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Biomedical subjects

Kathleen E Sullivan

Publications and source records attributed to Kathleen E Sullivan.

At least 19 recordsLinked to original sources
PubMed2006

ATM stabilizes DNA double-strand-break complexes during V(D)J recombination.

The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia.

Animals↗
PubMed2006

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS).

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.

Animals↗
PubMed2006

Failure of physiologic doses of pure UVA or UVB to induce lesions in photosensitive cutaneous lupus erythematosus: implications for phototesting.

BACKGROUND: Phototesting studies in cutaneous lupus erythematosus have yielded variable results, with most trials reporting photo-induction of lesions by both UVA and UVB in substantial numbers of patients. OBJECTIVES: To determine the minimal erythema dose in patients with subacute cutaneous lupus erythematosus (SCLE) and controls. PATIENTS/METHODS: We phototested nine patients with SCLE and 14 skin type-matched controls, using repetitive dosing of UVA1 and UVB, but with filters that removed most of the shorter UVC and longer infrared and visible light. In addition, DNA was isolated from anticoagulated blood to genotype the TNF-alpha 308 region in each patient and control. RESULTS: We were unable to demonstrate a difference in minimal erythema dose (MED) between patients and controls, or any correlation of MED with either TNF genotype or systemic drug therapy for SCLE. In addition, no SCLE skin lesions were induced in the nine patients with either UVA or UVB, and one patient cleared a skin lesion after low-dose UVA1 irradiation. CONCLUSIONS: The potential role of wavelengths outside the UVA and UVB range in the photo-induction of cutaneous lupus skin lesions needs to be investigated, and there is a need to standardize phototesting equipment and procedures for patients with cutaneous lupus erythematous.

Case-Control Studies↗
PubMed2005

Apoptotic cells, autoantibodies, and the role of HMGB1 in the subcellular localization of an autoantigen.

A current model for the evolution of systemic lupus erythematosus hypothesizes that there is a genetic predisposition coupled with an environmental or infectious trigger. This study investigated whether apoptotic cells given with a proinflammatory signal could induce features of lupus. Balb/c mice were injected with an apoptotic Balb/c-derived myeloid cell line, J774.1, either with or without the DNA-binding protein HMGB1 for five injections over 16 days in an IACUC approved study. Mice were sacrificed at 6 weeks and 12 weeks after treatment. Renal disease was assessed by immunofluorescence and autoantibodies were defined by ELISA. Western blotting was performed to characterize autoantigens. Mice injected with apoptotic cells developed antibodies to histones, SSA, ssDNA, and phospholipids. Antibodies to SSA and ssDNA persisted; however, antibodies to histones, and phospholipid declined at 12 weeks. IgG deposits in the kidney were detected at 6 weeks and persisted through 12 weeks primarily in animals that received both apoptotic cells and HMGB1. Autoantibodies in mice were diverse but the mice that received apoptotic cells developed particularly high titer antibodies to an unknown 78kDa protein. This protein became externalized on the surface of J774.1 cells in the presence of HMGB1. Mice that received apoptotic J774.1 cells with HMGB1 developed more extensive renal IgG deposition. While the mechanism is uncertain, an important effect of HMGB1 was to alter the subcellular distribution of a major autoantigen, making the autoantigen accessible for immune responses. This is the first description of an inflammatory stimulus altering the immunologic availability of a potential autoantigen.

Animals↗
PubMed2005

Immune abnormalities are a frequent manifestation of Kabuki syndrome.

Kabuki syndrome (KS) is associated with multiple organ system involvement. Characteristic features include long palpebral fissures with everted lower lids, prominent ears, skeletal abnormalities, mental retardation, and short stature. An increased incidence of infection has been reported in KS, and a few patients have been noted to have immune defects. However, the frequency and severity of the immune deficiency has not been clearly defined. Immunologic evaluation of 19 consecutive individuals with KS was performed at The Children's Hospital of Philadelphia. Decreased IgA levels were noted in 15/19 individuals (79%), 2 of whom had undetectable levels. Eight patients (42%) also had low total IgG levels. Specific IgG subclass abnormalities were found in 6 of 13 patients evaluated. IgM levels were less frequently decreased. One patient failed to generate anti-tetanus antibodies despite immunization. This study suggests that hypogammaglobulinemia is a frequent finding in children with KS. The pattern of antibody abnormalities seen in children with KS resembles common variable immune deficiency (CVID). Due to this increased susceptibility to infection, children with KS should have immunologic evaluations at the time of diagnosis in order to reduce preventable morbidity and mortality.

Abnormalities, Multiple↗