Interleukin‐2 treatment reverses effects of cAMP‐responsive element modulator α‐over‐expressing T cells in autoimmune‐prone mice

Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), are often characterized by a failure of self‐tolerance and result in an uncontrolled activation of B cells and effector T cells. Interleukin (IL)‐2 critically maintains homeostasis of regulatory T cells (T_reg) and effector T cells in the periphery. Previously, we identified the cAMP‐responsive element modulator α (CREMα) as a major factor responsible for decreased IL‐2 production in T cells from SLE patients. Additionally, using a transgenic mouse that specifically over‐expresses CREMα in T cells (CD2CREMαtg), we provided in‐vivo evidence that CREMα indeed suppresses IL‐2 production. To analyse the effects of CREMα in an autoimmune prone mouse model we introduced a Fas mutation in the CD2CREMαtg mice (FVB/Fas^–/–CD2CREMαtg). Overexpression of CREMα strongly accelerated the lymphadenopathy and splenomegaly in the FVB/Fas^–/– mice. This was accompanied by a massive expansion of double‐negative (DN) T cells, enhanced numbers of interferon (IFN)‐γ‐producing T cells and reduced percentages of T_regs. Treatment of FVB/Fas^–/–CD2CREMαtg mice with IL‐2 restored the percentage of T_regs and reversed increased IFN‐γ production, but did not affect the number of DNTs. Our data indicate that CREMα contributes to the failure of tolerance in SLE by favouring effector T cells and decreasing regulatory T cells, partially mediated by repression of IL‐2 in vivo .     

The medically compromised patient: Are dental implants a feasible option?

In healthy subjects, dental implants have evolved to be a common therapy to solve problems related to stability and retention of dentures as well as to replace failing teeth. Although dental implants are applied in medically compromised patients, it is often not well known whether this therapy is also feasible in these patients, whether the risk of implant failure and developing peri‐implantitis is increased, and what specific preventive measures, if any, have to be taken when applying dental implants in these patients. Generally speaking, as was the conclusion by the leading review of Diz, Scully, and Sanz on placement of dental implants in medically compromised patients (J Dent, 41, 2013, 195), in a few disorders implant survival may be lower, and the risk of a compromised peri‐implant health and its related complications be greater, but the degree of systemic disease control outweighs the nature of the disorder rather than the risk accompanying dental implant treatment. So, as dental implant treatment is accompanied by significant functional benefits and improved oral health‐related quality of life, dental implant therapy is a feasible treatment in almost any medically compromised patient when the required preventive measures are taken and follow‐up care is at a high level.     

Transmission of HIV in the dental clinic and elsewhere

This review focuses on the risk of transmission of HIV in dental practice in developed and developing countries; and as a result of oral sex, perinatal transmission and breast feeding. Postexposure prophylaxis (PEP) and practical measures to control cross-infection with TB are also discussed. There are few data from resource-poor countries where prevalence of HIV and risk of infection are higher – issues that deserve priority. Available information indicates that the risk of HIV transmission in the dental office is very low. Transmission of HIV from three healthcare workers to patients has been confirmed, including a dentist who infected six patients. There are >300 reports (102 confirmed) of occupational transmission to healthcare workers, including nine dental workers (unconfirmed). Exposure to HIV has been reported by 0.5% dentists/year. The risk of HIV infection after percutaneous exposure (0.3%) can be reduced by 81% with zidovudine PEP. However, risk assessment is required to assess the need and appropriate regimen. The risk of HIV transmission associated with orogenital sex exists, but is considered extremely low: barrier protection is recommended. Conversely, the proportion of babies who acquire HIV from untreated HIV-seropositive mothers is 15–25% in developed countries and 25–45% in developing countries. The frequency of HIV transmission attributable to breastfeeding is 16%. Airborne transmission of TB can be avoided by the prompt referral of known/suspected cases of active TB for chemotherapy, deferral of elective procedures until patients are not infectious, and the use of appropriate standard/isolation precautions including adequate ventilation of treatment areas.     

CXCR5 is critically involved in progression of lupus through regulation of B cell and double‐negative T cell trafficking

The recruitment of immune cells to sites of tissue inflammation is orchestrated by chemokine/chemokine receptor networks. Among these, the CXCL13/CXCR5 axis is thought to be involved critically in systemic lupus erythematosus (SLE) and lupus nephritis pathogenesis. Beyond B cell abnormalities, another hallmark of SLE disease is the occurrence of aberrant T cell responses. In particular, double‐negative (DN) T cells are expanded in the peripheral blood of patients with SLE and in lupus‐prone mice. DN T cells induce immunoglobulin production, secrete proinflammatory cytokines and infiltrate inflamed tissue, including kidneys. We aimed to investigate how CXCR5 deficiency changes immune cell trafficking in murine lupus. We therefore crossed CXCR5^–/– mice with B6/lpr mice, a well‐established murine lupus model. B cell numbers and B cellular immune responses were diminished in CXCR5‐deficient B6/lpr mice. In addition, we observed reduced accumulation of DN T cells in spleen and lymph nodes, paralleled by reduced splenomegaly and lymphadenopathy. In‐vivo migration assays revealed reduced migration of CXCR5‐deficient DN T cells into lymph nodes, and ex‐vivo‐activated CXCR5‐deficient DN T cells failed to infiltrate kidneys of recipients. Moreover, DN T cells and B cells of CXCR5‐deficient B6/lpr mice failed to migrate towards CXCL13 in vitro. We propose that CXCR5 is involved critically in B cell trafficking and germinal cell (GC) formation in murine lupus and in guiding pathogenic DN T cells into lymphoid organs and kidneys, and we therefore describe new pathomechanisms for the CXCL13/CXCR5 axis in SLE.     

β7 integrin controls immunogenic and tolerogenic mucosal B cell responses

IgA production in the gut-associated lymphoid tissue represents a pivotal defense mechanism against luminal pathogens. The other important challenge for the GALT is the induction of local and systemic hyporesponsiveness (tolerance) to dietary antigens and luminal bacterial flora to prevent allergies or deleterious immunologic reactions to food or environmental antigens. In this study we analyzed the impact of β7 integrin on immunogenic and tolerogenic B cell responses in the gastrointestinal tract. β7 integrin deficient mice failed to mount a normal intestinal IgA response to ovalbumin and cholera toxin, whereas the IgG response was unchanged in comparison to control mice. Oral B cell tolerance to ovalbumin, measured as the suppression of specific serum IgG responses, did not develop in the absence of β7 integrin. After adoptive transfer of spleen cells from β7 integrin +/+ mice into RAG-2 deficient or RAG-2/β7 integrin double deficient mice, only RAG-2 deficient mice were able to develop oral B cell tolerance. These observations suggest that β7 integrin expression on cells of the innate immune system contributes to the critical role of β7 integrin in the process of B cell tolerance.     

Fatty acid binding receptors in intestinal physiology and pathophysiology

Free fatty acids are essential dietary components and recognized as important molecules in the maintenance of cellular homeostasis. In the last decade, the molecular pathways for free fatty acid sensing in the gastrointestinal tract have been further elucidated by molecular identification and functional characterization of fatty acid binding receptors. These sensing molecules belong to the family of G protein-coupled receptors. In the intestine, four important receptors have been described so far. They differ in molecular structure, ligand specificity, expression pattern, and functional properties. In this review, an overview of intestinal fatty acid binding receptors and their role in intestinal physiology and pathophysiology is given.     

血管成形术和支架辅助血管成形术治疗颅内动脉粥样硬化的报告标准（下）

本刊经Philip M．Meyers博士代表写作组授权,将“ Reporting standards for angioplasty and stent-assisted angioplasty for intracranial atherosclerosis”译为中文在本刊刊登。标准中对患者的选择、颅内动脉狭窄程度的判断、最佳内科治疗、围手术期处理、血管内治疗、术后并发症等,进行了规范化总结,拟为今后的临床试验和研究的规范化确定标准,以保证结果的可比性,对神经介入医师具有重要的指导意义。