重症药疹免疫机制研究进展

重症药疹病情发展快、皮损广泛,内脏可受累,目前认为是药物诱导的免疫反应.本文对重症药疹发生发展相关的免疫细胞、免疫途径、HLA基因多态易感性及病毒在其发病中的作用机制作一综述.     

Tremelimumab (anti-CTLA4) mediates immune responses mainly by direct activation of T effector cells rather than by affecting T regulatory cells

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) blockade has shown antitumor activity against common cancers. However, the exact mechanism of immune mediation by anti-CTLA4 remains to be elucidated. Further understanding of how CTLA4 blockade with tremelimumab mediates immune responses may allow a more effective selection of responsive patients. Our results show that tremelimumab enhanced the proliferative response of T effector cells (Teff) upon TCR stimulation, and abrogated Treg suppressive ability. In the presence of tremelimumab, frequencies of IL-2-secreting CD4(+) T cells and IFN-γ-secreting CD4(+) and CD8(+) T cells were increased in response to polyclonal activation and tumor antigens. Importantly, Treg frequency was not reduced in the presence of tremelimumab, and expanded Tregs in cancer patients treated with tremelimumab expressed FoxP3 with no IL-2 release, confirming them as bona fide Tregs. Taken together, this data indicates that tremelimumab induces immune responses mainly by direct activation of Teff rather than by affecting Tregs.     

Is the observation of the human kinematics sufficient to activate automatic imitation of transitive actions?

Is the human kinematics automatically imitated when an individual observes transitive actions (i.e. directed upon an object) executed with different effectors and then executes either the same or a different action? In three experiments participants executed actions of reaching-grasping after observation of reaching-grasping, bringing-to-the-mouth, foot-touching, and arrow-touching. Both power and precision interactions were presented. The kinematics of all movements was those typical of humans. The observed variations in velocity due to the type of interaction were imitated when an interacting biological effector (i.e. arm, mouth and foot) was presented. In contrast, no imitation was observed when a non-biological effector (i.e. the arrow) was presented. The results of the present study suggest that there exists a kinematic representation of the rules governing the types of interaction of biological effectors with objects. It is automatically activated by action observation and affects kinematic landmarks of the successive action, i.e. the peak velocities and accelerations. This representation is common to different biological effectors probably because it shares the aim of those actions.     

Distinct orientation of the alloreactive monoclonal CD8 T cell activation program by three different peptide/MHC complexes

We have characterized three different programs of activation for alloreactive CD8 T cells expressing the BM3.3 TCR, their elicitation depending on the characteristics of the stimulating peptide/MHC complex. The high-affinity interaction between the TCR and the K(b)-associated endogenous peptide pBM1 (INFDFNTI) induced a complete differentiation program into effector cells correlated with sustained ERK activation. The K(bm8) variant elicited a partial activation program with delayed T cell proliferation, poor CTL activity and undetectable ERK phosphorylation; this resulted from a low-avidity interaction of TCR BM3.3 with a newly identified endogenous peptide, pBM8 (SQYYYNSL). Interestingly, mismatched pBM1/K(bm8) complexes induced a split response in BM3.3 T cells, with total reconstitution of T cell proliferation but defective generation of CTL activity that was correlated with strong but shortened ERK phosphorylation. Crystal structures highlight the molecular basis for the higher stability of pBM8/K(bm8) compared to pBM1/K(bm8) complexes that exist in two conformers. This study illustrates the importance of the stability of both peptide/MHC and peptide/MHC-TCR interactions for induction of sustained signaling required to induce optimal CTL effector functions. Subtle allelic structural variations, amplified by peptide selection, may thus orient distinct outcomes of alloreactive TCR-based therapies.     

Maintenance of pathogenic Th2 cells in allergic disorders

Immunological memory is an important protective mechanism that enables host organisms to respond rapidly and vigorously to pathogens that have been previously encountered. In addition to the protective function, memory CD4⁺ T helper (Th) cells play a central role in the pathogenesis of chronic inflammatory disorders, including asthma. Recently, several investigators have identified phenotypically and functionally distinct memory Th2 cell subsets that produce IL-5. These memory Th2 cell subsets play an important role in the pathology of allergic inflammation and function as memory-type “pathogenic Th2 (Tpath2) cells” both in mice and humans. We review the role of lung Tpath2 cells in the development of allergic inflammation and, in the context of recent findings, propose a mechanism by which Tpath2 cells not only survive but also continue to function at the sites where antigens were encountered. A greater understanding of the functional molecules or signaling pathways that regulate the inflammatory niche for Tpath2 cells may aid in the design of more effective treatments for chronic inflammatory disorders.     

Visuospatial reorienting signals in the human temporo-parietal junction are independent of response selection

This study contrasts visuospatial reorienting and response selection signals in the right temporo-parietal junction (TPJ) with functional magnetic resonance imaging. The overall goal was to investigate whether spatial orienting signals and motor signals interacted or were independent in TPJ. The right TPJ showed a greater response to targets at in-validly rather than validly cued locations, but no significant modulation from the effector used to respond. We suggest that TPJ may work as a modality-independent 'circuit breaker' for the dorsal fronto-parietal attention system, directing attention to salient events and enabling a variety of responses to those events.     

Hepatitis B specific T cell immunity induced by primary vaccination persists independently of the protective serum antibody level

In 2005, in accordance with recommendations made by the European Medicines Agency, the Italian Drug Agency ordered withdrawal of the hexavalent Hexavac^® vaccine (Sanofi Pasteur MSD) from the market. Concerns had been raised about the low immunogenicity of the hepatitis B virus component of the vaccine, assessed by measurement of serum antibody levels, and its potential consequences on long-term protection against hepatitis B infection. We evaluated memory T cell response to establish whether there are differences in the protective mechanisms among children who had received either Hexavac^® or Infanrix-hexa^® (GlaxoSmithKline) as their primary vaccination. Immunological memory was determined by measuring the ability of T cells to proliferate and secrete IFNγ by ELISA and intracellular cytokines (IFNγ and IL-2) when cultured with hepatitis B surface antigen (HBsAg). The different memory subsets of T cells were also measured.     

Mechanisms of autoimmunity in the non‐obese diabetic mouse: effector/regulatory cell equilibrium during peak inflammation

Immune imbalance in autoimmune disorders such as type 1 diabetes may originate from aberrant activities of effector cells or dysfunction of suppressor cells. All possible defective mechanisms have been proposed for diabetes‐prone species: (i) quantitative dominance of diabetogenic cells and decreased numbers of regulatory T cells, (ii) excessive aggression of effectors and defective function of suppressors, (iii) perturbed interaction between effector and suppressor cells, and (iv) variations in sensitivity to negative regulation. The experimental evidence available to date presents conflicting information on these mechanisms, with identification of perturbed equilibrium on the one hand and negation of critical role of each mechanism in propagation of diabetic autoimmunity on the other hand. In our analysis, there is no evidence that inherent abnormalities in numbers and function of effector and suppressor T cells are responsible for the immune imbalance responsible for propagation of type 1 diabetes as a chronic inflammatory process. Possibly, the experimental tools for investigation of these features of immune activity are still underdeveloped and lack sufficient resolution, in the presence of the extensive biological viability and functional versatility of effector and suppressor elements.