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Chella S David - One of the best experts on this subject based on the ideXlab platform.

  • Delineation of the minimal encephalitogenic epitope of proteolipid protein peptide(91-110) and critical residues required for induction of EAE in HLA-DR3 transgenic mice.
    Journal of neuroimmunology, 2020
    Co-Authors: Ashutosh K. Mangalam, Moses Rodriguez, Meenakshi Khare, Christopher J. Krco, Chella S David
    Abstract:

    Previously, we have reported that proteolipid protein (PLP) peptide 91-110 can induce experimental autoimmune encephalomyelitis (EAE) in HLA-DR3 transgenic (tg) mice. Here we, report that residues spanning 97-108 are the minimal epitope required for induction of EAE in DR3 mice. Utilizing a series of alanine-substituted peptides, positions 99, 101, 102, 103, 104, and 106 are identified as residues necessary for an immune response. Further analysis indicated that amino acid isoleucine (99), aspartate (102) and lysine (104) are anchor residues facilitating binding to HLA-DR3 molecules. These results may have applications in the future design of peptide based immunotherapy.

  • A Central Role for HLA-DR3 in Anti-Smith Antibody Responses and Glomerulonephritis in a Transgenic Mouse Model of Spontaneous Lupus
    Journal of Immunology, 2015
    Co-Authors: Vaidehi Chowdhary, Govindarajan Rajagopalan, Shu Man Fu, Ashenafi Y. Tilahun, Julie Hanson, Michele Smart, Joseph Peter Grande, Chella S David
    Abstract:

    MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRβ1*0301) and devoid of endogenous class II (both I-A and I-E genes, AE 0 ) on a lupus-prone NZM2328 background (NZM2328. DR3 + AE 0 ). Both NZM2328 and NZM2328. DR3 + AE 0 mice developed anti-dsDNA and glomerulonephritis, but anti-dsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328. DR3 + AE 0 mice (7.2 ± 4.3 and 8.6 ± 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3 + AE 0 mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p DR3 + AE 0 mice. Interestingly, NZM2328. DR3 + AE 0 mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328. DR3 + AE 0 mice that were completely devoid of endogenous class II ( AE -/ - ) but not in mice homozygous ( AE +/+ ) or heterozygous (AE +/− ) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4 + T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background.

  • Two discreet subsets of CD8 T cells modulate PLP 91-110 induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice
    Journal of Autoimmunity, 2012
    Co-Authors: Ashutosh K. Mangalam, Michele Smart, David Luckey, Shailendra Giri, Larry R. Pease, Moses Rodriguez, Chella S David
    Abstract:

    Abstract Previously we showed that transgenic mice expressing human HLA-DR3 gene are susceptible to PLP 91–110 induced experimental autoimmune encephalomyelitis (EAE) and can serve as an animal model of multiple sclerosis (MS). HLA-DR3 mice with EAE showed increased number of CD8 T cells indicating their important role in disease pathogenesis. The role of CD8 T cells in MS, an inflammatory demyelinating disease of CNS, has been enigmatic as it has been assigned both regulatory and pathogenic roles. Therefore, to evaluate the role of CD8 T cells, we generated CD8 deficient HLA-DR3 transgenic mice (DR3.CD8 −/− ). Immunization with PLP 91–110 led to more severe EAE in DR3.CD8 −/− mice compared to HLA-DR3 mice indicating a regulatory role for CD8 T cells. Interestingly, DR3.CD8 −/− mice with EAE showed decreased CNS pathology compared to DR3 mice thus suggesting a pathogenic role for CD8 T cells. We show that these two subsets of CD8 T cells can be differentiated based on the surface expression of CD122 (IL-2 Rβ chain). CD8 T cells expressing CD122 (CD8+CD122+) play a regulatory role while CD8+CD122− T cells act as a pathogenic subset. CD122 expressing CD8 T cells are the regulatory subset of CD8 T cells and regulate the encephalitogenic CD4 T cells through direct modulation of antigen presenting cells and/or through the release of immunoregulatory cytokines such as IL-10, IFNγ and TGFβ. We also showed that adoptive transfer of CD8CD122− T cells caused increased spinal cord demyelination indicating that these are pathogenic subset of CD8 T cells. Our study suggests that CD8+ T cells play both regulatory as well as pathogenic role in disease pathogenesis of EAE. A better understanding of these subsets could aid in designing novel therapy for MS patients.

  • HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD
    Journal of Autoimmunity, 2011
    Co-Authors: Umesh S. Deshmukh, Carol J. Kannapell, Felicia Gaskin, Govindarajan Rajagopalan, Chella S David, Shu Man Fu
    Abstract:

    Abstract Although systemic lupus erythematosus (SLE) is a multigenic autoimmune disorder, HLA-D is the most dominant genetic susceptibility locus. This study was undertaken to investigate the hypothesis that microbial peptides bind HLA-DR3 and activate T cells reactive with lupus autoantigens. Using HLA-DR3 transgenic mice and lupus-associated autoantigen SmD protein, SmD 79–93 was identified to contain a dominant HLA-DR3 restricted T cell epitope. This T cell epitope was characterized by using a T–T hybridoma, C1P2, generated from SmD immunized HLA-DR3 transgenic mouse. By pattern search analysis, 20 putative mimicry peptides (P2–P21) of SmD 79–93, from microbial and human origin were identified. C1P2 cells responded to SmD, SmD 79–93 and a peptide (P20) from Vibro cholerae . Immunization of HLA-DR3 mice with P20 induced T cell responses and IgG antibodies to SmD that were not cross-reactive with the immunogen. A T–T hybridoma, P20P1, generated from P20 immunized mice, not only responded to P20 and SmD 79–93 , but also to peptides from Streptococcus agalactiae (P17) and human-La related protein (P11). These three T cell mimics (P20, P11 and P17) induced diverse and different autoantibody response profiles. Our data demonstrates for the first time molecular mimicry at T cell epitope level between lupus-associated autoantigen SmD and microbial peptides. Considering that distinct autoreactive T cell clones were activated by different microbial peptides, molecular mimicry at T cell epitope level can be an important pathway for the activation of autoreactive T cells resulting in the production of autoantibodies. In addition, the novel findings reported herein may have significant implications in the pathogenesis of SLE.

  • HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD
    Journal of Autoimmunity, 2011
    Co-Authors: Umesh S. Deshmukh, Davis L. Sim, Carol J. Kannapell, Felicia Gaskin, Govindarajan Rajagopalan, Chao Dai, Chella S David, Shu Man Fu
    Abstract:

    Although systemic lupus erythematosus (SLE) is a multigenic autoimmune disorder, HLA-D is the most dominant genetic susceptibility locus. This study was undertaken to investigate the hypothesis that microbial peptides bind HLA-DR3 and activate T cells reactive with lupus autoantigens. Using HLA-DR3 transgenic mice and lupus-associated autoantigen SmD protein, SmD 79-93 was identified to contain a dominant HLA-DR3 restricted T cell epitope. This T cell epitope was characterized by using a T-T hybridoma, C1P2, generated from SmD immunized HLA-DR3 transgenic mouse. By pattern search analysis, 20 putative mimicry peptides (P2-P21) of SmD 79-93, from microbial and human origin were identified. C1P2 cells responded to SmD, SmD 79-93 and a peptide (P20) from Vibro cholerae. Immunization of HLA-DR3 mice with P20 induced T cell responses and IgG antibodies to SmD that were not cross-reactive with the immunogen. A T-T hybridoma, P20P1, generated from P20 immunized mice, not only responded to P20 and SmD 79-93, but also to peptides from Streptococcus agalactiae (P17) and human-La related protein (P11). These three T cell mimics (P20, P11 and P17) induced diverse and different autoantibody response profiles. Our data demonstrates for the first time molecular mimicry at T cell epitope level between lupus-associated autoantigen SmD and microbial peptides. Considering that distinct autoreactive T cell clones were activated by different microbial peptides, molecular mimicry at T cell epitope level can be an important pathway for the activation of autoreactive T cells resulting in the production of autoantibodies. In addition, the novel findings reported herein may have significant implications in the pathogenesis of SLE. © 2011 Elsevier Ltd.

A. Arnaiz-villena - One of the best experts on this subject based on the ideXlab platform.

  • Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as Type 11 (insulin-dependent)diabetes mellitus predictive risk markers in the Spanish population
    Diabetologia, 1992
    Co-Authors: J. L. Vicario, J. Martinez-laso, A. Corell, J. M. Martin-villa, P. Morales, G. Lledo, O. G. Segurado, D. Juan, A. Arnaiz-villena
    Abstract:

    The question of HLA susceptibility to Type 1(insulin-dependent) diabetes mellitus remains unresolved. In the present study, 127 diabetic patients and 177 unrelated control subjects have been analysed for their class I and class II serological antigens, class II (DR, DQ) DNA restriction fragment length polymorphisms and DQA1 and B1 exon-2 nucleotide sequences and their corresponding amino acid residues. By using the aetiologic fraction (δ) as an almost absolute measure of the strongest linkage disequilibrium of an HLA marker to the putative Type 1 diabetes susceptibility locus, it has been found that the strength of association of the HLA markers may be quantified as follows: DR4 < DR3 < DR3 or DR4 < non-Aspartate 57 ßDQ and Arginine 52 αDQ < Arginine 52 αDQ. Thus, molecular HLA-DQ markers appear to be more accurate as susceptibility markers than the classic serologically defined ones (DR3 and DR4); however, any effect of DQ markers disapears when non-DR3/DR4 individuals are considered, suggesting that DR factors (or others in between DQ and DR) are also important. In addition, a dominant non-Aspartate 57 ßDQ susceptibility theory does not hold (but a recessive one does) in our diabetic population (probably due to the high frequency of the protective DR7-non-Aspartate 57 ßDQ haplotypes); Arginine 52 aDQ is the best single HLA marker found in our population, both as a recessive or as a dominant one. Also there are 13 patients in our sample who bear neither Arginine 52 aDQ nor non-Aspartate 57 ßDQ susceptibility factors. On the other hand, a predominant Type 1 diabetes association of Spanish patients to the B18-DR3-Dw25 haplotype (and not to B8-DR3-Dw24) has been found; this distinctive association has also been recorded in adult systemic lupus patients and may reflect the existence of common pathogenetic HLA factors for both diseases present only in the B18-DR3-Dw25 haplotype in the Spanish population. These factors are probably placed at the non-coding regions which are different from the B8-DR3-Dw24 haplotype.

J. L. Vicario - One of the best experts on this subject based on the ideXlab platform.

  • Exploring the diabetogenicity of the HLA-B18-DR3 CEH: independent association with T1D genetic risk close to HLA-DOA
    Genes & Immunity, 2009
    Co-Authors: I Santin, J. L. Vicario, A Castellanos-rubio, A M Aransay, G Gutierrez, S Gaztambide, I Rica, J A Noble, L Castaño, J R Bilbao
    Abstract:

    The objective of this study was to identify additional diabetes susceptibility markers in the MHC that could be responsible for the differential diabetogenicity of different HLA-DR3 CEHs. High-resolution SNP genotyping of the MHC was carried out in 15 type 1 diabetes (T1D) patients and 39 non-diabetic controls, homozygous for DR3-DQ2 and with one copy of the A^*30-B^*18-MICA^*4-F1C30-DRB1^*0301-DQB1^*0201-DPB1^*0202 HLA haplotype. Significantly associated SNPs were replicated in an independent sample of 554 T1D patients and 841 controls without HLA matching. Electrophoretic mobility shift assay was used to show a functional effect of an associated SNP. Seven SNPs showed evidence of association in the initial discovery experiment. Upon replication, only rs419434 (upstream HLA-DOA gene) remained significant. A functional variant (rs432375) in complete LD with rs419434 was shown to affect USF-1 binding and could be responsible for the association signal in the region. We have identified a new susceptibility locus within the MHC with a modest contribution to T1D (OR=1.93; CI: 1.52–2.44; P =10^−8) that is independent of HLA-DRB1 locus.

  • Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as Type 11 (insulin-dependent)diabetes mellitus predictive risk markers in the Spanish population
    Diabetologia, 1992
    Co-Authors: J. L. Vicario, J. Martinez-laso, A. Corell, J. M. Martin-villa, P. Morales, G. Lledo, O. G. Segurado, D. Juan, A. Arnaiz-villena
    Abstract:

    The question of HLA susceptibility to Type 1(insulin-dependent) diabetes mellitus remains unresolved. In the present study, 127 diabetic patients and 177 unrelated control subjects have been analysed for their class I and class II serological antigens, class II (DR, DQ) DNA restriction fragment length polymorphisms and DQA1 and B1 exon-2 nucleotide sequences and their corresponding amino acid residues. By using the aetiologic fraction (δ) as an almost absolute measure of the strongest linkage disequilibrium of an HLA marker to the putative Type 1 diabetes susceptibility locus, it has been found that the strength of association of the HLA markers may be quantified as follows: DR4 < DR3 < DR3 or DR4 < non-Aspartate 57 ßDQ and Arginine 52 αDQ < Arginine 52 αDQ. Thus, molecular HLA-DQ markers appear to be more accurate as susceptibility markers than the classic serologically defined ones (DR3 and DR4); however, any effect of DQ markers disapears when non-DR3/DR4 individuals are considered, suggesting that DR factors (or others in between DQ and DR) are also important. In addition, a dominant non-Aspartate 57 ßDQ susceptibility theory does not hold (but a recessive one does) in our diabetic population (probably due to the high frequency of the protective DR7-non-Aspartate 57 ßDQ haplotypes); Arginine 52 aDQ is the best single HLA marker found in our population, both as a recessive or as a dominant one. Also there are 13 patients in our sample who bear neither Arginine 52 aDQ nor non-Aspartate 57 ßDQ susceptibility factors. On the other hand, a predominant Type 1 diabetes association of Spanish patients to the B18-DR3-Dw25 haplotype (and not to B8-DR3-Dw24) has been found; this distinctive association has also been recorded in adult systemic lupus patients and may reflect the existence of common pathogenetic HLA factors for both diseases present only in the B18-DR3-Dw25 haplotype in the Spanish population. These factors are probably placed at the non-coding regions which are different from the B8-DR3-Dw24 haplotype.

Salvatore Benvenga - One of the best experts on this subject based on the ideXlab platform.

  • Injections of Clostridium botulinum neurotoxin A may cause thyroid complications in predisposed persons based on molecular mimicry with thyroid autoantigens
    Endocrine, 2011
    Co-Authors: Edvina Gregoric, Jurji Avramovic Gregoric, Fabrizio Guarneri, Salvatore Benvenga
    Abstract:

    A woman with Hashimoto's thyroiditis, under replacement L-T4, repeatedly experienced, over a 10-year period, elevations of serum TSH after eyelid injections of Clostridium botulinum neurotoxin A (Btx). We hypothesized a link between Btx injections and TSH elevations via molecular mimicry, and aimed to verify our hypothesis. Using an in silico approach, we searched first for amino acid sequence homology between Btx and thyroid autoantigens, and next for HLA binding motifs within homologous segments. We found that (i) Btx and thyroid autoantigens share amino acid sequence homology; (ii) some homologous regions contain epitopes of both Btx and thyroid autoantigens; (iii) some of such regions contain HLA-DR3 and/or HLA-DR7 binding motifs, which predominate over other HLA-DRs. This is relevant because the patient's HLA-DR haplotype was DR3/DR7. In conclusion, clinical and bioinformatics data suggest a possible pathogenetic link between Btx and autoimmune thyroid diseases. Considering the wide and increasing medical and dermocosmetic use of Btx, and the frequently subclinical course of autoimmune thyroid diseases, we think that thyroid "complications" may pass frequently undetected in Btx-treated persons. 2010 Springer Science+Business Media, LLC

  • Reply: Does clostridium botulinum neurotoxin a exhibit molecular mimicry with thyroid autoantigens and cause thyroid complications in predisposed persons?
    Endocrine, 2011
    Co-Authors: Edvina Gregoric, Jurji Avramovic Gregoric, Fabrizio Guarneri, Salvatore Benvenga
    Abstract:

    A woman with Hashimoto's thyroiditis, under replacement L-T4, repeatedly experienced, over a 10-year period, elevations of serum TSH after eyelid injections of Clostridium botulinum neurotoxin A (Btx). We hypothesized a link between Btx injections and TSH elevations via molecular mimicry, and aimed to verify our hypothesis. Using an in silico approach, we searched first for amino acid sequence homology between Btx and thyroid autoantigens, and next for HLA binding motifs within homologous segments. We found that (i) Btx and thyroid autoantigens share amino acid sequence homology; (ii) some homologous regions contain epitopes of both Btx and thyroid autoantigens; (iii) some of such regions contain HLA-DR3 and/or HLA-DR7 binding motifs, which predominate over other HLA-DRs. This is relevant because the patient's HLA-DR haplotype was DR3/DR7. In conclusion, clinical and bioinformatics data suggest a possible pathogenetic link between Btx and autoimmune thyroid diseases. Considering the wide and increasing medical and dermocosmetic use of Btx, and the frequently subclinical course of autoimmune thyroid diseases, we think that thyroid "complications" may pass frequently undetected in Btx-treated persons.

Rosemarie Watson - One of the best experts on this subject based on the ideXlab platform.

  • Anti-Ro(SS-A) HLA-DR3-Positive Women: The Interrelationship Between Some ANA Negative, SS, SCLE, and NLE Mothers and SS/LE Overlap Female Patients
    Journal of Investigative Dermatology, 1993
    Co-Authors: Thomas T. Provost, Rosemarie Watson
    Abstract:

    During the past 15 years, the clinical spectrum associated with the anti-Ro(SS-A) antibody response has been defined. Various clinical presentations, including subacute cutaneous lupus erythematosus, the neonatal lupus syndrome, the Sjogren's syndrome/ lupus erythematous overlap syndrome, and primary Sjogren's syndrome, have been detected in association with the anti-Ro(SS-A) response. The anti-Ro(SS-A) antibody response is associated with the HLA-DR2 and HLA-DR3 phenotypes. There is now a good deal of evidence to suggest that many anti-Ro(SS-A) -positive HLA-DR3 women are genetically closely related, sharing in common an enriched frequency of the HLA-DR3-linked B8, DQw2, and DRW52 phenotypes. DNA sequence studies have confirmed this genetic relationship. These studies have led us to the following conclusions. (1) The HLA-DR2 and HLA-DR3 associations with systemic lupus erythematosus and the HLA-DR3 association with Sjogren's syndrome are related to the anti-Ro(SS-A) antibody response and not to the clinical disease expression. (2) HLA-DR3 anti Ro-positive female patients with first-degree Sjogren's syndrome, subacute cutaneous lupus erythematosus, or Sjogren's syndrome, or who are asymptomatic, are immunogenetically closely related even though the clinical presentations are strikingly different. All these HLA-DR3 anti-Ro(SS-A) antibody-positive women are at risk to give birth to a child with the neonatal lupus syndrome.

  • Anti-Ro(SS-A) HLA-DR3-positive women : the interrelationship between some ANA negative, SS, SCLE, and NLE mothers and SS/LE overlap female patients : Connective tissue diseases and the skin
    Journal of Investigative Dermatology, 1993
    Co-Authors: Thomas T. Provost, Rosemarie Watson
    Abstract:

    During the past 15 years, the clinical spectrum associated with the anti-Ro(SS-A) antibody response has been defined. Various clinical presentations, including subacute cutaneous lupus erythematosus, the neonatal lupus syndrome, the Sjogren's syndrome/lupus erythematous overlap syndrome, and primary Sjogren's syndrome, have been detected in association with the anti-Ro(SS-A) response. The anti-Ro(SS-A) antibody response is associated with the HLA-DR2 and HLA-DR3 phenotypes