Performing arts rheumatology.
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Cumulative Trauma Disorders↗
Biomedical subjects
J M Greer
Publications and source records attributed to J M Greer.
A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire.
Previously, six T cell clones, which are specific for an encephalitogenic determinant of myelin proteolipid protein (PLP) peptide residues 139 to 151 (HSLGKWLGHPDKF), were derived from SJL mice and shown to use diverse TCR genes. To design TCR antagonist peptides that could interfere with the activation of these clones in vitro and inhibit experimental allergic encephalomyelitis (EAE) in vivo, we first determined the TCR and MHC contact residues of the encephalitogenic peptide. The analysis indicated that residues 144 (tryptophan) and 147 (histidine) were the TCR binding sites and that residues 145 (leucine) and 148 (proline) were important for MHC class II (IAs) binding. On the basis of this information, a peptide analogue (leucine 144/arginine 147), in which both of the major TCR contact residues were substituted, was synthesized. This analogue acts as a TCR antagonist for the panel of PLP 139-151-specific T cell clones, does not cause EAE by itself, blocks the induction of disease by the native 139-151 peptide, and prevents clinical disease progression if administered at the first signs of disease. Thus, although multiple TCR genes are used by PLP 139-151-specific clones, a single peptide analogue can interfere with the disease process. This approach should be feasible for designing peptide analogues that can be tested for therapeutic efficacy in human autoimmune diseases in which the pathogenic Ags are known and TCR use is diverse.
Amino Acid Sequence↗
Immunolocalization of proteolipid protein peptide 103-116 in myelin.
Determination of the topographic orientation of proteolipid protein (PLP) within myelin is part of an overall understanding of the functions of PLP and the roles of its multiple domains in diseases that primarily affect central nervous system (CNS) myelin. As part of an analysis of PLP orientation, two mouse monoclonal antibodies (mAb) and a rabbit antiserum against a synthetic peptide corresponding to PLP residues 103-116 (YKTTICGKGLSATV) were tested for their reactivity on compact CNS myelin. By ELISA, the antibodies react with intact PLP and PLP residues 103-116, but not with other PLP peptides. Ultrathin cryosections of adult rat optic nerve were immunostained and antibody binding was localized using appropriate second antibodies coupled to 1 nm gold particles that were visualized by silver enhancement. Localization of the particles on the major or intermediate dense lines was determined by three independent observers. Using the PLP peptide mAb and the polyclonal antibody, we demonstrated that > or = 71% of the particles were localized on the major dense line. At least 66% of particles directed against myelin basic protein, which is known to occur on the major dense line, were also found in that location. These semiquantitative morphologic observations suggest that PLP residues 103-116 occur on the cytoplasmic face of the myelin membrane.
Amino Acid Sequence↗
Minireview: autoimmune responses to myelin proteolipid protein.
The authors present a brief historical sketch of the development of our understanding of immune responses to myelin proteolipid protein (PLP) and the acceptance of PLP as a potent antigen in the induction of experimental allergic encephalomyelitis (EAE). The distinct characteristics of the PLP molecule that may contribute to complex immune responses to this protein are reviewed and these responses are compared with those to MBP, both in the pathology of EAE and at the level of the T cell. Recent evidence demonstrating differences between T cell responses to PLP and MBP is reviewed. Finally, the potential contribution of immune responses to PLP in human diseases, particularly multiple sclerosis (MS), that have been identified to date are then summarized.
Amino Acid Sequence↗
Musculoskeletal problems of performing artists.
We have reviewed the frequency and variety of rheumatic problems among performing artists. For instrumentalists, injuries are related to the type of instrument played, the technique used and the effort expended in the quest for excellence. For dancers, musculoskeletal problems too reflect technique and effort. We should not be surprised at the frequency of these problems. Rheumatologists, as well as orthopaedic surgeons, physiotherapists, neurologists and other physicians, encounter performing artists as patients. We should be familiar with their problems and be able to knowledgeably diagnose and manage them. This may include observing the artist during actual performances. How is the instrument being held? What is the posture of the artist? What are the comments of the coach or teacher. What type of shoes does the ballerina wear? What movements in particular cause discomfort? These and similar observations will have direct bearing on the musculoskeletal problems of these artists. Published studies have related the variety, frequency and disabling nature of performance-related musculoskeletal problems. Unfortunately few if any of these are controlled, blinded or prospective. We need more and better information. We will want clear information about prevalence of problems, better definition of the musculoskeletal ailments, classification of the relationship of problems with performance and individual biomechanical features, information about response of specific problems to interventions, and data about the long-term consequences, if any, of these rheumatic problems to the musculoskeletal system. Artists as patients are unique. Minor problems can become potentially career-ending disabilities. Making music or performing dance may provide us with delightful entertainment but represents a source of livelihood to artists. Understanding their medical needs and enabling them to continue to perform is the challenge before us.
Adult↗
Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T cell clones to mediate experimental allergic encephalomyelitis.
We have derived a panel of CD4+, TCR-alpha/beta + T cell clones from SJL (H-2s) mice specific for an encephalitogenic determinant of myelin proteolipid protein (PLP) 139-151 (HSLGKWLGHPDKF). All the clones are Ag specific and IAs restricted, but they show heterogeneity in their ability to induce experimental allergic encephalomyelitis (EAE), i.e., one group induces EAE in naive mice, a second group induces disease only in mice that are pretreated with pertussis and irradiation, whereas a third group is essentially nonencephalitogenic. To determine the basis for this functional heterogeneity, the clones were tested for the expression of adhesion molecules and cytokines and for Ag-specific cytolytic activity. All of the clones expressed comparable levels of LFA-1 and CD44 but lacked expression of Mel 14. However, those clones that induced EAE only in irradiation- and pertussis-treated recipients did not express VLA4. Because pretreatment with pertussis has been suggested to increase permeability of the blood-brain barrier and facilitate migration of T cells into the central nervous system, the absence of VLA4 on this group of clones may account for the need for pretreatment to induce EAE. The nonencephalitogenic clones expressed all of the adhesion molecules tested but were not cytolytic in vitro and failed to produce one or more of the proinflammatory cytokines after Ag-specific stimulation. One nonencephalitogenic clone that did not produce many cytokines on activation with specific Ag, however, could be activated with Con A to express mRNA for most cytokines and this was accompanied by a concomitant change in the encephalitogenic potency of this clone. These results suggest that adhesion molecules and cytokines both play a critical role in the encephalitogenicity of PLP peptide-specific T cell clones. Furthermore, the nonencephalitogenicity of some clones may be related to a defect in Ag-mediated activation.
Amino Acid Sequence↗
Sequence heterogeneity and polymorphic gene arrangements of the Leishmania guyanensis gp63 genes.
The Leishmania GP63 major surface protein gene family encodes multiple isoforms which differ predominantly in the carboxyterminal region. We have isolated 4 full-length gp63 cDNA clones derived from stationary-phase promastigote RNA of a cloned isolate of Leishmania guyanensis, a member of the braziliensis complex. These genes, along with the previously published L. guyanensis gp63 gene sequence [15], appeared to be mosaics of different combinations of 5' and 3' untranslated regions and sequences encoding the propeptide, internal, and C-terminal regions of GP63. The predicted L. guyanensis GP63 isoforms shared as little as 55% sequence identity, comparable to the inter-species diversity of GP63. The genomic organization of gp63 genes in L. guyanensis is highly complex: there are at least 4 distinct polymorphic forms of tandemly linked gene clusters, with intra-gene cluster variation in gene sequence and in the number of gene repeats. Southern blot analysis suggested that the arrangement of gp63 genes in this L. guyanensis isolate did not differ from that in the parental lines.
Amino Acid Sequence↗
The 3G11+ antigen, a marker for murine CD4+ TH1 lymphocytes, is a ganglioside.
Two monoclonal antibodies (mAbs), SM3G11 and SM6C10, can be used to discriminate between functionally distinct murine CD4+ T cell subsets. In this study we use high-performance thin-layer chromatography and immunostaining techniques to show that the 3G11 mAb reacts with two bands of a ganglioside fraction from murine spleen and thymus, and rat spleen. The 6C10 antibody shows no evidence of glycolipid reactivity. The 3G11+ bands have a mobility between those of the reference gangliosides GD1a and GD1b from human brain. The 3G11+ reactive bands were eluted in the disialyl fraction of rat spleen gangliosides using DEAE anion-exchange chromatography. Treatment of spleen gangliosides with endoglycoceramidase eliminates 3G11 antibody binding over time, indicating that the antigen contains a Glc beta 1-1'ceramide linkage, characteristic of a glycosphingolipid. Treatment of thymus or spleen gangliosides with sialidase eliminates binding of 3G11, thus indicating that the 3G11 epitope is dependent on the expression of one or more sialic acid residues. Immunostaining studies with a variety of reagents indicate that the 3G11+ gangliosides: (i) probably do not contain either the asialo-GM1 or the GM1 core structures; (ii) are not recognized by mAbs specific for the oligosaccharides of asialo-GM2, GM2, GD2 and GD3 gangliosides; and (iii) are also not recognized by antibodies or reagents that are specific for several structures representative of other major glycosphingolipid classes. Overall, these studies strongly suggest that the 3G11+ gangliosides have structures that have not been previously recognized in murine lymphoid tissue. Structures that could account for the known properties of the 3G11+ molecules are described. Finally, ways in which the selective expression of 3G11+ gangliosides might be linked to functionally distinct T-cell behaviours are discussed.
Animals↗
What is lupus? What is not lupus?
Present understanding suggests that lupus reflects a spectrum of syndromes that share many clinical, inflammatory, and immunologic features. Those patients not fulfilling criteria for systemic lupus erythematosus (SLE) do not seem to evolve frequently to classic SLE, tend to have a good prognosis, and may be managed conservatively. This is important for clinical management. Whether this pertains to etiopathogenesis is speculative and will await information not yet available.
Antibodies, Antinuclear↗
Sweet's syndrome with an exogenous cause.
A sixty-six-year-old white man presented with a five-day history of painful erythematous papules, plaques, pustules, and hemorrhagic bullae on both hands. His history was remarkable for having prepared and pickled fifteen quarts of home-grown jalapeño peppers several days before the eruption occurred. The light microscopic examination of sections of lesional skin stained with hematoxylin and eosin revealed pathologic findings characteristic of Sweet's syndrome. We report this case because of its unusual presentation and apparent exogenous cause.
Aged↗
Identification and characterization of a second encephalitogenic determinant of myelin proteolipid protein (residues 178-191) for SJL mice.
We previously described a synthetic peptide of myelin proteolipid protein (PLP), peptide 139-151, which induces experimental allergic encephalomyelitis in SJL/J (H-2s) mice. We have now identified an additional determinant, PLP residues 178-191, that is also a potent encephalitogen in this strain. When PLP peptide 178-191 was compared with peptide 139-151 on an equimolar basis, the day of onset of disease induced by PLP 178-191 was earlier, but the incidence, severity, and histologic features were indistinguishable. Lymph node cells from animals immunized with the whole PLP molecule responded to both PLP 178-191 and 139-151, suggesting immunologic codominance of the two epitopes. PLP 178-191 elicited stronger proliferative responses and this may relate to the earlier onset of disease induced with this peptide. Two CD4+, peptide-specific, I-A(s)-restricted T cell lines, selected by stimulation of lymph node cells with either PLP 178-191 or 139-151, were each encephalitogenic in naive syngeneic mice. The presence of multiple encephalitogenic codominant PLP epitopes within a single mouse strain emphasizes the complexity of the immune response to PLP and its potential as a target Ag in autoimmune demyelinating diseases.
Amino Acid Sequence↗
Effects of anti-idiotype vaccine on tumour growth and on production of soluble factors modulating cell-mediated immunity in vitro.
The previous observation, that single i.p. doses of a monoclonal anti-idiotypic antibody (MAIA) injected into BALB/c mice induced suppressor factors, was extended to multiple i.v. doses. These induced enhancing factors, which were produced in spleen cell cultures, required L3T4+ cells for their formation, lacked the IJ marker, and bound to anti-immunoglobulin, showing them to be antibodies. Selective immunoabsorption demonstrated two separate enhancing antibodies; both bound to MAIA but they had different affinities for specific and non-specific tumour antigens. Subsequently, single and multiple MAIA doses were tested in vivo for their effects on tumour growth. The single doses had variable effects depending on time of administration, and these effects were tumour-specific; the multiple doses strongly inhibited tumour growth when given before tumour challenge, but also had non-specific effects on another tumour as anticipated from the in vitro results.
Animals↗
Distinctive molecular markers and biological activities in two tumour-specific murine T suppressor factors.
Murine suppressor factors (SF) in tumour-bearer serum (TBS) and tumour-bearer spleen cell culture supernatants (SCCS) were compared with regard to their molecular markers, cellular requirements and suppressive activities. Suppressor factors in SCCS bear the idiotype I-J, and markers recognized by B16G and anti-lipomodulin antibodies require Ly2+ I-J+ cells for their production and cells of the same phenotypes, for suppression to be manifested in leucocyte adherence inhibition (LAI) assays, are not immunoglobulin (Igh)-restricted and are active in both the afferent and efferent phases of the immune response. Suppressor factors from TBS resemble those from SCCS with regard to idiotype, I-J and lipomodulin-like markers, but in contrast, do not bind to B16G antibody, require Ly2+ but not I-J+ cells for suppression to be manifested in LAI assays, are Igh-restricted, and suppress delayed-type hypersensitivity (DTH) reactions only when injected in the afferent phase. These results show that the SF from the different sources in tumour-bearing mice are not identical; they may be different parts of a suppressor cascade, or they may belong to entirely separate suppressor cascades.
Animals↗
Comparison of T suppressor factors from tumour-bearing mice and mice immunized with a monoclonal anti-idiotypic antibody.
Certain dosage schedules of a monoclonal anti-idiotypic antibody (related to a murine bladder carcinoma) were found to induce suppressor factor production by syngeneic mice. This suppressor factor resembled the factor from tumour-bearing mice with respect to idiotype specificity, possession of molecular markers (reactive with anti-IJ and B16G antibodies) and production by Lyt2+IJ+ T cells in spleen cell cultures. The two factors differed with respect to Igh restriction in an in vitro assay (leucocyte adherence inhibition) and ability to suppress the induction of delayed-type hypersensitivity to tumour antigen.
Animals↗
Magnetic resonance imaging in patients with inflammatory arthritis of the knee.
Magnetic resonance imaging (MRI) permits visualization of anatomic structures not appreciated by conventional radiographic imaging and may quantify inflammatory disease and its progression with greater sensitivity than available techniques. We therefore compared MRI with clinical evaluation and with radiographic examination of 17 patients with inflammatory arthritis of the knee. We sought to determine anatomic integrity of bone, cartilage, menisci, and ligaments, and to quantify joint effusion and synovial proliferation. Patients studied had rheumatoid arthritis (10 patients), juvenile rheumatoid arthritis (4 patients), ankylosing spondylitis (1 patient), and monoarticular arthritis (2 patients). In all patients MRI revealed clinically important abnormalities not detected by physical or conventional radiographic exams. These included proliferative synovitis (13 patients), cartilage thinning (2 patients), cartilage erosion (8 patients), bone infarction (1 patient), meniscal injury (1 patient), and synovial invagination into bone (1 patient). Also MRI indicated inflammatory disease to be quantitatively greater than had been appreciated on clinical examination or routine X-ray studies--proliferative synovitis (12 patients), erosion (7 patients), effusion (8 patients), cartilage thinning (11 patients), and ligamentous/meniscal damage (1 patient). These findings led to reassessment of anatomic staging and influenced therapeutic decision for these patients. Thus MRI provides clinically important information about joint integrity and inflammatory disease, with a sensitivity and resolution considerably beyond conventional techniques.
Adult↗
Food induced ("allergic") arthritis: inflammatory synovitis in rabbits.
Progress in understanding rheumatoid (RA) and inflammatory arthritis has been limited in part because there has been no widely accepted animal model of naturally occurring human disease and because the clinical syndrome of RA may reflect the expression of multiple etiologies. We have considered that inflammatory joint disease may be induced and/or exacerbated by food related antigens. To facilitate our investigations, we studied inflammatory synovitis in rabbits induced by oral exposure to environmental antigens. In our preliminary experiments, we examined 9 Florida White, 30 New Zealand White, and 9 Old English rabbits. They were nourished with normal rabbit chow supplemented with either water or cow's milk beginning at age 7 to 26 weeks and observed for 81 to 204 days. Animals were then sacrificed. Histological sections of the knees were examined and graded in a blinded fashion for synovial cell hyperplasia, inflammation, and lymphoplasmocytic infiltration. In addition, serum levels of IgG antimilk, IgG antibovine serum albumin, IgG anticasein, and IgG-C3 complexes were quantified. We found no abnormalities among Florida White rabbits but observed histological synovitis in 53% of the milk fed New Zealand White (9/17), 40% of the water fed Old English (2/5), and all of the milk fed Old English rabbits (4/4) (p = 0.05, milk fed vs water fed animals). Milk fed animals had significantly (p less than 0.0005) greater levels of antibodies and complexes than water fed animals. Our data suggest that environmental antigens may be arthritogenic for some rabbit strains. These observations may provide an important model for the study of inflammatory joint disease analogous to oral, environmental antigen exposure in man.
Animal Husbandry↗
Pathogenesis of Treponema hyodysenteriae: induction of interleukin-1 and tumor necrosis factor by a treponemal butanol/water extract (endotoxin).
Biological activities of lipopolysaccharide-like (LPS-like, phenol/water extract) and endotoxin-like (butanol/water extract) preparations from Trepomena hyodysenteriae were examined. The treponemal phenol/water and butanol/water extracts were less toxic than E. coli LPS for murine peritoneal exudate cells (PECs). The treponemal phenol/water extract did not stimulate the production of interleukin-1 (IL-1) or tumor necrosis factor (TNF) from murine PECs. The treponemal butanol/water extract did induce production of IL-1 and TNF but at doses 5- to 50-fold higher than E. coli LPS. Natural killer cell activity was augmented by the treponemal butanol/water extract but not by the phenol/water extract. Suppression of a splenic anti-SRBC plaque forming cell response was observed when the LPS-like and endotoxin-like preparations from T. hyodysenteriae were administered 24 h prior to injection of the SRBC. These findings indicate that the butanol/water extracted material from T. hyodysenteriae is more biologically active than the phenol/water extracted material and that the treponemal endotoxin may contribute to the inflammatory response of swine dysentery by inducing IL-1 and TNF production.
Animals↗
Comparison of the biological responses induced by lipopolysaccharide and endotoxin of Treponema hyodysenteriae and Treponema innocens.
The chemical composition and classical biologic activities of lipopolysaccharide (LPS; phenol-water) and endotoxin (butanol-water) preparations from virulent Treponema hyodysenteriae and avirulent Treponema innocens were examined. The LPS and endotoxin preparations from T. hyodysenteriae B204 contained approximately 80.9 and 35.2% hexose, 0.12 and 0.45% thiobarbituric acid-reactive compound, and less than 1 and 11.3% protein, respectively. The LPS and endotoxin preparations of T. innocens B1555a contained approximately 56.3 and 37.8% hexose, 0.45 and 0.4% thiobarbituric acid-reactive compound, and less than 1 and 26% protein, respectively. A silver-stained 7.5 to 15% sodium dodecyl sulfate-polyacrylamide gel showed four bands for the T. hyodysenteriae preparations, while the T. innocens preparations failed to resolve into discrete bands on electrophoresis. We determined by the Limulus amebocyte lysate assay that the treponemal preparations had comparable amounts of endotoxin activity when Escherichia coli LPS was used as a standard. The 50% lethal doses of LPS and endotoxin from T. hyodysenteriae for BALB/cByJ mice were 380 and 80 micrograms, respectively. The treponemal preparations were poor adjuvants, failed to induce a dermal Shwartzman reaction, and were not pyrogenic. The treponemal LPS preparations, unlike the endotoxin preparations, were not mitogenic for murine spleen cells. Differences in virulence between the two treponemal species could not be associated with the biologic activities of the respective LPS or endotoxin moieties, but the endotoxin preparations were consistently more active than the purified LPS preparations.
Adjuvants, Immunologic↗