Role of MHC Gene Products in Immune Regulation

Benacerraf, Baruj

doi:10.1126/science.6165083

Cited by 643 publications

(220 citation statements)

References 116 publications

(56 reference statements)

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“…Major histocompatibility complex (MHC) 1 class II molecules play a fundamental role in presenting exogenous antigenic peptides to CD4 ϩ helper T lymphocytes (1). These activated CD4 ϩ T cells release stimulatory cytokines that augment the response of CD8 ϩ cytotoxic T lymphocytes (2).…”

mentioning

confidence: 99%

A Novel Element and a TEF-2-like Element Activate the Major Histocompatibility Complex Class II Transactivator in B-lymphocytes

Ghosh

Piskurich

Wright

et al. 1999

Journal of Biological Chemistry

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Major histocompatibility complex (MHC) class II molecules play a central role in immune responses, and transcription of this family of genes requires the MHC class II transactivator (CIITA). CIITA has four promoters, which are transcribed in a tissue-specific manner. CIITA promoter III is constitutively active in mature B-lymphocytes. This report now describes the minimal 319-base pair promoter region necessary for maximal transcriptional activity in B-lymphocytes. Ultraviolet light and dimethylsulfate in vivo genomic footprinting analyses reveal five occupied DNA sequence elements present in intact B-lymphocytes. Functional analysis of these elements using promoter deletions and site-specific mutations demonstrates that at least two of the sites occupied in vivo are critical for transcriptional activity. In vitro protein/DNA analysis suggests that one of the sites is a TEF-2-like element and the other is occupied by a novel transcription activator. In addition, nuclear factor-1 associates with the promoter both in vivo and in vitro. In myeloma cell lines, loss of CIITA transcription correlates with a completely unoccupied CIITA promoter III. These findings suggest that CIITA transcription in B-lymphocytes is activated through at least two strong promoter elements, while loss of expression in myeloma cells is mediated through changes in promoter assembly.Major histocompatibility complex (MHC) 1 class II molecules play a fundamental role in presenting exogenous antigenic peptides to CD4 ϩ helper T lymphocytes (1). These activated CD4 ϩ T cells release stimulatory cytokines that augment the response of CD8 ϩ cytotoxic T lymphocytes (2). Constitutive expression of MHC class II molecules is restricted to professional antigen-presenting cells, such as B lymphocytes and dendritic cells, and can be induced by interferon-␥ (IFN-␥) in macrophages, endothelial cells, and fibroblasts (3, 4). The MHC class II family of genes are coordinately regulated at the level of transcription through a conserved trimeric promoter motif (3, 5). A major component of this transcription complex was cloned by genetic complementation of an in vitro mutagenized MHC class II negative B cell line, RJ2.2.5. This component was named the MHC class II transactivator (CIITA) and restored MHC class II cell surface expression in one subgroup of bare lymphocyte syndrome patient cells (6). CIITA has since been shown to be a key regulatory molecule in the expression of all the known genes involved in the MHC class II antigen-presenting pathway (6 -9). CIITA is required for constitutive expression of MHC class II on B-lymphocytes (10) and with a few exceptions, such as in respiratory epithelial cells and dendritic cells (11,12), is required for cytokine-induced expression in other cell types. Mice in which functional CIITA protein was ablated clearly demonstrated an absolute requirement for CI-ITA in B cell expression of MHC class II (13). It has been shown that the CIITA gene has four distinct promoters each transcribing a unique first exon, which are lo...

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confidence: 99%

A Novel Element and a TEF-2-like Element Activate the Major Histocompatibility Complex Class II Transactivator in B-lymphocytes

Ghosh

Piskurich

Wright

et al. 1999

Journal of Biological Chemistry

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“…While MHC class II antigens (in man referred to as HLA-DR, DP or DQ) have limited expression on cells of the immune system, MHC Class I antigens are found on all somatic cells as heterodimeric molecules (Benacerraf, 1981;Linsk & Goodenow, 1986;Schwartz, 1982). The class I MHC molecule consists of three alpha regimes, covalently linked to beta-2-microglobulin (beta 2m), which are encoded by separate genes, and linked prior to expression at the cell membrane (Ploegh et al, 1981;Arce-Gomez, 1978).…”

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confidence: 99%

“…A series of ten colorectal and ten breast carcinomas, and their respective lymph node metastases, were examined immunohistologically using monoclonal antibodies (mAb) against both monomorphic and A2 polymorphic determinants, and beta-2-microglobulin (beta 2m). Four (Benacerraf, 1981;Linsk & Goodenow, 1986;Schwartz, 1982). The class I MHC molecule consists of three alpha regimes, covalently linked to beta-2-microglobulin (beta 2m), which are encoded by separate genes, and linked prior to expression at the cell membrane (Ploegh et al, 1981;Arce-Gomez, 1978 (Eisenbach et al, 1983;1985).…”

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confidence: 99%

Loss of monomorphic and polymorphic HLA antigens in metastatic breast and colon carcinoma

Goepel

Rees²,

Rogers³

et al. 1991

Br J Cancer

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Summary MHC class I antigens are intimately involved in intercellular communication, and recognition by cytotoxic T cells. Thus tumour cells that fail to express them may be at a growth or metastatic advantage. A series of ten colorectal and ten breast carcinomas, and their respective lymph node metastases, were examined immunohistologically using monoclonal antibodies (mAb) against both monomorphic and A2 polymorphic determinants, and beta-2-microglobulin (beta 2m). Four (Benacerraf, 1981;Linsk & Goodenow, 1986;Schwartz, 1982). The class I MHC molecule consists of three alpha regimes, covalently linked to beta-2-microglobulin (beta 2m), which are encoded by separate genes, and linked prior to expression at the cell membrane (Ploegh et al., 1981;Arce-Gomez, 1978 (Eisenbach et al., 1983;1985). Studies on the expression of human MHC class I antigens in primary vs metastatic tumour are limited; for example malignant melanoma, digestive tract, and laryngeal tumours (Ruiz-Cabello et al., 1989;Esteban et al., 1989). In these studies, both increased and decreased expression of monomorphic determinants of HLA class I was observed in the metastases compared with their primaries. In the present study we have used mAbs to evaluate a series of human primary colon and breast carcinomas, and their lymph node metastases, for the expression of monomorphic and polymorphic HLA class I determinants. Normal colon mucosa and, where possible, colon adenomas and liver metastases were included in the study. Many of the primary tumours at both sites showed reduced staining for monomorphic and polymorphic HLA class I determinants; metastases showed both greater and lesser degrees of loss of HLA expression when compared with their primary. Materials and methods Patients

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“…Immune responses to antigens have been reported to be genetically controlled by the major histocompatibility complex region (H-2 region) on the chromosome [28][29][30][31][32] . Furthermore, the strain difference in producing specific anti-OA antibodies has been investigated in mice sensitized by intraperitoneal injections of OA with alum.…”

Section: Discussionmentioning

confidence: 99%

Development of a Novel Mouse Anaphylaxis Model Produced by Intermittent Intravenous Injections of Ovalbumin without Adjuvant

et al. 2007

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Abstract:This study was performed to develop mouse anaphylaxis model using ovalbumin (OA) as an antigen, with no adjuvant, and an intravenous route of administration. OA at dose levels from 0.5 to 500 mg/kg was injected 3 times into the tail vein of female CD-1 (ICR) mice at 4-day intervals. Clinical signs and extravasation of Evans blue dye (vascular permeability) were observed, serum histamine levels and airway resistance were measured, and histopathological examinations were performed. Furthermore, to detect serum IgE and IgG, heterologous and homologous passive cutaneous anaphylaxis tests were performed. Additionally, strain differences in susceptibility to OA anaphylaxis was examined with 3 mouse strains: ICR, BALB/c and C57BL/6 mice. Shortly after the 3 rd injection, most of the animals exhibited systemic anaphylactic signs including death, and this was accompanied by increases in vascular permeability, plasma histamine levels, and airway resistance. Four days after the 2 nd injection, anti-OA IgE and IgG were detected in sera of mice injected with 0.5 and 5.0 mg/kg or higher doses of OA, respectively. Histological findings included: congestion in many tissues; detachment of mucosal epithelial cells in the gastrointestinal tract; enhanced death, decreased numbers of lymphocytes, and increased numbers of macrophages in the lymphoid tissues. ICR mice were shown to be most susceptible to the OA anaphylaxis of the 3 mouse strains examined. In conclusion, the results demonstrate that 3 intermittent intravenous injections of OA without adjuvant at 4-day intervals can induce anaphylactic shock in mice, in particular, most effectively in ICR mice, and that the anaphylaxis is characterized by specific IgE and IgG production. (J Toxicol Pathol 2007; 20: 237-244)

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Role of MHC Gene Products in Immune Regulation

Abstract: The immune system has evolved the capacity to react specifically with a very large number of foreign molecules with which it had no previous contact, while avoiding reactivity for autologous molecules, naturally antigenic in other species or in other individuals of the same species.

Cited by 643 publications

References 116 publications

A Novel Element and a TEF-2-like Element Activate the Major Histocompatibility Complex Class II Transactivator in B-lymphocytes

A Novel Element and a TEF-2-like Element Activate the Major Histocompatibility Complex Class II Transactivator in B-lymphocytes

Loss of monomorphic and polymorphic HLA antigens in metastatic breast and colon carcinoma

Development of a Novel Mouse Anaphylaxis Model Produced by Intermittent Intravenous Injections of Ovalbumin without Adjuvant

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