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Chella S David - One of the best experts on this subject based on the ideXlab platform.
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HLA Class II (DR0401) Molecules Induce Foxp3+ Regulatory T Cell Suppression of B Cells in Plasmodium yoelii Strain 17XNL Malaria
Infection and Immunity, 2013Co-Authors: Wathsala Wijayalath, Chella S David, Rebecca Danner, Yuliya Kleschenko, Sai Majji, Eileen Villasante, Thomas L. Richie, Teodor D. Brumeanu, Sofia CasaresAbstract:Unlike human malaria parasites that induce persistent infection, some rodent malaria parasites, like Plasmodium yoelii strain 17XNL (Py17XNL), induce a transient (self-curing) malaria infection. Cooperation between CD4 T cells and B cells to produce antibodies is thought to be critical for clearance of Py17XNL parasites from the blood, with major histocompatibility complex (MHC) class II molecules being required for activation of CD4 T cells. In order to better understand the correspondence between murine malaria models and human malaria, and in particular the role of MHC (HLA) class II molecules, we studied the ability of humanized mice expressing human HLA class II molecules to clear Py17XNL infection. We showed that humanized mice expressing HLA-DR4 (DR0401) molecules and lacking mouse MHC class II molecules (EA0) have impaired production of specific antibodies to Py17XNL and cannot cure the infection. In contrast, mice expressing HLA-DR4 (DR0402), HLA-DQ6 (DQ0601), HLA-DQ8 (DQ0302), or HLA-DR3 (DR0301) molecules in an EA0 background were able to elicit specific antibodies and self-cure the infection. In a series of experiments, we determined that the inability of humanized DR0401.EA0 mice to elicit specific antibodies was due to expansion and activation of regulatory CD4+ Foxp3+ T cells (Tregs) that suppressed B cells to secrete antibodies through cell-cell interactions. Treg depletion allowed the DR0401.EA0 mice to elicit specific antibodies and self-cure the infection. Our results demonstrated a differential role of MHC (HLA) class II molecules in supporting antibody responses to Py17XNL malaria and revealed a new mechanism by which malaria parasites stimulate B cell-suppressogenic Tregs that prevent clearance of infection.
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spontaneous lupus like syndrome in hla dq2 transgenic mice with a mixed genetic background
Lupus, 2010Co-Authors: Shadi Rashtak, Shen Cheng, Chella S David, Eric V Marietta, Joseph P Grande, Michael Camilleri, Mark R Pittelkow, Joseph A MurrayAbstract:: To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE(0)DQ2). These AE(0)DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE(0)DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE(0)DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE(0)DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE(0)DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a 'fingerprint' substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE(0)DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE(0)DQ2 mice compared with AE(0)DQ6 mice (p < 0.001). In conclusion, AE(0)DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815-829.
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HLA-DQ6 (DQB1*0601)-Restricted T Cells Protect against Experimental Autoimmune Encephalomyelitis in HLA-DR3.DQ6 Double-Transgenic Mice by Generating Anti-Inflammatory IFN-γ
Journal of Immunology, 2008Co-Authors: Ashutosh K. Mangalam, Moses Rodriguez, David Luckey, Eati Basal, Marshall D. Behrens, Chella S DavidAbstract:The human MHC class II genes are associated with genetic susceptibility to multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS of presumed autoimmune origin. These genes encode for proteins responsible for shaping immune response. The exact role of HLA-DQ and -DR genes in disease pathogenesis is not well-understood due to the high polymorphism, linkage disequilibrium, and heterogeneity of human populations. The advent of HLA class II-transgenic (Tg) mice has helped in answering some of these questions. Previously, using single-Tg mice (expressing the HLA-DR or -DQ gene), we showed that proteolipid protein (PLP)91–110 peptide induced classical experimental autoimmune encephalomyelitis only in DR3.Aβ° mice, suggesting that DR3 (DRB1*0301) is a disease susceptible gene in the context of PLP. Human population studies have suggested that HLA-DQ6 (DQB1*0601) may be a protective gene in MS. To test this disease protection in an experimental model, we generated double-Tg mice expressing both HLA-DR3 and -DQ6. Introduction of DQ6 onto DR3-Tg mice led to a decrease in disease incidence on immunization with PLP91–110 peptide indicating a dominant protective role of DQ6. This protective effect is due to high levels of IFN-γ produced by DQ6-restricted T cells, which suppressed proliferation of encephalitogenic DR3-restricted T cells by inducing apoptosis. Our study indicates that DQ6 modifies the PLP91–110-specific T cell response in DR3 through anti-inflammatory effects of IFN-γ, which is protective for experimental autoimmune encephalomyelitis. Thus, our double-Tg mouse provides a novel model in which to study epistatic interactions between HLA class II molecules in MS.
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Evaluating the role of HLA-DQ polymorphisms on immune response to bacterial superantigens using transgenic mice.
Tissue Antigens, 2007Co-Authors: Govindarajan Rajagopalan, Ginger Polich, Manisha Singh, B. E. Epstein, Anna K. Lytle, M. S. Rouse, Robin Patel, Chella S DavidAbstract:Bacterial superantigens bind directly to human leukocyte antigen (HLA) class II molecules and vigorously activate T cells expressing certain T-cell receptor variable region families. As interaction with HLA class II molecules is the primary step in this process, polymorphic variations in HLA class II can determine the extent of superantigen binding to HLA class II molecules, govern the magnitude of immune activation induced by given superantigens and determine the outcome of superantigen-mediated diseases. As direct assessment of the influence of HLA class II polymorphism in humans is impossible because of expression of more than one HLA class II alleles in a given individual and toxicity of superantigens, transgenic mice expressing HLA-DQ6 (HLA-DQA1*0103 and HLA-DQB1*0601) and HLA-DQ8 (HLA-DQA1*0301 and HLA-DQB1*0302) were used to achieve this goal. HLA-DQ6 and HLA-DQ8 elicited comparable in vitro and in vivo immune response to staphylococcal enterotoxins (SE) A, SEB, SEH and SEK, toxic shock syndrome toxin-1, streptococcal pyrogenic exotoxin (SPE) A and SPEC and streptococcal mitogenic exotoxin Z (SMEZ). However, each superantigen had a unique T-cell receptor activation profile. In vivo challenge with Streptococcus pyogenes, H305, capable of elaborating SPEA and SMEZ, yielded a similar clinical outcome in HLA-DQ6 and HLA-DQ8 transgenic mice. In conclusion, HLA-DQ6 and HLA-DQ8 elicited comparable response to certain bacterial superantigens. Our report highlights the advantages of HLA class II transgenic mice in such studies.
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HLA Transgenic Mice Provide Evidence for a Direct and Dominant Role of HLA Class II Variation in Modulating the Severity of Streptococcal Sepsis
Journal of Immunology, 2007Co-Authors: Mohammed M. Nooh, Chella S David, Nagala El-gengehi, Rita Kansal, Malak KotbAbstract:Our epidemiologic studies on invasive Group A Streptococci (GAS) infections identified specific HLA class II haplotypes/alleles conferring high-risk or protection from streptococcal toxic shock syndrome with a strong protection conferred by the DRB1*15/DQB1*06 haplotype. We used HLA-transgenic mice to provide an in vitro and in vivo validation for the direct role of HLA class II allelic variation in streptococcal toxic shock syndrome. When splenocytes from mice expressing the protective HLA-DQB1*06 (DQ6) allele were stimulated with a mixture of streptococcal superantigens (SAgs), secreted by the prevalent M1T1 strain, both proliferative and cytokine responses were significantly lower than those of splenocytes from mice expressing the neutral DRB1*0402/DQB1*0302 (DR4/DQ8) alleles (p < 0.001). In crisscross experiments, the presentation of SAgs to pure T cells from either the DQ6 or the DR4/DQ8 mice resulted in significantly different levels of response depending on the HLA type expressed on the APCs. Presentation by HLA-DQ6 APCs elicited significantly lower responses than the presentation by HLA-DR4/DQ8 APCs. Our in vitro data were supported by in vivo findings, as the DQ6 mice showed significantly longer survival post-i.v. infection with live M1T1 GAS (p < 0.001) and lower inflammatory cytokine responses as compared with the DR4/DQ8 mice (p < 0.01). The data presented here provide evidence for a direct role of HLA class II molecules in modulating responses to GAS SAgs and underscore the dominant role of HLA class II allelic variation in potentiating the severity of GAS systemic infections.
Takehiko Sasazuki - One of the best experts on this subject based on the ideXlab platform.
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Prevention of infection of influenza virus in DQ6 mice, a human model, by a peptide vaccine prepared according to the cassette theory.
Vaccine, 1999Co-Authors: N. Matsuki, Yoshinori Fukui, Takehiko Sasazuki, Kazumasa Ogasawara, Kimitaka Takami, Kenichi Namba, Akio Takahashi, Kazuya Iwabuchi, Robert A. Good, Kazunori OnoéAbstract:Abstract We proposed a strategy (cassette theory) in which non-binding peptides for murine major histocompatibility complex (MHC) class II molecules are introduced into a MHC-binding component to render the resultant hybrid peptides bound to the MHC and thus immunogenic in animals carrying the relevant MHC. It was shown that 46F/HA127–133/54A(18mer) peptide which was prepared by introducing hemagglutinin (HA)127–133 of influenza virus into the H-2A b binding component induced significant T cell responses and antibodies (Ab) specific for HA127–133 in H-2A b mice. Further we found that the H-2A b binding component had a supermotif for human class II molecules (i.e. HLA-DQ6). In the present study, a new peptide vaccine, H3–H3, was prepared by combining 46F/HA127–133/54A(18mer) as a carrier and HA127–133 attached to the C terminus of 46F/HA127–133/54A(18mer) as a hapten and the effect of vaccine was examined in DQ6 mice which carry HLA-DQ6 alone as MHC class II molecules and thus may be regarded as a model of the DQ6 positive individuals. Since 46F/HA127–133/54A(18mer) induced merely Ab against HA127-133, it was assumed that H3-H3 induced mainly HA127–133 specific Ab in DQ6 mice without undesirable Ab production against the carrier. Indeed, H3-H3 elicited T cell responses and induced HA127–133 specific Ab in DQ6 mice. Furthermore, administration of H3–H3 inhibited growth of influenza virus until 9 weeks after the last immunization in DQ6 mice.
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Identification of an HLA-DQ6-derived peptide recognized by mouse MHC class I H-2Db-restricted CD8+ T cells in HLA-DQ6 transgenic mice.
Journal of Human Genetics, 1997Co-Authors: Tsutao Takeshita, Yoshinori Fukui, Ken Yamamoto, Kazuaki Yamane, Takeshi Inamitsu, Nobuhiro Kamikawaji, Takehiko SasazukiAbstract:CD8+ T cells from C57BL/6(B6) mice show cytotoxicity to B cell blasts prepared from syngeneic transgenic mice expressing HLA-DQ6 molecules in a mouse MHC class I H-2Db restricted manner. Although these results suggest that CD8+ T cells recognize peptides derived from DQ6 molecule bound to H-2Db on target cells, no direct evidence so far has been obtained. To clarify this, we synthesized 23 peptides corresponding to DQ6α orβ chain and carrying the motifs of Db-binding peptides, and examined their capacity to induce cytotoxicity in the CD8+ T cell line. We show here that DQA1-2, one of these peptides, induced cytotoxicity of the CD8+ T cells when this peptide was pulsed to H-2Db expressing target cells, as efficiently as HLA-DQ6 expressing target cells did. Thus, our results suggest that DQA1-2 can be naturally processed from DQ6 molecules and recognized by the CD8+ T cells in the context of H-2Db molecules. These results suggest that allogeneic HLA class II molecules are involved in the rejection not only as the ligand for T cell receptor of alloreactive CD4+ T cells but also as self-peptides bound to HLA class I molecules recognized by CD8+ T cells.
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Identification of an HLA-DQ6-derived peptide recognized by mouse MHC class I H-2D^b-restricted CD8^+ T cells in HLA-DQ6 transgenic mice
Japanese Journal of Human Genetics, 1997Co-Authors: Tsutao Takeshita, Yoshinori Fukui, Ken Yamamoto, Kazuaki Yamane, Takeshi Inamitsu, Nobuhiro Kamikawaji, Takehiko SasazukiAbstract:CD8^+ T cells from C57BL/6(B6) mice show cytotoxicity to B cell blasts prepared from syngeneic transgenic mice expressing HLA-DQ6 molecules in a mouse MHC class I H-2D^b restricted manner. Although these results suggest that CD8^+ T cells recognize peptides derived from DQ6 molecule bound to H-2D^b on target cells, no direct evidence so far has been obtained. To clarify this, we synthesized 23 peptides corresponding to DQ6 α or β chain and carrying the motifs of D^b-binding peptides, and examined their capacity to induce cytotoxicity in the CD8^+ T cell line. We show here that DQA1-2, one of these peptides, induced cytotoxicity of the CD8^+ T cells when this peptide was pulsed to H-2D^b expressing target cells, as efficiently as HLA-DQ6 expressing target cells did. Thus, our results suggest that DQA1-2 can be naturally processed from DQ6 molecules and recognized by the CD8^+ T cells in the context of H-2D^b molecules. These results suggest that allogeneic HLA class II molecules are involved in the rejection not only as the ligand for T cell receptor of alloreactive CD4^+ T cells but also as self-peptides bound to HLA class I molecules recognized by CD8^+ T cells.
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functional interaction between human histocompatibility leukocyte antigen hla class ii and mouse cd4 molecule in antigen recognition by t cells in hla dr and dq transgenic mice
Journal of Experimental Medicine, 1994Co-Authors: Ken Yamamoto, Yoshinori Fukui, Kazuaki Yamane, Takeshi Inamitsu, Nobuhiro Kamikawaji, Yukio Esaki, Tohm Sudo, Akinori Kimura, Takehiko SasazukiAbstract:Studies in vitro have suggested that a species barrier exists in functional interaction between human histocompatibility leukocyte antigen (HLA) class II and mouse CD4 molecules. However, whether mouse CD4+ T cells restricted by HLA class II molecules are generated in HLA class II transgenic mice and respond to peptide antigens across this barrier has remained unclear. In an analysis of T cell responses to synthetic peptides in mice transgenic for HLA-DR51 and -DQ6, we found that DR51 and DQ6 transgenic mice acquired significant T cell response to influenza hemagglutinin-derived peptide 307-319 (HA 307) and Streptococcus pyogenes M12 protein-derived peptide 347-397 (M6C2), respectively. Inhibition studies with several monoclonal antibodies showed that transgenic HLA class II molecules presented these peptides to mouse CD4+ T cells. Furthermore, T cell lines specific for HA 307 or M6C2 obtained from the transgenic mice could respond to the peptide in the context of relevant HLA class II molecules expressed on mouse L cell transfectants that lack the expression of mouse MHC class II. These findings indicate that interaction between HLA class II and mouse CD4 molecules is sufficient for provoking peptide-specific HLA class II-restricted T cell responses in HLA class II transgenic mice.
Eric V Marietta - One of the best experts on this subject based on the ideXlab platform.
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a controlled trial of gluten free diet in patients with irritable bowel syndrome diarrhea effects on bowel frequency and intestinal function
Gastroenterology, 2013Co-Authors: Maria Vazquez Roque, Eric V Marietta, Joseph A Murray, Michael Camilleri, Thomas Christopher Smyrk, Jessica Oneill, Paula Carlson, Jesse Lamsam, Denise Janzow, Deborah J EckertAbstract:Background & Aims Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD). Methods We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed HE the GCD had a greater effect on bowel movements per day of HLA-DQ2/8–positive than HLA-DQ2/8–negative patients ( P = .019). The GCD was associated with higher SB permeability (based on 0−2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8–positive than HLA-DQ2/8–negative patients ( P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1 , claudin-1 , and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8–positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-α in response to gluten than rice (unrelated to HLA genotype). Conclusions Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8–positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.gov NCT01094041.
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spontaneous lupus like syndrome in hla dq2 transgenic mice with a mixed genetic background
Lupus, 2010Co-Authors: Shadi Rashtak, Shen Cheng, Chella S David, Eric V Marietta, Joseph P Grande, Michael Camilleri, Mark R Pittelkow, Joseph A MurrayAbstract:: To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE(0)DQ2). These AE(0)DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE(0)DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE(0)DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE(0)DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE(0)DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a 'fingerprint' substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE(0)DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE(0)DQ2 mice compared with AE(0)DQ6 mice (p < 0.001). In conclusion, AE(0)DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815-829.
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HLA-DQ8 is a predisposing molecule for detergent enzyme subtilisin BPN'-induced hypersensitivity.
Clinical Immunology, 2005Co-Authors: Svetlana P. Chapoval, Eric V Marietta, Vaidehi R. Chowdhary, Thomas A. Gaffey, Elizabeth S. Finn, Alex C. Pursifull, Chella S DavidAbstract:Abstract Several million individuals are exposed to agents in the workplace associated with atopy and asthma. Detergent enzymes have been implicated in occupationally induced hypersensitivity. However, the genetic susceptibility and T cell responses to detergent enzymes are undefined. We generated and used HLA-DQ6, -DQ8, -DR2, -DR3, and -DR4 transgenic mice to examine the immune and inflammatory components involved in the response to the detergent enzyme subtilisin BPN′. Based on in vitro and in vivo studies, for the first time, we present evidence that DQ8 is a strong susceptibility marker for BPN′-induced hypersensitivity. Only DQ8 mice showed consistent T cell responses to five immunodominant regions of BPN′ comprising peptides #14 to 16, 36–37, 42–43, 62–63, and 80–81. The DQ8 mice also developed allergic eosinophilic inflammatory reactions in the airways following intranasal instillations of this enzyme. The DQ8 mice also responded to BPN′ with a significant IgG1 and IgE production. We propose that the HLA Class II tg mice are useful for understanding allergenic responses to enzymes in humans, screening of allergenic and immunogenic properties of detergent enzymes, and for the development of modified enzymes to maintain efficient detergent qualities without allergic properties.
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HLA Class II transgenic mice as models to study the allergenicity of bacterial protease Y217L BPN
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: E.s. Finn, Eric V Marietta, Svetlana P. Chapoval, Vaidehi R. Chowdhary, Thomas A. Gaffey, A.c. Pursifull, Chella S DavidAbstract:Abstract Rationale HLA-DQ6, -DQ8, -DR3, and -DR4 transgenic (tg) mice were studied to examine the role of human Class II molecules on the Y217L BPN' respiratory immune response. Y217L BPN' is an industrial enzyme and a known occupational allergen. Methods Mice were immunized with Y217L BPN' and several parameters were evaluated: 1) T cell epitopes 2) IgG1/IgE and 3) histological analysis of lung and BAL. Results DQ8 mice were shown to be most susceptible to development of Th2 hypersensitivity to Y217L BPN' based on the development of significant levels of Ag-specific IgG1/IgE and eosinophilia after 5 immunizations. Several T cell epitopes were identified in DQ8 mice with major epitopes spanning 5 regions of the protein defined by amino acids 40-54, 73-90, 106-126, 184-213, and 238-255. Immunized DQ6 and DR3 mice exhibited low but detectable levels of Ag-specific IgG1/IgE but no eosinophilia or significant proliferative responses to synthetic peptides (T cell epitopes). This suggested that the time to peak Ab production and T cell proliferation may be longer in DQ6 and DR3 mice. Therefore, longer term repeated exposure to the enzyme in DQ6 mice was undertaken. With additional immunizations, DQ6 mice generated a robust IgG1 response. In addition, 3 major T cell epitope regions were identified and were similar to those seen in DQ8 mice: 67-87, 109-123 and 184-204. Conclusions HLA Class II molecules are important in development of IgG1/IgE and eosinophilia to Y217L BPN'. We propose that HLA Class II tg mice should be studied further as models to understand the allergic response to enzymes.
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Cryptic determinants and promiscuous sequences on human acetylcholine receptor: HLA-dependent dichotomy in T-cell function.
Human Immunology, 2002Co-Authors: Raghavanpillai Raju, Eric V Marietta, Javier Vinasco, Bianca M. Conti-fine, Anthony J. Infante, Chella S DavidAbstract:Abstract Experimental autoimmune myasthenia gravis can be induced in some strains of mice and rats by immunizing with acetylcholine receptor. Also, epidemiologic studies demonstrate an MHC linkage of myasthenia gravis in the man. In order to obtain direct experimental evidence for the influence of the genes of the MHC complex in the development of myasthenia gravis, we used mice transgenic to individual HLA molecules. We observed an increased susceptibility to the disease in HLA DQ8 transgenic mice compared to HLA DQ6 transgenic mice ( J. Immunol. 160:4169; 1998). These mice lacked endogenous mouse class II molecules. In the present study we mapped the cryptic and dominant sequences on the extra cellular region of human acetylcholine receptor. Although some epitopes ( e.g. , α11-30, α141-160, α171-190) were common between DQ8 and DQ6 transgenic mice, several others were disparately recognized. We also found a functional dichotomy in T cells from mice differing by one MHC molecule (HLA DQ8 or DQ6) when primed by sequences immunodominant in DQ8 and DQ6 tg mice. Differential disease manifestation in the two different HLA transgenic mice could be explained not only by differential recognition of peptides by these antigen presenting molecules, but also by the difference in the functional profile of T cells generated when primed by promiscuous sequence regions.
Todd E. Golde - One of the best experts on this subject based on the ideXlab platform.
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Immune responses against Aβ1–42 in HLA class II transgenic mice: implications for Aβ1–42 immune-mediated therapies
Neurobiology of Aging, 2003Co-Authors: Svetlana P. Chapoval, Victor Howard, Chella S David, Todd E. GoldeAbstract:Abstract We have investigated whether polymorphic differences in the major histocompatibility complex (MHC) class II molecules influence humoral and cellular immune responses against Aβ1–42. To analyze the effects of mouse MHC class II and tolerance effects of overexpression of human APP in mice, we immunized Tg2576 and non-transgenic littermates bred into two different MHC backgrounds with Aβ1–42 and compared both B and T cell responses. We found that in the presence of the mouse C57BL/6 background, both B and T cell responses against Aβ1–42 were significantly suppressed. To directly test the contribution of human MHC class II, we immunized various human HLA class II transgenic (TG) mice with Aβ1–42 and analyzed anti-Aβ immune responses. HLA-DR3 and HLA-DQ8 TG mice generated modest B and T cell responses against Aβ1–42. The presence of HLA-DR3/DQ8 in double TG mice enhanced the overall immune response against Aβ1–42. In contrast, HLA-DR4 TG mice mounted strong T cell responses but failed to generate high titer antibody responses against Aβ1–42, whereas, the HLA-DQ6 TG mice were not able to mount significant B or T cell responses against Aβ1–42. These studies in mice suggest that the presence of certain MHC class II molecules or combinations of class II molecules can potentially influence the overall immune response against Aβ1–42.
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Immune responses against Aβ1-42 in HLA class II transgenic mice: Implications for Aβ1-42 immune-mediated therapies
Neurobiology of Aging, 2003Co-Authors: Pritam Das, Svetlana Chapoval, Victor Howard, Chella S David, Todd E. GoldeAbstract:We have investigated whether polymorphic differences in the major histocompatibility complex (MHC) class II molecules influence humoral and cellular immune responses against Aβ1-42. To analyze the effects of mouse MHC class II and tolerance effects of overexpression of human APP in mice, we immunized Tg2576 and non-transgenic littermates bred into two different MHC backgrounds with Aβ1-42 and compared both B and T cell responses. We found that in the presence of the mouse C57BL/6 background, both B and T cell responses against Aβ1-42 were significantly suppressed. To directly test the contribution of human MHC class II, we immunized various human HLA class II transgenic (TG) mice with Aβ1-42 and analyzed anti-Aβ immune responses. HLA-DR3 and HLA-DQ8 TG mice generated modest B and T cell responses against Aβ1-42. The presence of HLA-DR3/DQ8 in double TG mice enhanced the overall immune response against Aβ1-42. In contrast, HLA-DR4 TG mice mounted strong T cell responses but failed to generate high titer antibody responses against Aβ1-42, whereas, the HLA-DQ6 TG mice were not able to mount significant B or T cell responses against Aβ1-42. These studies in mice suggest that the presence of certain MHC class II molecules or combinations of class II molecules can potentially influence the overall immune response against Aβ1-42. © 2003 Elsevier Science Inc. All rights reserved.
Svetlana P. Chapoval - One of the best experts on this subject based on the ideXlab platform.
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HLA-DQ8 is a predisposing molecule for detergent enzyme subtilisin BPN'-induced hypersensitivity.
Clinical Immunology, 2005Co-Authors: Svetlana P. Chapoval, Eric V Marietta, Vaidehi R. Chowdhary, Thomas A. Gaffey, Elizabeth S. Finn, Alex C. Pursifull, Chella S DavidAbstract:Abstract Several million individuals are exposed to agents in the workplace associated with atopy and asthma. Detergent enzymes have been implicated in occupationally induced hypersensitivity. However, the genetic susceptibility and T cell responses to detergent enzymes are undefined. We generated and used HLA-DQ6, -DQ8, -DR2, -DR3, and -DR4 transgenic mice to examine the immune and inflammatory components involved in the response to the detergent enzyme subtilisin BPN′. Based on in vitro and in vivo studies, for the first time, we present evidence that DQ8 is a strong susceptibility marker for BPN′-induced hypersensitivity. Only DQ8 mice showed consistent T cell responses to five immunodominant regions of BPN′ comprising peptides #14 to 16, 36–37, 42–43, 62–63, and 80–81. The DQ8 mice also developed allergic eosinophilic inflammatory reactions in the airways following intranasal instillations of this enzyme. The DQ8 mice also responded to BPN′ with a significant IgG1 and IgE production. We propose that the HLA Class II tg mice are useful for understanding allergenic responses to enzymes in humans, screening of allergenic and immunogenic properties of detergent enzymes, and for the development of modified enzymes to maintain efficient detergent qualities without allergic properties.
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HLA Class II transgenic mice as models to study the allergenicity of bacterial protease Y217L BPN
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: E.s. Finn, Eric V Marietta, Svetlana P. Chapoval, Vaidehi R. Chowdhary, Thomas A. Gaffey, A.c. Pursifull, Chella S DavidAbstract:Abstract Rationale HLA-DQ6, -DQ8, -DR3, and -DR4 transgenic (tg) mice were studied to examine the role of human Class II molecules on the Y217L BPN' respiratory immune response. Y217L BPN' is an industrial enzyme and a known occupational allergen. Methods Mice were immunized with Y217L BPN' and several parameters were evaluated: 1) T cell epitopes 2) IgG1/IgE and 3) histological analysis of lung and BAL. Results DQ8 mice were shown to be most susceptible to development of Th2 hypersensitivity to Y217L BPN' based on the development of significant levels of Ag-specific IgG1/IgE and eosinophilia after 5 immunizations. Several T cell epitopes were identified in DQ8 mice with major epitopes spanning 5 regions of the protein defined by amino acids 40-54, 73-90, 106-126, 184-213, and 238-255. Immunized DQ6 and DR3 mice exhibited low but detectable levels of Ag-specific IgG1/IgE but no eosinophilia or significant proliferative responses to synthetic peptides (T cell epitopes). This suggested that the time to peak Ab production and T cell proliferation may be longer in DQ6 and DR3 mice. Therefore, longer term repeated exposure to the enzyme in DQ6 mice was undertaken. With additional immunizations, DQ6 mice generated a robust IgG1 response. In addition, 3 major T cell epitope regions were identified and were similar to those seen in DQ8 mice: 67-87, 109-123 and 184-204. Conclusions HLA Class II molecules are important in development of IgG1/IgE and eosinophilia to Y217L BPN'. We propose that HLA Class II tg mice should be studied further as models to understand the allergic response to enzymes.
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Immune responses against Aβ1–42 in HLA class II transgenic mice: implications for Aβ1–42 immune-mediated therapies
Neurobiology of Aging, 2003Co-Authors: Svetlana P. Chapoval, Victor Howard, Chella S David, Todd E. GoldeAbstract:Abstract We have investigated whether polymorphic differences in the major histocompatibility complex (MHC) class II molecules influence humoral and cellular immune responses against Aβ1–42. To analyze the effects of mouse MHC class II and tolerance effects of overexpression of human APP in mice, we immunized Tg2576 and non-transgenic littermates bred into two different MHC backgrounds with Aβ1–42 and compared both B and T cell responses. We found that in the presence of the mouse C57BL/6 background, both B and T cell responses against Aβ1–42 were significantly suppressed. To directly test the contribution of human MHC class II, we immunized various human HLA class II transgenic (TG) mice with Aβ1–42 and analyzed anti-Aβ immune responses. HLA-DR3 and HLA-DQ8 TG mice generated modest B and T cell responses against Aβ1–42. The presence of HLA-DR3/DQ8 in double TG mice enhanced the overall immune response against Aβ1–42. In contrast, HLA-DR4 TG mice mounted strong T cell responses but failed to generate high titer antibody responses against Aβ1–42, whereas, the HLA-DQ6 TG mice were not able to mount significant B or T cell responses against Aβ1–42. These studies in mice suggest that the presence of certain MHC class II molecules or combinations of class II molecules can potentially influence the overall immune response against Aβ1–42.
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Allergic inflammatory response to short ragweed allergenic extract in HLA-DQ transgenic mice lacking CD4 gene.
Journal of Immunology, 2002Co-Authors: Svetlana P. Chapoval, Eric V Marietta, Koji Iijima, Michele Smart, Andrei I. Chapoval, Amy G. Andrews, Chella S DavidAbstract:To investigate the role of HLA-DQ molecules and/or CD4+ T cells in the pathogenesis of allergic asthma, we generated HLA-DQ6 and HLA-DQ8 transgenic mice lacking endogenous class II (Aβnull) and CD4 genes and challenged them intranasally with short ragweed allergenic extract (SRW). We found that DQ6/CD4null mice developed a strong eosinophilic infiltration into the bronchoalveolar lavage and lung tissue, while DQ8/CD4null mice were normal. However, neither cytokines nor eosinophil peroxidase in the bronchoalveolar lavage of DQ6/CD4null mice was found. In addition, the airway reactivity to methacholine was elevated moderately in DQ6/CD4null mice compared with the high response in DQ/CD4+ counterparts and was only partially augmented by CD4+ T cell transfer. The DQ6/CD4null mice showed Th1/Th2-type cytokines and SRW-specific Abs in the immune sera in contrast to a direct Th2 response observed in DQ6/CD4+ mice. The proliferative response of spleen mononuclear cells and peribronchial lymph node cells demonstrated that the response to SRW in DQ6/CD4null mice was mediated by HLA-DQ-restricted CD4−CD8−NK1.1− T cells. FACS analysis of PBMC and spleen mononuclear cells demonstrated an expansion of double-negative (DN) CD4−CD8−TCRαβ+ T cells in SRW-treated DQ6/CD4null mice. These cells produced IL-4, IL-5, IL-13, and IFN-γ when stimulated with immobilized anti-CD3. IL-5 ELISPOT assay revealed that DN T cells were the cellular origin of IL-5 in allergen-challenged DQ6/CD4null mice. Our study shows a role for HLA-DQ-restricted CD4+ and DN T cells in the allergic response.
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Cockroach Allergen-Induced Eosinophilic Airway Inflammation in HLA-DQ/Human CD4+ Transgenic Mice
Journal of Immunology, 2001Co-Authors: Bettina G. Papouchado, Eric V Marietta, Svetlana P. Chapoval, Catherine R. Weiler, Chella S DavidAbstract:Airway eosinophilic inflammation is a characteristic feature of allergic asthma. Exposure to allergens produced by the German cockroach ( Blattella germanica ) is a risk factor for allergic disease in genetically predisposed individuals, and has been linked to an increase in asthma morbidity among cockroach-sensitive inner city children. To determine the role and contribution of specific HLA class II in the pathogenesis of allergic airway inflammation in cockroach-induced asthma, we generated double-transgenic, double-knockout mice expressing human HLA-DQ8, HLA-DQ6, and CD4 molecules in the absence of mouse class II and mouse CD4. Mice were actively immunized and later challenged intranasally with cockroach allergen extract. These mice developed bronchoalveolar lavage fluid (BALF) eosinophilia and pulmonary eosinophilia. This was accompanied by an increase in total protein levels, IL-5, and IL-13 in BALF. There were also elevated levels of cockroach-specific serum IgG1 and total serum IgE. Histological analysis revealed peribronchial and perivascular eosinophilic inflammation in cockroach-treated mice. Other pathologic changes in the airways were epithelial cell hypertrophy and mucus production. Treatment with anti-DQ mAb significantly reduced pulmonary and BALF eosinophilia in cockroach allergen-sensitized mice. Aβ 0 mice and transgenic mice expressing human CD4 molecule alone (without class II) or human HLA-DQ8 molecule (without CD4) treated in the same fashion showed no eosinophilia in bronchoalveolar fluid and no pulmonary parenchymal inflammation. Our results provide direct evidence that HLA-DQ molecules and CD4 T cells mediate cockroach-induced eosinophilic inflammation in the airways.