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Biomedical subjects

G Starkebaum

Publications and source records attributed to G Starkebaum.

At least 37 records · Page 2Linked to original sources
PubMed1994

The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus.

To gain insight into the mechanisms of autoantibody induction, sera from 40 patients with systemic lupus erythematosus (SLE) were tested by ELISAs for antibody binding to denatured individual histones, native histone-histone complexes, histone-DNA subnucleosome complexes, three forms of chromatin, and DNA. Whole chromatin was the most reactive substrate, with 88% of the patients positive. By chi-square analysis, only the presence of anti-(H2A-H2B), anti-[(H2A-H2B)-DNA], and antichromatin were correlated with kidney disease measured by proteinuria > 0.5 g/d. SLE patients could be divided into two groups based on their antibody-binding pattern to the above substrates. Antibodies from about half of the patients reacted with chromatin and the (H2A-H2B)-DNA subnucleosome complex but displayed very low or no reactivity with native DNA or the (H3-H4)2-DNA subnucleosome complex. An additional third of the patients had antibody reactivity to chromatin, as well as to both subnucleosome structures and DNA. Strikingly, all sera that bound to any of the components of chromatin also bound to whole chromatin, and adsorption with chromatin removed 85-100% of reactivity to (H2A-H2B)-DNA, (H3-H4)2-DNA, and native DNA. Individual sera often bound to several different epitopes on chromatin, with some epitopes requiring quaternary protein-DNA interactions. These results are consistent with chromatin being a potent immunogenic stimulus in SLE. Taken together with previous studies, we suggest that antibody activity to the (H2A-H2B)-DNA component signals the initial breakdown of immune tolerance whereas responses to (H3-H4)2-DNA and native DNA reflect subsequent global loss of tolerance to chromatin.

Animals↗
PubMed1994

Decreased testosterone levels in men with rheumatoid arthritis: effect of low dose prednisone therapy.

OBJECTIVE: To determine whether men with rheumatoid arthritis (RA) have abnormal hypothalamic-pituitary-gonadal axis function and to measure the effects of low dose prednisone therapy in these patients. METHODS: We measured testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) in 36 men aged 38-75 (mean age +/- 1 sd = 62 +/- 10 years) who had longstanding active RA (mean disease duration = 17 +/- 12 years) and in 70 healthy elderly male controls, aged 53-83 (mean age 68 = +/- 6 years). We divided the group with RA into those taking no prednisone (n = 12) and those taking 5 to 10 mg/day of prednisone (n = 24) and analyzed these groups separately to determine whether low doses of prednisone affected testosterone levels. RESULTS: Compared to the healthy controls, patients with RA not taking prednisone had normal testosterone levels but significantly elevated levels of FSH and LH (p < 0.01 for both comparisons). In contrast, patients with RA taking prednisone had significantly lower testosterone levels (p < 0.05), but levels of FSH and LH were only slightly elevated compared to controls. Compared to patients not taking prednisone, patients taking prednisone had lower levels of testosterone, FSH, and LH. CONCLUSION: Male patients with RA who are not taking prednisone have significantly elevated levels of FSH and LH with normal testosterone levels, suggesting a state of compensated partial gonadal failure. Male patients with RA taking low doses of prednisone have lower testosterone and gonadotropin levels, suggesting that prednisone may suppress the hypothalmic-pituitary-testicular axis. Since testosterone affects immune function as well as bone and muscle metabolism, androgen deficiency in some men with RA may predispose these patients to more severe disease and to increased complications of steroid therapy such as myopathy and osteoporosis.

Adult↗
PubMed1993

Failure to detect Epstein-Barr virus DNA in peripheral blood mononuclear cells of most patients with large granular lymphocyte leukemia.

Clonal disease of large granular lymphocytes (LGLs) may arise from either CD3+ LGLs (LGL leukemia) or CD3- LGLs (natural killer [NK] cell leukemia). Other patients have chronic LGL proliferations that cannot be proven to be clonal (lymphoproliferative disease of granular lymphocytes [LDGL]). It was recently shown that clonally expanded CD3- LGLs from Japanese patients contain Epstein-Barr virus (EBV) DNA sequences, arguing for a direct causative role for EBV in NK cell leukemia. The aggressive clinical course and other clinical features of these Japanese patients differ markedly from the clinical features of LGL leukemia and CD3- LDGL patients in the United States and Europe, suggesting different pathogenic mechanisms. Therefore, we performed serologic and DNA hybridization studies for EBV in 31 patients from the United States and Europe (18 with LGL leukemia and 13 with chronic CD3- LDGL). All patients had serologic evidence for past infection with EBV. We did not detect EBV DNA sequences in peripheral blood mononuclear cell DNA from any of these patients in Southern blot hybridization analyses. EBV DNA sequences were detected after polymerase chain reaction amplification of peripheral blood mononuclear cell DNA in only 2 of 18 LGL leukemia patients and 4 of 13 chronic CD3- LDGL patients. These results argue against a direct causative role for EBV infection in LGL leukemia or chronic CD3- LDGL occurring in the United States and Europe.

Base Sequence↗
PubMed1992

Detection of human T-cell leukemia/lymphoma virus, type II, in a patient with large granular lymphocyte leukemia.

We studied a patient with large granular lymphocyte (LGL) leukemia for evidence of human T-cell leukemia/lymphoma virus (HTLV) infection. Serum from this patient was positive for HTLV-I/II antibodies by enzyme-linked immunosorbent assay (ELISA) and was confirmed positive in Western blot and radioimmunoprecipitation assays. Results of a synthetic peptide-based ELISA showed that the seropositivity was caused by HTLV-II and not HTLV-I infection. Analyses of enzymatic amplification of DNA from bone marrow sections using the polymerase chain reaction (PCR) were positive for HTLV-II specific gag, pol, env, and pX gene sequences. Cloning and sequencing of amplified products showed that the HTLV-II pol and pX sequences in patient DNA differed from the sequences of 17 other HTLV-II isolates examined in our laboratory. HTLV infection may have a role in some patients in the pathogenesis of LGL leukemia.

Base Sequence↗
PubMed1992

Drug induced systemic lupus erythematosus due to ophthalmic timolol.

We report a case of systemic lupus erythematosus (SLE) apparently induced by topical use of ophthalmic timolol maleate, a beta adrenergic blocking agent. The patient developed fever, malaise, pleurisy and recurrent sterile pleural effusions while taking no medication other than timolol. Antinuclear antibodies in a homogenous pattern, and markedly elevated histone antibodies (IgG anti-(H2A-H2B)-DNA) were present while antibodies to native DNA were absent. After discontinuation of the timolol, his symptoms improved promptly and the pleural effusions resolved. To our knowledge, this is the first report of timolol induced SLE.

Administration, Oral↗
PubMed1991

Establishment of an IL-2 independent, human T-cell line possessing only the p70 IL-2 receptor.

A continuous cell line was established from the blood of a patient (HH) with an aggressive cutaneous T-cell leukemia/lymphoma who lacked antibodies to human T lymphotrophic virus, type I. The immunophenotype of the cultured cells was CD2+, CD3+, CD4+, CD5+, CD8-, DR+ and CD25- (Tac, IL-2 receptor alpha chain). Southern-blot hybridization analysis of T-cell-receptor beta chain DNA demonstrated the same rearrangement in freshly isolated blood cells and cultured cells, indicating that the cell line was derived from the patient's malignant clone. Since cultured T-cells grew in complete medium without added IL-2, we investigated whether HH cells could be producing and responding to IL-2 in an autocrine fashion. However, no IL-2 was detectable in supernatant from the cell line, while antibodies to IL-2, or to the IL-2 receptor alpha or beta chains did not inhibit cell growth. In addition, no mRNA message for IL-2 was detectable in these cells. The results appear to exclude an autocrine IL-2-dependent mechanism of cell growth for this T-cell line. Although cultured HH cells lacked detectable IL-2 receptor alpha chain, they did show increased proliferation to exogenous IL-2. Binding studies with 125I-IL-2 demonstrated an intermediate affinity receptor for IL-2, KD = 1.7 nM, with 6400 binding sites per cell, suggesting the presence of an IL-2 receptor beta chain. Consistent with these findings 125I-IL-2 cross-linking studies demonstrated a single receptor calculated to be 75 kDa. Also, the beta chain of the IL-2 receptor was detected by immunofluorescence using specific monoclonal antibodies (MAbs). Nanomolar concentrations of an IL-2-diphtheria toxin fusion protein inhibited cellular protein synthesis, an effect abrogated by native IL-2. These findings indicate that the IL-2 receptor beta-chain was functional. This novel mature T-cell line may be useful in studies of IL-2 receptor regulation and in analysis of the mechanism of T-cell leukemogenesis.

DNA, Neoplasm↗
PubMed1990

Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes. A multicenter study.

Lymphoproliferative disease of granular lymphocytes (LDGL) is a recently recognized, relatively rare atypical lymphocytosis characterized by the presence of over 2000 lymphocytes with cytoplasmic azurophilic granules/mm3 in the peripheral blood. The clinical course is heterogeneous, varying from spontaneous regression to progressive, malignant disease. As a consequence, clinical intervention is not standardized. In a worldwide multicenter study, the authors observed 151 patients with LDGL for a mean follow-up time of 29 months. Forty-three patients were asymptomatic at the time of diagnosis. In the remaining cases, clinical symptoms included fever (41 cases), infections (58), neutropenia (47), anemia (17), and thrombocytopenia (12). In 69 cases, LDGL coexisted with an associated disease. Most patients had a nonprogressive clinical course despite the presence of severe symptoms. In 19 patients, death related to LDGL occurred within 48 months. The authors investigated which features at diagnosis were significantly associated with increased mortality. In the univariate analysis, lymph node and liver enlargement, fever at presentation, skin infiltration, a low (less than or equal to 5000/mm3) or high (greater than 20,000/mm3) peripheral leukocyte count, relatively low (less than or equal to 3000) or high (greater than 7000/mm3) absolute peripheral granular lymphocyte (GL) count, and a low (less than or equal to 15%) percentage of HNK-1-positive cells were found to be predictors of increased mortality. In the multivariate analysis, significant independent predictors were fever at diagnosis, a low (less than or equal to 15%) percentage of HNK-1-positive peripheral blood mononuclear cells (PBMC) and a relatively low (less than or equal to 3000) GL count. These results showed that about 25% of the patients with LDGL were diagnosed after a routine blood count and had no clinical symptoms. The remaining patients were symptomatic, with some experiencing a fatal clinical course. The author's analysis of the significant prognostic features of LDGL may help in understanding the heterogeneous nature of this syndrome.

Adolescent↗
PubMed1989

Reversal of neutropenia with methotrexate treatment in patients with Felty's syndrome. Correlation of response with neutrophil-reactive IgG.

We evaluated the clinical and hematologic response to methotrexate (MTX) in 4 women with Felty's syndrome (FS) who had had neutropenia for 1-3 years. Since immune complexes or antineutrophil antibodies are implicated in the pathogenesis of the neutropenia of FS, we also measured both direct and indirect levels of neutrophil-reactive IgG. All 4 patients showed a prompt and dramatic increase in neutrophil counts within 1-2 months of starting MTX therapy. In 3 patients, the symptoms of arthritis also improved; in the fourth patient, arthritis worsened. Recurring infections ceased in 3 patients. Neutrophil-reactive IgG levels, which were elevated in all patients prior to treatment, decreased toward normal while the patients were receiving MTX therapy. We conclude that MTX is effective in treating the neutropenia of FS, in part by lowering neutrophil-reactive IgG.

Aged↗
PubMed1989

The pathology of large granular lymphocyte leukemia.

The authors conducted a histopathologic study on tissues from 11 patients with the recently described syndrome of large granular lymphocyte (LGL) leukemia. Distinctive pathologic findings were found most often in the bone marrow, liver, and spleen. The bone marrow biopsies contained nonparatrabecular lymphoid infiltrates that were nodular or diffuse and interstitial. Plasmacytosis was found and in two cases there was myeloid maturation arrest. The liver biopsies contained sinusoidal and portal infiltrates and the spleen had red pulp cord and sinus infiltrates, plasmacytosis, and follicular hyperplasia. Lymph node involvement was nondiagnostic, consistent with the usual absence of lymphadenopathy. The morphologic findings were sometimes indistinguishable from other reactive or low-grade lymphoproliferative disorders, especially chronic lymphocytic leukemia/well-differentiated lymphocytic lymphoma (CLL/WDLL) and hairy cell leukemia. These results suggest the need to correlate peripheral blood cell counts and morphology as well as immunophenotypic studies with tissue histology to distinguish LGL leukemia from other disorders. Establishing a correct diagnosis of LGL leukemia may help clarify the etiology of unexplained peripheral blood cytopenias, arthritis, and other autoimmune manifestations in individual patients.

Adult↗
PubMed1988

Clonal proliferation of large granular lymphocytes in rheumatoid arthritis.

Some patients with chronically elevated large granular lymphocyte (LGL) numbers have rheumatoid arthritis (RA). Since these patients also may have neutropenia and splenomegaly, their symptoms resemble those of patients diagnosed as having Felty's syndrome (FS). We studied the immunophenotypic and genotypic characteristics of mononuclear cells from patients with RA and neutropenia to better determine the extent of heterogeneity in this condition. Four patients had markedly increased numbers of LGLs, which expressed HNK-1 antigen and IgG Fc receptors. In contrast, the remaining 8 patients, who had FS, had normal LGL counts, and surface marker studies showed normal numbers of HNK-1 and IgG Fc receptor positive cells. Clonal rearrangement of the T cell receptor beta chain gene was demonstrated in all 4 patients with excess LGLs, whereas a germline configuration of this gene was present in all 6 FS patients in whom this was studied. These results suggest that there are diverse groups among patients with RA and neutropenia. Since prognosis may differ, it is important to recognize that some patients who are considered to have Felty's syndrome may have a clonal proliferation of LGLs.

Antigens, Surface↗
PubMed1988

Suppression of in vitro granulocytopoiesis by captopril and penicillamine.

The mechanisms underlying drug-induced neutropenia are poorly characterized. We have examined the mechanism of suppression of granulocytopoiesis by captopril and penicillamine using human and canine bone marrow cells in an in vitro culture system. Addition of captopril caused no significant change in granulocyte-macrophage colony formation at concentrations up to 30 micrograms/ml. In the presence of CuSO4 (1-3 micrograms/ml), however, captopril caused significant inhibition of colony growth (p less than 0.05). Penicillamine, another agent associated with neutropenia and, like captopril, having a reactive thiol group, also inhibited colony formation in the presence of copper. Chemical congeners of captopril lacking a reactive thiol group and enalaprilic acid, an alternative angiotensin-converting enzyme (ACE) inhibitor, failed to show inhibition, suggesting that the thiol group and not ACE inhibition was responsible. Analysis of day-7 colonies (98% neutrophilic) and day-21 colonies (37% neutrophilic, 30% macrophagic, 27% eosinophilic, and 6% mixed) showed that neutrophil-containing colonies, but not nonneutrophilic colonies were inhibited by the addition of captopril plus copper. Catalase totally reversed the inhibition of colony formation caused by these agents. Direct measurement of oxygen consumption in the presence of captopril showed marked enhancement with the addition of CuSO4 and a 48% reduction in the presence of added catalase. These data indicate that drugs with a reactive thiol group can interact with copper to generate H2O2, which can be toxic to neutrophilic progenitor cells. We postulate that this may be an important mechanism for drug-associated neutropenia and a general mechanism for drug-induced marrow cell injury.

Animals↗
PubMed1988

Similar rearrangements of T-cell receptor beta gene in cell lines and uncultured cells from patients with large granular lymphocyte leukemia.

We established interleukin-2-(IL-2) dependent cell lines from three patients with large granular lymphocyte (LGL) leukemia. Phenotypic analysis demonstrated retention of the CD3+, CD8+ phenotype that was observed in the original leukemic LGL. Unique rearrangements of T-cell receptor beta gene occurring in uncultured leukemic LGL, were also found in cell lines, which suggests that the cell lines were derived from the original leukemic LGL clone in each case.

Antigens, Surface↗
PubMed1988

Rearrangement and expression of T-cell receptor genes in large granular lymphocyte leukemia.

Ten patients with large granular lymphocyte (LGL) leukemia were studied for rearrangement and expression of T cell receptor (TCR) genes. Eight patients with CD3+ LGL proliferation had unique TCR beta-gene rearrangements, supporting a clonal process. Each of five patients studied with CD3+ disease had evidence for expression of full-length TCR alpha-, beta-, and gamma-gene transcripts. In contrast, patients with CD3- LGL proliferation had no evidence for rearrangement or expression of TCR genes. These studies suggest that leukemic LGL arise from two different cell origins. Leukemic LGL may be a useful model for studying natural killer (NK) cell (CD3- LGL) and non-MHC-restricted cytotoxic T lymphocyte (CD3+ LGL) activation and differentiation.

DNA↗
PubMed1987

Serum reactivity to human T-cell leukaemia/lymphoma virus type I proteins in patients with large granular lymphocytic leukaemia.

To investigate the possibility that the recently recognised syndrome, leukaemia of large granular lymphocytes, could be associated with human T-cell leukaemia/lymphoma virus type I (HTLV-I), sera from 12 patients with this type of leukaemia were tested by the use of western-blot techniques for IgG antibodies to proteins related to human T-cell leukaemia/lymphoma virus type I (HTLV-I). Sera from 6 patients, including 2 patients with rheumatoid arthritis, reacted with p19 or p24 retroviral proteins or both. In contrast, no sample from 32 patients with uncomplicated rheumatoid arthritis, 27 with Felty's syndrome, 11 with other connective tissue disorders, or 21 normal individuals reacted with HTLV-I. The results suggest that leukaemia of large granular lymphocytes may be associated with a retrovirus related to HTLV-I.

Adult↗
PubMed1987

Genetic analysis of human B cell hybridomas expressing a cross-reactive idiotype.

We have examined the genetic basis for the expression of a human cross-reactive idiotype (CRI) commonly found on monoclonal IgM rheumatoid factors. The CRI was identified with a monoclonal antibody (17.109) and has been localized previously to the kappa-variable region. By using the human lymphoblastoid cell line WI-L2-729-HF2, and mononuclear cells from several sources, a panel of hybridomas was generated that produced 17.109 CRI-positive Ig. A recently cloned human germ-line V kappa III gene, Humkv305, served as a probe to identify genes which were rearranged and expressed in 17.109 CRI-positive and -negative hybridomas. This probe, when hybridized to human genomic DNA under stringent conditions, identified only two to five germ-line bands. In 10 separate 17.109 CRI-positive hybridoma clones, an additional rearranged V kappa band was identified. The probe did not anneal to rearranged V kappa bands in hybridoma clones that produced kappa-chains lacking the CRI. RNA dot-blot studies provided evidence for expression of genes hybridizing to the Humkv305 probe. The results indicate that the 17.109 CRI is a serologic marker for a single V kappa gene, or a small family of closely related V kappa genes, which is identified by the Humkv305 probe.

B-Lymphocytes↗
PubMed1987

Bone marrow transplantation in a patient with myelodysplasia associated with diffuse eosinophilic fasciitis.

A 34-year-old man with diffuse eosinophilic fasciitis and a hypocellular myelodysplastic syndrome underwent marrow transplantation from an HLA-identical brother. Prompt hematopoietic reconstitution was observed, strongly suggesting that the marrow hypocellularity was caused by neither a serum inhibitory factor nor a microenvironmental disorder. The patient died of disseminated cytomegalovirus infection too early to evaluate the impact of hematopoietic reconstitution on the eosinophilic fasciitis. Nevertheless, marrow transplantation may offer a therapeutic option for those patients with this disorder who develop severe hematopoietic dysfunction and who have a suitable marrow donor.

Adult↗
PubMed1987

Monocyte Fc receptor function in rheumatoid arthritis. Enhanced cell-binding of IgG induced by rheumatoid factors.

Monocytes from 11 patients with rheumatoid arthritis and 10 control subjects were purified by countercurrent elutriation. Rheumatoid arthritis monocytes had more cell-associated IgG (P less than 0.001) and bound more 125I-labeled heat-aggregated IgG in vitro (P less than 0.02) than did monocytes from control subjects. Interaction of rheumatoid factor (RF) with monocytes was then investigated. Purified 125I-labeled IgM-RF and IgG-RF bound directly to monocytes from normal individuals. Furthermore, preincubation of normal monocytes with RF augmented subsequent binding of aggregated IgG to the cells. We conclude that monocyte-associated RF can enhance binding of IgG-containing immune complexes to the cells and can exaggerate the measured number of Fc receptors. Such cell-bound RF may affect clearance of immune complexes by the reticuloendothelial system in vivo.

Arthritis, Rheumatoid↗