P.J. van den Elsen

REGULATION OF MHC CLASS I AND II GENE TRANSCRIPTION : DIFFERENCES AND SIMILARITIES

Major histocompatibility complex (MHC) molecules serve as peptide receptors. These peptides are derived from processed cellular or extra-cellular antigens. The MHC gene complex encodes two major classes of molecules, MHC class I and class II, whose function is to present peptides to CD8+ (cytotoxic) and CD4+ (helper) T cells, respectively. The genes encoding both classes of MHC molecules seem to originate from a common ancestral gene. One of the hallmarks of the MHC is its extensive polymorphism which displays locus and allele-specific characteristics among the various MHC class I and class II genes. Because of its central role in immunosurveillance and in various disease states, the MHC is one of the best studied genetic systems. This review addresses several aspects of MHC class I and class II gene regulation in human and in particular, the contribution to the constitutive and cytokine-induced expression of MHC class I and II genes of MHC class-specific regulatory elements and regulatory elements which apparently are shared by the promoters of MHC class I and class II genes.

Defective MHC class II expression in an MHC class II deficiency patient is caused by a novel deletion of a splice donor site in the MHC class II transactivator gene.

Abstract MHC class II deficiency patients are mutated for transcription factors that regulate the expression of major histocompatibility complex (MHC) class II genes. Four complementation groups (A–D) are defined and the gene defective in group A has been shown to encode the MHC class II transactivator (CIITA). Here, we report the molecular characterization of a new MHC class II deficiency patient, ATU. Cell fusion experiments indicated that ATU belongs to complementation group A. Subsequent mutation analysis revealed that the CIITA mRNA lacked 84 nucleotides. This deletion was the result of the absence of a splice donor site in the CIITA gene of ATU. As a result of this novel homozygous genomic deletion, ATU CIITA failed to transactivate MHC class II genes. Furthermore, this truncated CIITA of ATU did not display a dominant negative effect on CIITA-mediated transactivation of various isotypic MHC class II promoters.

Molecular analysis of an MHC class II deficiency patient reveals a novel mutation in the RFX5 gene

Abstract Patients suffering from major histocompatibility complex (MHC) class II deficiency, a rare primary immunodeficiency, are characterized by a lack of MHC class II expression which is the result of defects in trans-acting factors. At least four complementation groups, A, B, C, and D, can be discerned. The gene affected in group C patients is known to be RFX5 and encodes one of the subunits of the multimeric phosphoprotein complex, RFX. In the present study we fused fibroblasts of a recently identified MHC class II deficiency patient, OSE, with fibroblasts derived from patients representative of each of the four complementation groups. Transient heterokaryon analysis indicated that OSE belonged to complementation group C. Furthermore, transfection of wild-type RFX5 cDNA into OSE fibroblasts resulted in restoration of the defect. Mutation analysis revealed that the RFX5 mRNA lacked four nucleotides and that this deletion was the consequence of a G to A transition in a splice acceptor site. Genomic oligotyping demonstrated that OSE was homozygous for the splice site mutation.

Transcriptional regulation of HLA-G.

THE EXPRESSION of HLA class I molecules is essential in the immune response, as they present antigenderived peptides to cytotoxic T lymphocytes. The classical HLA class I genes (HLA-A, HLA-B, and HLA-C) are highly polymorphic and are ubiquitously expressed on most somatic cells. The nonclassical HLA class I molecules (HLA-E, HLA-F, and HLA-G) have a limited polymorphism and display a restricted expression pattern. In this respect, the expression of HLA-G is confined to extravillous cytotrophoblast cells. Coinciding with the expression of HLA-G in this tissue is a general lack of classical MHC class I expression. Together, this is proposed to be of importance for maternofetal tolerance. The differential expression of HLA-G and classical HLA class I molecules in trophoblasts suggest a tight transcriptional control. Transcriptional control of classical MHC class I genes is mediated by conserved cis-acting regulatory elements in the proximal promoter region. These regulatory elements include enhancer A, the ISRE and site a, and display locus and allele-specific differences. In this study, we investigated the regulation of HLA-G transactivation. We assessed the capacity of different putative regulatory elements in the promoter of HLA-G to bind transcription factors. Furthermore, we evaluated the presence of regulatory elements within the promoter and intronic sequences of HLA-G for a possible contribution to the (tissue-specific) transactivation of HLA-G by transient transfection studies of luciferase reporter constructs.

Conserved TcR beta chain usage for a single MHC class II-restricted heat shock protein peptide.

Abstract Previously we have shown that the T-cell response against the HLA-DR3 (17)-restricted heat shock protein (Mr 65 000)-derived peptide amino acids (aa) 3–13 (hsp65 aa 3–13) is recognized by the exclusive usage of the TRBV5 gene as well as a conserved CDR3 region in a tuberculoid leprosy patient. In the present study we analyzed the TcR of T-cell clones specific for hsp65 aa 3–13 derived from three healthy individuals with a response level similar to that of the leprosy patient. We show that unlike the tuberculoid leprosy patient, healthy high responders have a diverse T-cell response to hsp65 aa 3–13. However, a striking observation was made: even though high responders have a diverse specific TcR repertoire, TRBV5-expressing clones from two healthy individuals could be isolated that were nearly identical to a dominant clone in the tuberculoid leprosy patient. In conclusion, the data show that restriction of TcR specific for an antigen correlates with the presence of that antigen in disease. However, the preferred TcR can also be detected in healthy high responders. A natural infection in vivo, as with the tuberculoid leprosy patient, may be responsible for the observed trimming and preferential outgrowth of a certain TcR.

Type III bare lymphocyte syndrome associated with a novel RFXAP mutation: a case report

Type III bare lymphocyte syndrome (BLS) is a severe combined immunodeficiency disease caused by the absence of MHC Class II expression associated with low expression of class I molecules. Here, we report a case with type III BLS who lacked RFXAP (Regulatory factor X‐associated protein) expression as a result from a novel mutation introducing a premature stopcodon in DE‐region at amino acid 73.