Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1, control the threshold of self-antigen responses directed against cardiac troponin I (TnI). Here, we aimed at identifying how the immunoproteasome, the main proteolytic machinery in immune cells harboring three distinct protease activities in the LMP2, LMP7 and MECL1 subunit, affects TnI-directed autoimmune pathology of the heart. METHODS: TnI-directed autoimmune myocarditis (TnI-AM), a CD4(+) T cell-mediated disease, was induced in mice lacking all three immunoproteasome subunits, triple-ip(-/-), or lacking either the LMP2 or LMP7 gene, by immunization with a cardiac TnI peptide. Alternatively, prior to induction of TnI-AM or after establishment of AM, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in both experimental TnI-AM and in two cases of ICI-related myocarditis. RESULTS: All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower pro-inflammatory and chemotactic cytokines, less IL-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7(-/-) mice involved a changed balance between effector and regulatory CD4(+) T cells in the spleen, with CD4(+) T cells from LMP7(-/-) mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 and TLR7/8-engaged CD14(+) monocytes with ONX 0914, diminished pro-inflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4(+) T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing both the induction and progression of TnI-AM, when self-reactive CD4+ T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulinG deposition, IL-17 production in heart tissue and TnI-directed humoral autoimmune responses, was also present in two cases of ICI-related myocarditis, thus demonstrating the activation of heart-specific autoimmune reactions by ICI therapy. CONCLUSIONS: By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including cases with ICI-related heart-specific autoimmunity

EuFe2_2As2_2 under high pressure: an antiferromagnetic bulk superconductor

We report the ac magnetic susceptibility $\chi_{ac}$ and resistivity $\rho$ measurements of EuFe$_2$As$_2$ under high pressure $P$. By observing nearly 100% superconducting shielding and zero resistivity at $P$ = 28 kbar, we establish that $P$-induced superconductivity occurs at $T_c \sim$~30 K in EuFe$_2$As$_2$. $\rho$ shows an anomalous nearly linear temperature dependence from room temperature down to $T_c$ at the same $P$. $\chi_{ac}$ indicates that an antiferromagnetic order of Eu$^{2+}$ moments with $T_N \sim$~20 K persists in the superconducting phase. The temperature dependence of the upper critical field is also determined.Comment: To appear in J. Phys. Soc. Jpn., Vol. 78 No.

Recommendations for Addressing Priority Io Science in the Next Decade

Io is a priority destination for solar system exploration. The scope and importance of science questions at Io necessitates a broad portfolio of research and analysis, telescopic observations, and planetary missions - including a dedicated New Frontiers class Io mission

The Science Case for Io Exploration

Io is a priority destination for solar system exploration, as it is the best natural laboratory to study the intertwined processes of tidal heating, extreme volcanism, and atmosphere-magnetosphere interactions. Io exploration is relevant to understanding terrestrial worlds (including the early Earth), ocean worlds, and exoplanets across the cosmos

Over-expression of delta C-DCLK-short in mouse brain results in a more anxious behavioral phenotype

Products of the Doublecortin-Like Kinase (DCLK) gene are associated with cortical migration and hippocampal maturation during embryogenesis However the functions of those DCLK gene transcripts that encode kinases and are expressed during adulthood are Incompletely understood To elucidate potential functions of these DCLK gene splice variants we have generated and analyzed transgenic mice with neuronal over-expression of a truncated constitutively active form of DCLK-short designated delta C-DCLK-short Previously we have performed an extensive molecular characterization of these transgenic delta C-DCLK-short mice and established that a specific subunit of the GABA(A) receptor which is involved in anxiety-related GABAergic neurotransmission is down regulated in the hippocampus Here we show that delta C-DCLK-short mRNA is highly expressed in the hippocampus cortex and amygdala of transgenic mice We provide evidence that the delta C DCLK-short protein is expressed and functional In addition we examined anxiety-related behavior in delta C-DCLK short mice in the elevated plus maze Interestingly delta C-DCLK-short mice spend less time move less in the open arms of the maze and show a reduction in the number of rim dips These behaviors indicate that delta C DCLK-short mice display a more anxious behavioral phenotype (C) 2010 Elsevier Inc All rights reservedStress hormones and brain functio

The contribution of the right supra-marginal gyrus to sequence learning in eye movements.

We investigated the role of the human right Supra-Marginal Gyrus (SMG) in the generation of learned eye movement sequences. Using MRI-guided transcranial magnetic stimulation (TMS) we disrupted neural activity in the SMG whilst human observers performed saccadic eye movements to multiple presentations of either predictable or random target sequences. For the predictable sequences we observed shorter saccadic latencies from the second presentation of the sequence. However, these anticipatory improvements in performance were significantly reduced when TMS was delivered to the right SMG during the inter-trial retention periods. No deficits were induced when TMS was delivered concurrently with the onset of the target visual stimuli. For the random version of the task, neither delivery of TMS to the SMG during the inter-trial period nor during the presentation of the target visual stimuli produced any deficit in performance that was significantly different from the no-TMS or control conditions. These findings demonstrate that neural activity within the right SMG is causally linked to the ability to perform short latency predictive saccades resulting from sequence learning. We conclude that neural activity in rSMG constitutes an instruction set with spatial and temporal directives that are retained and subsequently released for predictive motor planning and responses

Organizational characteristics and information content of an archaeal genome: 156 kb of sequence from Sulfolobus solfataricus P2

We have initiated a project to sequence the 3 Mbp genome of the thermoacidophilic archaebacterium Sulfolobus solfataricus P2. Cosmids were selected from a provisional set of minimally overlapping clones, subcloned in pUC18, and sequenced using a hybrid (random plus directed) strategy to give two blocks of contiguous unique sequence, respectively, 100 389 and 56 105bp. These two contigs contain a total of 163 open reading frames (ORFs) in 26-29 putative operons; 56 ORFs could be identified with reasonable certainty. Clusters of ORFs potentially encode proteins of glycogen biosynthesis, oxidative decarboxylation of pyruvate, ATP-dependent transport across membranes, isoprenoid biosynthesis, protein synthesis, and ribosomes. Putative promoters occur upstream of most ORFs. Thirty per cent of the predicted strong and medium-strength promoters can initiate transcription at the start codon or within 10 nucleotides upstream, indicating a process of initial mRNA-ribosome contact unlike that of most eubacterial genes. A novel termination motif is proposed to account for 15 additional terminations. The two contigs differ in densities of ORFs, insertion elements and repeated sequences; together they contain two copies of the previously reported insertion sequence ISC1217, five additional IS elements representing four novel types, four classes of long non-IS repeated sequences, and numerous short, perfect repeats