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PubMed1998

Kinase inhibitors abrogate IFN-gamma-induced class II transactivator and class II MHC gene expression in astroglioma cell lines.

Multiple kinase events, involving both tyrosine (tyr) kinase and serine/threonine (ser/thr) kinase activity, are required for IFN-gamma-induced class II MHC mRNA and protein expression in primary rat astrocytes. In this study, we examined the necessity of ser/thr and tyr kinase activity for IFN-gamma-induced stimulation of class II MHC gene expression in the human astroglioma cell lines CRT and CH235, as well as the involvement of these kinases in IFN-gamma-induced expression of the class II transactivator (CIITA), a protein critical for IFN-gamma-induced transcription of class II MHC genes. We show that general ser/thr kinase inhibitors, inhibitors of the ser/thr kinase mitogen-activated protein kinase (MAPK), and tyr kinase inhibitors reduce IFN-gamma-induced class II MHC mRNA and protein expression in a dose-dependent manner. As well, these inhibitors abrogate IFN-gamma-induced CIITA mRNA expression in the astroglioma cell lines. We have further demonstrated that cells constitutively expressing the CIITA protein (2fTGH.CIITA) show no decrease in CIITA or class II MHC mRNA expression in the presence of ser/thr and tyr kinase inhibitors. Collectively, these data indicate that ser/thr kinase activity, possibly MAPK, and tyr kinase activity are required for IFN-gamma-induced expression of CIITA mRNA, and the subsequent expression of class II MHC genes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1999

Beta2-micro-free HLA class I heavy chain levels in sera of healthy individuals. Lack of association with beta2-micro-associated HLA class I heavy chain levels and HLA phenotype.

We have applied a double-determinant immune assay (DDIA) to measure soluble beta2-microglobulin (beta2-micro)-free HLA class I heavy chains in serum. The mean concentration of beta2-micro-free HLA class I heavy chains in serum from 120 healthy subjects was 0.21+/-0.24 microg/ml. The individual serum levels of beta2-micro-free HLA class I heavy chains had a wide distribution, did not seem to be related with HLA phenotype, were stable over time and did not change with age. The serum levels of soluble beta2-micro-free HLA class I heavy chains did not correlate with those of soluble beta2-micro-associated HLA class I heavy chains, suggesting that their release is independently regulated. Three forms of soluble beta2-micro-free HLA class I heavy chains, with apparent molecular masses of 44, 39 and 37-35 kD, respectively, circulate in human serum. These results provide a useful background to assess the serum level of soluble beta2-micro-free HLA class I heavy chains in pathological conditions and to evaluate their putative immunoregulatory function.

Adolescent↗

PubMed1997

IFN-gamma inducibility of class II transactivator is specifically lacking in human tumour lines: relevance to retinoblastoma protein rescue of IFN-gamma inducibility of the HLA class II genes.

We have previously reported that HLA class II induction by IFN-gamma is rescuable by reconstitution of functional retinoblastoma protein (RB) in two RB-defective tumour lines: the breast carcinoma line, MDA-468-S4 (S4) and the non-small cell lung carcinoma line, H2009. To determine the range of tumours and tumour types in which RB rescues HLA class II inducibility, we examined another RB-defective tumour line, the retinoblastoma line, WERI-Rb1. As in the case of S4 and H2009, HLA-DRA and -DRB were non-inducible by IFN-gamma in WERI-Rb1. However, neither inducibility of DRA nor DRB mRNA was resulted in an RB-positive stable transformant of WERI-Rb1, WLRB-8. While guanylate-binding protein (GBP) inducibility indicated that the basic IFN-gamma signal transduction pathway remained intact in WERI-Rb1, mRNA for class II transactivator (CIITA), a mediator of the IFN-gamma activation of the HLA class II genes and several other genes related to immune function, was not detectable in IFN-gamma-treated WERI-Rb1, indicating that the lack of CIITA expression was responsible, at least in part, for the inability of RB to rescue HLA class II-inducibility. The HLA class II-associated invariant chain (Ii), the expression of which is also up-regulated by CIITA, was non-inducible in WERI-Rb1, consistent with non-inducible CIITA. Also, IFN-gamma failed to activate the DRA, DRB and Ii promoters in WERI-Rb1. However, exogenous CIITA expression in WERI-Rb1 activated the DRA, DRB and Ii promoter-chloramphinocol acetyltransferase constructs, confirming that CIITA was not induced in WERI-Rb1 and indicating that other proteins required for activation of the class II and Ii promoters were functional in this cell line. Examination of additional cell lines for GBP and CIITA induction revealed that a specific lack of the CIITA IFN-gamma response is common in human tumour lines. The possible role of CIITA defects in tumorigenesis is discussed.

Chloramphenicol O-Acetyltransferase↗

PubMed1997

Inhibitor (IK) of IFN-gamma induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line.

The expression of major histocompatibility complex (MHC) class II antigens is constitutive in professional antigen presenting cells (APCs) but can also be induced by interferon-gamma (IFN-gamma) on the majority of the non professional APCs (e.g. fibroblasts). We have recently characterised a new factor called IK which is an efficient inhibitor of IFN-gamma induction of MHC class II antigens expression. Here, we demonstrate a novel role for IK in MHC class II expression since over-expression of this protein by stable transfection into human B cells led to a total disappearance of constitutive MHC class II mRNA expression. The class II transactivator (CIITA) is necessary for both constitutive and IFN-gamma induced MHC class II expressions. Examination of CIITA mRNA in IK stably transfected clones revealed a marked reduction of CIITA mRNA transcription. Taken together these results demonstrate that the IK protein plays a key role in the constitutive expression of MHC class II antigens and that inhibition induced by IK is upstream of CIITA in this regulatory pathway.

B-Lymphocytes↗

PubMed2004

Comparison of dental arch and alveolar widths of patients with Class II, division 1 malocclusion and subjects with Class I ideal occlusion.

This study evaluates dental arch and alveolar widths of patients with Class II, division 1 malocclusion. Thirty female patients with Class II, division 1 malocclusion were compared with 30 female subjects with Class I ideal occlusion. Patients with posterior crossbites even in a single tooth were excluded from the study. According to our results, arch widths measured between maxillary second premolars and maxillary first molars were found narrower in the Class II, division 1 group, and mandibular intercanine widths were narrower in the Class I group. Interalveolar widths showed no difference between the groups. These results suggested that transverse discrepancy in Class II, division 1 patients originated from upper posterior teeth and not from the maxillary alveolar base. Therefore, slow maxillary expansion rather than rapid maxillary expansion may be considered before or during the treatment of Class II, division 1 patients.

Adolescent↗

PubMed2004

The mechanism of Class II correction in surgical orthodontic treatment of adult Class II, division 1 malocclusions.

The purpose of this investigation was to assess the dentoskeletal effects and facial profile changes as well as the mechanism of Class II correction in adult Class II subjects treated by surgical mandibular advancement in combination with orthodontics. The subject material comprised 46 adults with a Class II, division 1 malocclusion treated by nonextraction with a mandibular sagittal split osteotomy as well as with pre- and postsurgical multibracket appliances. Lateral head films from before treatment and after treatment were analyzed. The results revealed the following statistically significant (P < .001) treatment changes: (1) the mandibular prognathism enhanced; (2) the sagittal interjaw base relationship improved; (3) the mandibular plane angle increased; (4) the lower anterior facial height increased; (5) the lower posterior facial height decreased; (6) the facial profile straightened; (7) the overjet and Class II molar relationship were corrected. Overjet reduction was accomplished by 63% skeletal and 37% dental changes. The Class II molar correction was accomplished by 81% skeletal 19% dental changes. In conclusion, it can be said that mandibular sagittal split osteotomy in combination with pre- and postsurgical orthodontics is an effective and consistent method for the correction of Class II, division 1 malocclusions and for the straightening of the facial profile. A negative effect of treatment counteracting Class II correction is an increase in the mandibular plane angle.

Adolescent↗

PubMed1990

Recognition by CD8 on cytotoxic T lymphocytes is ablated by several substitutions in the class I alpha 3 domain: CD8 and the T-cell receptor recognize the same class I molecule.

The CD8 molecule on class I-reactive cytotoxic T lymphocytes (CTLs) is believed to function as a coreceptor along with the alpha beta T-cell receptor. Whereas the alpha beta T-cell receptor recognizes polymorphic residues in the alpha 1/alpha 2 domains of the class I molecule, the CD8 molecule is believed to recognize monomorphic class I residues. Our previous experiments suggested that residue 227 in the alpha 3 domain of major histocompatibility complex class I molecules contributes to the determinant recognized by CD8. By using a panel of site-directed mutants of H-2Dd, this observation has been extended herein. Our findings indicate that for recognition by CD8-dependent CTLs, residue 227 must be either glutamic acid or aspartic acid and cannot be either basic or uncharged. However, the recognition by CD8-independent CTLs is unaffected by any of the substitutions at position 227 of H-2Dd. Similarly, alterations of other charged residues at positions 222, 223, and 229 have an analogous effect to substitution at residue 227, whereas substitutions at residues 192 and 232 do not affect the reactivity of CD8-dependent or CD8-independent CTLs. In addition, mutant H-2Dd molecules that are not recognized by CD8-dependent CTLs are unable to stimulate a primary CTL response, yet they can stimulate a secondary CD8-independent H-2Dd-specific CTL response. These findings suggest that CD8 recognition is obligatory for the priming of class I-dependent CTL responses. Since endogenous class I molecules were expressed by all of the transfected cell lines, these findings provide direct genetic evidence that CD8 and the alpha beta T-cell receptor must interact with the same class I molecule.

Amino Acids↗

PubMed1998

MHC class I heavy chain mRNA must exceed a threshold level for the reconstitution of cell surface expression of class I MHC complexes in cells transformed by the highly oncogenic adenovirus 12.

In primary embryonal fibroblasts from transgenic mice expressing H-2(b) genes and a miniature swine class I transgene (PD1), transformation with adenovirus 12 results in suppression of assembly and cell surface expression of all class I complexes. Cell surface expression of PD1 can be recovered by transfecting the cells with peptide transporter genes. However, reconstitution of the H-2Kb gene expression requires, in addition, a 2-fold increase in the steady state level of the H-2Kb mRNA that can be attained by treatment of the cells with interferons or by transfecting them with the H-2Kb gene. A detailed analyses of the biogenesis of class I molecules has revealed the steady state expression of free class I heavy chains that are not converted into conformed complexes even when peptide transporter genes are overexpressed. The fact that class I complex assembly seems to be highly inefficient in certain cell lines might be a major in vivo obstacle for the elimination of transformed or virus-infected cells by cytotoxic T lymphocytes, especially in view of the fact that the level of class I gene transcription is often down-regulated in cancer cells and/or that assembly of class I major histocompatibility complexes can be subverted by virus-encoded proteins.

Adenoviridae↗

PubMed1988

Identification of homologous regions in human immunodeficiency virus I gp41 and human MHC class II beta 1 domain. I. Monoclonal antibodies against the gp41-derived peptide and patients' sera react with native HLA class II antigens, suggesting a role for autoimmunity in the pathogenesis of acquired immune deficiency syndrome.

Homologous regions of five amino acids each, were identified in the NH2-terminal domain of human class II beta chains and the COOH terminus of HIV I envelope protein. The homologous regions are highly conserved among different DR and DQ alleles and also among different isolates of HIV. Septamers containing these sequences were synthesized and used for the generation of murine mAbs. The mAbs selected for this study were raised against the HIV I-derived peptide and reacted strongly not only with the immunizing peptide, but also with the homologous class II-derived peptide. These mAbs also reacted with native MHC class II antigens expressed on human B cell lines and on murine fibroblast L cell lines transfected with the genes coding for the alpha and beta chains of human class II antigens. Furthermore, sera from 36% of AIDS patients tested contained antibodies that reacted with the class II-derived peptide, as well as with intact class II molecule-rich cell extracts. Such antibodies in HIV I-infected individuals may recognize self class II antigens, triggering autoimmune mechanisms that could contribute to the development of immunodeficiency in AIDS patients.

Acquired Immunodeficiency Syndrome↗

PubMed1990

An immunodominant class I-restricted cytotoxic T lymphocyte determinant of human immunodeficiency virus type 1 induces CD4 class II-restricted help for itself.

We have observed that a peptide corresponding to an immunodominant epitope of the HIV-1 envelope protein recognized by class I MHC-restricted CD8+ CTL can also induce T cell help for itself. The help is necessary for restimulation of CTL precursors in vitro with peptide alone in the absence of exogenous lymphokines, can be removed by depletion of CD4+ T cells, and can be replaced by exogenous IL-2. Whereas the CTL in BALB/c or B10. D2 mice are restricted by the class I molecule Dd, the Th cells are restricted by the class II molecule Ad, and the help can be blocked by anti-Ad mAb. To examine the genetic regulation of the induction of help, we studied B10.A mice that share the class I Dd molecule, but have different class II molecules, Ak and Ek. Spleen cells of immune B10.A mice behave like CD4-depleted BALB/c spleen cells in that they cannot be restimulated in vitro by the peptide alone, but can with peptide plus IL-2. Therefore, in the absence of exogenous lymphokines, peptide-specific help is necessary for restimulation with this immunodominant CTL epitope peptide, and in H-2d mice, this peptide stimulates help for itself as well as CTL. We speculate on the implications of these findings for the immunodominance of this peptide in H-2d mice, and for the selective advantage of pairing certain class I and class II molecules in an MHC haplotype.

Animals↗

PubMed1991

Gorilla class I major histocompatibility complex alleles: comparison to human and chimpanzee class I.

14 gorilla class I major histocompatibility complex (MHC) alleles have been isolated, sequenced, and compared to their counterparts in humans and chimpanzees. Gorilla homologues of HLA-A, -B, and -C were readily identified, and four Gogo-A, four Gogo-B, and five Gogo-C alleles were defined. In addition, an unusual Gogo class I gene with features in common with HLA-A and its related pseudogene, HLA-H, is described. None of the gorilla alleles is identical or even closely related to known class I alleles and each encodes a unique antigen recognition site. However, the majority of polymorphic substitutions and sequence motifs of gorilla class I alleles are shared with the human or chimpanzee systems. In particular, elements shared with HLA-A2 and HLA-B27 are found in Gogo-A and -B alleles. Diversity at the Gogo-B locus is less than at the Gogo-A locus, a trend the opposite of that seen for HLA-A and -B. The Gogo-C locus also appears to have limited polymorphism compared to Gogo-A. Two basic Gogo-C motifs were found and they segregate with distinctive sets of HLA-C alleles. HLA-A allels are divided into five families derived from two ancient lineages. All chimpanzee A alleles derived from one of these lineages and all gorilla alleles derive from the other. Unlike chimpanzee Patr-A alleles, the Gogo-A alleles do not clearly partition with one of the HLA-A families but have similarities with two. Overall, gorilla class I diversity appears from this sampling to show more distinctions from class I HLA than found for chimpanzee class I.

Alleles↗

PubMed1993

Cell surface expression and function of an HLA class II molecule with class I domain configuration.

Recombinant major histocompatibility complex (MHC) class II molecules were expressed with extracellular polypeptide domains reorganized to form heavy (H) and light (L) chains (alpha 1-beta 1-beta 2 and alpha 2) analogous to class I. Accurate protein folding and dimerization is demonstrated by the ability of this 3+1-DR1 construct to bind class II-restricted peptides and stimulate CD4+ T cells. Cell surface expression of a functional class II molecule consisting of H and L chains supports the validity of current class II models and affirms the evolutionary relatedness of class I/II. MHC functions that differ between class I/II may be influenced by domain configuration, and the use of domain-shifted constructs will allow examination of this possibility.

Animals↗

PubMed2002

MHC class II-deficient tumor cell lines with a defective expression of the class II transactivator.

MHC class II expression defects have been evidenced in several human tumor cell lines originating from lung cancers or retinoblastoma. Accordingly, the mouse adenocarcinoma and fibrosarcoma cell lines, RAG and L(tk-), do not express I-A and I-E molecules even when treated with IFN-gamma. Here we show that fusion of both cell lines restores the inducible expression of MHC class II, thereby demonstrating that they present different and recessive alterations outside the MHC class II locus. CIITA, the MHC class II transactivator, controls the tissue-specific expression of MHC class II genes and creates the architecture of the transcriptional complex that binds to the MHC class II gene promoters. In L(tk-) cells, C2ta transcripts, expressed from the gene encoding CIITA, were indeed detected in severely limited amounts, with a defect in C2ta transcription initiation. In agreement we show here that the L(tk-) cell line does not express the CIITA protein. In contrast, in the RAG cell line, C2ta transcripts were expressed at normal levels, from the proper initiation site. The nucleotide sequencing of the CIITA cDNA from RAG did not reveal any mutation. However, the CIITA protein was not detected. These data evidence a new type of defect in a MHC class II-defective tumor cell line, as we show here that the alteration in the RAG cells occurs downstream of C2ta transcription. The RAG mutation might therefore reside in the C2ta transcript nuclear export or translation, or in the stability of the CIITA protein.

Animals↗

PubMed1995

General role of HLA class I molecules in the protection of target cells from lysis by natural killer cells: evidence that the free heavy chains of class I molecules are not sufficient to mediate the protective effect.

Some HLA-C alleles have been shown to exert a specific protective effect preventing target cells from lysis by groups of natural killer (NK) clones displaying a defined specificity. In this study, we analyzed whether class I-mediated protection is a more general phenomenon involving all NK cells. First, we utilized two anti-class I mAbs (6A4 of IgG1 isotype and A6-136 of IgM isotype), which had been shown to induce lysis of protected target cells by group 1 and group 2 NK clones. Addition of A6-136 or 6A4 used as F(ab')2 mAb resulted in lysis of protected target cells by all NK clones analyzed. Target cells were represented by a panel of HLA homozygous Epstein-Barr virus-transformed B cell lines (B-EBV) while NK clones were representative of clones displaying different GL183/EB6 surface phenotypes and/or different abilities to lyse allogeneic cells. Unselected NK clones derived from seven different individuals were tested against autologous target cells represented by phytohemagglutinin-induced blasts or B-EBV transformed cell lines. In both instances, addition of a mixture of 6A4 F(ab')2 and A6-136 mAbs resulted in lysis of autologous target cells, thus suggesting that class I molecules prevent lysis of normal cells by self NK cells. We further investigated whether the class I-mediated protection requires the complexed form of class I molecules (composed of alpha chain, beta 2-microglobulin and the antigen peptide) or rather the free alpha chain. Acidic treatment of the C1R (Cw4+) target cells or 81.22 (Cw3+, Cw4+) at pH 2.2 resulted in loss of reactivity with 6A4, A6-136 and W6-32 mAb (known to react with the assembled form of class I molecules) and in the de novo reactivity with L31 mAb (specific for the HLA-C free chain). While the untreated Cw+ C1R cells were resistant to lysis by the Cw4-specific group 1 NK clones, the pH 2.2-treated cells became highly susceptible to lysis by the same clones. These data indicate that, at least for the NK clones analyzed, the protection of target cells requires class I molecules in the complexed form.

Alleles↗

PubMed1997

Social class and coronary disease in rural population of north India. The Indian Social Class and Heart Survey.

OBJECTIVE: To demonstrate the association of socio-economic status with prevalence of coronary artery disease and coronary risk factors. DESIGN AND SETTING: Cross-sectional survey in two randomly selected villages in the Moradabad district in North India. SUBJECTS AND METHODS: One thousand seven hundred and sixty-seven subjects (894 males and 875 females; 25-64 years of age) were randomly selected from two villages. They were divided into social classes 1 to 4, according to education, occupation, housing conditions, ownership of land, ownership of consumer durables and per capita income. The survey was based on questionnaires administered by dietitians and physicians, physical examination and electrocardiography. RESULTS: Social classes 1 and 2 were mainly high and middle socio-economic groups and 3 and 4 low income groups. The prevalence of coronary artery disease was significantly higher among classes 1 and 2 in both sexes, and there was a higher prevalence of hypercholesterolaemia, hypertension, and sedentary lifestyle. This population also showed a significant association with higher serum cholesterol, body mass index, triglycerides and blood pressures. Logistic regression analysis with adjustment for age showed that social class positively related to coronary disease (odds ratio: men 0.83, women 0.61), hypercholesterolaemia (men 0.85, women 0.87), hypertension (men 0.89, women 0.87), body mass index (men 0.91, women 0.93) and smoking in men (0.68). Smoking and sedentary lifestyle were not associated with social class in women. The association between coronary artery disease and social class abated after adjustment for smoking, sedentary lifestyle, body mass index and blood pressure (odds ratio: men 0.96, women 0.81). CONCLUSION: Subjects in social classes 1 and 2 in rural North India have a higher prevalence of coronary artery disease and of the coronary risk factors hypercholesterolaemia, hypertension, higher body mass index and sedentary lifestyle. The overall prevalence of coronary artery disease was 3.3%.

Adult↗

PubMed1999

Individual hydrogen bonds play a critical role in MHC class II: peptide interactions: implications for the dynamic aspects of class II trafficking and DM-mediated peptide exchange.

Determination of the crystal structure of class II: peptide complexes has shown that in addition to pocket interactions involving the side chains of the peptide, peptide binding to MHC class II molecules is characterized by a series of hydrogen bonds which are contributed by genetically conserved amino acid residues in the class II molecule to the main chain of the peptide. Our experiments have revealed an unexpectedly large contribution of hydrogen bonds at the periphery of the MHC peptide binding pocket to MHC class II function. Kinetic studies have shown that peptide dissociation rates are profoundly accelerated by loss of a single hydrogen bonding residue. The magnitude of the effects seen with the loss in potential for a single hydrogen bond support a co-operative model in which individual bonds between class II and peptide are dependent on the integrity of neighboring interactions. Collectively our studies have revealed that MHC class II structure, peptide binding and intracellular trafficking events are critically dependent on the integrity of the hydrogen bonding network between class II molecules and its bound peptide.

Animals↗

PubMed1991

Class I and class II major histocompatibility complex antigens on hepatocytes: importance of the method of detection and expression in histologically normal and diseased livers.

Methodological differences in major histocompatibility complex (MHC) antigen detection were investigated on isolated, viable hepatocytes and cryostat hepatic sections from 27 children with liver disorders, six of whom had normal histology. Class I antigens were constantly found on sections using a three step immunoperoxidase technique after acetone/chloroform fixation, other techniques being less sensitive, or on isolated hepatocytes by indirect immunofluorescence alone. With mechanical isolation the percentage of positivity ranged from 85 to 100%, while with collagenase isolation it ranged from 22 to 49% on immediate testing, and from 53 to 80% after 24 hour incubation. Class II antigens were only detected in one patient with autoimmune chronic active hepatitis and two with primary sclerosing cholangitis. Flow cytofluorimetric analysis in 11 cases confirmed class II or class I positivity, or both, on isolated hepatocytes, allowing MHC antigen expression on hepatocytes to be measured. Class I and II antigen detection on hepatocytes is influenced by the technique used. Although class I antigens are invariably expressed on hepatocytes, class II antigens are only found on hepatocytes from patients with immune mediated liver disorders.

Adolescent↗

PubMed2006

Ii-Key/MHC class II epitope hybrids: a strategy that enhances MHC class II epitope loading to create more potent peptide vaccines.

Life-threatening diseases, such as cancer and pandemic influenza, demand new efforts towards effective vaccine design. Peptides represent a simple, safe and adaptable basis for vaccine development; however, the potency of peptide vaccines is insufficient in most cases for significant therapeutic efficacy. Several methods, such as Ligand Epitope Antigen Presentation System and ISCOMATRIX, have been developed to enhance the potency of peptide vaccines. One way of increasing the loading of MHC class II peptides occurs through the use of Ii-Key technology. Ii-Key (LRMK), a portion of the MHC class II-associated invariant chain (Ii), facilitates the direct loading of epitopes to the MHC class II molecule groove. Linking the Ii-Key moiety via a simple polymethylene bridge to an MHC class II epitope, to generate an Ii-Key/MHC class II epitope hybrid, greatly enhances the vaccine potency of the tethered epitope. The combination of such Ii-Key/MHC class II epitope hybrids with MHC class I epitope-containing peptides might generate a potent peptide vaccine for malignancies and infectious diseases. The Ii-Key hybrid technology is compared with other methods that enhance the potency of a peptide vaccine.

Animals↗