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PubMed2005

Seasonal influence on the onset of idiopathic inflammatory myopathies in serologically defined groups.

OBJECTIVE: To assess possible seasonal patterns in the onset of polymyositis (PM) and dermatomyositis (DM). METHODS: The study group comprised 503 patients who met the criteria for probable or definite PM or DM and for whom detailed data on the time of myositis onset were available. Statistical analyses were performed using a Poisson model that assessed associations of ethnicity, sex, autoantibody presence, and month of onset of muscle weakness. RESULTS: There were no significant seasonal patterns of disease onset in myositis patients as a whole or in the total PM or DM populations. Significant seasonal associations were present, however, in the serologically defined groups. In the 131 patients with antisynthetase autoantibodies who were categorized as non-black, myositis onset peaked in March-April (P = 0.03). Among the antisynthetase-positive patients, the association was predominantly in those with PM (n = 85; P = 0.05) and in men (n = 51; P = 0.042). Patients with anti-signal recognition particle autoantibodies, however, did not have a significant seasonal onset, which is in contrast to previous findings. Patients without myositis-specific autoantibodies showed a significant peak in summer, with myositis onset in June-July (n = 252; P = 0.03); this seasonal association was significant in women (n = 182; P = 0.005), whereas there was no seasonal pattern in men (P = 0.9). CONCLUSION: These findings, in conjunction with other data, suggest that diverse environmental agents, acting upon different immunogenetic backgrounds, result in distinct immune responses and clinical syndromes in the idiopathic inflammatory myopathies. Our results emphasize the importance of considering more homogeneous disease groups, based on clinicopathologic features, immune responses, ethnicity, and sex, when attempting to decipher the pathogeneses of autoimmune disorders.

Autoantibodies↗
PubMed2006

A novel autoantibody to a 155-kd protein is associated with dermatomyositis.

OBJECTIVE: In polymyositis and dermatomyositis (DM), identified autoantibodies occur in <50% of adult patients and in a smaller proportion of children. This study was undertaken as part of a larger effort to define novel autoantibodies that assist in the clinical evaluation of myositis. METHODS: Sera from children and adults satisfying criteria for idiopathic inflammatory myopathies and from patients with other connective tissue diseases (CTDs), patients with noninflammatory myopathies, and healthy individuals were tested for autoantibodies by immunoprecipitation (IP). A previously unrecognized autoantibody that immunoprecipitated a 155-kd protein along with a weaker 140-kd protein was seen. When the presence of this anti-p155 autoantibody in test sera was suggested based on IP results, it was confirmed by immunoblotting of immunoprecipitates. RESULTS: Sera from 51 of 244 myositis patients (21%), including 30 with juvenile DM (29%), 5 with juvenile CTD-associated myositis (33%), 8 with adult DM (21%), 6 with cancer-associated DM (75%), and 2 with adult CTD-associated myositis (15%), were found to have anti-p155 autoantibody. One of 49 patients with lupus, and none of 89 others without myositis, had anti-p155. Caucasian patients with anti-p155 had a unique HLA risk factor, DQA1*0301 (odds ratio 5.4, corrected P = 0.004). In adults with anti-p155, of several clinical features assessed only the frequency of V-sign rash was increased, but patients with this antibody were clinically distinct from those with autoantibodies to aminoacyl-transfer RNA synthetases. CONCLUSION: A newly recognized autoantibody, anti-p155, is associated with DM and cancer-associated DM, and is one of the most common autoantibodies in this condition, occurring as frequently in children as in adults. The clinical features and immunogenetics associated with anti-p155 differ from those associated with antisynthetases.

Adult↗
PubMed2006

HLA polymorphisms in African Americans with idiopathic inflammatory myopathy: allelic profiles distinguish patients with different clinical phenotypes and myositis autoantibodies.

OBJECTIVE: To investigate possible associations of HLA polymorphisms with idiopathic inflammatory myopathy (IIM) in African Americans, and to compare this with HLA associations in European American IIM patients with IIM. METHODS: Molecular genetic analyses of HLA-A, B, Cw, DRB1, and DQA1 polymorphisms were performed in a large population of African American patients with IIM (n = 262) in whom the major clinical and autoantibody subgroups were represented. These data were compared with similar information previously obtained from European American patients with IIM (n = 571). RESULTS: In contrast to European American patients with IIM, African American patients with IIM, in particular those with polymyositis, had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype; however, African Americans with dermatomyositis or with anti-Jo-1 autoantibodies shared the risk factor HLA-DRB1*0301 with European Americans. We detected novel HLA risk factors in African American patients with myositis overlap (DRB1*08) and in African American patients producing anti-signal recognition particle (DQA1*0102) and anti-Mi-2 autoantibodies (DRB1*0302). DRB1*0302 and the European American-, anti-Mi-2-associated risk factor DRB1*0701 were found to share a 4-amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. CONCLUSION: These data demonstrate that North American IIM patients from different ethnic groups have both shared and distinct immunogenetic susceptibility factors, depending on the clinical phenotype. These findings, obtained from the largest cohort of North American minority patients with IIM studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms and/or different gene-environment interactions.

Adenosine Triphosphatases↗
PubMed1976

Investigations of red cell glyoxalase in recombinant families.

The polymorphism of the red cell glyoxalase (GLO), which has recently been found to be linked with the major histocompatibility complex (HLA) in man, was investigated in a number of selected families showing various recombinations between HLA-A, HLA-B and the third locus of the phosphoglucomutase (PGM3). In two families with a recombination between HLA-A and HLA-B, the GLO allele travels with the HLA-B locus fragment of the chromosome, indicating that GLO is located on the side of the HLA-B locus. In other families, recombinations occurred between HLA-A and B on one side and GLO and PGM3 on the other side, demonstrating that GLO and PGM3 are located on the same side of HLA. Other recombinations separated PGM3 from GLO so that it can be assumed that GLO is located between HLA-B and PGM3. Thus the immunogenetic linkage group on human chromosome C6 has been increased by yet another outside marker gene to include now the following genes in this order: HLA-A--HLA-C--HLA-B--Bf--HLA-D--GLO--PGM3.

Chromosome Mapping↗
PubMed1990

Natural killer cells activated with interleukin 2 in vitro can be adoptively transferred and mediate hematopoietic histocompatibility-1 antigen-specific bone marrow rejection in vivo.

An adoptive transfer model was developed for examining natural killer (NK) cell-mediated bone marrow cell (BMC) graft rejection. Homogeneous populations of NK cells were obtained by culturing spleen cells from mice with severe combined immune deficiency in the presence of recombinant interleukin 2 for 7 days. These cells maintained a phenotypic (CD3-CD4-CD8-NK-2.1+ and asialo GM1+) and lytic pattern consistent with that of activated NK cells. The cells were infused into lethally irradiated recipients whose own NK cells were depleted by anti-NK-1.1 antibody treatment and could no longer reject marrow allografts. The transferred NK cells restored the ability of the hosts to reject BMC in a hematopoietic histocompatibility-1 (Hh-1) antigen-specific manner. Immunogenetic studies demonstrated that the rejection was a function of the donor, not host, NK cells. These studies demonstrate that NK cells can be cultured in vitro with recombinant interleukin 2 and are capable of mediating Hh-1-specific BMC rejection in vivo in the absence of other immune cell types.

Animals↗
PubMed1991

Sequences of the mouse F protein alleles and identification of a T cell epitope.

F protein is found predominantly in the liver and is of unknown function. The protein has been of interest to immunologists in the areas of self tolerance and the immunogenetics of the anti-F protein response. In the mouse there are two alleles (F1 and F2), and although mice are completely tolerant to the self form of the protein, mice of responder strains make a good antibody response to immunization with the non-self form. This response cross-reacts with the self form, implying firstly, that autoreactive B cells are present and that tolerance is therefore maintained at the T cell level, and secondly, that the difference between the two allelic products defines a T cell epitope. Primers based on the published sequence for rat F protein were used in the polymerase chain reaction to amplify the cDNA for the two mouse alleles. Subsequent sequencing shows a high degree of sequence identity between the rat and mouse cDNA. The two mouse cDNA are identical apart from a single A to G base change which predicts an asparagine (F1 protein) to aspartate (F2 protein) amino acid residue change. Using allele-specific oligonucleotide probes we confirmed that this base change has the same strain distribution as the previously determined F protein type. Isoelectric focusing shows that F1 protein migrates in a more basic position than F2 protein, as predicted by the asparagine to aspartate change. Finally, a synthetic peptide from the allovariable site of F2 protein will successfully restimulate T cells in vitro from an F1 type mouse primed in vivo with whole F2 protein, whereas the corresponding peptide from F1 protein will not. This is evidence that, as predicted, the allovariable site does indeed define a T cell epitope. Peptides covering the rest of the F2 protein molecule were not stimulatory.

Alleles↗
PubMed1993

The gene loci for immunoglobulin heavy chains in precursor B cell lines from a patient with severe combined immunodeficiency appear able to participate in DNA rearrangement but have a germ-line configuration.

In a previous study (Immunogenetics 1988. 27:330) with Epstein-Barr virus, we established lines of precursor B cells from bone marrow cells of a patient with severe combined immunodeficiency in whom the numbers of B cells and T cells were markedly reduced. Although based on their surface markers these cell lines appeared to be at an early stage of B cell differentiation, the gene loci for immunoglobulin heavy chains (IgH) retained the germ-line configuration on both chromosomes in almost all the transformants. In this study, we found that the enhancer sequence, located between the JH and mu genes, was hypomethylated and an abundance of the germ-line Cmu transcript was detected in these cell lines by Northern hybridization. These results suggest that the chromatin structure of the IgH gene locus in these cell lines is accessible to VDJ recombinase and is able to participate fully in DNA rearrangement. By contrast, we did not detect transcripts of the RAG-1 and RAG-2 genes, which are required for V(D)J recombination at gene loci for immunoglobulin and T cell receptors. Thus, it seems likely that these cell lines fail to initiate the V(D)J recombination process because of some deficiency in the formation of VDJ recombinase, which includes the inability to express RAG genes.

B-Lymphocytes↗
PubMed1993

Minute quantities of a single immunodominant foreign epitope are presented as large nested sets by major histocompatibility complex class II molecules.

The processing and presentation of immunogenetic peptides is an obligate event in the generation of an immune response. However, the degree of complexity with which an immunogenic foreign epitope is presented is still unclear. This question was addressed by analyzing the naturally processed peptides generated from exogenously-derived hen egg white lysozyme (HEL) bound to the murine major histocompatibility complex (MHC) class II molecule, H-2Ak. Using reversed-phase chromatography (RPC), T cell hybridomas and mass spectrometry, 16 peptides were identified that contain the minimal MHC binding epitope 52-61. These peptides exhibited substantial N- and C-terminal extensions and ranged from 13-28 amino acids in length. In contrast, MHC class I molecules present peptides of 8-11 residues and each foreign epitope appears to be represented by only a single peptide. The data here also show that only approximately 0.8% of the total bound peptide was derived from this single HEL epitope. These findings provide direct evidence that relatively small amounts of processed peptide are required to stimulate an effective T cell response.

Amino Acid Sequence↗
PubMed1996

Expression levels of stress protein gp96 are not limiting for major histocompatibility complex class I-restricted antigen presentation.

Immunization of mice with gp96 induces CTL with specificity for proteins that are expressed in the cells from which gp96 was isolated (Arnold et al., J. Exp. Med. 1995. 182: 885, Udono et al., Proc. Natl. Acad. Sci. USA 1994. 91: 3077). Recently, it has been shown that gp96 from cells transfected with vesicular stomatitis virus (VSV) nucleocapsid protein as well as gp96 loaded in vitro with peptides containing an epitope of this protein are taken up by phagocytic cells which obtain thereby the capacity for stimulating VSV-specific cytotoxic T lymphocytes (Suto and Srivastava, Science 1995. 269: 1585). The immunization experiments together with the peptide transfer from gp96/peptide complexes to major histocompatibility complex (MHC) class I molecules of phagocytic cells are consistent with the hypothesis that the endoplasmic reticulum-resident protein gp96 plays a crucial role in the antigen presentation of a cell (Srivastava et al., Immunogenetics 1994. 29: 93). To examine the involvement of gp96 in class I-restricted antigen presentation, we reduced gp96 RNA and protein levels by transfecting P13.1 cells with a vector containing part of gp96 cDNA in antisense orientation to the promotor. We found that antisense clones expressing strongly reduced levels of gp96 mRNA and gp96 protein show normal levels of MHC class I molecules on the cell surface and are recognized by T cells to the same extent as wild-type cells. Thus, our results show that normal levels of gp96 expression in a cell are not limiting for class I-restricted antigen presentation.

Amino Acid Sequence↗
PubMed1996

HLA-associated inverse correlation between T cell and antibody responsiveness to islet autoantigen in recent-onset insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is a T cell-dependent immune-mediated disease. Recently, a novel islet cell antigen (ICA69) recognized by autoantibodies was described. We tested T cell responsiveness to ICA69 in peripheral blood of patients with recent onset IDDM (n = 46), patients with long-standing IDDM (n = 44), non-diabetic age-matched, islet cell autoantibody- and glutamic acid decarboxylase (GAD)65 antibody-negative first-degree relatives of IDDM patients (n = 15) and rheumatoid arthritis patients (n = 22). T cell responsiveness was significantly higher in recent onset IDDM patients, compared to IDDM patients post-disease onset, non-diabetic first degree relatives and rheumatoid arthritis patients (p < 0.001). In responding IDDM patients a significant inverse correlation between T cell and autoantibody responsiveness to ICA69 was observed (p < 0.0005). Immunogenetic evaluation revealed an association of HLA-DR3 with T cell responsiveness to ICA69 (p < 0.02) and absence of ICA69-reactive autoantibodies (p < 0.04). The increased T cell reactivity to ICA69 in the absence of antibody reactivity at onset of IDMM is associated with an HLA class II immune response gene, and therefore suggestive of a genetically controlled selective activation of T helper subsets to a specific autoantigen in humans.

Antibody Formation↗
PubMed1996

Glutamine and tetrapeptide repeat variations affect the biological activity of different mouse interleukin-2 alleles.

Mouse interleukin-2 (IL-2) was thought to be encoded by a single allele. We have recently described N-terminal differences in five IL-2 molecules from nine mouse strains analyzed (Matesanz, F., Alcina, A. and Pellicer, A., Immunogenetics 1993. 38: 300). In this study, we isolated and sequenced the cDNA of three polymorphic IL-2 molecules and constructed two recombinant IL-2 molecules to cover representative structural changes and to address the functional significance of these changes using human and mouse cellular assays in vitro. Apart from punctual codon changes, major differences include an expanding CAG codon (translated into glutamine) and the presence of the tetrapeptide Pro-Thr-Ser-Ser repeated 1, 2, or 3.5 times which is also present once in human IL-2. This tetrapeptide repeat includes an O-glycosylation site. These recombinant IL-2 proteins were expressed at high levels in bacteria and purified by preparative SDS-PAGE with a complete activity recovery. Differences in growth-inducing activity on mouse primary splenocytes were observed in some of them, although no differences were observed in proliferative stimulation of CTLL cells. In human peripheral blood lymphocytes and the T cell line Kit-225, the growth stimulation capacity was inversely dependent on the size of the glutamine stretch and the number of tetrapeptide repeats. These results suggest an evolutionary adaptation of the mouse IL-2/IL-2 receptor system that maintains polyglutamine extensions in the IL-2 molecule. In summary, mouse IL-2 polymorphism results in different bioactivities which may determine susceptibility or resistance to disease.

Alleles↗
PubMed1997

The endoplasmic reticulum-resident stress protein gp96 binds peptides translocated by TAP.

The endoplasmic reticulum (ER)-resident stress protein gp96 induces a major histocompatibility complex class I-restricted cytotoxic T lymphocyte (CTL) response against antigens present in the cells from which it has been prepared. In this study, photoreactive peptides were translocated into the ER by the transporter associated with antigen processing (TAP). These peptides can be cross-linked specifically to gp96. Thus, we provide the first evidence that gp96 binds TAP-translocated peptides which have been implicated in the induction of specific CTL responses after immunization with gp96 (Srivastava, P. K. et al., Immunogenetics 1994. 39: 93).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Combined structural and immunological refinement of HIV-1 HLA-B8-restricted cytotoxic T lymphocyte epitopes.

This study demonstrates that use of structural information improves the definition and optimization of cytotoxic T lymphocyte (CTL) epitopes. Epitope optimization usually requires numerous truncated peptides or a reverse immunogenetic approach, where the peptide binding motif is used to predict epitopes. These binding motifs do not reliably predict all peptides which are CTL epitopes. Comparison of 24 peptides eluted from HLA-B8 with 10 HLA-B8-restricted defined CTL epitopes demonstrated that known epitopes varied considerably at anchor positions. We used structural information based on determination of the crystal structure of the HLA-B8-GGKKKYKL complex to reassess previously described CTL epitopes, to predict new epitopes, and to predict the consequences of naturally occurring variation within epitopes. These predictions were confirmed by cytotoxicity and binding assays. Use of combined structural and immunological data more accurately defines the true peptide-binding motif of a restriction element than eluted peptide data allows.

Antigenic Variation↗
PubMed2004

Disease-related epitope spread in a humanized T cell receptor transgenic model of multiple sclerosis.

While EAE has been an invaluable model for the immunopathogenesis of multiple sclerosis, it has sometimes been difficult to bridge the gap between findings and therapies in the rodent models and the cellular and molecular interactions that can be studied in the human disease. Humanized transgenic models offer a means of achieving this, through the expression of disease-implicated HLA class II molecules, co-expressed with a cognate HLA-class II-restricted, myelin-specific TCR derived from a human T cell clone implicated in disease. We have generated such a transgenic line, called line 8, that co-expresses a high level of HLA-DR15 and a human TCR specific for HLA-DR15/MBP 85-99. T cells from the transgenic line are skewed to the CD4 single-positive compartment and produce IFN-gamma in response to peptide from mylein basic protein. Mice develop a spontaneous disease phenotype, showing poverty of movement, although this rarely develops into paralysis except following immunization with peptide. On induction of paralysis by immunization with peptide, disease correlates with epitope spread to a number of additional, HLA-DR15-restricted myelin epitopes. This model should be valuable for analyzing epitope spread in a humanized immunogenetic environment and for the testing of specific immunotherapies.

Animals↗
PubMed2005

An integrative approach to CTL epitope prediction: a combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions.

Reverse immunogenetic approaches attempt to optimize the selection of candidate epitopes, and thus minimize the experimental effort needed to identify new epitopes. When predicting cytotoxic T cell epitopes, the main focus has been on the highly specific MHC class I binding event. Methods have also been developed for predicting the antigen-processing steps preceding MHC class I binding, including proteasomal cleavage and transporter associated with antigen processing (TAP) transport efficiency. Here, we use a dataset obtained from the SYFPEITHI database to show that a method integrating predictions of MHC class I binding affinity, TAP transport efficiency, and C-terminal proteasomal cleavage outperforms any of the individual methods. Using an independent evaluation dataset of HIV epitopes from the Los Alamos database, the validity of the integrated method is confirmed. The performance of the integrated method is found to be significantly higher than that of the two publicly available prediction methods BIMAS and SYFPEITHI. To identify 85% of the epitopes in the HIV dataset, 9% and 10% of all possible nonamers in the HIV proteins must be tested when using the BIMAS and SYFPEITHI methods, respectively, for the selection of candidate epitopes. This number is reduced to 7% when using the integrated method. In practical terms, this means that the experimental effort needed to identify an epitope in a hypothetical protein with 85% probability is reduced by 20-30% when using the integrated method. The method is available at http://www.cbs.dtu.dk/services/NetCTL. Supplementary material is available at http://www.cbs.dtu.dk/suppl/immunology/CTL.php.

ATP-Binding Cassette Transporters↗
PubMed1990

Evolution of the Pittsburgh studies of the epidemiology of insulin-dependent diabetes mellitus. Pittsburgh Diabetes Epidemiology and Etiology Research Group.

The Pittsburgh project evaluating the epidemiology and etiology of insulin-dependent diabetes mellitus (IDDM) is currently one of the large ongoing studies of childhood diabetes. This paper traces the evolution of the project, from the initial basic epidemiologic approach in the early 1980s, to the current thrust where complex molecular genetic approaches are being incorporated into population-based research. The epidemiology models employed in the Pittsburgh project are similar to those that could be used in many areas of chronic disease research. The integration of immunogenetics into epidemiology produces a powerful approach for understanding the complex interaction of host susceptibility and environmental agents that contribute to the development of IDDM.

Adolescent↗
PubMed1991

Clustering of hepatocellular carcinoma in Alaska Native families.

Alaska Natives have a high incidence of hepatocellular carcinoma (HCC), with regional, ethnic, village, and familial clustering. During 1969-1988, 15 of the 45 incident cases of HCC in Alaska Natives occurred in 5 families. This report presents epidemiologic, virologic, and immunogenetic data on these 5 families. The results of hepatitis B virus (HBV) serologic testing indicates that HBV infection was an important factor in 4 of the 5 families. Human lymphocyte antigen (HLA) testing was performed in 3 families. The HLA results are reviewed in relationship to the familial clustering of HCC.

Adolescent↗
PubMed1995

Association of primary biliary cirrhosis with the allele HLA-DPB1*0301 in a German population.

The major histocompatibility complex class II alleles at the HLA-DPB1 locus were investigated in 32 German Caucasoid patients with primary biliary cirrhosis (PBC) and compared with those from 47 normal control patients using molecular genotyping techniques. The second exon of the HLA-DPB1 gene was amplified by polymerase chain reaction (PCR) and hybridized with 25 sequence-specific oligonucleotides (SSOs) to assign the HLA-DPB1 alleles on the basis of known sequence variations, according to the protocols of the Eleventh International Histocompatibility Workshop. A strong association of PBC was found with the allele HLA-DPB1*0301. The allele HLA DPB1*0301 was present in 50% (16 of 32) of the patients with PBC compared with 13% (6 of 47) of normal controls (P corrected < .015), whereas the other HLA-DPB1 alleles showed no significant differences in both groups. The relative risk (RR) estimate for the allele HLA-DPB1*0301 was 6.8 (95% confidence limits: 2.27 to 20.57). In summary, this study clearly demonstrates an association of PBC with the HLA-DPB1*0301 allele in German Caucasoids and may add new data to the immunogenetic background of PBC, suggesting a contribution of the HLA-DPB1 gene to the genetic susceptibility of the disease.

Adult↗