Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06126 (CD1a)
 2,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two common features in human immunodeficiency virus infection and acquired immunodeficiency syndrome, rheumatoid arthritis, and hematologic malignancies including multiple myeloma are elevated serum levels of beta(2)-microglobulin (beta(2)M) and activation or inhibition of the immune system. We hypothesized that beta(2)M at high concentrations may have a negative impact on the immune system. In this study, we examined the effects of beta(2)M on monocyte-derived dendritic cells (MoDCs). The addition of beta(2)M (more than 10 microg/mL) to the cultures reduced cell yield, inhibited the up-regulation of surface expression of human histocompatibility leukocyte antigen (HLA)-ABC, CD1a, and CD80, diminished their ability to activate T cells, and compromised generation of the type-1 T-cell response induced in allogeneic mixed-lymphocyte reaction. Compared with control MoDCs, beta(2)M-treated cells produced more interleukin-6 (IL-6), IL-8, and IL-10. beta(2)M-treated cells expressed significantly fewer surface CD83, HLA-ABC, costimulatory molecules, and adhesion molecules and were less potent at stimulating allospecific T cells after an additional 48-hour culture in the presence of tumor necrosis factor-alpha and IL-1beta. During cell culture, beta(2)M down-regulated the expression of phosphorylated mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), and mitogen-induced extracellular kinase (MEK), inhibited nuclear factor-kappaB (NF-kappaB), and activated signal transducer and activator of transcription-3 (STAT3) in treated cells, all of which are involved in cell differentiation and proliferation. Thus, our study demonstrates that beta(2)M at high concentrations retards the generation of MoDCs, which may involve down-regulation of major histocompatibility complex class I molecules, inactivation of Raf/MEK/ERK cascade and NF-kappaB, and activation of STAT3, and it merits further study to elucidate the underlying mechanisms.
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PMID:Beta 2-microglobulin as a negative regulator of the immune system: high concentrations of the protein inhibit in vitro generation of functional dendritic cells. 1253 97

While vaccination with antigen-pulsed dendritic cells (DCs) represents a promising therapeutic strategy in multiple myeloma (MM), clinical benefit, so far, has been limited to individual patients. To identify potential problems with this approach, we have analyzed the influence of treatment parameters, in particular high-dose chemotherapy (HD-CTX) and thalidomide, on in vitro DC generation and peripheral blood lymphocyte subsets in MM patients. From a total of 25 MM patients, including 14 patients on thalidomide treatment and 11 after HD-CTX, in vitro DC generation from peripheral blood monocytes under serum-free condition was investigated. In addition, peripheral blood lymphocyte subsets were assessed in 17 patients including 10 patients on thalidomide treatment and 9 patients after HD-CTX. Efficient in vitro generation of DCs (median 7.1x10(6)/100 ml peripheral blood; range 0.1-42.5x10(6)/100 ml peripheral blood) expressing DC-typical surface markers was observed in 23 MM patients (92%), although reduced expression of CD1a, CD40, CD83, and HLA-DR was observed in patients treated with thalidomide. With respect to lymphocyte subsets, MM patients showed significantly (p<0.05) reduced B and CD4+ lymphocytes in the peripheral blood. This effect was most prominent within 6 months of HD-CTX and in patients receiving thalidomide (usually in combination with CTX). CD8+ lymphocytes were significantly increased in MM patients. Thus, despite the well-known deficiencies in their immune system, adequate numbers of DCs can be generated in most myeloma patients. In patients treated with thalidomide, however, it remains to be seen whether the reduced expression of co-stimulatory molecules has functional relevance.
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PMID:In vitro dendritic cell generation and lymphocyte subsets in myeloma patients: influence of thalidomide and high-dose chemotherapy treatment. 1575 Aug 34

Previous studies demonstrated that circulating dendritic cells (DCs) in myeloma patients were functionally abnormal. However, the phenotype and function of patients' monocyte-derived DCs (MoDCs), which are commonly used for immunotherapy, were poorly defined. This study was undertaken to examine the quality of MoDCs from myeloma patients compared with cells from healthy donors. We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterparts, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR and were poor at activating alloreactive T cells, presenting recall antigen, and activating autologous antigen- and myeloma-specific T cells. These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and, more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield but also produced MoDCs that were as functional as their normal counterparts. Thus, this study has delineated the mechanistic defects of MoDCs from myeloma patients and identified ways for restoring the function of the cells to improve the efficacy of DC-based immunotherapy in this disease.
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PMID:Optimizing immunotherapy in multiple myeloma: Restoring the function of patients' monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells. 1691 8

Dear Editor, An 83-year-old woman developed yellow-brownish infiltrates, nodules, and tumors mimicking xanthomas, mostly involving the periorbital and chest area within three months (Figure 1). She had no abnormalities in serum cholesterol or triglycerides levels. A detailed laboratory analysis revealed the presence of mild monoclonal gammopathy with a presence of immunoglobulin G (IgG) kappa light chains; however, according to hematologist consultation, it did not require medical intervention. Imaging assessment and ultrasound examination did not show any specific involvement of internal organs. The skin biopsy demonstrated necrobiotic areas alternated with foci of xanthogranulomatous infiltration throughout the reticular dermis with extension into subcutaneous tissue. The granulomatous infiltrate was composed of epithelioid, foamy histiocytes in addition to conspicuous giant cells of the Touton type and foreign body type, as well as variable numbers of lymphocytes, plasma cells, and neutrophiles. Lipid vacuoles were seen within the foci of necrobiosis and xanthogranulomatous infiltration (Figure 2). Two months after first admission to our department, the first signs of necrosis within the lesions were noted, and massive necrosis of skin lesions occurred after the following 5 months (Figure 1). Based on the clinical manifestation and histological and laboratory findings, the diagnosis of necrobiotic xanthogranuloma (NXG) was established. In our patient, the extremely late onset of the disease, its very aggressive course, and the absence of malignant hematological disorder were remarkable. The general condition improved after local treatment and a low dose of prednisone. However, patient anamnesis revealed myocardial infarction in the past, congestive heart failure, and atrial fibrillation. Eventually, the patient died due to acute heart failure before alkylating agents could be administered; we consider the patient's death to have been unrelated to NXG. NXG is a rare, chronic granulomatous disorder which was first described in 1980 by Kossard and Winkelmann (1). Currently, less than one hundred fifty cases of this syndrome have been reported in the literature worldwide (2,3). The disease occurs during adulthood, slightly more frequently in women, and usually after the age of 60 years, although the youngest reported patient was 17 years old (3). The disease initially manifests as xanthoma-like eruptions of yellowish or red-orange papules and nodules that coalesce into indurated plaques (4). The size of the lesions typically increases over time or with the next recurrences. In comparison to hyperlipemic and normolipemic xanthomas, the lesions are firmer, more prominent, and more polymorphic (3) with superficial telangiectasias, sometimes erythematous and/or violaceous borders, and atrophy (5). Ulcerations of the lesions were observed in about 50% of patients and tended to be extensive and progressive (4). Skin lesions of NXG can occur anywhere on the body. However, about two-thirds of patients had periorbital involvement, particularly on the upper and/or lower eyelids or elsewhere on the face. The second most commonly affected site was the trunk, predominantly the chest (3-6). However, many skin lesions first appear on the trunk or extremities and subsequently involve the periorbital area (4). More than one body area was affected in about 90% of the published cases (3,4). In individual cases, the occurrence of NXG was noted within scars, after trauma, or in a previously X-ray irradiated area (5). Lesions may be asymptomatic; however, over half of patients asked reported various symptoms, predominantly itching but also burning, tenderness, and even pain (4,5). Periorbital skin lesions are often accompanied by ophthalmic manifestations, mainly scleritis, choroiditis, or conjunctivitis (3), and with complications such as blepharoptosis, restricted ocular motility, and proptosis (4,5). Extracutaneous lesions are most commonly seen in the respiratory tract, including the lungs and larynx, followed by the myocardium, oral cavity, skeletal muscles, kidneys, ovaries, intestine, and other sites (5,6). Extracutaneous involvement was reported in less than 20% of cases (3), but its frequency seems to have increased in recent years (5). Regarding laboratory abnormalities, the majority of patients with NXG (70% and up to 90% depending on the studied population) have a monoclonal gammopathy (more often IgG-kappa than IgG-lambda). Elevated erythrocyte sedimentation rate, anemia, leukopenia, low C1 and C4 levels, and cryoglobulinemia are also frequently present (3-6). Incisional biopsy is recommended to confirm the diagnosis of NXG, but correlations between the clinical presentation and specific histopathologic findings have been poorly characterized so far. The histopathology shows an inflammatory infiltrate composed of macrophages, foam cells, plasma cells, and other inflammatory cells as well as Touton and foreign body-type giant cells in the dermis and subcutaneous tissue. Necrobiosis is usually present, and nodular lymphoid aggregates are common. Cholesterol clefts or asteroid bodies are rare or absent. The epidermis may be atrophic or normal. Special stains are not helpful in establishing the diagnosis of NXG, but immunohistochemistry for CD68 is positive while it is always for CD1a and PS100 negative, like in non-X histiocytosis (4,5). In patients without a known myeloproliferative disorder, bone marrow biopsy may reveal atypical or increased plasma cells and, very rarely, true multiple myeloma (5). As mentioned above, NXG can be a manifestation of multiple myeloma. However, chronic lymphocyte leukemia, B-cell lymphoma, and other lymphoproliferative diseases have also been reported in patients with NXG (3). Remarkably, hematological disorders may emerge many years before or after the onset of skin lesions (even up to 11 years) (4). According to available literature data, the course of the disease is usually chronic and slowly progressive, and the prognosis is relatively good in the absence of co-occurrence of malignant hematological disorders ([5-7). Aside from hyperlipemic and normolipemic xanthomas, the differential diagnosis of NXG includes multifocal necrobiosis lipoidica, granuloma annulare, foreign-body granuloma, juvenile xanthogranuloma, rheumatoid nodules, and amyloidosis (4). In 5 cases from the literature, xanthoma and NXG were present at the same time (3). Despite several hypotheses, the etiopathogenesis of NXG remains unknown (3,4,8). For that reason and due to the rarity of the disease, the optimal therapy has not been not defined. Frequently, chlorambucil or melphalan have been used alone or in combination with prednisone (4). Treatment may result in remission of symptoms on the skin, but it does not provide a permanent cure (8). There are also single reports of the successful use of thalidomide, lenalidomide, cyclophosphamide, dexamethasone, interferon 2a and 2b, plasmapheresis and hydroxychloroquine, azathioprine, infliximab, and autologous bone marrow transplantation (3). Methotrexate seems to be ineffective (9). Local therapy, including local steroids, laser CO2, or radiotherapy, results in partial improvement (3,4). Skin lesions which relapsed or were unresponsive to treatment could be excised surgically and the defects resurfaced with skin grafts. [2].
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PMID:Xanthoma-like Skin Changes in an Elderly Woman with a Normal Lipid Profile. 2887 36


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