Biomedical subjects

Jennifer M McNiff

Publications and source records attributed to Jennifer M McNiff.

At least 19 recordsLinked to original sources

PubMed2026

Endothelial MHC expression is required to initiate T cell-mediated rejection of 3D-printed skin grafts.

Vascularized skins were 3D printed using single donor human fibroblasts, pericytes, keratinocytes, and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks after grafting with human PBMCs autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+ T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection, despite MHC molecule expression on other graft cell types.

Animals↗

PubMed2006

Rab33A: characterization, expression, and suppression by epigenetic modification.

Rab33A, a member of the small GTPase superfamily, is an X-linked gene that is expressed in brain, lymphocytes, and normal melanocytes, but is downregulated in melanoma cells. We demonstrate that in normal melanocytes Rab33A colocalizes with melanosomal proteins and that a constitutively active GTPase mutant suppresses their transport to the melanosomes. In the brain, Rab33A is present throughout the cortex, as well as in the hippocampal CA fields. A survey of melanocytic lesions demonstrated that aberrant downregulation of Rab33A is an early event that is already prevalent in melanocytes of giant congenital nevi. Analyses of bisulfite-modified DNA revealed that Rab33A is regulated by DNA methylation of a specific promoter region proximal to the transcription initiation site, and that suppression of Rab33A in melanoma cells recapitulates normal processes that control silencing of X-linked genes, but not tissue specific gene expression. This information is important for understanding carcinogenesis as well as other aberrant processes because Rab33A may have an important role in disorders involving X-chromosome-linked genes associated with vesicular transport.

Amino Acid Sequence↗

PubMed2006

Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome.

BACKGROUND: The spectrum of clinical findings associated with PTEN tumor suppressor gene germline mutations, referred to as PTEN hamartoma-tumor syndrome (PHTS), includes Cowden and Bannayan-Riley-Ruvalcaba syndromes. Although the skin is the ectodermal structure most often affected by these autosomal dominant genodermatoses, abnormalities of neural tissues are frequently observed. OBSERVATIONS: We describe a 5-year-old boy with macrocephaly, prominent corneal nerves, and progressive development of multiple painful, dome-shaped, translucent pink to skin-colored papules on the vermilion portion of the upper lip, fingers, palms, and shins. Histologic evaluation demonstrated dermal proliferation of well-demarcated nerve bundles associated with abundant mucin and surrounded by a distinct perineural sheath, findings diagnostic of a nonencapsulated neuroma. Genetic analysis revealed a novel heterozygous germline nonsense mutation in PTEN, predicted to result in a truncated PTEN protein. To our knowledge, this represents the first report of multiple neuromas as the sole mucocutaneous manifestation of PHTS. CONCLUSIONS: This article highlights neuromas as a cutaneous sign of PHTS, drawing attention to manifestations of PHTS in neural tissues of the skin, eye, gastrointestinal tract, and brain. Along with multiple endocrine neoplasia type 2B, PHTS should be considered in the differential diagnosis of multiple mucocutaneous neuromas, particularly those involving extrafacial sites.

Child, Preschool↗

PubMed2006

Abrogation of skin disease in LUPUS-prone MRL/FASlpr mice by means of a novel tylophorine analog.

OBJECTIVE: To test the therapeutic effect of DCB-3503, a synthetic compound derived from a natural product that inhibits NF-kappaB, on end-organ disease in the MRL-Fas(lpr) murine model of systemic lupus erythematosus (SLE). METHODS: Eight-week-old female MRL/Fas(lpr) mice were treated intraperitoneally with a low (2 mg/kg) or high (6 mg/kg) dose of DCB-3503 for 10 weeks. Control groups were administered vehicle treatment alone (negative control) or 25 mg/kg cyclophosphamide (positive control). Mice were bled before (8 weeks) and during (13 weeks) treatment, and when they were killed (20 weeks), and serum samples were analyzed for total IgM and IgG levels and autoantibody titers. When the mice were killed, spleen and lymph nodes (axillary, brachial, and cervical) were examined by flow cytometric analysis. The presence of skin and renal disease was determined by histopathologic analysis. RESULTS: DCB-3503 reduced anti-double-stranded DNA and antichromatin autoantibodies and nearly abrogated inflammatory skin disease in MRL/Fas(lpr) mice; however, it had little effect on histologic kidney disease. Treated mice did not have hematologic or hepatic toxicity. These data indicate that end-organ disease in MRL/Fas(lpr) mice responds differentially to NF-kappaB inhibitor. CONCLUSION: DCB-3503 causes significant abrogation of skin disease in MRL/Fas(lpr) mice and may potentially be beneficial in the treatment of inflammatory skin disease in SLE.

Alkaloids↗

PubMed2005

Memory T cells and their costimulators in human allograft injury.

Both CD4(+) and CD8(+) human memory but not naive T cells respond to allogeneic human dermal microvascular endothelial cells (HDMEC) in vitro by secreting cytokines and by proliferating. Several recently identified costimulators, namely, 4-1BB ligand, ICOS ligand, and OX40 ligand, are up-regulated on cultured HDMEC in response to TNF or coculture with allogeneic T cells. Blockade of these costimulators each partially reduces IFN-gamma and IL-2 secretion and proliferation of previously resting memory T cells. The effects of these costimulators are overlapping but not identical. Memory but not naive T cells are the principal effectors of microvascular injury in human skin allografts following adoptive transfer into immunodeficient mice. Furthermore, blocking 4-1BB ligand, ICOS ligand, or OX40 ligand in this model reduces human skin allograft injury and T cell effector molecule expression. These data demonstrate that human memory T cells respond to microvascular endothelial cells and can injure allografts in vivo without priming. Furthermore, several recently described costimulators contribute to these processes.

4-1BB Ligand↗

PubMed2005

Multiple facial angiofibromas: a cutaneous manifestation of Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHDS) is an uncommon autosomal dominant genodermatosis characterized by a triad of skin tumors--fibrofolliculomas, trichodiscomas, and acrochordons--together with an increased risk of renal tumors and spontaneous pneumothoraces. This report describes multiple facial angiofibromas as the predominant initial manifestation of BHDS. The patient had a total of 41 facial papules removed via shave excision, initially for diagnostic and then for therapeutic purposes; histologic evaluation revealed diagnostic features of angiofibroma in 39 lesions and fibrofolliculoma in only 2. BHDS should be considered, along with tuberous sclerosis and multiple endocrine neoplasia type 1, in the differential diagnosis of multiple facial angiofibromas, particularly when onset is in adulthood.

Adult↗

PubMed2005

Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum.

Chronic cutaneous graft-versus-host disease (GVHD) is classically divided into two major clinical categories--lichenoid and sclerodermoid. Although diffuse areas of sclerosis as in scleroderma characterize the more advanced stages of the sclerodermoid form, the initial circumscribed plaques would be more correctly described as morpheaform. Eosinophilic fasciitis (EF) (a fibrosing disorder related to deep morphea) and lichen sclerosus (LS) have also been reported as manifestations of sclerodermoid GVHD. However, these two presentations of GVHD have not been emphasized in the dermatologic literature. We describe 6 patients, all of whom developed LS and two of whom also developed EF in the context of chronic GVHD. Each patient presented clinically with hypopigmented plaques that exhibited wrinkling, scaling, and follicular plugging. These lesions demonstrated the classic histologic features of LS including epidermal atrophy; a subepidermal zone of pale-staining, homogenized collagen; and a bandlike lymphocytic infiltrate. Although all patients eventually developed morpheaform and/or sclerodermoid GVHD, LS was a prominent part of the initial presentation of chronic cutaneous GVHD in every case. The LS lesions tended to occur on the neck and upper to mid aspect of the trunk, whereas morpheaform lesions favored the lower aspect of the trunk. EF involved the extremities (sparing the hands and feet), and was characterized clinically by an acute onset of pain and edema followed by induration with a rippled appearance. This case series serves to expand the spectrum of sclerodermoid GVHD, with LS as the most superficial and EF as its deepest manifestation.

Adult↗

PubMed2005

Cross-comparison of patch test and lymphocyte proliferation responses in patients with a history of acute generalized exanthematous pustulosis.

An adverse cutaneous reaction to a systemically administered drug may rarely manifest as acute generalized exanthematous pustulosis (AGEP). Several recent reports have documented positive patch test results in patients with a history of AGEP, while two have demonstrated drug-specific in vitro lymphocyte proliferative responses. These findings suggest that drug-specific T cells mediate AGEP. We describe two patients with a history of AGEP who each demonstrated positive patch test results specific for the inciting drug: Patient #1 to the antibiotic metronidazole, and Patient #2 to the calcium channel-blocker diltiazem. Histologic examination of biopsy specimens taken from the patch test sites of these patients revealed spongiotic dermatitis and perivascular lymphocytes consistent with a delayed-type hypersensitivity reaction, rather than demonstrating subcorneal neutrophilic pustules more typical of AGEP. In vitro testing by measuring peripheral T cell proliferative responses to chemically purified drug correlated with the clinical response. In a direct cross-comparison, patch test results were shown to correlate with in vitro lymphocyte proliferative responses in two patients with a history of AGEP to different drugs. These findings provide additional evidence that the pathogenesis of AGEP involves a T cell-mediated immune response.

Adult↗

PubMed2005

Cellular digital fibromas: distinctive CD34-positive lesions that may mimic dermatofibrosarcoma protuberans.

BACKGROUND: Digital fibromas are common benign acral tumors typically reported as angiofibromas (AFs) or acquired digital fibrokeratomas (ADFs). Cellular variants are not well recognized. METHODS: We collected 14 acral fibrocytic lesions showing a spindle cell morphology from our files, and evaluated CD34, Factor XIIIa, epithelial membrane antigen (EMA), and S100 protein staining of these lesions. We compared the histologic and immunohistochemical features of these cellular fibromas with five digital AFs, five ADFs, and five digital dermatofibromas. RESULTS: The 14 cellular digital fibromas showed intersecting fascicles of thin delicate bland spindle cells in the superficial reticular dermis with a fibrotic-to-slight myxoid stroma. The spindle cells in all cases stained strongly for CD34, and only scattered stromal cells stained for Factor XIIIa. Five tested cases were negative for EMA and S100 protein. The digital AFs, fibrokeratomas, and dermatofibromas stained predominately for Factor XIIIa, with no or minimal staining for CD34. CONCLUSIONS: These findings suggest that a subset of digital fibromas is characterized by a dense cellular proliferation of CD34-positive spindle cells. Awareness of this variant of digital fibroma and its staining pattern is critical in preventing misdiagnosis as dermatofibrosarcoma protuberans, particularly in superficial biopsies.

Adult↗

PubMed2005

CD56 staining in Merkel cell carcinoma and natural killer-cell lymphoma: magic bullet, diagnostic pitfall, or both?

BACKGROUND: Antibodies to CD56 label natural killer (NK) cell lymphomas and neuroendocrine tumors such as Merkel cell carcinoma (MCC). In MCC altered by crush artifact or obscured by lymphocytes, the histologic features coupled with CD56 positivity can lead to an erroneous impression of NK-cell lymphoma. METHODS: Eighteen cases of MCC were stained for CD56, CK20, MNF116, and pankeratin. The results were compared to histologic features and CD56 staining pattern of three NK-cell lymphomas. RESULTS: Three of 18 cases of MCC histologically resembled lymphoma, and CD56 positivity with CD3 and CD20 negativity initially raised the possibility of NK-cell lymphoma. Two additional cases were obscured by dense inflammation, again suggesting the diagnosis of lymphoma. Seventeen of 18 MCC labeled for CD56 and an equal number stained for CK20. All MCC tested were positive for CAM5.2 (14/14) and MNF116 (17/17). Antibodies to pankeratin labeled only one of 18 MCC. Staining for CD56 was stronger in MCC than NK-cell lymphomas. CONCLUSIONS: CD56 is a sensitive marker for MCC as well as for NK-cell lymphoma, but is not specific. Importantly, CD56 positivity in crushed or inflamed biopsies of MCC may lead to an erroneous impression of NK lymphoma. Awareness of this potential pitfall will prevent misdiagnosis. McNiff JM, Cowper SE, Lazova R, Subtil A, Glusac EJ. CD56 staining in Merkel cell carcinoma and natural killer-cell lymphoma: Magic bullet, diagnostic pitfall, or both?

Aged↗

PubMed2005

Primary cutaneous carcinosarcoma arising in a patient with nevoid basal cell carcinoma syndrome.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCC) is an autosomal dominant disorder characterized by developmental abnormalities and neoplasms including basal cell carcinoma (BCC) and sarcomas (i.e. leiomyosarcoma, rhabdomyosarcoma, and fibrosarcoma). Primary cutaneous carcinosarcoma (PCC), a rare tumor composed of malignant epithelial and mesenchymal components, has never been previously described in association with this syndrome. CASE REPORT: A 61-year-old Hispanic man with a history of NBCC presented with a 4 cm nodule on the right proximal medial thigh. PATHOLOGIC FINDINGS: Areas of typical BCC merged with intersecting fascicles of large atypical spindle cells that stained for vimentin and were negative for actin, desmin, CD-34, and S-100 protein. Scattered bizarre solitary cytokeratin-positive epithelioid cells were embedded within the fibrocytic proliferation. CONCLUSIONS: Several carcinosarcomas have been reported to contain BCC as the malignant epithelial component, but to our knowledge, this is the first report of PCC associated with NBCC. Mutation in patched tumor suppressor gene on chromosome 9q occurs in BCCs of NBCC, and aberrancies on chromosome 9q are also reported in some carcinosarcomas. It is possible that the known genetic defect on chromosome 9 in this patient contributed to the development of carcinosarcoma. Bhattacharjee P, Leffell D, McNiff JM. Primary cutaneous carcinosarcoma arising in a patient with nevoid basal cell carcinoma syndrome.

Basal Cell Nevus Syndrome↗

PubMed2004

Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ.

The application of allogeneic stem cell transplantation (alloSCT) is limited by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic forms that likely have different requirements for initiation and pathogenesis mechanisms. In prior studies we demonstrated that residual host antigen-presenting cells (APCs) were required to initiate acute GVHD (aGVHD) mediated by CD8 T cells. In contrast, here we demonstrate that either donor or host APCs can initiate CD4-mediated GVHD in a model that has features of chronic GVHD (cGVHD). Both donor and host APCs must provide CD80/86-dependent costimulation to elicit maximal cGVHD, and there is no GVHD when both donor and host lack CD80/86. Finally, we were surprised to find that, although either donor or host APCs are sufficient to stimulate skin cGVHD, donor APCs play a dominant role in intestinal cGVHD. Both CD40 and CD80/86 are critical for donor APC function in intestinal cGVHD, but only CD80/86 is required for skin cGVHD. Thus, there are target-tissue-specific differences in APC requirements. These results identify differences in APC requirements between CD8-mediated aGVHD and CD4-mediated cGVHD. They further highlight donor APCs as additional targets for GVHD therapy.

Animals↗

PubMed2004

Target antigens determine graft-versus-host disease phenotype.

Chronic graft-vs-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Phenotypically, cGVHD differs from patient to patient; in particular, a subset of patients develops extensive cutaneous fibrosis. Similarly, graft-vs-host disease (GVHD) is distinct in inbred murine donor:recipient pairings, indicating a genetic component to disease phenotype. The B10.D2 -->BALB/c (H-2d) strain pairing uniquely recapitulates key pathologic features of fibrotic human cutaneous cGVHD. To distinguish whether this genetic component is due to differences in genes that modulate immune responses or to the specific Ags targeted, we asked whether skin-dominant cGVHD also develops in the B10 -->BALB.B (H-2b) and B10.BR -->BALB.K (H-2k) MHC-congenic pairings. Because each MHC haplotype presents different peptides and selects different T cell repertoires, GVHD in each donor:recipient pair undoubtedly targets different Ags. We found that, in contrast to BALB/c recipients, BALB.B mice never manifested skin disease while BALB.K mice developed a modified form of skin disease. Instead, BALB.B and BALB.K recipients developed systemic GVHD which was absent in BALB/c mice. Moreover, in (B10 x B10.D2)F1 -->(BALB.B x BALB/c)F1 H-2b/d transplants, recipients developed both cutaneous and systemic disease. Thus, the selection of immunodominant Ags determines the target and character of GVHD, providing insight into the genetic basis for different forms of GVHD.

Animals↗

PubMed2004

Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is an increasingly common cause of morbidity and mortality in allogeneic stem cell transplantation (alloSCT). Relative to acute GVHD (aGVHD), much less is understood about cGVHD. Using the B10.D2 --> BALB/c murine cGVHD model, which shares critical pathologic features with human cGVHD, we find that radiation-resistant host T cells regulate cGVHD. We initially observed that recipients lacking all lymphocytes developed accelerated and more severe cGVHD. Using genetically deficient recipients, we determined that alphabeta+CD4+ T cells were required to regulate cGVHD. Increased cGVHD severity was not due to the absence of T cells per se. Rather, the potency of regulation was proportional to host T-cell receptor (TCR) diversity. Only CD4+CD25+, and not CD4+CD25-, host T cells ameliorated cGVHD when added back, indicating that host T cells acted not via host-versus-graft activity or by reducing homeostatic proliferation but by an undefined regulatory mechanism. Thus, preparative regimens that spare host CD4+CD25+ T cells may reduce cGVHD. Donor CD4+CD25+ T cells also reduced cGVHD. Depletion of CD4+CD25+ cells from the inoculum exacerbated disease, whereas transplantation of additional CD4+CD25+ cells protected against severe cGVHD. Additional CD4+CD25+ cells also promoted healing of established lesions, suggesting that their effects persist during the evolution of cGVHD.

Animals↗

PubMed2004

Primary cutaneous B-cell lymphoma treated with radiotherapy: a comparison of the European Organization for Research and Treatment of Cancer and the WHO classification systems.

PURPOSE: To determine the relationship between the WHO and European Organization for Research and Treatment of Cancer (EORTC) pathologic classifications for primary cutaneous B-cell lymphoma (CBCL) and the implication of this relationship on initial treatment. PATIENTS AND METHODS: Patients with primary CBCL treated with radiotherapy were identified retrospectively. Initial biopsy specimens were reviewed by two dermatopathologists and classified according to the EORTC and WHO systems. Primary outcomes were recurrence-free and overall survival. RESULTS: Thirty-four patients were identified; initial biopsy specimens were adequate for classification in 32 patients. Four different composite histopathologic subtypes of lymphoma were identified: 53% (17 of 32) follicle center cell by EORTC and diffuse large B-cell by WHO (FCC/DLB), 25% (eight of 32) follicle center cell by EORTC and follicular by WHO (FCC/Fol), 13% (four of 32) marginal zone by EORTC and WHO (MZ/MZ), and 9% (three of 32) large B-cell of the leg by EORTC and diffuse large B-cell by WHO (Leg/DLB). Five-year relapse-free survival ranged from 62% to 73% for FCC/DLB, FCC/Fol, and MZ/MZ but was 33% for Leg/DLB (P =.6). Five-year overall survival was 100% for FCC/DLB, FCC/Fol, and MZ/MZ but was 67% for Leg/DLB (P =.07). At 5 years, 21% of all patients had developed extracutaneous disease. CONCLUSION: Two-thirds of primary cutaneous FCC lymphomas by EORTC criteria satisfy WHO criteria for DLB lymphoma. Unlike DLB lymphoma presenting in nodal or noncutaneous sites, these lesions are associated with an indolent course and may be treated with local radiotherapy alone.

Aged↗

PubMed2004

IL-11 protects human microvascular endothelium from alloinjury in vivo by induction of survivin expression.

IL-11 can reduce tissue injury in animal models of inflammation but the mechanism(s) is unknown. When C.B-17 SCID/beige mice bearing human skin grafts are injected i.p. with human PBMC allogeneic to the donor skin, infiltrating T cells destroy human microvessels by day 21. Intradermal injection of human IL-11 (500 ng/day) delays the time course of graft microvessel loss without reducing the extent of T cell infiltration. Protective actions of IL-11 are most pronounced on day 15. IL-11 has no effect on T cell activation marker, effector molecule, cytokine expression, or endothelial ICAM-1 expression. IL-11 up-regulates the expression of survivin, a cytoprotective protein, in graft keratinocytes and endothelial cells. Topical application of survivin antisense oligonucleotide down-regulates survivin expression in both cell types and largely abrogates the protective effect of IL-11. We conclude that in this human transplant model, IL-11 exerts a cytoprotective rather than anti-inflammatory or immunomodulatory effect mediated through induction of survivin.

Adjuvants, Immunologic↗

PubMed2004

Flow cytometric DNA ploidy analysis of peripheral blood from patients with sezary syndrome: detection of aneuploid neoplastic T cells in the blood is associated with large cell transformation in tissue.

We reviewed and screened 219 cutaneous T-cell lymphoma (CTCL) cases for Sezary syndrome (SS); 63 met the criteria for SS. Of these, 17 (27%) demonstrated circulating aneuploid cells and 46 (73%) showed only euploid cells in blood samples. Of 17 aneuploid cases, DNA ploidy study was essential for initial blood-based diagnosis of SS in 4 (24%) and important in monitoring minimal residual disease after treatment in 9 (53%) in which neoplastic T cells showed otherwise unremarkable or nonspecific flow cytometric immunophenotypic findings. Tissue biopsy slides (predominantly skin and lymph node) at the time of DNA ploidy studies were available for 47 of 63 cases. Of 14 cases with circulating aneuploid cells, 11 (79%) showed large cell transformation (LCT; 6 [43%]) or markedly increased large cells (ILC; 5 [36%]) in tissue, whereas only 10 (30%) of 33 euploid cases showed LCT (4 [12%]) or ILC (6 [18%]) (P < .01). There was no significant difference in blood tumor burden, immunophenotype, or proliferation index between euploid and aneuploid groups or histologic high- and low-grade groups. DNA ploidy study by flow cytometry is important for blood-based diagnosis of SS and detection of minimal residual disease in aneuploid SS after treatment. Detection of aneuploid neoplastic T cells in peripheral blood samples of patients with CTCL is associated with LCT in skin, lymph node, or other tissues.

Aneuploidy↗

PubMed2003

TRAIL induces apoptosis and inflammatory gene expression in human endothelial cells.

Human TRAIL can efficiently kill tumor cells in vitro and kill human tumor xenografts in mice with little effect on normal mouse cells or tissues. The effects of TRAIL on normal human tissues have not been described. In this study, we report that endothelial cells (EC), isolated from human umbilical veins or human dermal microvessels, express death domain-containing TRAIL-R1 and -R2. Incubation with TRAIL for 15 h causes approximately 30% of cultured EC to die, as assessed by propidium iodide uptake. Death is apoptotic, as assessed by Annexin V staining, 4',6'-diamidino-2-phenylindole staining, and DNA fragment ELISA. EC death is increased by cotreatment with cycloheximide but significantly reduced by caspase inhibitors or transduced dominant-negative Fas-associated death domain protein. In surviving cells, TRAIL activates NF-kappaB, induces expression of E-selectin, ICAM-1, and IL-8, and promotes adhesion of leukocytes. Injection of TRAIL into human skin xenografts promotes focal EC injury accompanied by limited neutrophil infiltration. These data suggest that TRAIL is an inducer of tissue injury in humans, an outcome that may influence antitumor therapy with TRAIL.

Animals↗