Search

CD4+FOXP3+ Tregs are currently explored to develop cell therapies against immune‐mediated disorders, with an increasing focus on antigen receptor‐engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG‐3 and CTLA‐4 in LNs, while IL‐10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL‐10, CTLA‐4, and LAG‐3 were nonredundantly required for the protective function of antigen receptor‐engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg‐derived IL‐10 and CTLA‐4 were both required to suppress acute autoreactive CD4+ T‐cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor‐engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies with nuclear antigen (nAg) specificity. Using (SWRxNZB)F1 (SNF1) mice, we showed higher levels of Immunoglobulin A (IgA) production in the intestine and the nAg reactivity of faecal IgA under lupus susceptibility. Here, we determined whether the faecal IgA abundance and nAg reactivity are higher in, different among, various lupus‐prone preclinical models (MRL/lpr, NZBxNZW‐F1, SNF1, NZM2410 and NZM2328). We also determined whether the faecal IgA nAg reactivity at preseropositive ages correlates with the eventual serum autoantibody levels in males and females of these mouse models. We show that age‐dependent increase in the abundance and nAg reactivity of faecal IgA can vary among different lupus‐prone mouse models. Importantly, faecal IgA in these mice show significant levels of nAg reactivity, starting as early as at juvenile age. Furthermore, the pre‐seropositive stage nAg reactivity of faecal IgA in most lupus‐prone strains correlates well with that of eventual, seropositive stage systemic autoantibody levels. Gender differences in serum autoantibody levels were preceded by similar differences in the faecal IgA abundance and nAg reactivity. These observations suggest that faecal IgA features, nAg reactivity particularly, could serve as a biomarker for early prediction of the eventual systemic autoimmunity in lupus‐prone subjects. [ABSTRACT FROM AUTHOR]

I propose a T-cell receptor (TcR)-based mechanism by which immunity mediates both 'genetic self' and 'microbial self' thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross-reactivity with 'self,' resulting in selection for a TcR repertoire mimicking 'genetic self.' Second, evolution has selected for a 'microbial self' that mimics 'genetic self' so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR-microbiome mimicry 'holoimmunity' to denote immune tolerance to the 'holobiont self.' Logically, microbiome-host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross-react with host antigens producing 'holoautoimmunity.' [ABSTRACT FROM AUTHOR]

The purpose of this study was to understand the autoimmune response and immunogenicity of a tumour-associated antigen IMP2/p62 in breast cancer. Autoantibody responses to IMP2/p62 were evaluated by enzyme-linked immunosorbent assay ( ELISA), Western blotting and indirect immunofluorescence assay in sera from patients with breast cancer, benign breast tumour and normal human individuals. Immunohistochemistry ( IHC) study with breast cancer tissues was also performed to analyse protein expression of IMP2/p62. The results have demonstrated that IMP2/p62 can induce a relatively higher frequency of autoantibody response in breast cancer (14.3%, 7/49) compared to patients with benign breast tumour (5.6%, 2/36) and normal individuals (2.2%, 1/44). The frequency of IMP2/p62 expression in breast cancer tissues was significantly higher than that in normal tissues ( P < 0.01). The data suggest that autoantibody against IMP2/p62 may be a useful serum biomarker for early-stage breast cancer screening and diagnosis. [ABSTRACT FROM AUTHOR]

Autoimmunity in the central nervous system ( CNS) seems to be a physiological process that might normally occur from the very early stages of fetal development. There is some evidence suggesting that CNS autoimmunity could participate in brain structuring, early antigen recognition and immune tolerance. Interestingly, clues to the occurrence of such early events can be discovered in cord blood samples from newborns and peripheral blood, as well as cerebrospinal fluid samples from adults by means of antibody profiling, through antigen microarray technology. In the past, results from those studies raised the possibility for the existence of a physiological autoantibody network recognizing self-key antigens, as proposed by Irun Cohen many years ago. After examining those findings, I suggest the existence of a specific autoantibody network recognizing resident antigens, which would eventually behave as a two-sided sword in the CNS. It might act as a framework for the organization of local immune homeostasis, which is necessary for the maintenance of neurophysiological processes. On the contrary, it might also participate in the pathogenesis of abnormal autoimmunity after the loss of tolerance to resident antigens. The disturbance of this synchronic homeostasis by environmental stimuli might trigger abnormal reactivity, influenced by favorable genetic conditions. In this regard, the evidence supporting some cutting-edge concepts that are intended to comprehensively characterize the molecular and cellular mechanisms likely implicated in abnormal CNS autoimmunity (primarily in multiple sclerosis) is presented. Finally, the usefulness of the detection of specific disease-associated autoantibodies and autoantibody profiling as clinical tools is also approached. [ABSTRACT FROM AUTHOR]