Regulation of Peripheral Inflammation by the Central Nervous System

In inflammatory disorders such as rheumatoid arthritis, cytokines and danger signals are sensed by the central nervous system, which adapts behavior and physiologic responses during systemic stress. The central nervous system can also signal the periphery to modulate inflammation through efferent hormonal and neuronal pathways. The brain and spinal cord are involved in this bidirectional interaction. A variety of neuronal pathways that modulate synovial inflammation have been implicated, including the sympathetic and the parasympathetic branches of the autonomic system. Another mechanism, the dorsal root reflex, involves antidromic signaling along somatic afferent fibers that influences joint inflammation by releasing neuropeptides and other neuromediators in the periphery. Some of the neurotransmitters and neuroreceptors involved have been identified in preclinical models and represent novel targets for the treatment of rheumatic diseases

Maturation of Dendritic Cells Is Accompanied by Rapid Transcriptional Silencing of Class II Transactivator (Ciita) Expression

Cell surface expression of major histocompatibility complex class II (MHCII) molecules is increased during the maturation of dendritic cells (DCs). This enhances their ability to present antigen and activate naive CD4+ T cells. In contrast to increased cell surface MHCII expression, de novo biosynthesis of MHCII mRNA is turned off during DC maturation. We show here that this is due to a remarkably rapid reduction in the synthesis of class II transactivator (CIITA) mRNA and protein. This reduction in CIITA expression occurs in human monocyte-derived DCs and mouse bone marrow–derived DCs, and is triggered by a variety of different maturation stimuli, including lipopolysaccharide, tumor necrosis factor α, CD40 ligand, interferon α, and infection with Salmonella typhimurium or Sendai virus. It is also observed in vivo in splenic DCs in acute myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalitis. The arrest in CIITA expression is the result of a transcriptional inactivation of the MHC2TA gene. This is mediated by a global repression mechanism implicating histone deacetylation over a large domain spanning the entire MHC2TA regulatory region

Selective Abrogation of Major Histocompatibility Complex Class II Expression on Extrahematopoietic Cells in Mice Lacking Promoter IV of the Class II Transactivator Gene

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-γ–induced MHCII expression on a wide variety of non-bone marrow–derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4+ T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-γ–activated cells of the macrophage lineage. pIV−/− mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease

Etude in vivo des promoteurs de C2TA

Les malades qui souffrent du syndrome des lymphocytes dénudés souffrent d'infections à répétition. La plupart sont porteurs de mutations dans le gène CIITA qui empêchent le complexe majeur d'histocomptabilité de classe II (MHCII) de s'exprimer normalement. Ce travail décrit deux lignées de souris auxquelles il manque une, respectivement deux des trois séquences d'ADN qui règlent l'expression de CIITA. Dans la première lignée, les lymphocytes B, les cellules dendritiques, les macrophages et la microglie sont toujours capables d'exprimer le MHCII. Par contre, les cellules épithéliales du cortex du thymus et les tissus périphériques n'expriment plus le MHCII. La sélection positive des lymphocytes T CD4+ est donc abolie. La deuxième lignée présente les mêmes défauts d'expression du MHCII auxquels s'ajoutent l'absence sélective de MHCII sur les lymphocytes B et les cellules dendritiques plasmacytoïdes

Regulation of MHC class II gene expression by the class II transactivator

MHC class II molecules are pivotal for the adaptive immune system, because they guide the development and activation of CD4+ T helper cells. Fulfilling these functions requires that the genes encoding MHC class II molecules are transcribed according to a strict cell-type-specific and quantitatively modulated pattern. This complex gene-expression profile is controlled almost exclusively by a single master regulatory factor, which is known as the class II transactivator. As we discuss here, differential activation of the three independent promoters that drive expression of the gene encoding the class II transactivator ultimately determines the exquisitely regulated pattern of MHC class II gene expression

Lessons from the bare lymphocyte syndrome: molecular mechanisms regulating MHC class II expression

Major histocompatibility complex class II (MHCII) molecules drive the development, activation and homeostasis of CD4* T-helper cells. They play a central role in key processes of the adaptive immune system, such as the generation of T-cell-mediated immune responses, the regulation of antibody production and the development and maintenance of tol erance. It is thus not surprising that the absence of MHCII expression results in a severe primary immunodeficiency disease (the bare lymphocyte syndrome (BLS)). The genetic defects responsible for BLS do not lie within the MHCII locus, but in genes encoding transcription factors required for MHCII expression. A great deal of our current knowledge about the mechanisms regulating expression of MHCII genes has been derived from the study of BLS. Four different MHCII regulatory genes have been identified. These genes encode RFXANK, RFXS, RFXAP and CIITA. The first three are subunits of RFX, a ubiquitously expressed factor that binds to the promoters of all MHCII genes. RFX binds co-operatively with other factors to form a highly stable multiprotein complex referred to as the MHCII enhanceosome. This enhanceosome serves as a landing pad for the co-activator CIITA, which is recruited via protein-protein interactions CIITA is the master control factor for MHCII expression. The highly regulated expression pattern of CIITA ultimately dictates the cell type specificity, induction and level of MHCII expression