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J D Taurog

Publications and source records attributed to J D Taurog.

At least 19 recordsLinked to original sources
PubMed1995

Characterization of psoriasiform and alopecic skin lesions in HLA-B27 transgenic rats.

We have previously reported a multisystem inflammatory disease in transgenic rat lines with high expression of HLA-B*2705 and human beta 2 microglobulin. Skin disease in these rats includes two predominant lesions: 1) marked psoriasiform dermatitis of the tail and digits; and 2) progressive alopecia of face, neck, trunk, and extremities. Here we present the results of a systematic survey of these lesions. Tail and digit skin showed psoriasiform hyperplasia of the epidermis associated with parakeratosis, with marked dermal and epidermal inflammation. The alopecic skin showed perifollicular and follicular mononuclear infiltration and increased numbers of atrophic follicles. Immunohistochemical analysis revealed that B27 expression was prominent on keratinocytes in hyperplastic epidermis where lymphocytic infiltrates were prominent, but was absent in the absence of inflammation. In alopecic lesions, B27 was strongly expressed on follicular epithelium and dermal hair papillae associated with mononuclear infiltrates. T cells, both CD8 and CD4, were most prominent in inflammatory lesions and rat MHC-II expression on keratinocytes, and follicular epithelium was dramatically increased. This study suggests that T cell-mediated immune mechanisms participate in development of cutaneous lesions in HLA-B27 transgenic rats.

Alopecia↗
PubMed1992

In vitro mutagenesis of HLA-B27: single and multiple amino acid substitutions at consensus B27 sites identify distinct monoclonal antibody-defined epitopes.

The consensus HLA-B27 sequence includes a unique constellation of amino acid residues along the peptide-binding cleft. To investigate the potential role of this region in the antigenic structure of HLA-B27, a panel of transfected cell lines was produced expressing 24 mutant B27 molecules with single or multiple substitutions within this constellation of residues. The cells were analyzed by flow cytometry with a panel of four anti-B27 mAb: ME1, GSP5.3, GS145.2, and B27M2. Previous studies have suggested that position 67 exerts a conformational effect on the ME1, GSP5.3, and GS145.2 epitopes. This was further supported in these studies by the observation that additional substitutions at the flanking residues 63 and 70 could reverse the disruption of these mAb epitopes by large residues at 67. Substitutions at positions 69-71 disrupted the binding of ME1 and GSP5.3, apparently by a direct effect. Individual substitutions at either of the two positions bearing residues unique to B27, 70 and 97, had no significant influence on the binding of any of the four mAb. The region of amino acid positions 63-71 in HLA-B27 thus appears to participate in the formation of at least three distinct epitopes shared by B27 and B7, identified by ME1, GSP5.3, and GS145.2.

Amino Acid Sequence↗
PubMed1991

The Second International Simmons Center Conference on HLA-B27-Related Disorders.

The Second International Simmons Center Conference on HLA-B27-Related Disorders presented a number of new observations related to the molecular biology of the HLA-B27 molecule, its functional biology as a peptide-binding molecule, and the clinical implications of the association of B27 with the spondylarthropathies, as well as new clinical information concerning these diseases. As a result of the rapid developments in these fields, new insights into the pathogenesis of the B27-related spondylarthropathies will emerge.

Animals↗
PubMed1991

Mechanisms of disruption of the articular cartilage surface in inflammation. Neutrophil elastase increases availability of collagen type II epitopes for binding with antibody on the surface of articular cartilage.

We recently observed that specific antibodies to type II collagen do not bind in appreciable amounts to the intact surface of articular cartilage, whereas antibodies to the minor collagen types V, VI, and IX do. These results suggest that the outermost cartilage surface layer prevented interaction of the antibodies with the major collagen type in articular cartilage. The present studies were designed to investigate the pathogenic mechanisms involved in the disruption of the cartilage surface layer in inflammatory arthritis. Articular cartilage obtained from rabbits undergoing acute antigen-induced arthritis of 72 h duration showed a significant increase in binding of anti-type II antibody to cartilage surfaces compared with normal control cartilage (P less than 0.01). Augmentation of anti-type II binding was also observed upon in vitro incubation of bovine articular slices or intact rabbit patellar cartilage for 1 h with human polymorphonuclear neutrophils (PMN), PMN lysates, or purified human PMN elastase. This increase was not inhibited by sodium azide, nor was it enhanced by incubation of cartilage with the strong oxidant hypochlorous acid. Chondrocyte-mediated matrix proteoglycan degradation in cartilage explants cultured in the presence of cytokines failed to increase antibody binding appreciably. The augmentation in antibody binding seen with PMN lysates was inhibited by the nonspecific serine-esterase inhibitor PMSF, but not by the divalent metal chelator EDTA. The elastase-specific inhibitor AAPVCMK also inhibited most of the PMN-induced increase in antibody binding, whereas the cathepsin G-specific inhibitor GLPCMK was much less effective. Incubation of intact cartilage with purified human PMN elastase indicated that this serine esterase could account for the increase in anti-type II collagen antibody binding to intact cartilage surfaces. These studies suggest that in an inflammatory response, PMN-derived elastase degrades the outer layer of articular cartilage, exposing epitopes on type II collagen. They also help clarify the pathogenic mechanisms involved in early articular cartilage damage in inflammatory joint diseases.

Animals↗
PubMed1990

Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders.

Humans who have inherited the human class I major histocompatibility allele HLA-B27 have a markedly increased risk of developing the multi-organ system diseases termed spondyloarthropathies. To investigate the role of B27 in these disorders, we introduced the B27 and human beta 2-microglobulin genes into rats, a species known to be quite susceptible to experimentally induced inflammatory disease. Rats from one transgenic line spontaneously developed inflammatory disease involving the gastrointestinal tract, peripheral and vertebral joints, male genital tract, skin, nails, and heart. This pattern of organ system involvement showed a striking resemblance to the B27-associated human disorders. These results establish that B27 plays a central role in the pathogenesis of the multi-organ system processes of the spondyloarthropathies. Elucidation of the role of B27 should be facilitated by this transgenic model.

Animals↗
PubMed1990

Analysis of T cell signaling by class I MHC molecules: the cytoplasmic domain is not required for signal transduction.

The structural requirements for signal transduction by class I major histocompatibility complex (MHC) molecules were examined. Native or mutant HLA-A2 or HLA-B27 constructs lacking most of their cytoplasmic domains were co-transfected with pSV2neo into Jurkat cells. Transfection of either native or mutant constructs resulted in a comparable expression of the gene products. Stimulation of transfectants expressing either native or truncated A2 or B27 molecules with specific mAb evoked an increase in [Ca2+]i upon crosslinking. Moreover, crosslinking native or truncated A2 or B27 induced IL-2 production upon co-stimulation with phorbol myristate acetate. These results confirm that crosslinking class I MHC molecules transduces an activation signal to human T cells. Effective signaling was observed when all but four of the intracytoplasmic residues were deleted, indicating that signal transduction does not require this portion of the molecule.

Animals↗
PubMed1990

In vitro mutagenesis of HLA-B27. Amino acid substitutions at position 67 disrupt anti-B27 monoclonal antibody binding in direct relation to the size of the substituted side chain.

The class I MHC molecule HLA-B27 bears an unpaired Cys residue at position 67, which is predicted to face the Ag binding pocket, based on the x-ray crystallographic model of HLA-A2. To investigate the potential of this residue in the antigenic structure of HLA-B27, a panel of 11 mutant HLA-B27 genes has been created, each bearing a separate amino acid substitution at position 67. The genes were transfected into mouse L cells and the resulting cells analyzed by cytofluorography with a panel of antibodies reactive with the wild-type B27 molecule. Although previous studies had indicated that all mAb that bound the B27 molecule on human lymphocytes bound comparably to L cells transfected with the wild-type B27 gene in the absence of h beta 2-m (human beta 2-microglobulin), the first of the mutant B27 genes was found to express several mAb epitopes in the presence but not in the absence of a h beta 2-m gene. Therefore, subsequent analysis of the B27 mutant panel was conducted in L cells coexpressing the h beta 2-m gene. Under these circumstances, all of the mutants bound the monomorphic anti-class I HLA mAb W6/32 and B.9.12.1, as well as the broadly polymorphic mAb B.1.23.2. Binding to the mutant transfectants of three anti-B27 mAb that cross-react with HLA-B7, ME1, GS145.2, and GSP5.3, was directly proportional to the size of the substituted amino acid side chain. The binding of another anti-B27 mAb, B27M2, that recognizes a B27 determinant that includes the region of amino acids 77-81, was not affected by the Cys67- greater than Tyr67 substitution. Rabbit antibodies to a synthetic peptide composed of B27 amino acids 61-84 bound to both the wild-type B27 and to the Tyr67 mutant. This binding, but not the binding of ME1 or B27M2, was inhibited by the synthetic peptide. These data are interpreted as suggesting that the large amino acid substitutions at position 67 induce a limited conformational change that disrupts the epitopes of the three anti-B27, B7 mAb, that are themselves at least partially conformational. The potential implications of these findings for the role of HLA-B27 in disease pathogenesis are discussed.

Amino Acid Sequence↗
PubMed1988

Studies of HLA-B27-associated disease.

Several rheumatic diseases were first shown to be associated with human leukocytic antigen (HLA)-B27 in 1973. Recent developments in understanding this association include the finding that there are at least six variants of HLA-B27 at the molecular level, with no one variant preferentially associated with disease. Detailed studies of the structure of the HLA-B27 molecular family are in progress in several laboratories. Mice expressing HLA-B27 and transmitting it to their offspring (transgenic mice) have been produced and are being studied for their response to bacteria that are known to trigger reactive arthritis in B27+ humans. A particular restriction fragment length polymorphism was recently claimed to be a genetic marker for an additional risk factor in ankylosing spondylitis, but two other laboratories have failed to confirm this finding.

Animals↗
PubMed1988

HLA-B27 in inbred and non-inbred transgenic mice. Cell surface expression and recognition as an alloantigen in the absence of human beta 2-microglobulin.

A gene encoding the H chain of the human class I MHC Ag HLA-B27 was introduced into the germ lines of inbred C57BL/6 (B6) and non-inbred (B6 X SJL/J) F2 mice. By immunofluorescence and flow cytometry, the HLA-B27 gene product was expressed on lymphoid cells at levels comparable to the endogenous H-2b and H-2s class I MHC molecules. In both primary and secondary MLC between responder spleen cells from non-transgenic (B6 X SJL/J) F1 mice and transgenic stimulator cells, CTL were generated that specifically lysed mouse L cell (H-2k) or human B cell targets expressing HLA-B27, and this lysis thus appeared largely unrestricted by H-2. These results indicate that transgenic mice express a functional HLA-B27 gene product on cell surfaces in the absence of the human beta 2-microglobulin gene. These transgenic mice promise to be a valuable resource in the investigation of the unique role of HLA-B27 in inflammatory human disease.

Animals↗
PubMed1988

Adjuvant arthritis.

Explore the source record for details and available documents.

Adjuvants, Immunologic↗
PubMed1988

In vitro mutagenesis of HLA-B27. Substitution of an unpaired cysteine residue in the alpha 1 domain causes loss of antibody-defined epitopes.

The HLA class I molecules identified serologically as HLA-B27 are highly associated with ankylosing spondylitis and related human disorders. All known HLA-B27 amino acid sequences contain a cysteine residue at position 67; no other published HLA class I sequence contains a cysteine within the hypervariable region of the alpha 1 domain, which extends from amino acid residues 63-84. To investigate the role of this cysteine residue in the antigenic structure of HLA-B27, we isolated a genomic clone encoding a molecule of the HLA-B27.1 subtype and performed oligonucleotide-directed mutagenesis to convert the cysteine at position 67 to a tyrosine. When transfected into mouse L cells, both the wild-type and Cys67----Tyr67 mutant B27 genes directed the synthesis and surface expression of molecules reactive with the monomorphic anti-HLA class I antibody W6/32. However, only the L cells transfected with the wild-type B27 gene reacted with the anti-B27 antibody ME1; L cells transfected with the mutant B27 were completely unreactive with this antibody. Experiments with hybrid exons created from the HLA-B27 and HLA-A2 genes yielded results consistent with the mapping of the ME1 epitope to the B27 alpha 1 domain. A second anti-B27 antibody, GS145.2, also showed markedly reduced binding to the Cys67----Tyr67 mutant. These studies document the importance of the unique Cys67 residue in the antigenic structure of HLA-B27.

Amino Acid Sequence↗
PubMed1988

Restriction fragment length polymorphism of T cell receptor alpha and beta chain genes in patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is very strongly associated with the class I major histocompatibility (MHC) antigen HLA-B27. Because class I MHC antigens function as restricting elements recognized by T cell antigen receptors, we sought to determine if there is preferential association between AS and particular T cell (TcR) alleles. In 49 patients with AS and 23 controls, we determined the frequencies of restriction fragment length polymorphisms linked to genes encoding the TcR alpha and beta chain constant regions. There was no significant difference between patients with AS and controls with respect to the frequencies of possible TcR genotypes. Although T cells may play a role in the pathogenesis of AS, these results provide no evidence for a distinctive germline T cell repertoire associated with AS.

Alleles↗
PubMed1988

Association between ankylosing spondylitis and a 9.2 kb Pvu II class I HLA DNA restriction fragment: a reassessment.

Recently, McDaniel, et al (Arthritis Rheum 1987;30:894) reported a statistically significant association between ankylosing spondylitis (AS) and the presence in Pvu II digested genomic DNA of a 9.2 kb restriction fragment hybridizing with an HLA-B7 cDNA probe. The fragment was found in 35 of 48 unrelated HLA-B27+ Caucasian patients with primary AS and in 25 of 107 controls. We report finding this restriction fragment in only 10 of 33 such patients and in 17 of 41 controls. We are thus unable to confirm an association between AS and the restriction fragment identified by McDaniel, et al.

Autoradiography↗
PubMed1985

Synergy between adjuvant arthritis and collagen-induced arthritis in rats.

Adjuvant arthritis (AA) in rats is susceptible to cell-mediated passive transfer. Collagen-induced arthritis (CIA) in rats is susceptible to passive transfer with antibody to type II collagen. We report here the development of strikingly severe arthritis in Lewis rats as the result of synergy between passively transferred antibody to type II collagen from rats with CIA and concanavalin A (Con A)-stimulated lymph node or spleen cells from syngeneic rats with AA. Similar synergy was seen in rats with AA given anticollagen antibody, in rats with CIA given Con A-stimulated adjuvant spleen cells, and in rats actively immunized with CII and complete Freund's adjuvant. The synergistic process caused a very severe polyarthritis, characterized by marked swelling and erythema in all the joints of the distal extremities, with histologic and radiographic evidence of early, extensive erosion of articular cartilage. Synergy was apparent if the lymphoid cells from AA rats were given up to 1 mo after a single injection of anticollagen antibody. No synergy was seen when normal rat immunoglobulin or anti-ovalbumin antibody was substituted for anticollagen antibody, when Con A-stimulated lymphoid cells from normal rats or donors with CIA were used, or when Con A-stimulated AA lymphoid cells were irradiated before transfer. Synergy between separate immune effector mechanisms may represent a general phenomenon in the pathogenesis of inflammatory joint disease.

Animals↗