The role of lymphotoxin signaling in the development of autoimmune pancreatitis and associated secondary extra-pancreatic pathologies

The pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis, have so far remained elusive. Treatment options for AIP are currently limited and disease relapse is frequent. Still, AIP can be characterized by specific clinical and histologic features. It has turned out that as described in other autoimmune diseases the generation of tertiary lymphoid organs is also a hallmark of patients with AIP. We have recently demonstrated that pancreata derived from human AIP patients display overexpression of lymphotoxin (LT) α and β and LTβR-target genes expressed by immune cells but also by irradiation resistant cells of the pancreas (e.g. acinar cells). Expression of LT α and β on acinar cells in murine pancreata Tg(Ela1-Lta,b) mice led to chronic pancreatitis and sufficed to reproduce key features of human AIP including the development of autoimmunity and AIP associated secondary extra pancreatic pathologies. Here, we review how aberrant and ectopic expression of LT α and β can induce inflammation and autoimmune diseases in general and how this knowledge might specifically lead to an alternative treatment for patients suffering from autoimmune pancreatitis.     

Tumor Progression Locus 2 (Tpl2) Kinase Promotes Chemokine Receptor Expression and Macrophage Migration during Acute Inflammation

In autoimmune diseases, the accumulation of activated leukocytes correlates with inflammation and disease progression, and, therefore, the disruption of leukocyte trafficking is an active area of research. The serine/threonine protein kinase Tpl2 (MAP3K8) regulates leukocyte inflammatory responses and is also being investigated for therapeutic inhibition during autoimmunity. Here we addressed the contribution of Tpl2 to the regulation of macrophage chemokine receptor expression and migration in vivo using a mouse model of Tpl2 ablation. LPS stimulation of bone marrow-derived macrophages induced early CCR1 chemokine receptor expression but repressed CCR2 and CCR5 expression. Notably, early induction of CCR1 expression by LPS was dependent upon a signaling pathway involving Tpl2, PI3K, and ERK. On the contrary, Tpl2 was required to maintain the basal expression of CCR2 and CCR5 as well as to stabilize CCR5 mRNA expression. Consistent with impairments in chemokine receptor expression, tpl2^−/− macrophages were defective in trafficking to the peritoneal cavity following thioglycollate-induced inflammation. Overall, this study demonstrates a Tpl2-dependent mechanism for macrophage expression of select chemokine receptors and provides further insight into how Tpl2 inhibition may be used therapeutically to disrupt inflammatory networks in vivo.     

Killer Artificial Antigen Presenting Cells (KaAPC) for Efficient In Vitro Depletion of Human Antigen-specific T Cells

Current treatment of T cell mediated autoimmune diseases relies mostly on strategies of global immunosuppression, which, in the long term, is accompanied by adverse side effects such as a reduced ability to control infections or malignancies. Therefore, new approaches need to be developed that target only the disease mediating cells and leave the remaining immune system intact. Over the past decade a variety of cell based immunotherapy strategies to modulate T cell mediated immune responses have been developed. Most of these approaches rely on tolerance-inducing antigen presenting cells (APC). However, in addition to being technically difficult and cumbersome, such cell-based approaches are highly sensitive to cytotoxic T cell responses, which limits their therapeutic capacity. Here we present a protocol for the generation of non-cellular killer artificial antigen presenting cells (KaAPC), which allows for the depletion of pathologic T cells while leaving the remaining immune system untouched and functional. KaAPC is an alternative solution to cellular immunotherapy which has potential for treating autoimmune diseases and allograft rejections by regulating undesirable T cell responses in an antigen specific fashion.     

A multi-etiology model of systemic degeneration in schizophrenia

We discuss the possibility of multiple underlying etiologies of the condition currently labeled as schizophrenia. We support this hypothesis with a theoretical model of the prefrontal-limbic system.We show how the dynamical behavior of this model depends on an entire set of physiological parameters, representing synaptic strengths, vulnerability to stress-induced cortisol, dopamine regulation and rates of autoantibody production. Malfunction of such different parameters produces similar outward dysregulation of the system, which may readily lead to diagnostic difficulties for a clinician.Techniques that provide a spectrum/profile of neural and steroid functions may be helpful in clarifying these diagnostic dilemmas.     

An Approach to Searching Protein Sequences for Superfamily Relationships or Chance Similarities Relevant to the Molecular Mimicry Hypothesis: Application to the Basic Proteins of Myelin

A rapid method for similarity searches (FASTP program) was used to identify similarities between a protein database and the human basic proteins from myelin [P2 protein and 17.2K, 18.5K, and 21.5K variants of myelin basic protein (MBP)]. From similarity scores, we concluded that none of the presently known proteins are in a family containing the MBPs. No new members were found for the lipid-binding family of which P2 is a member. Sequence similarities deemed relevant to the molecular mimicry hypothesis for virus-induced autoimmunity were identified in FASTP data with the aid of microcomputer programs. Several MBP/viral protein similarities were found that have not been reported previously. Of note because of their association with demyelinating conditions were proteins from visna and vaccinia. Similarity with visna was specific to the 21.5K and 20.2K MBPs. The most interesting new possibility for mimicry involving the P2 protein was between the influenza A NS2 protein and a sequence region of P2 thought to be neuritogenic in animals and mitogenic for lymphocytes from some patients with Guillain-Barré syndrome (GBS). This may have relevance for some cases of GBS associated with the 1976 U.S.A. swine flu vaccination program. Because FASTP reports only the best similarities between proteins, searches with FASTP may not have detected all the examples of mimicry present in the database. Searches might also be more effective if similarities could be scored on immunological rather than structural relatedness.     

免疫性血小板减少性紫癜动物模型建立方法与应用评价

免疫性血小板减少性紫癜(immune thrombocytopenic purpura,ITP)是血液系统自身免疫性疾病,临床以皮肤、黏膜自发性出血为主要症状。鉴于ITP发病机理目前尚不清晰,因此,探讨人类ITP发病相近或相似的动物模型有助于对ITP发病机制的认识与治疗效果的评估。但就目前状况分析,被动型与主动型的ITP造模方法虽对研究ITP发病机制与药理学研究提供了研究工具,但也存在一些尚待解决的实际问题。因此,系统回顾ITP动物模型复制方法,并给予适当评价,有助于发现、应用并完善现有的动物模型,也能更好的探索新的ITP动物模型来研究发病过程与药物治疗的效应机制。     

Diabetes mellitus induced by low-dose interleukin-2

 Interleukin-2 (IL-2) is a potent immunomodulator that has been associated with the clinical development of autoimmune disorders. However, diabetes mellitus has not been reported in patients treated with single-agent IL-2. We conducted a clinical trial of a protracted daily schedule of subcutaneously administered low-dose IL-2. A patient with advanced colorectal cancer, treated with 1.5×10⁶ international units of IL-2 daily, developed insulin-requiring diabetes during therapy. Hyperglycemia improved during treatment interruption and recurred with reinstitution of IL-2. The diabetes in this patient developed in the context of T cell and natural killer cell expansion, and the presence of islet cell autoantibodies was documented. We postulate that, in this patient, IL-2 reversed the anergy of autoreactive T cells that had escaped clonal deletion. It is possible that prolonged daily exposure to immunomodulatory doses of IL-2 will result in the development of autoimmune phenomena not observed with other schedules of administration. Received: 15 April 1996 / Accepted: 1 August 1996     

白细胞介素17 在妊娠合并乙肝中的表达

目的：观察白细胞介素17（Interleukin-17,IL-17）在乙肝孕妇和正常孕妇胎盘中表达差异来反映胎盘内的细胞免疫应答的情 况,为外源性细胞因子在增强机体免疫、清除病毒及阻断和治疗HBV宫内感染提供新的科学依据。方法：选择择期剖宫产的足月 妊娠妇女46 例,其中血清HBsAg（+）30 例,血清HBsAg（-）的对照组16 例,采用免疫组化方法检测胎盘组织IL-17 的表达。结 果：IL-17 主要表达在胎盘绒毛的合体滋养层细胞胞浆、毛细血管内皮细胞胞浆以及基质中。血清HBsAb（+）孕妇与HBsAb（-）孕 妇比较,无显著差异（P＞0.05）,HBsAg（+）乙肝孕妇与对照组的表达比较差异有统计学意义（P＜0.05）,HBeAg（+）孕妇与HBeAg （-）孕妇的表达比较差异有统计学意义（P＜0.05）。结论：IL-17 在乙肝孕妇胎盘组织中的表达高于正常孕妇,IL-17 的表达不但加 强了机体的防御功能,且能促进炎性反应。     

Hg1, novel peptide inhibitor specific for Kv1.3 channels from first scorpion Kunitz-type potassium channel toxin family

The potassium channel Kv1.3 is an attractive pharmacological target for autoimmune diseases. Specific peptide inhibitors are key prospects for diagnosing and treating these diseases. Here, we identified the first scorpion Kunitz-type potassium channel toxin family with three groups and seven members. In addition to their function as trypsin inhibitors with dissociation constants of 140 nM for recombinant LmKTT-1a, 160 nM for LmKTT-1b, 124 nM for LmKTT-1c, 136 nM for BmKTT-1, 420 nM for BmKTT-2, 760 nM for BmKTT-3, and 107 nM for Hg1, all seven recombinant scorpion Kunitz-type toxins could block the Kv1.3 channel. Electrophysiological experiments showed that six of seven scorpion toxins inhibited ~50-80% of Kv1.3 channel currents at a concentration of 1 μM. The exception was rBmKTT-3, which had weak activity. The IC(50) values of rBmKTT-1, rBmKTT-2, and rHg1 for Kv1.3 channels were ~129.7, 371.3, and 6.2 nM, respectively. Further pharmacological experiments indicated that rHg1 was a highly selective Kv1.3 channel inhibitor with weak affinity for other potassium channels. Different from classical Kunitz-type potassium channel toxins with N-terminal regions as the channel-interacting interfaces, the channel-interacting interface of Hg1 was in the C-terminal region. In conclusion, these findings describe the first scorpion Kunitz-type potassium channel toxin family, of which a novel inhibitor, Hg1, is specific for Kv1.3 channels. Their structural and functional diversity strongly suggest that Kunitz-type toxins are a new source to screen and design potential peptides for diagnosing and treating Kv1.3-mediated autoimmune diseases.