key: cord-0009189-fqqqodne authors: Ransohoff, R.M. title: Regulation of class II major histocompatibility complex genes: Relation to multiple sclerosis date: 2002-12-09 journal: Res Immunol DOI: 10.1016/0923-2494(89)90087-4 sha: 237898ac24bdee989edb832243d04c45d984755c doc_id: 9189 cord_uid: fqqqodne nan Susceptibility to certain autoimmune diseases is highly correlated with specific polymorphic residues in molecules encoded by the class II region of the major histocompatibility complex (MHC) [42] . Therefore, sequence analysis of the protein-coding regions of class II MHC genes has been of considerable importance in clarifying mechanisms of autoimmunity [41] . It has also been proposed that aberrant expression of class II MHC genes may predispose to autoimmumty [41] . Class II MHC molecules have a highly restricted tissue distribution, being normally expressed only on B lymphocytes, macrophages, dendritic cells and activated T lymphocytes [14] . Ectopic expression of class II MHC molecules has been demonstrated in a variety of organ-specific autoimmune states, including thyroid disease, insulindependent diabetes mellitus and multiple sclerosis (MS) (reviewed in [32, 431) . In vitro, the presence of class II MHC molecules is sufficient for effective antigen presentation (reviewed in [13] ); therefore it has been speculated that ec-tGpic class II MHC expression could facilitate local immune responses. Understanding the regulation of class II MHC expression may therefore provide insight into the pathogenesis of organspecific autoimmunity. Furthermore, the regulation of this well-characterized family of genes is a model for analysing tissue-specific and inducible gene expression. In this review, I will focus primarily on the regulation of transcription of human class II MHC genes. Class II MHC structures are ~/~ heterodimers; both subunits are integral membrane glycoproteins. In human cells, at least three types of class II MHC molecules, HLA-DR, HLA-DQ and HLA-DP, are expressed. Polymorphic genes within the MHC on chromosome six encode the individual ~-and [3-subunits. Induction of each haterndimerie eln~ il I~II-IC ~trnetnre involves the coordinate transcription of both subunit genes. A further requirement for constitutive or induced expression may be the presence of a third glycoprotein, the invariant chain, which associates intracellularly with class II MHC ~-and ~-subunits [7] . The potential role of the invariant chain was recently discussed, within the context of comprehensive review of posttranslational processing of class II MHC antigens [7] . There is a spectrum of class II MHC expression at the level of the individual cell. Along this spectrum, four general phenotypic states can be distinguished. Constitutive class II MHC expression at a high level of cell surface density is observed in B lymphocytes and activated human T lymphocytes. Macrophages and dendritic cells constitutively express class II MHC molecules at lower cell surface density and can be induced to enhanced expression. A wide variety of parenchymal cells, on which class II MHC molecules are normally undetectable, can be induced to class II MHC expression both in tissue-culture and in vivo [6] . Finally, class II MHC molecules cannot be induced on a minority of cell types, including human foetal neurons in tissue culture [27] . The detailed characterization of mechanisms which permit this degree of flexibility in class II MHC gone expression would be of considerable interest. In several laboratories including our own, it has been documented that expression of class II MHC molecules is directly correlated with the abundance of mRNA encoding class II MHC products (reviewed in [17, 11, 34] ). Therefore, processes affecting the steadystate levels of these mRNA are crucially important in regulating the expression of class II MHC molecules. It is likely that a major contribution to increased steadystate levels of class II MHC mRNA in cells exposed to interferon-y results from increased transcription of the cognate genes [4] . The accurate and efficient transcription of eukaryotic genes requires regulatory DNA sequence elements designated as promoters; for genes transcribed by RNA polymerase II, these elements are located 5' of the mRNA-cap site. Sequence analysis of Y-flanking regions of numerous class II MHC genes has revealed several conserved sequences, which by virtue of their conservation are candidate regulatory elements (reviewed in [17, 18, 30] ). In particular, two short DNA segme~ts, which have been designated class II MHC X and Y boxes, haw." been identified in the promoters of all human class II MHC genes (reviewed in [17, 40] ). Homologous sequence elements are present in the promoters of murine class II MHC genes as well [.26 ]. In the human DR-= promoter region, the X box is located at -108 to -95 relative to the mRNA-cap site; the Y box is located downstream at -74 to -61 [17] . The Y box contains contains an inverted form of the sequence CCAAT. This sequence element is a general transcriptional activator, ~Ld it has been proposed that the Y box exerts its function in part by associating with the universal CCAAT-binding tr~mscription factor [9, 10] . Boss and Sl~rominger demonstrated the relevance of the conserved X and Y boxes for expression of a transfected DQ-[3 gene in human fibroblasts [5] . Plasmids containing DQ-[3 genes truncated progressively within 5'-flanking sequences were assayed in stably transfected cells for their ability to direct the synthesis of DQ-[~ mRNA [5] . Deletions encroaching upon the X-and Y-box sequences resulted in decreased basal DQ-[3 expression, suggesting that these se:luence elements were positive regulators of class II MHC expression. L~et.ions which eliminated the uI~stream X box and portions of the spacer between the X and Y boxes directed the synthesis of suprabasal DQ-[3 mRNA, suggesting that a negative regulatory element could be present in the spacer [5] . An additional conserved DNA sequence has been ident~.fied in all human class II MHC promoters analysed to is homologous to the octamer sequence, Wl'liCh was first characterized in the promoters of immunoglobulin genes and has subsequently been identified in promoters of numerous eukaryotic genes [37, 39] . Whereas octamer sequences occur in a fixed position upstream of all immunoglobulin genes, their location in class II MHC genes is not conserved, and theLr rdevance for class II MHC expression has not been addressed by deletion analysis. Several conserved elements in class II MHC gone promoters have been analysed with regard to their potential significance for tissue-sr.ecific or interferon-~--inducible expression. Promoter elements extending approximately 200 nucleotides upstream of the cap site are sufficient for both tissue-specific and interferon-f-inducible expression of transfected genes in several cell types, including human glioblastoma cells [ 3° 36] . For the expression of the DQ-[~ gene in fibroblasts, deletion to -128, within an element designated the W box, abolishes interferon-y inducibility, but elevates basal expression levels, suggesting that the W box may contain an interferon-y-inducible negative regulatory element [5] . Another putative regulatory element, termed the Z box, is similarly located upstream of the X box in the DR-~-gene promoter [40] . The mechanism by which individual DNA elements provide promoter and enhancer function involves association with specific putative transcription factors. It was recently demonstrated that interferon-T-induced transcription of DR-~ genes in HeLa cells requires de novo protein synthesis [4] . This observation suggested that the synthesis of a transcription factor or production of an activity capable of modifying a preexisting factor is essential for the induction of class II MHC expression by interferon-y in HeLa cells [4] . This requirement was specific for class II MHC gene transcription, since expression of class l MHC genes was insensitive t¢ ir.~hibition of protein synthesis Several lines of additional evidence indicate that trans-regulatory factors, at least some of which are encoded outside the MHC, are essential for both constitutive and induced class II MHC expression. A particularly convincing demonstration has come from analysis of the severe combined immunodeficiency (SCID) phenotype, in which cells fail to express class II MHC antigens or their transcripts, and cannot be induced to express class II MHC molecules by interferon-y, but contain invariantchain transcripts [31] . The SCID phenotype has been mapped genetically outside the MHC [31] . In an elegan. series of experiments, Reith and co-~orkers assayed nuclear extracts of B lymphocytes from SCID patients and normal controls for activities which bound DR-Qt putative regulatory se-quences [35] . Whereas control nuclear extracts contained potential transcription factors which bound X box, Y box and immunoglobulin-gene-related octamer sequences, several SCID extracts exhibited a striking defidency of the X-box-binding activity, indicating its centrality in this phenotype [35] . It has also been documented that nuclear extracts of Raji cells (a B-lymphoma-derived human line), contain activities which exhibit sequence-specific association with DNA fragments containing W-box, X-box and Y-box sequences [28] . The specificity of this binding was demonstrated by gel retardation, DNase-I-footprinting and methylation interference analyses [28] . No differences were observed, however, between class-II-MHC-expressing Raji cells and class-II-MHC-negative variants, indicating that the Raji cell nuclear factors which associate with these sequence elements are not sufficient for expression of class II MHC genes [28] . The recent isolation by Liou and coworkers of cDNA clones corresponding to potential X-box-binding transregulatory factors will facilitate investigation of their physiologic role in governing class II MHC expression [20] . Surprisingly, two clones identified by screening a lambda-phage expression library with labelled oligodeoxynucleotides were distinct, although both encoded X-box-binding activities [20] . Furthermore, the binding activity was specific for the murine class II A-~ promoter, in that fragments containing E-= X-box sequences were not bound [20] . It is unclear how the interaction of interferon-y with its receptor results in transcription of specific genes. The successful cloning of the human receptor for interferon-y by Aguet and coworkers should facilitate rapid progress m characterization of this transmembrane-signaling event [1] . In addition to the prototypic inducer, interferon--r, a great diversity of other influences have been demonstrated to affect class II MHC expression. Other positive modulators of class II MHC expression include murine coronavirus particles, which specifically induce class II MHC expression in rat asUocytes, but not in microglia [23] . Simian immunodeficiency virus induces class II MHC expression in infected tissue culture cells [16] . Tumour necrosis factor can synergize with interferon-~, or measles virus infection for induction of class II MHC expression [25, 33] . B-cell stimulation factor type 1 (BSF-1) enhances expression of class II MHC on resting B lyrnphocytes; intriguingly, interferon-~, appears to downregulate this induction [29] . Varied additional influences downregulate class II MHC expression. These include immune complexes and a-foetoprotein, as well as hormones such as interferons-a/13, norepinephrine, prostaglandins, cortic,,asteroids and transforming growth factor [~1 [2, 8, 11, 12, 15, 19, 21, 38, 44] . Although almost no information is available about the mechanism of action of these agents, it has been demonstrated in several cases ~hat decreased expression of class II MI[-IC rnnloenla~ i~ aeenrnnanlod hv ...... It" J decreased abundance of the cognate mRNA [8, 11] . The impression which arises from these studies of regulation of class II MHC transcription is one of formidable complexity, which is apparent in several respects: regulation involves multiple cis-regulatory DNA elements and a diversity of trans-acting protein factors, which may function differently in different cell types and in response to varying physiologic stimuli. Finally, the individual class II MHC molecules, DR, DQ and DP, are differentially expressed, both in cells constitutively class-II-MHC-positive and under certain conditions of induction [17] . In addition to the already evident complexity of class II MHC regulation at the single-cell level, there i~ clearly genetic variability in control of class II MHC expression in populations of organisms. Furthermore, these variations may be specific to cell types or tissues. Most relevant for MS, it has been demonstrated that inducibility of class II MHC on astrocytes by interferon-T and by the coronavirus JHM correlates with susceptibility to experimental autoimmune encephalomyelitis (EAE) [22, 24] . Several testable hypotheses about the relationship of regulation of class II MHC expression to MS may be formulated. 1) Susceptibility to MS may correlate with a generalized (non-tissue-specific) abnormality of regulation of MHC expression; this abnormality cauld be isotype-limited. 2) Pre~sposition for developing MS may correlate with a geneticallydetermined or -acquired class-II-MHChyperinducibility, which is expressed only in neuroepithelial cells. 3) MS susceptibility could correlate with physiologic abnormalities in regard to one of the hormones implicated in regulation of class II MHC expression. The rapid acquisition of knowledge about the regulation of class rI MHC expression should permit these issues to be addressed in the near future. Molecular cloning and expression of the human interferon-T receptor Interferon beta impairs induction of HLA-DR antigen on cultured adult human astrocytes Identification of an interferon-~, response region 5' of the human histocompatibility leukocyte antigen DR-0t chain which is active in human glioblastoma cells Transcriptional activation of HLA-DR-a by interferon-~" requires a trans-acting protein Regulation of a transfected human class II major histocompatibility complex gene in human fibroblasts Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelim cells and dermal fibroblasts Biosynthesis and processing of human class II histocompatibility antigens Transforming growth factor a~ modulates the expression of class II histocompatibility antigens on human cells A multiplicity of CCAAT-box-binding proteins The conserved MHC class II boxes X and Y are transcriptional control elements and specifically bind nuclear proteins Induction of macrophage Ia-antigen expression by rIFN-y and down-regulation by IFN-a/[3 and dexamethasone are mediated by changes in steady-state !eveB of !a mP~NA Norepinephrine inhibits -t-interferon-induced major histocompatibility class II (Ia) antigen expression on cultured astrocytes via beta2-adrenergic signal transduction mechanisms Analysis of the expression and function of class-II major histocompatibility complex-encoded molecules by DNA-medicated gene transfer Tissue distribution of Ia antigens and their expression on lymphocyte populations Contrasting effects of ~/[~-and -l'-interferons on expression of macrophage Ia antigens Simian immunodeficiency virus induces expression of class II histocompatibility complex structures on infected target cells in vitro Human class II major histocorapatibility complex genes and proteins Complete nucleotide sequence of a functional HLA-DP-[~ gene and the region between the DP-~-I and DP-0t-I gent: comparison of the 5' ends of HLA class II genes Antagonistic effect of interferon-J3 on the interferon-T-induced expression of Ia antigen in murine macrophages Distinct cloned class-II-MHC-DNAbinding proteins recognize the X-box transcription element ~t-fetoprotein inhibits macrophage expression of Ia antigens Inducibility of Ia antigen on astrocytes by murine coronavirus JHM is rat-strain-dependent Viral particles induce Ia expression on astrocytes Hyperinducibility of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis (EAE) Tumor necrosis factor amplifies measles-virus-mediated la induction on astrocytes The murine E-a immune response gene Differential expression and regulation of major histocompatibility complex (MHC) products in neural and glial cells of the human fetal brain Sequence-specific interactions of nuclear factors with conserved sequences of human class II major histocompatibility complex genes Interferon-T suppresses B cell stimulation factor (BSF-I) induction of class II MHC determinants on B cells Gene organization of DC and DX subregions of the human major kistocompatibility complex A transacting class II regulatory gene unlinked to the MHC controls expression of HLA class II genes Inappropriate major histocompatibility complex class II expression by thyroid follicular cells in thyroid autoimmune disease and by pancreatic beta islet cells in type I diabet~ HLA class II induction in human cells by interferon-~' plus tumor necrosis factor or lymphotoxin Effect of interferons on la gene expression in human astrocytic cells Congenital immunodeficiency with a regulatory defect in class II MHC expression lacks a specific HLA-DR promoterbinding protein Upstream sequences required for tissuespecific expression of the HLA-DR-a gene Interaction of a common factor with conserved promoter and enhancer sequences in histone H2B, immunoglobulin and U2 small nuclear RNA (snRNA) genes Prostaglandins modulate macrophage la expression A lymphoid-specific protein binding to the octamer motif of immunoglobu!in genes A model for the transcriptional regulation of MHC class II genes, lmmunol A molecular basis for MHC-class-II-associated autoimmunity HLA-DQ-[~ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus On the presence of Ia-positive endothelial cells and astrocytes in multiple sclerosis lesions and its relevance to antigen presentation Immune complex effects on murine macrophages. --1. Immune complexes suppress interferon-,t' induction of Ia expression