Pathogenic Memory Research Articles

IMprinting of PAthogenic Memory in Berlin

Immunological memory is not only protective against recurrent pathogens but it also contributes to the pathogenesis of chronic inflammation, especially in rheumatic diseases. The Joint Meeting of the Henry Kunkel Society (HKS) and the Research Consortium IMPAM (IMprinting of the PAthogenic Memory for rheumatic inflammation), which took place in June 2012 in Berlin, was devoted to discussing the basic mechanisms involved in the generation and maintenance of immunological memory, as well as the implications of immunological memory for the pathogenesis and therapy of rheumatic diseases, cancer and vaccine development as outlined in this Meeting Report.

Th2 Mediated Airway Diseases Strongly Linked to Fungal T Cell Memory

The role of fungi in the pathophysiology of T helper cell type 2 (Th2)-dependent airway diseases remains controversial. We hypothesized that pathogenic fungi and Th2 cell memory to fungi would be commonly associated with Th2 airway diseases supporting its role in these chronic inflammatory conditions.

S16-2 Pathogenic memory Th2 cells in the airway and regulation by activated NKT cells in vivo(Allergy and Innate Immunity (English Session))

S16-2 Pathogenic memory Th2 cells in the airway and regulation by activated NKT cells in vivo(Allergy and Innate Immunity (English Session))

Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells

ObjectiveInterleukin (IL)-7 is mainly produced in bone marrow (BM) that forms the niche for B cells. We previously demonstrated that BM also retains pathogenic memory CD4 T cells in murine...

Antigen-targeting to dendritic cells is required for engraftment of antigen-encoding bone marrow and long-term tolerance under non-myeloablative conditions (171.27)

Abstract Transplantation of hematopoietic stem cells (HSC) or bone marrow (BM) engineered to encode antigens is a means of inducing antigen-specific tolerance that might be suitable for ‘turning off’ pathogenic effector and memory T-cell responses. However, transplantation into primed hosts under non-myeloablative conditions could lead to rejection of engineered HSC or BM. We hypothesized targeting antigen expression to mature APC would alleviate rejection of engineered HSC while still permitting expression in the ‘tolerogenic’ cells that arise after transplantation. Using non-myeloablative conditions, we compared engraftment and ‘tolerogenicity’ in naïve or immune hosts of BM encoding an antigen that was ubiquitously expressed, targeted to diverse APC, or targeted to DC. When antigen was expressed ubiquitously, engraftment failed (<1%) but targeting antigen to DC, permitted high levels of BM engraftment (≈40%). Unexpectedly, BM failed to engraft (<1%) when antigen was targeted using a MHC class II promoter. This was due low level MHC class II expression by HSC leading to antigen expression and subsequent immune rejection of engrafting HSC. Long-term tolerance of antigen-specific memory T cells occurred only when engraftment was facilitated by targeting antigen to DC. For clinical translation, careful selection for a promoter that optimally targets DC will be imperative to ensure engraftment of antigen-encoding cells and long-term tolerance.

Regulation of pathogenic effector/memory T helper 1 lymphocyte survival by microRNA

Backgroundand objectivesAuto-antigen specific effector memory T helper type 1 lymphocytes (Th1) are critically involved in the development and maintenance of chronic inflammation in autoimmune diseases. These cells reside at inflamed...

Interleukin-7 promotes autoimmune disease by enabling memory T cells to escape PD-1-mediated tolerance (164.21)

Abstract An important challenge in the therapy of immune-mediated inflammatory diseases is to control established disease, largely because autoreactive memory T lymphocytes are difficult to suppress or eliminate. Memory T cells depend on interleukin-7 (IL-7) for their generation and maintenance and genomic studies have associated the cytokine’s receptor, IL-7Rα, with increased risk for autoimmune diseases such as type 1 diabetes. Here we show that IL-7Rα blockade reverses hyperglycemia in the non-obese diabetic (NOD) mouse model of type 1 diabetes. Diabetogenic memory T cells deprived of IL-7 signals remained present in the lymphoid organs but expressed the inhibitory molecule Programmed Death 1 (PD-1), which is critical for preventing autoimmunity. Blocking the interaction of PD-1 with its ligand, PD-L1, in cured mice rapidly induced hyperglycemia, demonstrating that this mechanism inhibited memory responses to pancreatic islets after IL-7Rα blockade. Conversely, IL-7 suppressed PD-1 expression after T cell activation, indicating that IL-7 contributes to the pathogenesis of autoimmune diabetes by keeping memory T cells in a functionally competent, tolerance-resistant state. Our data uncover a novel link between IL-7 and the PD-1/PD-L1 tolerance pathway and identify IL-7Rα blockade as a potential therapeutic approach to induce PD-1-mediated inhibition of pathogenic memory T cells in established T cell-dependent inflammatory diseases.

Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo

Regulatory T (Treg) cells play a central role in maintaining immune homeostasis. However, little is known about the stability of Treg cells in vivo. In this study, we demonstrate that a significant percentage of cells exhibited transient or unstable Foxp3 expression. These exFoxp3+ T cells express an activated-memory T cell phenotype, and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers increased in inflamed tissues under autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid-onset of diabetes. Finally, T cell receptor repertoire analyses suggested that exFoxp3 cells develop from both natural and adaptive Treg cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.

IL-17 Secreted by Tumor Reactive T Cells Induces IL-8 Release by Human Renal Cancer Cells

TH17 is a newly identified pathogenic memory CD4 T-cell lineage with potent agonist effects in some murine experimental autoimmunity models, however, its role in tumor immunology is still unclear. Clinical experience with interleukin (IL)-2 and ipilumumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody], particularly in treating immunogenic malignancies such as melanoma and renal cell carcinoma (RCC), has suggested an association between a variety of autoimmune phenomena and tumor regression. To investigate this issue in patients with RCC, we isolated T-cell clones from peripheral blood that released IL-17 on stimulation with their autologous RCC tumor line. Clones were generated from 1 patient before any systemic treatment by in vitro stimulation with dendritic cells, autologous tumor, and IL-2 in the presence of anti-CTLA4 antibody. That patient subsequently received treatment with ipilimumab and showed both objective tumor regression and immune-mediated colitis. Limiting dilution cloning of his tumor-dendritic cell-stimulated T cells produced the 3G8D CD4+ clone, which secreted both IL-17 and interferon-gamma when cocultured with the autologous RCC line (transduced with class II transactivation molecule to induce major histocompatibility complex-class II expression). Broader analysis of its cytokine secretion profile showed large amounts of IL-8 when cocultured with RCC, but not when triggered with phorbol 12-myristate 13-acetate and ionomycin. This led to the discovery that IL-8 was being produced by the RCC cells in response to T-cell-derived IL-17. This effect of exogenous IL-17 on IL-8 release from tumor was seen in 5 of 8 RCCs, but not in other tumors tested. Preliminary data on the frequency of IL-17-secreting T cells in the lymphocytes infiltrating RCCs suggest that there may be a positive correlation between this frequency and IL-8 production by nonlymphoid cells as determined by quantitative reverse transcription-polymerase chain reaction. This report extends the known bidirectional interactions between immune cells and malignant cells in the tumor microenvironment that can shape and modulate the host immune response to cancer.

Autoregulation of Th1-mediated inflammation by twist1

The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor κB (NF-κB)–dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-κB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-γ, IL-2, and tumor necrosis factor-α, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.

Placing the mnemonic model in context: Diagnostic, theoretical, and clinical considerations.

The mnemonic model of posttraumatic stress disorder (PTSD) proposed by D. C. Rubin, D. Berntsen, and M. K. Bohni presents some provocative and potentially insightful ideas about this mental disorder. D. C. Rubin et al. suggested that PTSD is caused and maintained through a "pathogenic memory" (D. C. Rubin et al., 2008, p. 985) of a negative event rather than by exposure to a traumatic event per se. The present authors examine the mnemonic model in the context of relevant diagnostic, theoretical, and clinical considerations. Specifically, to evaluate the arguments and evidence provided in support of the mnemonic model of PTSD, the present authors focus on 4 issues: (a) problems inherent with comparing a theoretical model (i.e., the mnemonic model) with a diagnostic model (i.e., the DSM-IV-TR model), (b) problems with not comparing the mnemonic model with relevant cognitive and memory models of PTSD, (c) problems with the degree to which the research reviewed provides support for the mnemonic model, and (d) concerns that memory in PTSD is confounded with the basic disorder, rather than causing PTSD. The present authors conclude with suggestions for future theory and research to help differentiate between memory's role in the origins of PTSD and memory's role in the clinical course of the disorder.

Efalizumab, a reversible T-cell modulator for psoriasis

The humanized monoclonal antibody (MAb) efalizumab (Raptiva) was developed to meet a longstanding need for specific, safe, and effective anti-psoriatic treatments. Efalizumab, which is directed at the lymphocyte surface protein LFA-1, prevents multiple interactions between T cells and other cell types. Here, we review the inflammatory pathway that drives the development of psoriasis, and we discuss several mechanisms by which efalizumab suppresses skin inflammation in psoriasis. Efalizumab reversibly increases circulating T-cell counts, as T cells--including pathogenic CD8 memory T cells that are prominent in psoriatic lesions-- are specifically restrained from leaving the bloodstream and entering the skin. Within two weeks of the onset of efalizumab treatment, cell surface and intracellular LFA-1 pools are substantially cleared by lysosomal degradation. Residual surface LFA-1 molecules remain saturated with bound efalizumab for some weeks following cessation of treatment. Efalizumab's pharmacodynamic properties are consistent with its profound and reversible beneficial effects on the histopathology of psoriatic skin.

IL-7 exacerbates chronic colitis with expansion of memory IL-7RhighCD4+mucosal T cells in mice

We have previously demonstrated that mucosal CD4(+) T cells expressing high levels of IL-7 receptor (IL-7R(high)) are pathogenic cells responsible for chronic colitis. Here we investigate whether IL-7 is directly involved in the expansion of IL-7R(high) memory CD4(+) mucosal T cells and the exacerbation of colitis. We first showed that CD4(+) lamina propria lymphocytes (LPLs) from wild-type, T cell receptor-alpha-deficient (TCR-alpha(-/-)), and recombinase-activating gene (RAG)-2(-/-)-transferred mice with or without colitis showed phenotypes of memory cells, but only CD4(+) LPLs from colitic mice showed IL-7R(high). In vitro stimulation by IL-7, but not by IL-15 and thymic stromal lymphopoietin, enhanced significant proliferative responses and survival of colitic CD4(+), but not normal CD4(+) LPLs. Importantly, in vivo administration of IL-7 mice accelerated the expansion of IL-7R(high) memory CD4(+) LPLs and thereby exacerbated chronic colitis in RAG-2(-/-) mice transferred with CD4(+) LPLs from colitic TCR-alpha(-/-) mice. Conversely, the administration of anti-IL-7R monoclonal antibody significantly inhibited the development of TCR-alpha(-/-) colitis with decreased expansion of CD4(+) LPLs. Collectively, the present data indicate that IL-7 is essential for the expansion of pathogenic memory CD4(+) T cells under pathological conditions. Therefore, therapeutic approaches targeting the IL-7R pathway may be feasible in the treatment of human inflammatory bowel disease.

Removing Pathogenic Memories: A Neurobiology of Psychotherapy

Experimental research examining the neural bases of nondeclarative memory has offered intriguing insight into how functional and dysfunctional implicit learning affects the brain. Long-term modifications of synaptic transmission, in particular, are currently considered the most plausible mechanism underlying memory trace encoding and compulsions, addiction, anxiety, and phobias. Therefore, an effective psychotherapy must be directed to erase maladaptive implicit memories and aberrant synaptic plasticity. This article describes the neurobiological bases of pathogenic memory disruption to provide some insight into how psychotherapy works. At least two mechanisms of unwanted memory erasing appear to be implicated in the effects of psychotherapy: inhibition of memory consolidation/reconsolidation and extinction. Behavioral evidence demonstrated that these two ways to forget are profoundly distinct in nature, and it is increasingly clear that their cellular, synaptic, and molecular underpinnings are different. Accordingly, the blockade of consolidation/reconsolidation erases memories by reversing the plasticity associated with memory maintenance, whereas extinction is a totally new form of plasticity that, similar to the plasticity underlying the old memory, requires protein synthesis-dependent synaptic remodeling.

The Efficacy of Alefacept in the Treatment of Chronic Plaque Psoriasis

With the completion of several phase 2 and phase 3 clinical studies, the efficacy and tolerability of alefacept in patients with chronic plaque psoriasis is now well studied. The majority of patients treated with a single course of intravenous or intramuscular alefacept experienced a clinically meaningful response. The efficacy of alefacept correlated with its ability to selectively target and reduce the number of pathogenic memory T cells. A second course of alefacept resulted in further clinical improvement, with increasing response rates and prolonged response duration following treatment cessation. Sub-population analyses demonstrated that alefacept is effective in a broad spectrum of patients with psoriasis, regardless of disease severity, history of and response to prior antipsoriatic treatment, or whether patients are refractory to or have contraindications to other systemic psoriasis therapies or phototherapy.

The Efficacy of Alefacept in the Treatment of Chronic Plaque Psoriasis

With the completion of several phase 2 and phase 3 clinical studies, the efficacy and tolerability of alefacept in patients with chronic plaque psoriasis is now well studied. The majority of patients treated with a single course of intravenous or intramuscular alefacept experienced a clinically meaningful response. The efficacy of alefacept correlated with its ability to selectively target and reduce the number of pathogenic memory T cells. A second course of alefacept resulted in further clinical improvement, with increasing response rates and prolonged response duration following treatment cessation. Subpopulation analyses demonstrated that alefacept is effective in a broad spectrum of patients with psoriasis, regardless of disease severity, history of and response to prior antipsoriatic treatment, or whether patients are refractory to or have contraindications to other systemic psoriasis therapies or phototherapy.

CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism.

CD4(+)CD25(+) regulatory T (Treg) cells suppress naive T cell responses, prevent autoimmunity, and delay allograft rejection. It is not known, however, whether Treg cells suppress allograft rejection mediated by memory T cells, as the latter mount faster and stronger immune responses than their naive counterparts. Here we show that antigen-induced, but not naive, Treg cells suppress allograft rejection mediated by memory CD8(+) T cells. Suppression was allospecific, as Treg cells induced by third-party antigens did not delay allograft rejection. In vivo and in vitro analyses revealed that the apoptosis of allospecific memory CD8(+) T cells is significantly increased in the presence of antigen-induced Treg cells, while their proliferation remains unaffected. Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8(+) T cells was observed when Treg cells lacked CD30 or when CD30 ligand-CD30 interaction was blocked with anti-CD30 ligand Ab. This study therefore provides direct evidence that pathogenic memory T cells are amenable to suppression in an antigen-specific manner and identifies CD30 as a molecule that is critical for the regulation of memory T cell responses.

Central role of defective apoptosis in autoimmunity.

Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development likely induces cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accelerated apoptosis, are now demonstrated as central defects in diverse murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor Fas (CD95) and its ligand, FasL (CD95 L), have been identified. These errors create a lymphoid system resistant to apoptosis. In contrast, select lymphoid subpopulations of maturing autoimmune prone non-obese diabetic mice have identifiable and pathogenic T cells with both in vivo and in vitro heightened apoptosis after drug interventions. In part, these defects are due to faulty activation of transcription factors such as nuclear factor-kappaB (NF-kappaB) that normally protect against apoptotic death. The genetic basis of interrupted NF-kappaB in pathogenic memory T cells in diabetes is attributable to a developmentally controlled gene defect in an essential subunit of the proteasome. No specific gene in most common forms of human autoimmune disease has yet been identified. Functional assays from diverse laboratories repeatedly demonstrate heightened apoptosis in multiple cellular signaling pathways for cell death, suggesting a common theme in disease causality.

T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire.

T cells that can respond to self-antigens are present in the peripheral immune repertoire of all healthy individuals. Recently we have found that unmanipulated SJL mice that are highly susceptible to EAE also maintain a very high frequency of T cells responding to an encephalitogenic epitope of a myelin antigen proteolipid protein (PLP) 139-151 in the peripheral repertoire. This is not due to lack of expression of myelin antigens in the thymus resulting in escape of PLP 139-151 reactive cells from central tolerance, but is due to expression of a splice variant of PLP named DM20, which lacks the residues 116-150. In spite of this high frequency, the PLP 139-151 reactive cells remain undifferentiated in the periphery and do not induce spontaneous EAE. In contrast, SJL TCR transgenic mice expressing a receptor derived from a pathogenic T cell clone do develop spontaneous disease. This may be because in normal mice, autoreactive cells are kept in check by an alternate PLP 139-151 reactive nonpathogenic repertoire, which maintains a balance that keeps them healthy. If this is the case, selective activation of one repertoire or the other may alter susceptibility to autoimmune disease. Since T cells are generally cross-reactive, besides responding to nonself-antigens, they also maintain significant responses to self-antigens. Based on the PLP 139-151 system, we propose a model in which activation with foreign antigens can result in the generation of pathogenic memory T cells that mediate autoimmunity. We also outline circumstances under which activation of self-reactive T cells with foreign antigens can generate selective tolerance and thus generate protective/regulatory memory against self while still maintaining significant responses against foreign antigens. This provides a mechanism by which the fidelity and specificity of the immune system against foreign antigens is improved without increasing the potential for developing an autoimmune disease.

La dissociation hystérique dans les textes de Janet et Freud avant 1911

Before the introduction by Bleuler of the concept of Spaltung (translated into French as dissociation) in schizophrenia, Pierre Janet and Freud described this mechanism in hysterical states. In the present study, the different definitions of the word dissociation have been examined. In the studies of Janet, four functions in the mechanism of dissociation can be distinguished: disaggregation, in which the phenomena uncontrolled by the state of consciousness are separated from the psyche; reversible recomposition in which the dissociated representations recombine and may form a new personality; the suppression or hiding from oneself of the pathogenic traumatic memory; the beneficial effect of clinical intervention which aims to modifying the memory of the traumatic event, by representing it in a different light. In the texts written between 1892 and 1895, Freud considered the process of dissociation in hysterical states; it may indica te the mechanism by which certain representations are excluded from consciousness due to an intense affective involvement. In preference to the theory of degeneration, Freud favoured Breuer's notion, which was inspired by Moebius, of the hypnoid state. He distinguished two phases of this mechanism: dissociation ( Dissoziation in German) and splitting ( Spaltung) of consciousness; the latter state maintains those representations outside consciousness, which may provoke an effect that is comparable to a traumatism. In 1893, Freud introduced the notion of repression, which partly arises from the mechanisms of dissociation and splitting, but which does not fully replace them. It is important to differentiate between the mechanism of dissociation and that of repression; the former should be studied as a separate entity in its various pathological manifestations, with hysteria considered as the basis.