Catálogo de publicaciones - libros

In the immune system, integrins have essential roles in leukocyte trafficking and function. These include immune cell attachment to endothelial and antigen-presenting cells, cytotoxicity, and extravasation into tissues. The integrin leukocyte function-associated antigen-1 (LFA-1), which is exclusively expressed on hematopoietic cells, has been intensely studied since this receptor is important for many functions of the immune system. LFA-1 is involved in a) the interaction between T-cells and antigen presenting cells, b) the adhesion of cells to post-capillary high endothelial venules or to activated endothelium at sites of inflammation (extravasation), c) the control of cell differentiation and proliferation, and d) the regulation of T-cell effector functions. Therefore, a precise understanding of the spatial and temporal control of LFA-1 interaction with its cellular counter-receptors, the intercellular adhesion molecules (ICAM) -1, -2 and -3, in the various contexts, is of high interest. LFA-1 mediated adhesion is induced by several extracellular stimuli in different cell types. In T-cells, LFA-1 becomes activated upon signaling from the T-cell receptor (TCR), and upon cytokine and chemokine sensing. Adhesion of monocytes to ICAM-1 is induced by lipopolysaccharide (LPS), a component of the bacterial cell wall. To investigate the regulation of LFA-1 adhesiveness, research has focused on the identification of interaction partners of the intracellular portions of the integrin alpha and beta subunits. This review will highlight recent developments on transmembrane and intracellular signaling proteins, which have been implicated in beta-2 integrin activation.

The central nervous system (CNS) has long been regarded as an immune privileged organ implying that the immune system avoids the CNS to not disturb its homeostasis, which is critical for proper function of neurons. Meanwhile, it is accepted that immune cells do in fact gain access to the CNS and that immune responses can be mounted within this tissue. However, the unique CNS microenvironment strictly controls these immune reactions starting with tightly controlling immune cell entry into the tissue. The endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid (CSF) barrier, which protect the CNS from the constantly changing milieu within the bloodstream, also strictly control immune cell entry into the CNS. Under physiological conditions, immune cell migration into the CNS is kept at a very low level. In contrast, during a variety of pathological conditions of the CNS such as viral or bacterial infections, or during inflammatory diseases such as multiple sclerosis, immunocompetent cells readily traverse the BBB and likely also the choroid plexus and subsequently enter the CNS parenchyma or CSF spaces. This chapter summarizes our current knowledge of immune cell entry across the blood CNS barriers. A large body of the currently available information on immune cell entry into the CNS has been derived from studying experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Therefore, most of this chapter discussing immune cell entry during CNS pathogenesis refers to observations in the EAE model, allowing for the possibility that other mechanisms of immune cell entry into the CNS might apply under different pathological conditions such as bacterial meningitis or stroke.

The immune system is designed to defend the organism from hazardous infection. The way by which cells of the immune system perform this function can be dangerous for the survival and function of the neuronal network in the brain. An attack of immune cells inside the brain includes the potential for severe neuronal damage or cell death and therefore impairment of CNS function. To avoid such undesirable action of the immune system, the CNS harbours an impressive arsenal of cellular and molecular mechanisms enabling strict control of immune reactions – the so-called “immune privilege”. Under inflammatory and pathological conditions, loss of control of the CNS immune system results in the activation of neuronal damage cascades frequently associated with neurological disease. On the other hand, processes of neuroprotection and neurorepair after neuronal damage depend on a steady and tightly controlled immune surveillance. Accordingly, the immune system serves a highly specialized function in the CNS including negative feedback mechanisms that control immune reactions. Recent studies have revealed that endocannabinoids participate in one of the most important ones of the brain's negative feedback system. The CNS endocannabinoid system consists of cannabinoid receptors, their endogenous ligands and enzymes for the synthesis and degradation of endocannabinoids. It participates crucially in neuronal cell-cell-communication and signal transduction, e.g., by modulating synaptic input and protecting neurons from excitotoxic damage. Over the last decade, it has also become evident that endocannabinoids play an important role in the communication between immune cells, and in the interaction between nerve and immune system during CNS damage. Thus, therapeutic intervention in the CNS endocannabinoid system may help to restore the well-controlled and finely tuned balance of immune reactions in pathological conditions.