Spontaneous fetal loss is associated with herpes simplex virus (HSV) infection as deduced from epidemiologic data. To date, the underlying mechanisms remain to be elucidated, but an immune component ...is suspected. HLA-G is a class I MHC molecule selectively expressed on extravillous cytotrophoblast; this cell type does not express conventional HLA-A or -B, whereas expression of novel HLA-C-like products has been reported. While its function remains unclear, a role for HLA-G in silencing NK cells that would otherwise attack cells devoid of classical class I molecules has been invoked. We here show that expression of HLA class I molecules is abrogated in HSV-infected choriocarcinoma cells, a phenomenon mediated by the virally encoded inhibitor of the transporter associated with Ag presentation, ICP47. These observations may provide a link between HSV infection and spontaneous fetal loss.
Major histocompatibility complex class II antigen presentation requires the participation of lysosomal proteases in two convergent processes. First, the antigens endocytosed by the antigen‐presenting ...cells must be broken down into antigenic peptides. Second, class II tnolecules are synthesized with their peptide‐binding site blocked by invariant chain (li), and they acquire the capacity to bind antigens only after Ii has been degraded in the compartments where peptides reside. The study of genetically modified tnice deficietit in single lysosomal proteases has allowed us to determine their role in these processes, Cathepsins (Cat) B and D. previously considered major players in MHC class II antigen presentation, are dispensable for degradation of Ii and for generation of several antigenic determinants. By contrast, Cat S plays an essential role in removal of Ii in B cells and dendritic cells, whereas Cat L apparently does so in thymic epithelial cells. Accordingly, the absence of Cat S and L have major consequences for the onset of humoral immtine responses and for T‐cell selection, respectively. It is likely that other as yet uncharacterized lysosomal enzymes also play a role in Ii degradation and in generation of antigenic determinants. Experiments involving drugs that interfere with protein traffic suggest that more than one mechanism for Ii removal, probably involving different proteases, can co‐exist in the same antigen‐presenting cell. These findings may allow the development of protease inhibitors with possible therapeutic applications.
The human high affinity receptor for IgE (FcɛRI) is a cell surface structure critical for the pathology of allergic reactions. Human FcɛRI is expressed as a tetramer (αβγ
2
) on basophils or mast ...cells and as trimeric (αγ
2
) complex on antigen-presenting cells. Expression of the human α subunit can be down-regulated by a splice variant of FcɛRIβ (β
var
). We demonstrate that FcɛRIα is the core subunit with which the other subunits assemble strictly cotranslationally. In addition to αβγ
2
and αγ
2
, we demonstrate the presence of αβ and αβ
var
γ
2
complexes that are stable in the detergent Brij 96. The role of individual FcɛRI subunits for the formation of functional, immunoglobulin E–binding FcɛRI complexes during endoplasmic reticulum (ER) assembly can be defined as follows: β and γ support ER insertion, signal peptide cleavage and proper N-glycosylation of α, whereas β
var
allows accumulation of α protein backbone. We show that assembly of FcɛRI in the ER is a key step for the regulation of surface expression of FcɛRI. The ER quality control system thus regulates the quantity of functional FcɛRI, which in turn controls onset and persistence of allergic reactions.
The human high affinity receptor for IgE (FcepsilonRI) is a cell surface structure critical for the pathology of allergic reactions. Human FcepsilonRI is expressed as a tetramer (alphabetagamma(2)) ...on basophils or mast cells and as trimeric (alphagamma(2)) complex on antigen-presenting cells. Expression of the human alpha subunit can be down-regulated by a splice variant of FcepsilonRIbeta (beta(var)). We demonstrate that FcepsilonRIalpha is the core subunit with which the other subunits assemble strictly cotranslationally. In addition to alphabetagamma(2) and alphagamma(2), we demonstrate the presence of alphabeta and alphabeta(var)gamma(2) complexes that are stable in the detergent Brij 96. The role of individual FcepsilonRI subunits for the formation of functional, immunoglobulin E-binding FcepsilonRI complexes during endoplasmic reticulum (ER) assembly can be defined as follows: beta and gamma support ER insertion, signal peptide cleavage and proper N-glycosylation of alpha, whereas beta(var) allows accumulation of alpha protein backbone. We show that assembly of FcepsilonRI in the ER is a key step for the regulation of surface expression of FcepsilonRI. The ER quality control system thus regulates the quantity of functional FcepsilonRI, which in turn controls onset and persistence of allergic reactions.
MHC class II molecules usually bind peptides in the endocytic pathway, but can also present endogenous peptides from newly synthesized proteins in a chloroquine‐insensitive manner, suggesting that ...peptide binding might occur in the endoplasmic reticulum (ER). We used in vitro translation of HLA‐DR1 class II molecules in the presence of microsomes to study peptide binding in the ER. Formation of functional class II molecules in vitro depends on formation of disulfide bridges in alpha and beta chains. The class II alpha beta heterodimers made by in vitro translation resemble class II molecules synthesized in cells in (i) their reactivity with conformation‐specific antibodies, (ii) their assembly with Ii chain homotrimers, (iii) the generation of SDS‐stable dimers upon peptide binding and (iv) their specificity of peptide binding. The assembly of class II molecules occurs via an alpha beta intermediate and can occur post‐translationally, but only in intact microsomes. Class II alpha beta heterodimers are able to bind peptides in ER‐derived microsomes, a process that precludes subsequent association of class II molecules with Ii chain. This mechanism might explain presentation of endogenous peptides by class II molecules.
We screened natural chemical compounds which inhibit the expression of newly-synthesized MHC class II molecules on the cell surface. IFN-γ stimulates Colo 205 adenocarcinoma cells to induce the ...expression of MHC class I, MHC class II, and 1C AM-1 molecules on the cell surface. We show here that concanamycin B inhibits the expression of MHC class II molecules on Colo 205 cells, whereas it does not affect the expression of MHC class I and ICAM-1 molecules. Concanamycin B also abrogates the enhancement of the MHC class II expression by IL-4 on mouse lymphocytes. Furthermore, concanamycin B suppresses the antigen presentation by MHC class II molecules.
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