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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.
The Joint Meeting of the Henry Kunkel Society (HKS) and the Research Consortium IMprinting of the PAthogenic Memory (IMPAM) on Immunological Memory in Health and Disease took place between the 4th and the 6th of June 2012 in Berlin, Germany. The HKS is an organization dedicated to promoting the tradition, exemplified by Henry Kunkel's scientific life, of defining fundamental principles of human biology through the careful study of patients with disorders of the immune system. With this meeting, the Society celebrated 20 years of fostering the development of patient-oriented research and translational immunology. IMPAM is a collaborative research project funded by the German Federal Ministry of Education and Science (Bundesministerium fur Bildung und Forschung –BMBF) as part of a nationwide program to advance research networks focusing on musculo-skeletal diseases. The IMPAM consortium consists of different research groups in Germany investigating rheumatic diseases and is coordinated by Andreas Radbruch (Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin, Germany; Fig. 1).
Figure 1. Westley H. Reeves, President of the HKS and Andreas Radbruch, Coordinator of IMPAM. Photographer: Arne Sattler
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This meeting focused on the basic mechanisms involved in the generation and maintenance of immunological memory. Such memory is the ability of the immune system to respond more rapidly
and effectively to pathogens that have been encountered previously, and reflects the pre-existence of a clonally expanded and educated population of antigen-specific lymphocytes. Specific memory is maintained by distinct populations of long-lived memory cells and by lymphocytes which undergo chronic stimulation by residual antigen. In both cases, when memory cells specific for self-antigens develop and persist, they can perpetuate chronic inflammation, as in the case of rheumatic diseases. Current state-of-the-art treatments, while being able to effectively suppress on-going immune reactions, are in most cases not curative .
The immunological concept underlying the work of the Research Consortium IMPAM is that pathogenic memory for chronic rheumatic inflammation, which is refractory to conventional immunosuppression, is maintained by a local network of memory lymphocytes and non-immune cells, such as mesenchymal cells, within the inflamed tissue. It is the goal of IMPAM to understand the mechanisms of the pathogenic memory driving chronic rheumatic inflammation, its players and its imprinting, and to develop advanced diagnostic tools and therapies for chronic inflammatory rheumatic diseases. With the aim of generating an integrated picture of the pathogenic memory for rheumatic inflammation, the meeting brought together expert speakers covering immunological memory, chronic inflammation and the role of mesenchymal cells in supporting immunological memory and inflammation.
Therapeutic strategies targeting pathogenic memory during chronic autoimmune diseases need to take into account the complexity and the heterogeneity of memory B cells, plasma cells and T cells. Over the past few years, long-lived memory plasma cells have gained increased attention regarding their protective as well as pathogenic functions. Jean-Claude Weill (Inserm, Paris, France) discussed the role of long- and short-lived plasma cells in the pathogenesis of Immune thrombocytopenia (ITP), a bleeding disorder mediated by auto-antibodies that mediate platelet destruction in the spleen. Anti-CD20 therapy is widely used in ITP-patients. Weill and Reynaud's group found increased levels of BAFF in the spleens of Rituximab-treated patients, probably due to a lack of consumption by B cells, along with an increased number of CD138− CD54hi CD11a+ CD86hi long-lived plasma cells. These splenic long-lived plasma cells interact closely with CD4+ T cells, indicating a previously unknown role for these T cells in promoting plasma cell survival in the spleen, presumably via the provision of IL-21 .
Falk Hiepe (Charité University Medicine, Berlin, Germany) talked about the relevance of long-lived plasma cells in the pathogenesis of systemic lupus erythematosus (SLE). Targeting autoreactive memory plasma cells by proteasome inhibition using bortezomib has become a promising therapy for lupus patients who don´t respond to conventional immunosuppressive drugs. Bortezomib-treated patients, who were refractory to conventional immunosuppressive drugs, showed a reduction in disease activity along with a significant reduction in serum autoantibody titers. The analysis of bone marrow samples from patients before and after bortezomib treatment confirmed a significant reduction in plasma cell frequencies.
Michael Cancro (University of Pennsylvania, Philadelphia, USA) elaborated on the mechanisms supporting the survival of long-lived plasma cells in the bone marrow. He provided evidence that plasma cells generated in T-cell-dependent immune responses express RANKL, in contrast to those plasma cells generated in T-cell-independent responses. In addition, plasma cells can induce expression of the plasma cell survival factor APRIL in RANK+ bone marrow macrophages. Thus, some long-lived plasma cells seem to foster their own survival via the RANK-RANKL axis. Indeed, BrdU labelling experiments revealed that RANKL expression is an exclusive feature of some long-lived bone marrow plasma cells and can be used to distinguish subsets of short- and long-lived antibody secreting cells.
Hans-Martin Jäck (University of Erlangen-Nürnberg, Germany) talked about the role of micro-RNAs in the control of plasma-cell differentiation. He identified an miRNA up-regulated in Blimp1+ plasma cells, suggesting a role for this micro-RNA in plasma-cell development. Ectopic overexpression of this micro-RNA in murine B cells favoured plasma-cell differentiation concomitant with immunoglobulin secretion and up-regulation of the plasma cell marker CD138. Bach2 and MiTF, transcription factors known to negatively regulate the plasma cell gene regulatory network, were identified as targets of this plasma cell signature miRNA.
Thomas Dörner (Charité University Medicine, Berlin, Germany) presented data from patients with different auto-immune diseases (RA, SLE) treated with distinct B-cell-directed strategies. He showed that plasmablasts generated in mucosal immune responses are resistant to anti-CD20 (Rituximab) treatment: a population of HLA-DRhi IgA+ plasma blasts was identified in the blood of patients during Rituximab treatment, with the expression of β7-Integrin and functional CCR10 confirming the mucosal origin of this population. Moreover, IgA+ antibody-secreting cells could be detected in the lamina propria of patients during anti-CD20 therapy. He further presented data on epratuzumab, another B-cell-targeted therapy using antibodies directed against CD22. He showed that, rather than depleting B cells, epratuzumab modulates the migration of naive B cells and inhibits the phosphorylation of Syk and PLC-γ2 in naïve, as well as memory, B cells.
Max Cooper (Emory University School of Medicine, Atlanta, USA) demonstrated that, in jawless vertebrates, leucine-rich-repeat gene segments are used to generate a large repertoire of antigen receptors. These variable lymphocyte receptors (VLRs) are secreted by lamprey plasma cells as antigen-specific antibodies and can also be produced as recombinant monoclonal antibodies with high antigen-binding affinity . Due to the phylogenetic distance to mammals, jawless vertebrates seem to be particularly well suited for the generation of VLR antibodies with novel specificities that may be useful for diagnostic purposes, such as the identification of lymphoma cells.
Identification of the signals governing generation, differentiation, persistence and localization of protective and pathogenic effector/memory T cells is crucial in order to develop therapeutic strategies targeting selectively pathogenic effector/memory T cells. The heterogeneity and flexibility of human CD4+ T cells was discussed by Federica Sallusto (Institute for Research in Biomedicine, Bellinzona, Switzerland) and Lorenzo Cosmi (University of Florence, Italy). Federica Sallusto proposed an organization of effector and memory T helper (Th) cell subsets based on functional modules that were related to distinct effector functions and migratory properties. She also presented data on the selective distribution of microbe-specific, autoreactive and allergen-reactive cells in human effector and memory T-cell subsets. Lorenzo Cosmi provided evidence of the plasticity of human Th17 cells towards both Th1 and Th2 effector phenotypes and showed that Th17/Th2 and Th17/Th1 cells were enriched in patients with chronic asthma  and in the synovial fluid of children with oligoarticular Juvenile Idiopathic Arthritis (JIA)  respectively. Moreover, Lorenzo Cosmi identified CD161 as a link between Th17, Th17/Th1 and Th17/2 subsets, thus suggesting that CD161 may represent a possible target for the treatment of chronic inflammatory disorders.
The quality of the Th response is strongly influenced by the location. A possible strategy to treat chronic inflammation is to identify the specific niches which could potentially preserve pathogenic memory T cells. Koji Tokoyoda (Chiba University, Japan) identified the bone marrow (BM) as a main site where professional memory CD4+ T cells specific for a recall antigen rest and are maintained on IL-7-expressing stromal niches . BM memory CD4+ T cells express Ly-6C, CD49b and CD69, and loss of CD49b and CD69 decreases memory CD4+ T cell numbers in the BM, by preventing the transmigration of antigen-experienced CD4+ T cells via bone sinusoids . Rachael Clark (Harvard Medical School, Boston, USA) demonstrated that memory T cells can also reside in peripheral tissues such as the skin . The non-circulating skin-resident memory T cells provide local skin immunity and protected from local infection independent of recruitment of T cells from the peripheral blood. In contrast to memory CD4+ T cells specific for a recall antigen, effector/memory CD4+ T cells involved in chronic inflammation apparently reside mainly in the inflamed tissue, a notion supported by data provided by Chaim Jacob (USC School of Medicine, Los Angeles, USA). He explained that, by using sophisticated isolation methods, memory T cells have been shown to reside in the glomeruli and the tubulo-interstitial tissue of inflamed kidneys from lupus mice. Mechanisms by which pro-inflammatory Th cells adapted and were maintained during chronic inflammation were discussed by Hyun-Dong Chang (DRFZ Berlin, Germany). He discussed how pro-inflammatory Th1 cells adapted to chronic immune reactions by up-regulating the transcription factors Twist1 and Hopx, both of which contribute to the enhanced survival and persistence of Th1 cells at the site of inflammation [9, 10].
The pathogenic processes in chronic rheumatic diseases escape the mechanisms of immunoregulation and this could be due to intrinsic deficiencies in the regulatory pathways and/or the resistance of the pathogenic effectors to regulation. These processes were discussed by Thomas Kamradt (Jena University Hospital, Germany) who showed that, in a glucose-6-phosphate isomerase (G6PI)-induced arthritis model, the clinical course of arthritis can be switched from acute and self-limiting to non-resolving and destructive by transient depletion of regulatory T (Treg) cells . Among the ex vivo correlates of non-resolving G6PI-induced arthritis an altered phenotype of synovial fibroblasts, i.e. a more destructive and invasive behaviour, could be observed. These findings are in-line with the observations reported by Birgit Zimmerman (University of Giessen, Germany) from the group of Ulf Müller-Ladner and Elena Neumann who showed that synovial fibroblasts isolated from RA patients could be categorized into two subpopulations: a migratory and non-migratory population. In a SCID mouse model of RA, the migratory fibroblasts displayed higher invasiveness and lower responsiveness to anti-inflammatory treatment as compared with non-migratory fibroblasts [12, 13]. Thomas Pap (University of Muenster, Germany) has looked at the signals regulating the aggressive behaviour of synovial fibroblasts and could nicely demonstrate that the synovial fibroblasts interact with the extracellular matrix, in particular, with integrins and heparan sulphate proteoglycans such as syndecans. This interaction mediates the attachment, activation and invasion into the cartilage matrix. Targeting this interaction could offer therapeutic possibilities preventing tissue destruction in RA .
More recently, it has become clear that the hallmarks of adaptive immunity can also be found in lymphocytes subsets other than B cells and T cells, such as natural killer (NK) and γδ T cells, which are generally regarded as part of the innate immune system . The adaptive features of γδ T cells were discussed by Leo Lefrançois (UCONN Health Center, Farmington, US) who reported that oral Listeria monocytogenes (L.m.) infection induced a unique population of γδ T cells in the mesenteric lymph nodes and lamina propria that was maintained into immunologic memory and which differed from innate γδ T cells in their function, proliferation, and Vγ usage. The responding mucosal γδ T cell subset was comprised of both IL-17A and IFN-γ producers and expanded more rapidly and more robustly to a secondary oral L.m. infection but not to challenge with an oral Salmonella infection, indicating contextual specificity to the priming pathogen. Further, this population was capable of providing protection together with αβ T cells following secondary oral challenge, demonstrating physiological significance in vivo. Adaptive features of NK cells were described by Joseph Sun (Memorial Sloan-Kettering Cancer Center, New York, US). Using a mouse model of cytomegalovirus infection, he could show that NK cells expressing the CMV-specific receptor Ly49H could potentially expand 100–1000 fold in an antigen-specific manner and reside as long-lived memory cells in lymphoid and nonlymphoid organs. These self-renewing memory NK cells could rapidly degranulate, produce cytokines, and undergo secondary and tertiary expansion to mediate protective immunity against virus challenge . Furthermore, he could show that IL-12 and STAT4 signalling were indispensable for the generation of virus-specific NK-cell memory .
The annual Henry Kunkel Lecture was given by Louis Staudt (National Cancer Institute, NIH, Bethesda, USA). He gave insight into a large-scale screen in which loss-of-function analysis by genome-wide RNAi, in combination with high-throughput genomic sequencing, led to the discovery of novel therapeutic targets for the treatment of B-cell lymphoma. In this screen, the constitutive activation of signalling molecules downstream of the B cell receptor was discovered to be critical for the survival of diffuse large B-cell non-Hodgkin lymphoma. Blockade of the BCR-signalling component BTK led to the death of the lymphoma cells. Initial clinical trials using the BTK inhibitor ibrutinib have shown clinical success in refractory lymphoma patients. Thus, it was impressively demonstrated how an intelligently designed large-scale screen can lead to the development of novel therapies.
Thanks to the excellent speakers and the great location, the meeting was an excellent opportunity to have an intimate and in-depth scientific exchange between senior and young investigators. From the presentations and the resulting discussion, a picture of the dynamics and the mechanisms driving pathogenic memory cells, and their network with non-immune cells, emerged; one which might help to further develop new therapeutic targets for the treatment of chronic rheumatic diseases.