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Biomedical subjects

G C Sharp

Publications and source records attributed to G C Sharp.

At least 19 recordsLinked to original sources
PubMed2005

How much margin reduction is possible through gating or breath hold?

We determined the relationship between intra-fractional breathing motion and safety margins, using daily real-time tumour tracking data of 40 patients (43 tumour locations), treated with radiosurgery at Hokkaido University. We limited our study to the dose-blurring effect of intra-fractional breathing motion, and did not consider differences in positioning accuracy or systematic errors. The additional shift in the prescribed isodose level (e.g. 95 %) was determined by convolving a one-dimensional dose profile, having a dose gradient representing an 8 MV beam through either lung or water, with the probability density function (PDF) of breathing. This additional shift is a measure for the additional margin that should be applied in order to maintain the same probability of tumour control as without intra-fractional breathing. We show that the required safety margin is a nonlinear function of the peak-to-peak breathing motion. Only a small reduction in the shift of isodose curves was observed for breathing motion up to 10 mm. For larger motion, 20 or 30 mm, control of patient breathing during irradiation, using either gating or breath hold, can allow a substantial reduction in safety margins of about 7 or 12 mm depending on the dose gradient prior to blurring. Clinically relevant random setup uncertainties, which also have a blurring effect on the dose distribution, have only a small effect on the margin needed for intra-fractional breathing motion. Because of the one-dimensional nature of our analysis, the resulting margins are mainly applicable in the superior-inferior direction. Most measured breathing PDFs were not consistent with the PDF of a simple parametric curve such as cos4, either because of irregular breathing or base-line shifts. Instead, our analysis shows that breathing motion can be modelled as Gaussian with a standard deviation of about 0.4 times the peak-to-peak breathing motion.

Humans↗
PubMed2001

Expression and regulation of Fas and Fas ligand on thyrocytes and infiltrating cells during induction and resolution of granulomatous experimental autoimmune thyroiditis.

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin-sensitized spleen cells activated in vitro with mouse thyroglobulin, anti-IL-2R, and IL-12. G-EAT lesions reach maximal severity 19-21 days after cell transfer, and lesions almost completely resolve by day 35. Depletion of CD8+ cells delays resolution and reduces Fas ligand (FasL) mRNA expression in thyroids. This study was undertaken to analyze Fas and FasL protein expression in the thyroid during induction and resolution of G-EAT and to determine whether CD8+ cells might regulate Fas or FasL expression in the thyroid. Fas and FasL expression was analyzed by immunohistochemical staining or in situ hybridization in thyroids of mice with or without depletion of CD8+ cells. Fas and FasL proteins were not detectable in normal thyroids, but expression of both proteins increased during development of G-EAT. Fas was expressed primarily by inflammatory cells; some enlarged thyrocytes were also Fas+. Thyrocytes had intense FasL immunoreactvity, and many CD8+ cells were also FasL positive. Depletion of CD8+ cells resulted in decreased FasL expression by thyrocytes and inflammatory cells, but had no effect on Fas expression. TUNEL assay detected many apoptotic inflammatory cells in proximity to thyrocytes. CD8-depleted thyroids had ongoing inflammation with fewer apoptotic infiltrating cells at day 35. Administration of a neutralizing anti-FasL mAb had no apparent effects on development of G-EAT, but anti-FasL was as effective as anti-CD8 in preventing G-EAT resolution. These results suggested that CD8+ T cells and thyrocytes may kill inflammatory cells through the Fas pathway, contributing to G-EAT resolution.

Animals↗
PubMed2001

Induction of experimental autoimmune thyroiditis in IL-12-/- mice.

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by transfer of mouse thyroglobulin (MTg)-sensitized spleen cells activated in vitro with MTg and anti-IL-2R or MTg and IL-12. Previous work suggested that IL-12 was required in vitro for development of G-EAT. To determine whether IL-12 was also required during the induction and/or effector phases, DBA/1 mice with a disrupted IL-12-P40 gene (IL-12(-/-)) were used for EAT induction. Cells from MTg-sensitized IL12(-/-) donors activated in vitro by MTg or MTg and anti-IL2R induced severe EAT in recipient mice. Compared with effector cells from IL-12(+/+) donors, effector cells from IL-12(-/-) donors induced thyroid lesions dominated by lymphocytes with minimal granulomatous changes. Thyroids of recipients of IL-12(-/-) cells expressed less IFN-gamma mRNA and more TGF-beta, IL-4, and IL-10 compared with recipients of IL-12(+/+) cells. When IL-12 was added during in vitro activation, cells from both IL-12(-/-) and IL-12(+/+) donors induced severe G-EAT, and expression of all cytokines except IL-12 was comparable in thyroids of both IL-12(+/+) and IL-12(-/-) recipients. Transfer of cells from IL-12(+/+) or IL-12(-/-) donors into IL-12(+/+) or IL-12(-/-) recipients indicated that IL-12 expressed in thyroids was derived from recipients. Thus, endogenous IL-12 is not absolutely essential for the sensitization and activation of EAT effector cells to induce severe EAT, although it is required in vitro to promote activation of cells to induce severe granulomatous histopathology.

Adoptive Transfer↗
PubMed2001

Transforming growth factor-beta has contrasting effects in the presence or absence of exogenous interleukin-12 on the in vitro activation of cells that transfer experimental autoimmune thyroiditis.

Mouse thyroglobulin (MuTg)-sensitized spleen cells activated in vitro with MuTg induce experimental autoimmune thyroiditis (EAT) in recipient mice with a thyroid infiltrate consisting primarily of lymphocytes. A more severe and histologically distinct granulomatous form of EAT (G-EAT) is induced when donor cells are activated with MuTg together with anti-interferon-gamma (IFN-gamma), anti-interleukin-2 receptor (IL-2R) monoclonal antibody (mAb), and IL-12. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that can both suppress and exacerbate autoimmune diseases and often has inhibitory effects on lymphocytes. To determine if TGF-beta could modulate the in vitro activation of effector cells for G-EAT, TGF-beta was added to cultures of MuTg-sensitized donor spleen cells together with MuTg. Cells activated in the presence of 2 ng/ml TGF-beta induced moderately severe G-EAT in recipient mice. G-EAT induced by cells activated in the presence of TGF-beta was histologically similar but less severe than the G-EAT induced by cells activated in the presence of IL-12. IL-12 and TGF-beta modulate the activation of G-EAT effector cells by distinct mechanisms, as cells activated by TGF-beta could induce G-EAT in the presence of anti-IL-12, and TGF-beta inhibited the effects of IL-12 on EAT effector cells. TGF-beta exerted its activity during the first 24 h of the 72-h culture, whereas IL-12 functioned primarily during the final 24 h of culture. These results indicate that thyroid lesions with granulomatous histopathology can be induced by both IL-12-dependent and IL-12-independent mechanisms, and TGF-beta can exert both positive and negative effects on the effector cells for G-EAT.

Adoptive Transfer↗
PubMed2000

Apoptosis of thyrocytes and effector cells during induction and resolution of granulomatous experimental autoimmune thyroiditis.

Experimental autoimmune thyroiditis (EAT) with granulomatous histopathology (G-EAT) can be induced by cells from mouse thyroglobulin (MTg)-immunized donors activated in vitro with MTg and IL-12. G-EAT lesions reach maximum severity 18-21 days after cell transfer and, if some thyroid follicles remain, lesions almost completely resolve by day 35. CD8(+) cells are required for G-EAT resolution. To begin to determine the mechanisms involved in G-EAT resolution, apoptosis in thyroids was analyzed by TUNEL staining. Apoptotic thyrocytes and inflammatory cells were present in the thyroids of both CD8(+) and CD8-depleted recipient mice at day 19-21. By day 35, apoptotic cells were rare in thyroids of mice whose lesions had resolved; the few apoptotic inflammatory cells were generally in close proximity to thyroid follicles. Thyroids of CD8-depleted mice had ongoing inflammation at day 35 and most apoptotic cells were thyroid follicular cells. The expression of Fas and Fas ligand (FasL) mRNA in thyroids was also determined by RT-PCR in both CD8(+) and CD8-depleted recipient mice. Fas was expressed in normal thyroids and its expression was relatively constant throughout the course of disease. FasL mRNA was not expressed in normal thyroids. FasL mRNA expression generally correlated with G-EAT severity, being maximal at day 21 and diminishing as lesions resolved. However, FasL mRNA expression in thyroids of CD8-depleted mice in which resolution was delayed was decreased compared to thyroids of CD8(+) mice with comparable disease severity, suggesting that FasL expressed by CD8(+) cells may play a role in G-EAT resolution.

Animals↗
PubMed2000

Adoptive transfer murine model of granulomatous experimental autoimmune thyroiditis.

Experimental autoimmune thyroiditis (EAT) is a chronic inflammatory autoimmune disease that can be induced in genetically susceptible animals by immunization with mouse thyroglobulin (MTg) in an appropriate adjuvant or by the adoptive transfer of MTg-sensitized donor spleen cells, activated in vitro with MTg, into naive recipients. In the adoptive transfer model used in our laboratory, donor cells activated with MTg alone induce a relatively mild chronic lymphocytic form of EAT (L-EAT), in which the thyroid infiltrate consists primarily of mononuclear cells, and the thyroid inflammation persists for several months. When the same donor cells are activated with MTg together with anti-IL-2R and/or IL-12, a more severe and histologically distinct granulomatous form of EAT is induced in recipient mice. In addition to having distinct histopathologic features, granulomatous EAT (G-EAT) differs from L-EAT in that granulomatous thyroid lesions are not chronic. After reaching maximal severity 21 days after cell transfer, G-EAT thyroid lesions either resolve or the thyroids become atrophic and fibrotic by day 35. In this review, the histopathologic features of G-EAT and L-EAT are described, and our studies with the adoptive transfer G-EAT model which have focused on the mechanisms involved in induction of G-EAT in mice, and the evolution of G-EAT lesions to resolution of inflammation or fibrosis, are reviewed.

Adoptive Transfer↗
PubMed2000

Characterization of thyroid fibrosis in a murine model of granulomatous experimental autoimmune thyroiditis.

This study was initiated to identify and characterize thyroid fibrosis in a murine model of granulomatous experimental autoimmune thyroiditis (G-EAT) and determine if TGF-beta1 might be involved in fibrosis. G-EAT was induced by transfer of mouse thyroglobulin-sensitized spleen cells activated in vitro with thyroglobulin, anti-IL-2R, and IL-12. There was almost complete destruction of thyroid follicles, leading to fibrosis of the gland and reduced serum T4 levels. Fibrosis was confirmed by staining for collagen and alpha smooth-muscle actin, a marker of myofibroblasts. Kinetic studies characterized the onset and development of thyroid fibrosis. TGF-1beta was increased at mRNA and protein levels, and expression of TGF-beta1 protein paralleled G-EAT severity. Comparison of staining patterns showed that TGF-beta1 was expressed in areas of myofibroblast and collagen accumulation, implying that TGF-beta1 may play a role in fibrosis in G-EAT. Further studies demonstrated that myofibroblasts, macrophages, and thyrocytes contributed to TGF-beta1 production. This provides an excellent model to study the mechanisms of fibrosis associated with autoimmune damage.

Actins↗
PubMed1999

Human RNA helicase A is a lupus autoantigen that is cleaved during apoptosis.

Proteolytic cleavage by caspases is the central event in cells undergoing apoptosis. Cleaved proteins are often targeted by autoantibodies, suggesting that the cleavage of self Ags enhances immunogenicity and is prone to induce an autoimmune response. We found autoantibodies that immunoprecipitated a 140-kDa RNA-associated protein, provisionally designated Pa, in 11 of 350 patient sera that were positive for antinuclear Abs in an immunofluorescence test. The Pa protein gave rise to three fragments with m.w. ranging from 120-130 kDa during anti-Fas-activated apoptosis. Pure caspase-3 cleaved the Pa protein into a 130-kDa fragment corresponding to the largest of these three products. Peptide sequence analysis of a tryptic digest from immunoaffinity-purified Pa showed 100% identity to human RNA helicase A (RHA). The identity of Pa with RHA was further confirmed by immunoblotting with rabbit anti-RHA Ab using anti-Pa immunoprecipitates as substrates. All 10 anti-RHA-positive patients who were clinically analyzed were diagnosed as having systemic lupus erythematosus, and 7 of them had lupus nephritis. RHA is a multifunctional protein with roles in cellular RNA synthesis and processing. Inactivation of RHA by cleavage may be an important part of the process leading to programmed cell death. The cleaved RHA fragments that are produced during apoptosis may trigger an autoimmune response in systemic lupus erythematosus.

Amino Acid Sequence↗
PubMed1999

B7.2 has opposing roles during the activation versus effector stages of experimental autoimmune thyroiditis.

APCs provide costimulatory and down-regulatory signals to Ag-activated T cells through interactions between B7.1 and B7.2 on APCs with either CD28 or CTL Ag-4 expressed on T cells. Recipients of mouse thyroglobulin (MTg)-primed spleen cells activated in the presence of anti-B7.2 had decreased experimental autoimmune thyroiditis (EAT) severity compared with recipients of cells cultured with control rat Ig or anti-B7.1. Blocking B7.2 during in vivo priming also suppressed the ability of MTg-primed spleen cells to transfer EAT, implicating a role for B7.2 for priming and in vitro activation of EAT effector cells. In contrast, administration of anti-B7.2 or anti-B7.2 Fab to recipients of MTg-activated spleen cells increased the severity of EAT compared with recipients receiving control Ig. Thyroids from anti-B7.2-treated recipients had increased expression of IL-4 mRNA compared with thyroids from rat Ig-treated controls. Both B7.1 and B7.2 molecules were expressed in the thyroids of mice with EAT, although B7.2 was more prevalent than B7.1. Administration of both anti-B7.1 and anti-B7.2 to recipient mice suppressed the development of EAT, while anti-B7.1 treatment alone had no effect on EAT severity. The suppression of EAT was not observed when anti-B7.1 and anti-B7.2 treatment was delayed until 7 days after cell transfer, suggesting a requirement for B7 in the initiation of EAT in recipient mice. These results suggest that costimulation is required during the effector phase of EAT and that B7.2 may have opposing roles in the activation versus effector stages of autoreactive T cells.

Abatacept↗
PubMed1999

Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings.

OBJECTIVE: To determine the long-term clinical and immunologic outcomes in a well-characterized cohort of 47 patients with mixed connective tissue disease (MCTD), including reactivity with U small nuclear RNP (snRNP) polypeptides. METHODS: Patients were followed up over a period of 3-29 years with immunogenetic and systematic clinical and serologic analysis. Sera were analyzed for reactivity with snRNP polypeptides U1-70 kd, A, C, B/B', and D, for anti-U1 RNA, and for anticardiolipin antibodies (aCL). RESULTS: The typical core clinical features of MCTD tended to develop over time; features of inflammation as well as Raynaud's phenomenon and esophageal hypomotility diminished, while pulmonary hypertension, pulmonary dysfunction, and central nervous system disease persisted, following treatment. A favorable outcome was observed in 62% of patients; 38% had continued active disease or had died, with death associated with pulmonary hypertension and aCL. All patients had autoantibodies to the U1-70 kd polypeptide of snRNP, and most were positive for anti-U1 RNA. An orderly progression of intramolecular spreading of autoantibody reactivity against snRNP polypeptides was observed, as was the novel finding of "epitope contraction" followed by disappearance of anti-snRNP autoantibodies during prolonged remission. CONCLUSION: These patients demonstrated the typical immunogenetic, clinical, and serologic findings of MCTD, and the condition rarely evolved into systemic lupus erythematosus or systemic sclerosis. The majority of patients had favorable outcomes, with pulmonary hypertension being the most frequent disease-associated cause of death. Intramolecular spreading of autoantibody reactivity against snRNP polypeptides was observed, followed by "epitope contraction" and ultimate disappearance of anti-snRNP autoantibodies during prolonged disease remission.

Autoantibodies↗
PubMed1999

Diverse antibody recognition patterns of the multiple Sm-D antigen polypeptides.

Anti-Sm antibodies are intrinsically associated with systemic lupus erythematosus. The major targets are the so-called B and D polypeptides. The number of Sm targets increased upon the report that SDS-PAGE conditions could be manipulated to display not one, but three Sm-D polypeptides. To characterize the relative reactivities of Sm-D1, Sm-D2, and Sm-D3, both human and murine autoantibodies were screened. These sera displayed two distinct patterns of reactivity. The Sm-D1/D3 pattern was at least four times more common than Sm-D1/D2/D3 recognition. The predominant immunoreactive protein was Sm-D1. We screened over 40 monoclonal antibodies that were derived from MRL mice and were selected as anti-Sm positive. Of these, 27 reacted with at least one Sm-D polypeptide by protein blot, but in contrast to the MRL sera, none of these antibodies reacted with Sm-D2. Rather, there were two recognition patterns of approximately equal abundance, against Sm-D1/D3 or Sm-D1 alone. Last, we explored the immune response to isolated Sm-D (containing all three D antigens) from rabbit thymus. The autoantibody produced reacted only with Sm-D2. There is accumulating evidence that the anti-Sm response is at least partially antigen-driven. The details of the intragroup relationships within the Sm-D family of proteins provide further insight into the Sm autoimmune response.

Animals↗
PubMed1999

Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice.

NOD.H-2h4 mice, which express I-Ak on the NOD genetic background, spontaneously develop autoimmune thyroiditis (SAT) and anti-mouse thyroglobulin (MTg) autoantibodies. The incidence of SAT is nearly 100% in mice of both sexes 6-8 weeks after administration of 0.05% NaI in the drinking water. After reaching maximum severity, inflammation is chronic over the next 3-4 months. All mice that develop thyroid lesions also produce MTg-specific IgG1 and IgG2b autoantibodies. Thyroid lesions and anti-MTg autoantibodies did not develop in CBA/J (H-2(k)) or NOD.SWR(H-2(q)) mice after administration of NaI water. Both CD4(+)and CD8(+)T cells are involved in the initial development of SAT. Depletion of CD4(+), but not CD8(+), T cells after thyroid lesions have developed also markedly reduced SAT severity, indicating that CD4(+)T cells are required for both developing and maintaining SAT. Analysis of cytokine gene expression indicated that both Th1 and Th2 cytokines were expressed in thyroids of NOD.H-2h4 mice with SAT. Th1 and proinflammatory cytokines were maximally expressed 4-6 weeks after mice began receiving NaI water, while Th2 cytokine gene expression was greatest at 8-15 weeks, when lesions had reached maximal severity and were in the chronic phase. TGF-beta was highly expressed in NOD.H-2h4 thyroids, irrespective of whether the mice had received NaI water or had thyroid lesions.

Animals↗
PubMed1998

IFN-gamma-deficient mice develop severe granulomatous experimental autoimmune thyroiditis with eosinophil infiltration in thyroids.

To study the role of IFN-gamma in the development of granulomatous experimental autoimmune thyroiditis (EAT), DBA1 mice with a disrupted IFN-gamma gene were used for adoptive EAT induction. Effector cells from either IFN-gamma(+/+) or IFN-gamma(-/-) donor mice activated with mouse thyroglobulin and anti-IL-2R mAb induced severe granulomatous EAT. A predominant infiltration of the thyroid by eosinophils was observed in recipients of IFN-gamma(-/-) effector cells but not in recipients of IFN-gamma(+/+) cells. Compared with wild-type mice, thyroids of recipients of IFN-gamma(-/-) effector cells had decreased expression of mRNA for Th1 cytokines and inducible nitric oxide synthetase. Expression of Th2 cytokine mRNA was comparable to that of IFN-gamma(+/+) mice, and expression of eotaxin was increased in the thyroids of recipients of IFN-gamma(-/-) effector cells. Activation of cells from either IFN-gamma(+/+) or IFN-gamma(-/-) donors in the presence of IL-12 also induced severe granulomatous EAT. Eosinophil infiltration in recipients of IFN-gamma(-/-) cells was unaffected when effector cells were activated with IL-12, and thyroids expressed predominantly Th2 cytokines. The extent of fibrosis of recipient thyroids was generally greater when donor IFN-gamma(+/+) and IFN-gamma(-/-) cells were activated with IL-12. Compared with IFN-gamma(+/+) mice, IFN-gamma(-/-) mice produced lower levels of mouse thyroglobulin-specific autoantibodies after immunization with MTg and LPS. These results indicate that cells from both IFN-gamma(+/+) and IFN-gamma(-/-) donors can induce severe granulomatous EAT. However, damage of thyroid follicles by IFN-gamma(-/-) and that by IFN-gamma(+/+) cells appear to involve different mediators of inflammation.

Animals↗
PubMed1998

Effects of prolactin in stimulating disease activity in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE), a chronic autoimmune illness, is influenced by hormones. High prolactin concentrations were associated with early death from autoimmune renal disease in NZB/NZW mice, an animal model of severe SLE. NZB/NZW mice that delivered and nursed pups and those that underwent pseudopregnancy had changes in serum IgG and autoantibodies. NZB/NZW mice treated with the prolactin-suppressing drug bromocriptine had prolonged lives. Elevated serum prolactin concentrations are reported in SLE patients of both sexes. We found four women with long-standing hyper-prolactinemia who developed SLE. A survey of premenopausal women whose sera were submitted for autoantibody testing showed that 20% with anti-ds-DNA antibodies also had high prolactin levels. Many hyperprolactinemic patients whose sera were referred to an endocrinology laboratory had positive FANA tests (women 33%, men 53%) but did not have SLE. Disease activity was suppressed in six of seven SLE patients treated with bromocriptine. All had elevated disease activity and five became unexpectedly hyperprolactinemic after treatment stopped. Manipulating serum prolactin affords a means of treating clinical SLE activity.

Bromocriptine↗
PubMed1998

Induction of granulomatous experimental autoimmune thyroiditis in IL-4 gene-disrupted mice.

To study the role of IL-4 in development of granulomatous experimental autoimmune thyroiditis (EAT), IL-4 gene-disrupted mice expressing the EAT-susceptible H-2k haplotype were generated and used for EAT induction. Spleen cells from mouse thyroglobulin (MTg) and LPS-primed IL-4(+/+) and IL-4(-/-) donors could induce severe granulomatous EAT when spleen cells were activated with MTg and anti-IL-2R mAb in the presence of IL-12. Thyroid lesions had extensive follicular cell proliferation, large numbers of histiocytes, polymorphonuclear leukocytes, and multinucleated giant cells, in addition to lymphocytes and other mononuclear cells. Expression of IFN-gamma gene mRNA and production of IFN-gamma by effector spleen cells stimulated with MTg and IL-12 were similar for both IL-4(+/+) and IL-4(-/-) mice. Although IL-4 was undetectable in IL-4(-/-) mice, expression of mRNA for IL-5, IL-10, and IL-13 and production of IL-5 by both MTg-activated spleen cells and anti-CD3-activated CD4+ T cells were comparable for cells from IL-4(+/+) and IL-4(-/-) mice, indicating that the absence of IL-4 did not prevent production of other Th2 cytokines. Production of MTg-specific IgG1 was very low or undetectable in IL-4(-/-) mice. IL-4 gene mRNA and MTg-specific IgG1 could be detected in IL-4(+/+) or IL-4(-/-) recipients only when they received effector cells from IL-4(+/+) donor mice, indicating that IL-4- and IgG1-secreting cells are of donor origin. These results demonstrate that IL-4 is not essential for development of granulomatous EAT.

Animals↗
PubMed1998

Human autoantibodies recognizing a native macromolecular structure composed of Sm core proteins in U small nuclear RNP particles.

OBJECTIVE: Monoclonal antibody (mAb) F78 recognizes a heat-labile particle composed of Sm core proteins designated F78P. The objective of this study was to identify human autoantibodies recognizing the conformational structure of F78P. METHODS: Immunoblots using HeLa cell extracts without heating prior to sodium dodecyl sulfate-polyacrylamide gel electrophoresis were used to identify autoantibodies recognizing F78P. To confirm reactivities with F78P, immunoprecipitates of mAb F78 were used as a substrate for immunoblots. To identify reactivities against the F78P structure in classic anti-Sm-positive sera, autoantibodies to individual Sm core proteins were absorbed with purified U1 small nuclear RNP before immunoblotting. RESULTS: We identified 2 sera that, like F78, recognized only F78P and not its component polypeptides. When classic anti-Sm antibodies were preabsorbed, the presence of F78-like, particle-specific antibodies was revealed in all of the anti-Sm-positive sera tested. CONCLUSION: Autoantibodies against the F78P structure were commonly present in sera from patients with systemic rheumatic diseases, often in combination with4=1998 M autoantibodies.

Antibodies, Monoclonal↗