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PubMed1999

Absence of MHC class II gene expression in a patient with a single amino acid substitution in the class II transactivator protein CIITA.

We investigated the underlying genetic defect in an immunodeficient patient who presented with recurrent bacterial infections in his late twenties and demonstrated a transcriptional defect in major histocompatibility complex (MHC) class II regulation. Transient heterokaryon analysis implicated functional loss of CIITA, the MHC class II transactivator protein, and in support of this MHC class II antigen expression was restored by stable transfection with the wild-type molecule. A single amino acid substitution, phenylalanine to serine, in the COOH-terminal portion of the CIITA sequence correlated with reduced transcription of both classical (HLA-DP, -DQ, and -DR) and nonclassical (HLA-DM and -DO) class II genes. The long survival of the patient, although remarkable, was not associated with partial CIITA function as evidenced by residual MHC class II expression. These data define at high resolution a region of CIITA that is essential for function in both professional and nonprofessional antigen presenting cells and which could potentially constitute a target for therapeutic intervention by novel factors with a propensity to downregulate MHC class II antigen expression.

Adult↗

PubMed1991

De novo HLA class II and enhanced HLA class I molecule expression in SV40 transfected human thyroid epithelial cells.

Human thyroid follicular cells normally synthesize and express HLA Class I molecules but in glands affected by autoimmune or neoplastic diseases they express Class II molecules. We have investigated the effect of SV40 virus transformation on the expression of MHC molecules in human thyrocytes. Primary cultures of human thyroid from two different glands were transfected with the plasmid pX-8, containing the 'early' region of SV40 virus, and two continuous lines of thyrocytes were obtained. The cell lines maintained features of parental thyroid epithelial cells showing the characteristic cytokeratin filament network, microvillar protrusion and tight junctions. In addition, the SV40-transfected cells responded to graded doses of TSH with increased c-AMP production. Thyrocytes from both cell lines hyperexpressed Class I molecules and a significant proportion of them also acquired constitutive Class II expression, as determined by indirect immunofluorescence (IFL), flow cytometry and Northern blotting hybridization using a DR beta probe. These cells were found to be normally up-regulated by interferon (IFN)-gamma. Indirect IFL and flow cytometry analysis were used to detect and quantify the expression of HLA-DR, DP and DQ subregions. A co-ordinated expression (DR greater than DP much greater than DQ), reminiscent of the inappropriate HLA expression found in thyroid autoimmune disease in vivo and of the in vitro regulation in normal thyrocytes, was observed. Clones derived from these cell lines differed in their level of constitutive Class II expression and in their sensitivity to Class II induction by IFN-gamma. In conclusion, these thyroid cell lines could provide a useful tool for further investigation of HLA gene regulation in thyroid cells and for elucidating on the mechanism involved in the inappropriate HLA expression described in autoimmune and neoplastic diseases of the thyroid.

Autoantigens↗

PubMed2006

15-Deoxy-12,14-prostaglandin J2 inhibits interferon gamma induced MHC class II but not class I expression on ARPE cells through a PPAR gamma independent mechanism.

Retinal pigment epithelial (RPE) cells constitute the external part of the blood-retinal-barrier and play a pivotal role in the regulation of retinal immunity. In the present work, we investigated the effects of 15-deoxy-12,14-prostaglandin J2 (15 PGJ2), an endogenous ligand of PPARgamma, on the IFNgamma-induced expression of MHC class II on RPE cells. Indeed, pathological expression of MHC class II molecules at the surface of RPE cells is a common feature of many blinding conditions. We demonstrated that 15 PGJ2 inhibited the IFNgamma-mediated induction of MHC class II on RPE cells without affecting the level of MHC class I and CD54 expression. The other PPARgamma agonist rosiglitazone or troglitazone had no similar effects. Moreover, the inhibitory effect of 15 PGJ2 was not abrogated by co-incubation with PPARgamma antagonists and did not involve the modulation of STAT-1, AKT or ERK1/2 phosphorylation, nor CIITA, IRF1 or IRF2 transcription. In conclusion, 15 PGJ2 inhibits strongly and specifically the IFNgamma-induced MHC class II expression on RPE cells by a PPARgamma independent mechanism. Given the differential role of MHC classes I and II in the development of autoimmune uveitis and the potential toxicity of 15 PGJ2, our data's suggest that the development of novel small molecules targeting similar PPARgamma independent pathways would be useful for the future management of uveitis.

Cell Line↗

PubMed2003

Assessment of killer cell immunoglobulinlike receptor expression and corresponding HLA class I phenotypes demonstrates heterogenous KIR expression independent of anticipated HLA class I ligands.

Natural killer (NK) cell-mediated cytolysis is stimulated and downregulated through the interaction of distinct human leukocyte antigen (HLA) class I molecules on target cells with specific killer cell immunoglobulinlike receptors (KIRs) on NK cells. Killer cell immunoglobulinlike receptors are highly polymorphic and are clonally distributed on NK cell populations within individuals. However, the regulation of KIR expression by individual HLA class I phenotypes is not well understood. To examine a potential influence of the HLA class I phenotype on KIR expression patterns we studied the KIR expression in individuals that were subgrouped according to the major HLA-C encoded KIR-epitopes (group C1 versus C2). In these individuals, NK cells were analyzed for KIR expression using flow cytometry and RNA-based expression analysis. Our results demonstrate that KIR genes are transmitted very heterogeneously with two main patterns of KIR genotypes as previously described; group A and group B (with 21 different genotypes). There are distinct populations exhibiting different densities of CD158a and/or CD158b positive NK cells that coexist in all individuals. A clear correlation between KIR expression and the currently known HLA class I ligands was not observed. In conclusion, the surface expression of KIRs in individuals with different HLA class I genotypes indicates that other non-HLA class I encoded factors contribute to the shaping of the KIR repertoire.

Blood Donors↗

PubMed1998

Social class and substance use disorders: the value of social class as distinct from socioeconomic status.

The relationship between social class and substance use disorders (SUDs) is explored and compared to the relationship between SES and SUDs. Social class and SES are two different conceptualizations of socioeconomic inequality (SEI) which emanate from two different theoretical orientations in sociology. SES is commonly used in epidemiological research and is usually measured in terms of education, income or occupational prestige. Social class is less known and less used. Here, following the work of Wright et al. (Wright, E. O., Hachen, D. and Costello, C. et al. (1982) The American class structure. American Sociological Review 47, 709-726) it is measured in terms of four types of control people have in their work place: ownership, control over budget decisions, control over other workers, and control over one's own work. Data are derived from an epidemiological survey, conducted in Israel, using a two stage sampling procedure for the identification of cases. In the first stage 4914 respondents were screened with the Psychiatric Epidemiological Research Interview (PERI). In the second stage (n = 2741), those who screened positive (and a sample of the negatives) were diagnosed by psychiatrists using a structured interview that yielded diagnoses according to the Research Diagnostic Criteria (RDC). The results indicate that those who are advantaged in terms of ownership, i.e. self-employed, have higher rates of SUDs compared to employees. Furthermore, it appears that most disorders have an onset subsequent to entry into the current job, indicating that ownership plays a causal role in the onset of SUDs rather than the other way around. These results are contrasted with those of a previous report from the same study by Dohrenwend et al. (Dohrenwend, B. P., Levav, I. and Shrout, P. E. et al. (1992) Socioeconomic status and psychiatric disorders: the causation selection issue. Science 255, 946-952) which showed just the opposite association between SES and SUDs, i.e. those who are advantaged in terms of SES have lower rates of SUDs. As an explanation of these apparently conflicting results, the possibility is entertained that social class and SES represent independent causal pathways to the onset of SUDs with social class mainly related to primary SUDs and SES mainly to secondary SUDs.

Adult↗

PubMed2004

MHC class Ia-restricted memory T cells inhibit expansion of a nonprotective MHC class Ib (H2-M3)-restricted memory response.

Listeria monocytogenes infection generates major histocompatibility complex (MHC) class Ia-restricted and MHC class Ib-(H2-M3)-restricted effector and memory CD8+ T cells. However, only MHC class Ia-restricted memory cells expand after rechallenge, and it is unknown if MHC class Ib-restricted memory CD8+ T cells generated by vaccination are protective. We show here that H2-M3-restricted memory CD8+ T cells were capable of secondary expansion but, in contrast to primary H2-M3-restricted effector cells, failed to provide protective immunity. In lm-immune mice, MHC class Ia-restricted memory CD8+ T cells prevented the expansion of H2-M3-restricted memory T cell populations by limiting dendritic cell antigen presentation. Thus, protective immunity by H2-M3-restricted T cells is limited to primary infection, indicating that memory MHC class Ia-restricted T cells prevent nonessential immune responses during secondary infection.

Animals↗

PubMed1989

Cloning of the major histocompatibility complex class II promoter binding protein affected in a hereditary defect in class II gene regulation.

The regulation of major histocompatibility complex class II gene expression is directly involved in the control of normal and abnormal immune responses. In humans, HLA-DR, -DQ, and -DP class II heterodimers are encoded by a family of alpha- and beta-chain genes clustered in the major histocompatibility complex. Their expression is developmentally controlled and normally restricted to certain cell types. This control is mediated by cis-acting sequences in class II promoters and by trans-acting regulatory factors. Several nuclear proteins bind to class II promoter sequences. In a form of hereditary immunodeficiency characterized by a defect in a trans-acting regulatory factor controlling class II gene transcription, we have observed that one of these nuclear factors (RF-X) does not bind to its target sequence (the class II X box). A cDNA encoding RF-X was isolated by screening a phage expression library with an X-box binding-site probe. The recombinant protein has the binding specificity of RF-X, including a characteristic gradient of affinity for the X boxes of HLA-DR, -DP, and -DQ promoters. RF-X mRNA is present in the regulatory mutants, indicating a defect in the synthesis of a functional form of the RF-X protein.

Base Sequence↗

PubMed1985

Multiple class I and class II major histocompatibility complex allospecificities are generated with T cell receptor variable (V) domains created by a single Ti beta V gene family.

10 alloreactive cytotoxic T lymphocytes using REX Ti beta variable region (V) gene segments in formation of their antigen/major histocompatibility complex (MHC) T3-Ti receptor were selected, cloned, and characterized in an effort to examine the extent of receptor diversity created by this one V gene family. Multiple and distinct class II as well as class I allospecificities were generated from the formation of different Ti beta V domains. Five allospecificities were directed at various class I epitopes whereas the other five were directed at class II MHC gene products. The following conclusions were drawn: (a) Ti beta V genes do not segregate into those that encode class I and those that encode class II allospecificities; and (b) there is no restriction on the Ti beta V gene pool available to T4+ vs. T8+ T lymphocytes.

Animals↗

PubMed1985

Properties of purified T cell subsets. I. In vitro responses to class I vs. class II H-2 alloantigens.

In light of the widely accepted view that Ia-restricted L3T4+ T helper cells play a decisive role in controlling the differentiation of Lyt-2+ cells, experiments were designed to examine whether Lyt-2+ cells can respond to antigen in the absence of L3T4+ cells. The results showed that highly purified Lyt-2+ cells gave high primary mixed lymphocyte reactions (MLR) to various class I differences, including both mutant and allelic differences; responses to class II (Ia) differences were generally undetectable with Lyt-2+ cells. The intensity of MLR to class I differences was not affected by addition of anti-L3T4 monoclonal antibodies (mAb) to the cultures or by removing T cells from the stimulator populations. Negative selection experiments showed that Lyt-2+ cells could respond to class I differences across Ia barriers. MLR of purified Lyt-2+ cells peaked on days 3-4 and then fell sharply; background responses with syngeneic stimulators (auto-MLR) were virtually absent. Parallel experiments with purified L3T4+ cells showed that this subset responded in MLR only to class II (Ia) and not class I differences, reached peak responses only on day 6 rather than days 3-4, and often gave high auto-MLR. Within the first 3-4 d of culture, MLR were generally higher with Lyt-2+ cells than L3T4+ cells. Although no evidence could be found that Ia-restricted L3T4+ cells were required for the response of Lyt-2+ cells, presentation of antigen by Ia+ cells appeared to be essential. Thus, responses were ablated by pretreating stimulator cells with anti-Ia mAb plus C'. Significantly the failure of Lyt-2+ cells to respond to anti-Ia plus C'-treated stimulators could not be restored by adding syngeneic spleen cells; addition of IL-2 led to only a minor (15%) restoration of the response. It is suggested that Ia+ cells provide an obligatory second signal required by Lyt-2+ cells.

Animals↗

PubMed1991

The major histocompatibility complex class II-linked cim locus controls the kinetics of intracellular transport of a classical class I molecule.

The dominant trans-acting major histocompatibility complex (MHC)-linked class I modifier (cim) locus, previously recognized through its ability to determine altered alloantigenicity of a rat class I molecule, RT1.A3, is shown here to influence class I intracellular transport. The MHC recombinant laboratory rat strains PVG.R1 and PVG.R8 display unusually long retention of RT1.Aa within the endoplasmic reticulum or cis-Golgi. In appropriate F1 hybrid cells heterozygous for RT1.Aa and another class I MHC allele, RT1.Ac, only the RT1.Aa protein is subject to slow transport. The cim gene product therefore shows class I allele specificity in its action, cim appears to be a polymorphic locus whose product is directly involved in the processes of class I MHC assembly and/or intracellular transport.

Animals↗

PubMed2006

In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules.

Endoplasmic reticulum (ER)-associated aminopeptidase (ERAP)1 has been implicated in the final proteolytic processing of peptides presented by major histocompatibility complex (MHC) class I molecules. To evaluate the in vivo role of ERAP1, we have generated ERAP1-deficient mice. Cell surface expression of the class Ia molecules H-2Kb and H-2Db and of the class Ib molecule Qa-2 was significantly reduced in these animals. Although cells from mutant animals exhibited reduced capacity to present several self- and foreign antigens to Kb-, Db-, or Qa-1b-restricted CD8+ cytotoxic T cells, presentation of some antigens was unaffected or significantly enhanced. Consistent with these findings, mice generated defective CD8+ T cell responses against class I-presented antigens. These findings reveal an important in vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules.

Aminopeptidases↗

PubMed1996

Functional consequences of the binding of MHC class II-derived peptides to MHC class II.

Three MHC class II-derived synthetic peptides (I-A beta (g7)1-16, I-A beta (g7)52-77 and I-A alpha (g7)63-82YC) were analyzed for their ability to bind to syngeneic and allogeneic MHC class II molecules using a whole cell, competitive peptide binding assay. These studies demonstrated that the A beta (g7)1-16 peptide was able to specifically bind to syngeneic as well as to four allogeneic MHC class II molecules. The A alpha (g7)63-82YC peptide bound to self MHC class II molecules with a lower relative affinity and was able to bind to three out of the four allogeneic cells tested. The binding of the three I-A(g7)-derived peptides to the self MHC class II was functionally significant. The A beta (g7)1-16 and A beta (g7)52-77 peptides inhibited the proliferation of a heat shock protein 60 peptide-specific Th1 clone by MHC blockade. Interestingly, the A alpha (g7)63-82YC peptide appeared to interact directly with T cells as pretreatment of the Th1 clone with this peptide resulted in inhibition of antigen-induced proliferation. This phenomenon was analyzed in more detail and it was found that this peptide could behave as a partial agonist. Incubation of T cells with the A alpha (g7)63-82YC peptide resulted in up-regulation of IL-2R alpha chain expression and induction of IFN-gamma secretion. In addition T cells pretreated with this peptide were rendered hyporesponsive to further antigenic stimulation. Thus, a peptide derived from MHC class II may be used in an immunoregulatory capacity.

ATP-Binding Cassette Transporters↗

PubMed1987

The role of class I and class II MHC antigens in the rejection of vascularized heart allografts in mice.

We have examined the role of entire major histocompatibility complex (MHC) disparity, individual class II or class I alloantigens in the rejection of vascularized heart allografts. Our results demonstrate that entire MHC, as well as both class II and class I disparities, may induce acute heart graft rejection or severe and irreversible heart muscle destruction. However, in 1 of 2 combinations differing at class II and 1 of 5 differing at class I, hearts have shown a good function greater than 100 days postgrafting. Furthermore, each donor-recipient combination has demonstrated a unique pattern of heart allograft function as well as a degree of heart muscle damage. In conclusion, these data suggest that the rejection process depends upon multiple factors such as the immune-response-gene-regulated immunoresponsiveness of the recipient as well as the expression of alloantigens on heart grafts during the induction and effector phases of the immune response.

Animals↗

PubMed2002

Is there MHC Class II restriction of the response to MHC Class I in transplant patients?

BACKGROUND: In this study, we evaluated distinct HLA-DRB1 alleles to determine class II restriction of the production of HLA-A2-specific antibodies in renal transplant patients. METHODS: Data from 217 renal transplant patients who received an HLA-A2-mismatched renal graft were analyzed with regard to HLA-A2 humoral responsiveness. High-resolution DNA typing of class II HLA-DR alleles was performed by polymerase chain reaction-sequence-specific primer. Patients who had one of the following eight HLA-DRB1 alleles were included in the study: -*0101, -*0301, -*0401, -*0701, -*1101, -*1301, -*1401, and -*1501. Serum samples were screened posttransplantation with the standard complement-dependent cytotoxicity procedure. In addition, recombinant HLA-A2 monomers (the "MonoLISA" assay) were used as a target for the detection of HLA-A2 group-specific antibodies. The following HLA-A2 amino acid positions (termed "epitopes") that are responsible for the induction of an antibody response were defined: 74H, 65-66GK, 62G, 114H, 142-145TTKH, and 107W-127K. The definition of the "HLA-DR permittors" of anti-HLA-A2 response was based on a "class II restriction table" designed for this purpose. Prediction of immunogenic and/or nonimmunogenic HLA-A2 peptides was based on an MHC database. RESULTS: The HLA-DRB1-*0101 and -*1401 alleles had a trend toward a positive correlation with the production of HLA class I-specific antibodies against the HLA-A2 shared (public) epitopes 65-66GK and -62G, respectively. Only the DRB1-*1501 allele had higher trend toward a positive correlation with the production of antibodies against the HLA-A2 private (74H) epitope. In 42 patients with the HLA-DRB1-*1501 allele, 11 (26%) patients produced HLA-specific antibodies against the HLA-A2 group of epitope(s). Moreover, in these patients, spreading of the alloreactivity against "other" HLA antigens was detected. Many of these other HLA antigens did not belong to HLA-A2 group but had newly defined shared epitopes with this group. Furthermore, the epitope prediction, based on an MHC database, revealed differences in the ligation strength (score) to the HLA allele (class I and II) for a specific HLA-A2 peptide in the 42 patients (responders and nonresponders). CONCLUSIONS: The data presented in this paper suggest that the HLA class II allele and the type of the bound allopeptide may influence the humoral and cellular response. The immunogenicity of these allopeptides could be predicted with an MHC database (high-scored peptide=activating peptide and low-scored peptide=suppressor peptide). In the future, production of synthetic peptide analogues, on the basis of these predictions, could be used for induction of T-cell anergy and/or tolerance. In the short term, algorithms, on the basis of our approach, could be tested for influence on graft survival and allosensitization in current high-quality data sets.

Alleles↗

PubMed1990

The class II major histocompatibility complex antigen deficiency syndrome: consequences of absent class II major histocompatibility antigens for lymphocyte differentiation and function.

The class II major histocompatibility complex antigen deficiency syndrome is a rare immunodeficiency disease associated with defective expression of the class II antigens encoded for by the major histocompatibility complex. Clinically, this syndrome is manifest as a combined immunodeficiency presenting early in life, and affected individuals are susceptible to a variety of severe and/or opportunistic infections. Chronic, severe diarrhea and malabsorption are also characteristically found, and death is common within the first few years of life. Although the precise molecular lesions responsible for the failure of membrane antigen expression in this syndrome have not yet been identified, the pathogenetic mechanisms involve regulatory defects in the transcription of structural genes encoding for class II antigens. The absence of class II MHC antigens results in profound abnormalities in lymphocyte function and differentiation. Of central importance is the defective MHC-restricted interactions between CD4+ "helper" T lymphocytes and the various types of antigen-presenting cells found in the skin and elsewhere. The absence of class II MHC antigens also appears to alter the ability of affected B cells to be activated by a variety of membrane-mediated stimuli, and it profoundly disrupts both the intrathymic development and post-thymic differentiation of immunoregulatory T cells. This "experiment of nature" thus demonstrates the critical role of class II MHC antigens in the proper development and function of the immune system.

Animals↗

PubMed1984

Serological cross-reactivities of murine and human class II antigen determined by murine xeno anti-human class II antibody.

Murine anti-human class II antibodies were shown to cross-react with polymorphic determinants of murine class II antigens. The cross-reacting antibodies were raised in B10.S(9R) mice by immunizing with human nylon wool adherent cells (Ad cells) from peripheral blood leukocytes. The B10.S(9R) anti-human Ad cell antiserum bound to the molecules consisting of two chains with molecular weights of 35K and 28K dimers which were purified with a lentil-lectin column. The B10.S (9R) anti-human class II antiserum was also revealed to contain two distinct cross-reacting antibodies with polymorphic determinants of murine class II antigens coded for by the I-A subregion of the H-2. One is specific for a determinant of class II molecules coded for by I-Ab,d,q, and the other seems to be specific for class II molecules coded for by I-Aa,k,r.

Animals↗

PubMed1990

T-cell activation. III. Attempts to activate MHC class I-negative and class I-transfected EL4 T-lymphoma cells by immobilized anti-CD3 antibody.

The aim of this study was to examine whether the unresponsiveness of MHC class I-negative subclones of the EL4 thymoma to CD3 cross-linking can be restored by transfection of class I genes into the H-2-negative cells. Cell activation experiments with selected MHC class I-negative subclones and H-2b- and H-2Ld-positive transfectants showed that these cells are equally capable of secreting interleukin 2 (IL-2) after exposure to the phorbol ester phorbol 12-myristate 13-acetate (PMA) and ionomycin. In contrast, only the parental H-2-positive EL4 cells are capable of responding to treatment with immobilized anti-CD3 antibody with IL-2 secretion and IL-2 receptor expression. Measurements of intracellular free Ca2+ (Ca2+i) following anti-CD3 antibody-induced cross-linking of parental EL4 cells and H-2-negative and H-2b gene-transfected subclones showed that the parental cells and two of the class I transfectants, one H-2-positive and one H-2-negative, responded with a slow rise in Ca2+i, whereas one H-2-positive transfected cell clone was completely refractory to CD3 cross-linking. Modulation experiments using parental EL4 cells, H-2-negative subclones and H-2-positive transfectants demonstrated that the CD3 and class I molecules of these different cells are modulated to the same extent after exposure to specific antibodies. The present findings thus indicate that the unresponsiveness of H-2-negative EL4 subclone cells to CD3 cross-linking is not functionally associated with a lack of class I surface expression.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2000

A multivariate analysis of the association between social class of origin and current social class with self-rated general health and psychological health among 16-year-old Australians.

BACKGROUND: A recent review of international literature concludes that there is a relative absence of social class differentials in health in early youth. There is an absence of Australian studies on the effect of social class on the health of this age group. AIMS: To examine the association between social class and health among 16-year-old Australians. METHODS: The data on 1048 16-year-olds came from the fifth wave (1993) of the Australian Youth Survey conducted by the former Department of Employment, Education and Training. Outcome measures were self-rated general health and psychological health (GHQ-12). Binary logistic regression was used to analyse data. RESULTS: Neither social class of origin nor current social class was associated with self-rated general health or psychological health. CONCLUSION: The argument that social class inequalities in health exist in childhood, disappear during early youth, and reappear later appears to hold ground within the Australian context.

Adolescent↗