Current Immunology Reviews (Discontinued) - Volume 4, Issue 1, 2008

A unique feature of secretory cells is the proliferation of the endoplasmic reticulum (ER) and Golgi network. The high demand imposed by protein synthesis and folding in secretory cells constitutes an endogenous source of stress due to the accumulation of toxic misfolded intermediaries. Adaptation to ER stress is mediated by the activation of a complex signal transduction pathway known as the unfolded protein response (UPR). Evidence from genetic manipulation of the UPR supports the notion that components of the pathway are essential to sustain the function of secretory cells. Expression of the UPR transcriptional factor X-Box binding protein-1 (XBP-1) is essential for the proper function of plasma B cells and exocrine cells of pancreas and salivary glands. Active XBP-1 is generated by the direct processing of its mRNA by the ER stress sensor IRE1α through the formation of a complex signaling platform at the ER membrane, here termed as UPRosome. XBP-1 controls the expression of genes involved in almost every aspect of the secretory pathway including folding, protein quality control, ER translocation, glycosylation, and remodeling of ER and Golgi structure. In this article we discuss recent advances in understanding the mechanisms through which XBP-1 controls secretory cell function and the possible involvement of this pathway in disease conditions related to irreversible ER damage. Current therapeutic strategies to modulate ER function are also discussed.

Regulatory CD4+ T cells are generated in the thymus and are distinguished from effector T cells by the expression of specific membrane antigens and by the intracellular expression of the transcription factor Foxp3. While the target antigens for regulatory T cells and their mechanisms of action remain poorly defined, several investigations have shown that these cells can contribute to the prevention of organ-specific autoimmunity. In the case of systemic autoimmune diseases such as systemic lupus erythematosus (SLE), it has recently emerged that regulatory T cells may play an important role in the control of the abnormal autoreactivity. The finding that the number of circulating Tregs decreases in active lupus patients and that the extent of such decrease correlates with clinical disease severity - together with the data obtained in murine models of lupus - have suggested the possibility of targeting Tregs for the modulation of the clinical course of SLE. This review highlights the advances and limitations of the studies on regulatory T cells in SLE, and critically discusses the most recent findings in this rapidly evolving field.

The migration of naïve T cells to secondary lymphoid organs and their subsequent encounter with dendritic cells (DCs) ensures the efficient priming of adaptive T cell-mediated immune responses. The expression of particular sets of adhesion molecules and chemokine receptors allows effector T cells and natural killer (NK) cells to migrate to inflamed non-lymphoid tissues. Thus, the segregation of immune functions by specialized cell subsets relies in part on their migratory competence. Recent studies have shown, however, that NK cells and effector T cells can migrate to activated lymph nodes and impact on the magnitude and quality of the primary T cell response. This is in part due to inflammation-related events that modify the adhesive properties of the high endothelial venules (HEVs). In this review we highlight recent findings that challenge the current idea of the lymph node as an exclusive niche for naive T cells and underline the unique role that NK cells and effector T cells have in models of acute and chronic inflammation when recruited to peripheral lymph nodes.

Over the past decade, the advent of genomics has facilitated the implementation of post-genomic strategies, including the application of new high-throughput technologies. Among the noticeable achievements is the protein microarray approach, a technology that is still in its infancy but that would greatly improve the diagnosis of bacterial pathogens. The present review summarizes the recent developments of this promising technique, including both antibody and protein microarrays. Several examples of the successful identification of infectious agents, such as Yersinia pestis, Bartonella and Tropheryma whipplei, are depicted. The multiplex detection, by protein microarrays, of several pathogens from a clinical sample is also discussed.

The defense against microbial infection by innate and adaptive immune responses bears the intrinsic risk of immune-mediated inflammatory “collateral” damage to host tissue. The cytokine interleukin-10 plays a central role in the control mechanisms, which limit inflammatory responses in order to prevent immunopathology. This pleiotropic soluble factor can be produced by a broad spectrum of different cell types. Interestingly, efficient control of immune responses to different stimuli seems to require the release of IL-10 from different cellular sources. This review summarizes recent experiments demonstrating that production of IL-10 by different cell types can serve distinct and non-redundant functions in vivo.

Activation of T cells is known to be modulated by positive or negative co-signaling molecules. The B7-family of costimulatory molecules has received the greatest attention in the past, and intervention in B7-family signaling pathways has proven to be an efficacious strategy for treating autoimmune diseases in the clinic. In recent months a new family of molecules has garnered interest -- the butyrophilins -- and early data is suggesting that these butyrophilin and butyrophilin- like molecules have the potential for influencing the nature of immune and inflammatory responses. In vitro studies have revealed that butyrophilins, such as butyrophilin-like 2 (BTNL2), can negatively regulate T cell proliferation and cytokine production. Additionally, genetic studies have described polymorphisms in BTNL2 which are reported to be associated with disorders such as sarcoidosis, myositis and ulcerative colitis. The potential for interdicting the butyrophilin pathways highlights potential opportunities for developing new therapeutic strategies for treating autoimmune and inflammatory disorders. This review will focus on the emerging information of this new class of regulatory molecules.