Molecular Mechanisms of Peripheral T cell Tolerance : Identification of Dickkopf 3 as a novel immune modulator

Protection of tissues from the devastating effects of immune responses is essential for the integrity of the organism. Tolerance mechanisms, such as T cell depletion or anergy induction by natural and adaptive regulatory T cells, tolerogenic dendritic cells and parenchymal cells control potentially auto-reactive lymphocytes. In addition, organs that are particularly sensitive to damage by inflammation, so called immune privileged sites, are protected by tissue barriers and contain an immunosuppressive microenvironment. There is increasing evidence that processes establishing immune privilege overlap with those associated with tolerance induction. However, there is much yet to learn about the molecules with a role in immune regulation. This knowledge could help in the understanding of systemic diseases, such as autoimmunity and cancer, and introduce novel principles concerning transplantation tolerance. Aim of this study was the identification of novel molecules that are potential mediators of peripheral tolerance. Starting from a transgenic mouse model for peripheral CD8 T cell tolerance, identification of such candidate genes was attempted by wide range gene expression analysis. Dickkopf 3 (Dkk3) was 10-fold upregulated in regulatory CD8 T cells. Interestingly, Dkk3 mRNA was previously shown to be present in peripheral tissues, such as the brain, the eye, the spinal cord, the ovary and the uterus, pointing to a possible role in immune privilege. Moreover, Dkk3 was reported to inhibit the ERK MAPK pathway in tumor cells, which is also crucial for T cell receptor signal transduction. Taking all the above into consideration, it was hypothesized that Dkk3 might be involved in immune regulation. Here, Dkk3 was identified as a novel modulator of immune responses. Dkk3 protein was shown to be expressed by the transgenic regulatory CD8 T cells and was indispensable for the suppression of naïve T cells. In detail, Dkk3 deficient transgenic mice displayed no CD8 T cell tolerance and regulatory CD8 T cells could not exert their suppressive function in the presence of anti-Dkk3 blocking antibody. The immune regulatory function of Dkk3 was not limited to the transgenic mouse model of CD8 T cell tolerance. Polyclonal T cells from Dkk3 deficient mice showed hyperproliferation and increased IL-2 production. This effect could be explained by the fact that the ERK MAPK is overactivated in the absence of Dkk3. Among the tissues that express Dkk3 in high amounts are the immune privileged organs(central nervous system (CNS), ovaries, placenta), the liver, which is a crucial site for the establishment of T cell tolerance to oral antigens, the heart and the lung. On the other hand, Dkk3 expression could not be detected in the lymphoid organs and the serum. Given the observed suppressive activity of Dkk3. it might control potentially harmful T cell responses in the above mentioned immune privileged organs. Indeed, the immune regulatory role of Dkk3 in the CNS could be demonstrated in the context of experimental autoimmune encephalitis (EAE). Absence of neuron-derived Dkk3 led to severe and persistent EAE, due to lack of suppression of activated CD8 T cells. In addition, blocking of the secreted Dkk3 with the respective anti-Dkk3 antibody resulted in increased disease chronicity. In conclusion, Dkk3 is a universal immune regulator, employed by transgenic tolerant CD8 T cells and immune privileged organs in order to control excessive T cell responses

Bilingualism in a Case of the Non-fluent/agrammatic Variant of Primary Progressive Aphasia

There is a growing body of research on language impairment in bilingual speakers with neurodegenerative diseases. Evidence as to which language is better preserved is rather inconclusive. Various factors seem to influence language performance, most notably age of acquisition, level of proficiency, immersion and degree of exposure to each language. The present study examined fluency, lexical, discourse and grammatical abilities of a Greek-French late bilingual man with the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA). Speech samples derived from three different narrative tasks in both languages were analyzed using quantitative production analysis (QPA) and fluency measures. The first aim of the study was to compare the participant's connected speech production to that of Greek-speaking normal controls. The second aim was to determine whether Greek (L1) and French (L2) were differentially impaired. To our knowledge, this is the first report of connected speech deficits in a Greek-speaking patient with PPA and the first study which uses QPA to compare L1 and L2 narratives in a bilingual speaker with PPA. Compared to neurologically healthy controls, our participant was impaired in lexical, discourse and grammatical productivity measures, but did not differ in measures of grammatical accuracy. The presence of dysfluencies, reduced speech rate and simplified syntax is consistent with the pattern of impairment reported for the nfvPPA. Results showed that narrative production measures did not differ significantly between languages. However, they suggest a slightly worse performance in his second, non-dominant, language despite a similar pattern of impairment in both languages. Lengthy exposure to L2 and regular activation of L2 through daily use may explain the preservation of discourse abilities in his non-dominant language. This study calls attention to factors such as language dominance, proficiency, patterns of use, and exposure to a language. These factors play a key role in assessing bilingual individuals with PPA and making clinical decisions

Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons.

An increasing number of studies show that the activation of the innate immune system and inflammatory mechanisms play an important role in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Intracellular pathways, linking immune and inflammatory response to ion channel expression and function, have been recently identified. Among ion channels, the transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes.In this review, we summarize current knowledge of interactions between immune cells and PRRs and ion channels of TRP families with PAMPs and DAMPs to provide new insights into the pathogenesis of inflammatory diseases. TRP channels have been found to interfere with innate immunity via both nuclear factor-kB and procaspase-1 activation to generate the mature caspase-1 that cleaves pro-interleukin-1ß cytokine into the mature interleukin-1ß.Sensory neurons are also adapted to recognize dangers by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. As immune cells, they possess many of the same molecular recognition pathways for danger. Thus, they express PRRs including Toll-like receptors 3, 4, 7, and 9, and stimulation by Toll-like receptor ligands leads to induction of inward currents and sensitization in TRPs. In addition, the expression of inflammasomes in neurons and the involvement of TRPs in central nervous system diseases strongly support a role of TRPs in inflammasome-mediated neurodegenerative pathologies. This field is still at its beginning and further studies may be required.Overall, these studies highlight the therapeutic potential of targeting the inflammasomes in proinflammatory, autoinflammatory and metabolic disorders associated with undesirable activation of the inflammasome by using specific TRP antagonists, anti-human TRP monoclonal antibody or different molecules able to abrogate the TRP channel-mediated inflammatory signals