The Experts below are selected from a list of 14170890 Experts worldwide ranked by ideXlab platform
William H. Hildebrand - One of the best experts on this subject based on the ideXlab platform.
-
nucleotide sequence analysis of hla b 1523 and b 8101 dominant α helical motifs produce complex serologic recognition patterns for the hla b dt and hla b nm5 antigens
Human Immunology, 1995Co-Authors: Mary Ellexson, G A Teresi, Guozhong Zhang, Dod Stewart, Paul I Terasaki, William H. HildebrandAbstract:Abstract Assigning a precise serologic specificity to the class I HLA-B“NM5” and HLA-B“DT” molecules has proven difficult, with patterns of serologic crossreactivity suggesting that NM5 is most like antigens in the B5 CREG and that DT is either B7 or B40 like. To better understand the relationship these antigens share with other HLA-B molecules we determined the nucleotide sequence of the alleles encoding HLA-B“NM5” and HLA-B“DT”. Sequencing results show that NM5 shares the most overall sequence homology with the B70 antigens and that differences at the α-helical Bw4/Bw6 epitope preclude serologic cross-reactivity between NM5 and the B70 antigens. Accordingly, NM5 has been assigned the name B∗1523. The strong serologic impact of helical sequence conservations and variations is reiterated for the class I HLA-B“DT” molecule. Comparative analysis demonstrates that sequence conservations in the first domain's α-helix stimulate cross-reactivity between HLA-B“DT” and HLA-B7, whereas epitopes conserved in the second domain's α-helix impel cross-reactivity between HLA-B“DT” and HLA-B48. To convey the unique lineage of this hybrid B7/B48 molecule the name HLAB∗8101 has been assigned to HLA-B“DT”.
-
Nucleotide sequence analysis of HLA-B∗1523 and B∗8101 dominant α-helical motifs produce complex serologic recognition patterns for the HLA-B “DT” and HLA-B “NM5” antigens
Human immunology, 1995Co-Authors: Mary Ellexson, G A Teresi, Guozhong Zhang, Dod Stewart, Paul I Terasaki, M. Lau, Bruce A. Roe, William H. HildebrandAbstract:Assigning a precise serologic specificity to the class I HLA-B"NM5" and HLA-B"DT" molecules has proven difficult, with patterns of serologic cross-reactivity suggesting that NM5 is most like antigens in the B5 CREG and that DT is either B7 or B40 like. To better understand the relationship these antigens share with other HLA-B molecules we determined the nucleotide sequence of the alleles encoding HLA-B"NM5" and HLA-B"DT". Sequencing results show that NM5 shares the most overall sequence homology with the B70 antigens and that differences at the alpha-helical Bw4/Bw6 epitope preclude serologic cross-reactivity between NM5 and the B70 antigens. Accordingly, NM5 has been assigned the name B*1523. The strong serologic impact of helical sequence conservations and variations is reiterated for the class I HLA-B"DT" molecule. Comparative analysis demonstrates that sequence conservations in the first domain's alpha-helix stimulate cross-reactivity between HLA-B"DT" and HLA-B7, whereas epitopes conserved in the second domain's alpha-helix impel cross-reactivity between HLA-B"DT" and HLA-B48. To convey the unique lineage of this hybrid B7/B48 molecule the name HLA-B*8101 has been assigned to HLA-B"DT".
-
hla bw22 a family of molecules with identity to hla b7 in the alpha 1 helix
Journal of Immunology, 1992Co-Authors: William H. Hildebrand, J A Madrigal, A M Little, Peter ParhamAbstract:Various HLA-B molecules exhibit serologic cross-reactions with HLA-B7, including HLA-B27, B40, Bw42, and Bw22. Of this group, primary structures for the three serologic subdivisions of HLA-Bw22, HLA-Bw54, Bw55, and Bw56, have yet to be determined. Here, we describe the nucleotide sequences of five distinctive HLA-Bw22 alleles isolated from cells of different ethnic origins typed either for Bw54, Bw55, or Bw56. Heterogeneity in molecules typed as Bw55 and Bw56 was defined. The five HLA-Bw22 alleles form a closely related family that appears to have evolved by a series of simple gene conversion events, all of which alter the antigen recognition site of the encoded proteins. Of note, HLA-Bw54 is the product of a gene conversion between HLA-B and C alleles. All the Bw22 alleles encode an alpha 1-helix identical in amino acid sequence to that of HLA-B7 and Bw42, a feature almost certainly responsible for the serologic cross-reactivity of these molecules. Shared substitutions in the alpha 1-helix can also explain the cross-reactivity of Bw22 and B7 with B27. Patterns of amino acid substitution in the alpha 2-domain of Bw22 heavy chains correlate with certain antibody and T cell cross-reactivities, thereby implicating particular amino acids in their target epitopes.
Andres Jaramillo - One of the best experts on this subject based on the ideXlab platform.
-
Association of the HLA-DR15/HLA-DQ6 haplotype with development of choroidal neovascular lesions in presumed ocular histoplasmosis syndrome.
Human Immunology, 2003Co-Authors: Humeyra Dabil, Donna Phelan, Brian Duffy, Thalachallour Mohanakumar, Henry J Kaplan, Andres JaramilloAbstract:Abstract Associations of human leukocyte antigen DR2 (HLA-DR2) and HLA-B7 with presumed ocular histoplasmosis syndrome (POHS) in the United States has been previously described. However, these associations were determined by means of low-resolution, complement-dependent cytotoxicity assays for HLA-A, HLA-B, and HLA-DR molecules. To determine whether POHS is associated with other HLA alleles within the HLA-A, HLA-B, HLA-DR, and HLA-DQ loci, we performed a case control study of 34 patients diagnosed with macular choroidal neovascular membrane secondary to POHS and 45 healthy control individuals. Peripheral blood-derived DNA from the study patients was typed for HLA genes by means of sequence-specific primers that gave low-medium allele resolution. Significant associations were observed between HLA-B7 (X2 = 14.30, pc = 0.004, relative risk = 8.23), HLA-DR15 (X2 = 29.08, pc = 0.000001, relative risk = 27.50), and HLA-DQ6 (X2 = 23.09, pc = 0.00001, relative risk = 27.43) and POHS. Because there are strong linkage disequilibria between HLA-DR15 (a subtype of HLA-DR2) and HLA-B7 as well as HLA-DQ6, the significantly higher association of HLA-DR15 and HLA-DQ6 with POHS as compared to HLA-B7 suggests that the former alleles mediate susceptibility to the disease. In conclusion, there is a significant association between the HLA-DR15/HLA-DQ6 haplotype and development of choroidal neovascular lesions in POHS.
-
association of the hla dr15 hla dq6 haplotype with development of choroidal neovascular lesions in presumed ocular histoplasmosis syndrome
Human Immunology, 2003Co-Authors: Humeyra Dabil, Donna Phelan, Brian Duffy, Thalachallour Mohanakumar, Henry J Kaplan, Andres JaramilloAbstract:Associations of human leukocyte antigen DR2 (HLA-DR2) and HLA-B7 with presumed ocular histoplasmosis syndrome (POHS) in the United States has been previously described. However, these associations were determined by means of low-resolution, complement-dependent cytotoxicity assays for HLA-A, HLA-B, and HLA-DR molecules. To determine whether POHS is associated with other HLA alleles within the HLA-A, HLA-B, HLA-DR, and HLA-DQ loci, we performed a case control study of 34 patients diagnosed with macular choroidal neovascular membrane secondary to POHS and 45 healthy control individuals. Peripheral blood-derived DNA from the study patients was typed for HLA genes by means of sequence-specific primers that gave low-medium allele resolution. Significant associations were observed between HLA-B7 (X2 = 14.30, pc = 0.004, relative risk = 8.23), HLA-DR15 (X2 = 29.08, pc = 0.000001, relative risk = 27.50), and HLA-DQ6 (X2 = 23.09, pc = 0.00001, relative risk = 27.43) and POHS. Because there are strong linkage disequilibria between HLA-DR15 (a subtype of HLA-DR2) and HLA-B7 as well as HLA-DQ6, the significantly higher association of HLA-DR15 and HLA-DQ6 with POHS as compared to HLA-B7 suggests that the former alleles mediate susceptibility to the disease. In conclusion, there is a significant association between the HLA-DR15/HLA-DQ6 haplotype and development of choroidal neovascular lesions in POHS.
Maxime Breban - One of the best experts on this subject based on the ideXlab platform.
-
HLA–B27 Subtypes Predisposing to Ankylosing Spondylitis Accumulate in an Endoplasmic Reticulum–Derived Compartment Apart From the Peptide-Loading Complex
Arthritis and Rheumatology, 2020Co-Authors: Nadège Jah, Maxime Breban, Aude Jobart-malfait, Kétia Ermoza, Aurélie Noteuil, G. Chiocchia, Claudine AndréAbstract:Objective: It was previously shown that HLA–B27 subtypes predisposing to spondyloarthritis (SpA), i.e., B*27:02, B*27:05, and B*27:07, displayed an increased propensity to form intracellular oligomers and to accumulate at a high density in cytoplasmic vesicles, as compared to the non–SpA-associated HLA–B*07:02 and HLA–B*27:06. This study was undertaken to characterize the nature and content of HLA–B–containing vesicles and to further examine their relevance to SpA predisposition. Methods: Vesicles containing HLA–B proteins were detected in transfected HeLa cells and in cells from SpA patients or HLA–B27/human β2-microglobulin (hβ2m)–transgenic rats, by microscopy. The nature and content of HLA–B–containing vesicles were characterized in colocalization experiments with appropriate markers. Results: The SpA-associated HLA–B*27:04 subtype accumulated at higher levels (P < 10−5) in cytoplasmic vesicles compared to HLA–B*27:06, from which it differs only by 2 substitutions, reinforcing the correlation between vesicle formation and SpA predisposition. Colocalization studies showed that those vesicles contained misfolded HLA–B heavy chain along with β2m and endoplasmic reticulum (ER) chaperones (calnexin, calreticulin, BiP, glucose-regulated protein 94-kd) and belonged to the ER but were distinct from the peptide-loading complex (PLC). Similar vesicles were observed in immune cells from HLA–B27+ SpA patients, in greater abundance than in healthy controls (P < 0.01), and in dendritic cells from HLA–B27/hβ2m transgenic rats, correlating with SpA susceptibility. Conclusion: Accumulation of misfolded HLA–B heavy chain along with β2m and ER chaperones into ER-derived vesicles distinct from the PLC is a characteristic feature of HLA–B27 subtypes predisposing to SpA. This phenomenon could contribute to HLA–B27 pathogenicity, via a noncanonical mechanism.
-
expression of hla b27 causes loss of migratory dendritic cells in a rat model of spondylarthritis
Arthritis & Rheumatism, 2012Co-Authors: Lotta Utriainen, Maxime Breban, D Firmin, Iain B. Mcinnes, Vuk Cerovic, P Wright, Simon MillingAbstract:Objective In rats transgenic for human HLA–B27 and β2-microglobulin (B27-transgenic rats), colitis and peripheral inflammation develop spontaneously. Therefore, B27-transgenic rats provide a model of spondylarthritis. Because inflammation in these rats requires CD4+ T lymphocytes and involves intestinal pathology, we hypothesized that dendritic cells (DCs) that migrate from the intestine and control CD4+ T cell differentiation would be aberrant in B27-transgenic rats. Methods Migrating intestinal lymph DCs were collected via thoracic duct cannulation from B27-transgenic and control (HLA–B7–transgenic or nontransgenic) rats. The phenotypes of these DCs and of mesenteric lymph node DCs were assessed by flow cytometry. The ability of DCs to differentiate from bone marrow precursors in vitro was also assessed. Results Lymph DCs showed increased activation and, strikingly, lacked the specific DC population that is important for maintaining tolerance to self-antigens. This population of DCs was also depleted from the mesenteric lymph nodes of B27-transgenic rats. Furthermore, in vitro culture of DCs from bone marrow precursors revealed a defect in the ability of B27-transgenic rats to produce DCs of the migratory phenotype, although the DCs that were generated induced enhanced interleukin-17 (IL-17) production from naive CD4+ T cells. Conclusion We describe 2 different mechanisms by which HLA–B27 may contribute to inflammatory disease: increased apoptotic death of B27-transgenic DCs that normally function to maintain immunologic tolerance and enhanced IL-17 production from CD4+ T cells stimulated by the surviving B27-transgenic DCs.
-
Expression of HLA–B27 causes loss of migratory dendritic cells in a rat model of spondylarthritis
Arthritis and rheumatism, 2012Co-Authors: Lotta Utriainen, Maxime Breban, P. B. Wright, D Firmin, Iain B. Mcinnes, Vuk Cerovic, Simon MillingAbstract:Objective In rats transgenic for human HLA–B27 and β2-microglobulin (B27-transgenic rats), colitis and peripheral inflammation develop spontaneously. Therefore, B27-transgenic rats provide a model of spondylarthritis. Because inflammation in these rats requires CD4+ T lymphocytes and involves intestinal pathology, we hypothesized that dendritic cells (DCs) that migrate from the intestine and control CD4+ T cell differentiation would be aberrant in B27-transgenic rats. Methods Migrating intestinal lymph DCs were collected via thoracic duct cannulation from B27-transgenic and control (HLA–B7–transgenic or nontransgenic) rats. The phenotypes of these DCs and of mesenteric lymph node DCs were assessed by flow cytometry. The ability of DCs to differentiate from bone marrow precursors in vitro was also assessed. Results Lymph DCs showed increased activation and, strikingly, lacked the specific DC population that is important for maintaining tolerance to self-antigens. This population of DCs was also depleted from the mesenteric lymph nodes of B27-transgenic rats. Furthermore, in vitro culture of DCs from bone marrow precursors revealed a defect in the ability of B27-transgenic rats to produce DCs of the migratory phenotype, although the DCs that were generated induced enhanced interleukin-17 (IL-17) production from naive CD4+ T cells. Conclusion We describe 2 different mechanisms by which HLA–B27 may contribute to inflammatory disease: increased apoptotic death of B27-transgenic DCs that normally function to maintain immunologic tolerance and enhanced IL-17 production from CD4+ T cells stimulated by the surviving B27-transgenic DCs.
-
defective costimulatory function is a striking feature of antigen presenting cells in an hla b27 transgenic rat model of spondylarthropathy
Arthritis & Rheumatism, 2004Co-Authors: Cecile Hacquardbouder, Géraldine Falgarone, A Bosquet, D Monnet, Faïza Smaoui, M. Ittah, Maxime BrebanAbstract:Objective A disease resembling the human spondylarthropathies develops in HLA–B27–transgenic rats. This disease in rats is mediated by CD4+ T cells, but antigen-presenting cells (APCs) may also play a role. Dendritic cells (DCs) have been reported to be defective in allogeneic mixed lymphocyte culture in this model. Here, we further investigated the functional defect of APCs. Methods DCs and B cells from nontransgenic, HLA–B27 (33–3)–transgenic, and HLA–B7 (120–4)–transgenic rats were used to stimulate T cells. Surface expression of HLA–B transgene and rat molecules on APCs and the formation of conjugates between DCs and T cells were monitored by flow cytometry. Results We observed a strikingly defective stimulation of allogeneic and syngeneic T lymphocytes by APCs from HLA–B27 but not HLA–B7 rats, even if stimulation was driven in the presence of anti–T cell receptor (TCR) antibody. We found no evidence that HLA–B27 DCs were immature, lacked production of some diffusible factor, or produced an inhibitory factor for T cells. When comparing the levels of expression of class II major histocompatibility complex, CD2, intercellular adhesion molecule 1, lymphocyte function–associated antigen 1, B7, and CD40 molecules at the surface of DCs from 33-3, 120-4, and nontransgenic rats, we found little difference. However, HLA–B27–transgenic DCs formed fewer conjugates with T cells than did nontransgenic DCs. Furthermore, the proportion of conjugates formed between DCs and T cells, as well as the difference between nontransgenic and HLA–B27–transgenic DCs, were in large part reduced by blocking CD86 on DCs. Conclusion We confirmed defective stimulation of T cells by APCs in HLA–B27 rats, the mechanism of which appears to implicate APC/T cell contact, independent of TCR engagement. In addition, decreased use of the CD86 costimulatory molecule by B27 DCs was observed. Impaired costimulatory function could result in a loss of tolerance toward microbial flora in this model.
-
Defective costimulatory function is a striking feature of antigen‐presenting cells in an HLA–B27–transgenic rat model of spondylarthropathy
Arthritis & Rheumatism, 2004Co-Authors: Cécile Hacquard-bouder, Géraldine Falgarone, A Bosquet, D Monnet, Faïza Smaoui, M. Ittah, Maxime BrebanAbstract:Objective A disease resembling the human spondylarthropathies develops in HLA–B27–transgenic rats. This disease in rats is mediated by CD4+ T cells, but antigen-presenting cells (APCs) may also play a role. Dendritic cells (DCs) have been reported to be defective in allogeneic mixed lymphocyte culture in this model. Here, we further investigated the functional defect of APCs. Methods DCs and B cells from nontransgenic, HLA–B27 (33–3)–transgenic, and HLA–B7 (120–4)–transgenic rats were used to stimulate T cells. Surface expression of HLA–B transgene and rat molecules on APCs and the formation of conjugates between DCs and T cells were monitored by flow cytometry. Results We observed a strikingly defective stimulation of allogeneic and syngeneic T lymphocytes by APCs from HLA–B27 but not HLA–B7 rats, even if stimulation was driven in the presence of anti–T cell receptor (TCR) antibody. We found no evidence that HLA–B27 DCs were immature, lacked production of some diffusible factor, or produced an inhibitory factor for T cells. When comparing the levels of expression of class II major histocompatibility complex, CD2, intercellular adhesion molecule 1, lymphocyte function–associated antigen 1, B7, and CD40 molecules at the surface of DCs from 33-3, 120-4, and nontransgenic rats, we found little difference. However, HLA–B27–transgenic DCs formed fewer conjugates with T cells than did nontransgenic DCs. Furthermore, the proportion of conjugates formed between DCs and T cells, as well as the difference between nontransgenic and HLA–B27–transgenic DCs, were in large part reduced by blocking CD86 on DCs. Conclusion We confirmed defective stimulation of T cells by APCs in HLA–B27 rats, the mechanism of which appears to implicate APC/T cell contact, independent of TCR engagement. In addition, decreased use of the CD86 costimulatory molecule by B27 DCs was observed. Impaired costimulatory function could result in a loss of tolerance toward microbial flora in this model.
T Mohanakumar - One of the best experts on this subject based on the ideXlab platform.
-
identification of immunodominant hla b7 restricted cd8 cytotoxic t cell epitopes derived from mammaglobin a expressed on human breast cancers
Breast Cancer Research and Treatment, 2011Co-Authors: Haseeb Ilias Basha, Venkataswarup Tiriveedhi, Timothy P Fleming, William E Gillanders, T MohanakumarAbstract:Mammaglobin-A (MGBA), a 10-kD protein, is over expressed in 80% of primary and metastatic human breast cancers. Breast cancer patients demonstrate high frequencies of CD8+ cytotoxic T lymphocytes (CTL) specific to MGBA. Defining CD8+ CTL responses to HLA class I-restricted MGBA-derived epitopes assumes significance in the context of our ongoing efforts to clinically translate vaccine strategies targeting MGBA for prevention and/or treatment of human breast cancers. In this study, we define the CD8+ CTL response to MGBA-derived candidate epitopes presented in the context of HLA-B7, which has a frequency of 17.7% in Caucasian and 15.5% in African American populations. We identified seven MGBA-derived candidate epitopes with high predicted binding scores for HLA-B7 using a computer algorithm. Membrane stabilization studies with TAP-deficient T2 cells transfected with HLA-B7 indicated that MGBA B7.3 (VSKTEYKEL), B7.6 (KLLMVLMLA), B7.7 (NPQVSKTEY), and B7.1 (YAGSGCPLL) have the highest HLA-B7 binding affinities. Further, two CD8+ CTL cell lines generated in vitro against T2.B7 cells individually loaded with MGBA-derived candidate epitopes showed significant cytotoxic activity against MGBA B7.1, B7.3, B7.6, and B7.7. In addition, the same CD8+ CTL lines lysed the HLA-B7+/MGBA+ human breast cancer cell line DU-4475 but had no significant cytotoxicity against HLA-B7− or MGBA− breast cancer cell lines. Cold-target inhibition studies strongly suggest that MGBA B7.3 is an immunodominant epitope. In summary, our results define HLA-B7-restriced, MGBA-derived, CD8+ CTL epitopes with all of the necessary features for developing novel vaccine strategies against HLA-B7 expressing breast cancer patients.
-
Identification of immunodominant HLA-B7-restricted CD8 + cytotoxic T cell epitopes derived from mammaglobin-A expressed on human breast cancers
Breast cancer research and treatment, 2010Co-Authors: Haseeb Ilias Basha, Venkataswarup Tiriveedhi, Timothy P Fleming, William E Gillanders, T MohanakumarAbstract:Mammaglobin-A (MGBA), a 10-kD protein, is over expressed in 80% of primary and metastatic human breast cancers. Breast cancer patients demonstrate high frequencies of CD8+ cytotoxic T lymphocytes (CTL) specific to MGBA. Defining CD8+ CTL responses to HLA class I-restricted MGBA-derived epitopes assumes significance in the context of our ongoing efforts to clinically translate vaccine strategies targeting MGBA for prevention and/or treatment of human breast cancers. In this study, we define the CD8+ CTL response to MGBA-derived candidate epitopes presented in the context of HLA-B7, which has a frequency of 17.7% in Caucasian and 15.5% in African American populations. We identified seven MGBA-derived candidate epitopes with high predicted binding scores for HLA-B7 using a computer algorithm. Membrane stabilization studies with TAP-deficient T2 cells transfected with HLA-B7 indicated that MGBA B7.3 (VSKTEYKEL), B7.6 (KLLMVLMLA), B7.7 (NPQVSKTEY), and B7.1 (YAGSGCPLL) have the highest HLA-B7 binding affinities. Further, two CD8+ CTL cell lines generated in vitro against T2.B7 cells individually loaded with MGBA-derived candidate epitopes showed significant cytotoxic activity against MGBA B7.1, B7.3, B7.6, and B7.7. In addition, the same CD8+ CTL lines lysed the HLA-B7+/MGBA+ human breast cancer cell line DU-4475 but had no significant cytotoxicity against HLA-B7− or MGBA− breast cancer cell lines. Cold-target inhibition studies strongly suggest that MGBA B7.3 is an immunodominant epitope. In summary, our results define HLA-B7-restriced, MGBA-derived, CD8+ CTL epitopes with all of the necessary features for developing novel vaccine strategies against HLA-B7 expressing breast cancer patients.
Robert A. Colbert - One of the best experts on this subject based on the ideXlab platform.
-
The role of HLA-B*27 in spondyloarthritis
Best practice & research. Clinical rheumatology, 2017Co-Authors: Robert A. Colbert, Fatemeh Navid, Tejpal GillAbstract:Abstract The mechanism by which HLA-B*27 predisposes to spondyloarthritis remains unresolved. Arthritogenic peptides have not been defined in humans and are not involved in experimental models of spondyloarthritis. Aberrant properties of HLA-B*27 can activate the IL-23/IL-17 axis in HLA-B*27 transgenic rats and humans. In HLA-B*27-independent rodent models, spondyloarthritis can be driven by IL-23 triggering entheseal-resident CD4-/CD8- T cells or CD4+ Th17 T cells. These findings point toward noncanonical mechanisms linking HLA-B*27 to the disease and provide a potential explanation for HLA-B*27-negative spondyloarthritis. Gut microbial dysbiosis may be important in the development of spondyloarthritis. HLA-B*27-induced changes in gut microbiota are complex and suggest an ecological model of dysbiosis in rodents. The importance of the IL-23/IL-17 axis in ankylosing spondylitis has been demonstrated by studies showing efficacy of IL-17. Although deciphering the precise role(s) of HLA-B*27 in disease requires further investigation, considerable progress has been made in understanding this complex relationship.
-
hla b27 alters the response to tumor necrosis factor α and promotes osteoclastogenesis in bone marrow monocytes from hla b27 transgenic rats
Arthritis & Rheumatism, 2013Co-Authors: Gerlinde Layhschmitt, Eva Y Yang, Grace Kwon, Robert A. ColbertAbstract:Objective To determine whether HLA–B27 expression alters the response of bone marrow monocytes from HLA–B27/human β2-microglobulin–transgenic (B27-Tg) rats to tumor necrosis factor α (TNFα) and, if so, whether this affects the cells involved in bone homeostasis. Methods Bone marrow monocytes were treated with RANKL or with TNFα to promote osteoclast formation. Osteoclasts were quantified by counting. Gene expression was measured using quantitative polymerase chain reaction analysis, and protein was detected by enzyme-linked immunosorbent assay, immunoblotting, or immunofluorescence. Effects of endogenously produced cytokines on osteoclast formation were determined with neutralizing antibodies. Results TNFα treatment enhanced osteoclast formation 2.5-fold in HLA–B27–expressing cells as compared to wild-type or to HLA–B7/human β2-microglobulin–expressing monocytes. TNFα induced ∼4-fold up-regulation of HLA–B27, which was associated with the accumulation of misfolded heavy chains, binding of the endoplasmic reticulum (ER) chaperone BiP, and activation of an ER stress response, which was not seen with HLA–B7. No differences were seen with RANKL-induced osteoclastogenesis. Enhanced interleukin-1α (IL-1α) production from ER-stressed bone marrow monocytes from B27-Tg rats was found to be necessary and sufficient for enhanced osteoclast formation. However, bone marrow monocytes from B27-Tg rats also produced more interferon-β (IFNβ), which attenuated the effect of IL-1α on osteoclast formation. Conclusion HLA–B27–induced ER stress alters the response of bone marrow monocytes from B27-Tg rats to TNFα, which is associated with enhanced production of IL-1α and IFNβ, cytokines that exhibit opposing effects on osteoclast formation. The altered response of cells expressing HLA–B27 to proinflammatory cytokines suggests that this class I major histocompatibility complex allele may contribute to the pathogenesis of spondyloarthritis and its unique phenotype through downstream effects involving alterations in bone homeostasis.
-
hla b27 misfolding in transgenic rats is associated with activation of the unfolded protein response
Journal of Immunology, 2005Co-Authors: Matthew Turner, Joel D. Taurog, Robert A. Colbert, Dawn P Sowders, Monica L Delay, Rajashree Mohapatra, Shuzhen Bai, Judith A Smith, Jaclyn R BrandewieAbstract:The mechanism by which the MHC class I allele, HLA-B27, contributes to spondyloarthritis pathogenesis is unknown. In contrast to other alleles that have been examined, HLA-B27 has a tendency to form high m.w. disulfide-linked H chain complexes in the endoplasmic reticulum (ER), bind the ER chaperone BiP/Grp78, and undergo ER-associated degradation. These aberrant characteristics have provided biochemical evidence that HLA-B27 is prone to misfold. Recently, similar biochemical characteristics of HLA-B27 were reported in cells from HLA-B27/human β 2 -microglobulin transgenic (HLA-B27 transgenic) rats, an animal model of spondyloarthritis, and correlated with disease susceptibility. In this study, we demonstrate that the unfolded protein response (UPR) is activated in macrophages derived from the bone marrow of HLA-B27 transgenic rats with inflammatory disease. Microarray analysis of these cells also reveals an IFN response signature. In contrast, macrophages derived from premorbid rats do not exhibit a strong UPR or evidence of IFN exposure. Activation of macrophages from premorbid HLA-B27 transgenic rats with IFN-γ increases HLA-B27 expression and leads to UPR induction, while no UPR is seen in cells from nondisease-prone HLA-B7 transgenic or wild-type (nontransgenic) animals. This is the first demonstration, to our knowledge, that HLA-B27 misfolding is associated with ER stress that results in activation of the UPR. These observations link HLA-B27 expression with biological effects that are independent of immunological recognition, but nevertheless may play an important role in the pathogenesis of inflammatory diseases associated with this MHC class I allele.