p>Phylogenetic trees of 56 HPgV <b>(A)</b> complete genome sequences (8851 nt after degapping) and <b>(B)</b> 5’UTR sequences (366 nt) of 8 Cameroonian sequenced by NGS in this study, were constructed with bootstrap values indicated at each branch. GBV-C<i>tro</i> was used as the outgroup and the genetic distance scale is indicated. References are labeled individually with accession number and country of origin; Cameroonian sequences are in bold text.</p

Breakpoint analysis for rare, complex recombinants endemic to Cameroon.

<p>Bootscan plots are shown for <b>(A)</b> CRF11_cpx, <b>(B)</b> CRF13_cpx, <b>(C)</b> CRF18_cpx and <b>(D)</b> CRF37_cpx isolates. In each panel the profile for a reference strain is shown on top and a representative new strain is on the bottom. Vertical dashed lines indicate recombination breakpoints determined by Find Site; genome structure is diagramed below each plot. Bootscan analysis was performed using a window of 400 base pairs and 20 base pair step.</p

Full genome bootscanning reveals the true extent of recombination.

<p>Sequences 920–49 <b>(A)</b> and 789–10 <b>(B)</b> were evaluated in SIMPLOT against pure subtype reference sequences and both found to be subtype G throughout the genome (red line). Specimen 876–14 <b>(C)</b> and 1252–11 <b>(D)</b> were subjected to SIMPLOT bootscanning analysis; the vertical dashed lines indicate recombination breakpoints. The genomic structure is diagramed below each bootscan plot. Bootscan and SIMPLOT analysis was performed using a window of 400 base pairs and 20 base pair step.</p

Genetic organization of unique recombinant forms obtained by NGS.

<p>Nine unique recombinants are shown with the legend at the bottom indicating the classification of each sub-genomic fragment. Genomic coordinates for each recombination breakpoint are described in detail in the Supplemental information.</p

Phylogeny of full length genomes obtained by NGS illustrates HIV diversity in Cameroon.

<p>A phylogenetic tree of 92 HIV-1 complete genome reference sequences and 25 Cameroonian sequences was constructed from a 7387 bp gap-stripped alignment with bootstrap values indicated at each branch. Group O strain ANT70 was used as the outgroup and the genetic distance scale is indicated.</p