Mice deficient in programmed cell death 1 (PD-1, Pdcd1), an immunoinhibitory receptor belonging to the CD28͞cytotoxic T lymphocyte-associated antigen-4 family, spontaneously develop lupus-like autoimmune disease and autoimmune dilated cardiomyopathy on C57BL͞6 and BALB͞c backgrounds, respectively. However, how PD-1 deficiency induces different forms of autoimmune diseases on these two strains was unknown. Here, we report that PD-1 deficiency specifically accelerates the onset and frequency of type I diabetes in NOD (nonobese diabetic) mice, with strong T helper 1 polarization of T cells infiltrating into islets. These results suggest that PD-1 deficiency accelerates autoimmune predisposition of the background strain, leading to the induction of different forms of autoimmune diseases depending on the genetic background of the strain. Using NOD-Pdcd1 ؊/؊ mice as an efficient animal model of type I diabetes, we screened diabetes-susceptible loci by genetic linkage analysis. The diabetic incidence of NODPdcd1 ؊/؊ mice was controlled by five genetic loci, including three known recessive loci [Idd (insulin-dependent diabetes) 1, Idd17, and Idd20] and two previously unidentified dominant loci [Iddp (Idd under PD-1 deficiency) 1 and Iddp2].autoimmunity ͉ coreceptor ͉ Idd locus ͉ Th1 ͉ linkage analysis M ultiple genes are involved in the initiation and progression steps of the organ-specific autoimmune diseases. In theory, these genes could be classified into two groups: (i) genes involved in general immune responses, such as cytokines, and (ii) genes involved in the organ specificity, such as MHC. Extensive genetic linkage studies have been carried out on human families as well as animal models of various autoimmune diseases to identify responsible genetic loci for autoimmune diseases (1-3). The NOD (nonobese diabetic) mouse, an animal model of type I diabetes, greatly contributed to the understanding of the genetic basis of type I diabetes (4-6). So far, 28 susceptible loci 4.1, 4.2, 5.1, 5.2,[6][7][8] 9.1, 9.2, 9.3,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] have been identified on the NOD chromosomes by several different crosses and generation of congenic mice.Although many diabetes-susceptible loci have been identified by using NOD mice, the identification of their responsible genes and͞or the analyses of the immunological function of each locus have not been carried out smoothly. The difficulty is likely due in part to the late onset and the low penetrance of type I diabetes in NOD mice (40-70% and 20-40% at 30 weeks of age for females and males, respectively) and also to the involvement of many genes. Therefore, the establishment of a better animal model of type I diabetes is required for efficient and refined genetic analyses of type I diabetes. In addition, the low penetrance of the disease in the NOD mouse made the linkage analyses possible only with BC1 (backcross 1) progenies by backcrossing F1 mice on NOD mice, by which dominant loci could not be analyzed (7).Programmed cell death 1 (PD-1,...

Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4 mediated ubiquitination in human cancer cell lines. Both CRISPR-Cas9-based knockout of DCAF15 and a single amino acid substitution of CAPERα conferred resistance against sulfonamide-induced CAPERα degradation and cell-growth inhibition. Thus, these sulfonamides represent selective chemical probes for disrupting CAPERα function and designate DCAFs as promising drug targets for promoting selective protein degradation in cancer therapy.

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimer's disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimer's disease and other neurodegenerative diseases (progressive supranuclear palsy, Pick's disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimer's brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimer's disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Pick's bodies in Pick's disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimer's disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimer's disease.

A new mouse model of spontaneous autoimmune disease reveals an important role for the inhibitory co-receptor LAG-3 in suppressing autoimmunity.

The deficiency of programmed cell death 1 (PD-1, Pdcd1), a negative immuno-receptor belonging to the CD28/cytotoxic T lymphocyte antigen 4 (CTLA-4) family, can support various tissue-specific autoimmune conditions. Here, we analyzed the effect of PD-1 deficiency in MRL mice that is genetically predisposed to systemic autoimmunity. MRL-Pdcd1(-)(/-) mice developed a fatal myocarditis, which is reminiscent of CTLA-4-deficient (Ctla4(-)(/-)) mice. Massive infiltration of CD4(+) and CD8(+) T cells and myeloid cells was found in hearts of MRL-Pdcd1(-)(/-) mice concomitant with the production of high-titer auto-antibodies against cardiac myosin. In contrast to Ctla4(-)(/-) mice in which most of the CD4(+) T cells are non-specifically activated and invade various organs, T cells in the heart but not in the spleen and lymph nodes are activated in MRL-Pdcd1(-)(/-) mice, suggesting that myocarditis is mediated by antigen-specific autoimmune response. Heart infiltrating myeloid cells strongly suppressed the allogenic response of T cells in vitro, suggesting that these Mac1(+)Gr1(+) myeloid cells are phenotypically similar to myeloid suppressor cells, which can be found in tumor-bearing hosts. These findings unravel the hidden heart-specific autoimmune predisposition of MRL mice and provide MRL-Pdcd1(-)(/-) mice as a useful animal model of lymphocytic myocarditis.