Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MRL/Mpj-lpr/lpr (MRL/lpr) mice develop autoimmune disorders, including lymphoproliferation, glomerulonephritis, autoantibody production, and hypergammaglobulinemia. To investigate the role of the costimulatory molecule CD28 in the development of these disorders, MRL/lpr mice lacking CD28 were generated by gene targeting. Compared with CD28+/+ MRL/lpr mice, CD28-/- MRL/lpr mice showed decreased lymphadenopathy but increased splenomegaly associated with the expansion of abnormal B220+ TCRalphabeta+ T cells. Although levels of IgM Abs were unchanged in CD28-/- MRL/lpr mice, the production of anti-DNA IgG Abs and IgG rheumatoid factors were suppressed. IgG deposition in the glomeruli was markedly decreased, and the development of glomerulonephritis was significantly retarded. Furthermore, renal vasculitis and arthritis were absent in CD28-/- MRL/lpr mice. These results indicate that, although CD28 is not required for the generation of the abnormal T cell population in MRL/lpr mice, it does play an important role in the development of autoimmune disease in these animals.
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PMID:Role of the costimulatory molecule CD28 in the development of lupus in MRL/lpr mice. 1047 82

Chronic natural killer cell lymphocytosis is a persistent state of natural killer (NK) cell (CD3-CD16/CD56+) excess in the peripheral blood that is not associated with clinical lymphoma. In 16 consecutive patients (median age 60.5 years, range 7-77), males were overrepresented (M:F 7:1) and the median absolute NK cell count was 4.09 x 10(9)/l (range 1.2-16.6). Bone marrow examination was performed in 14 patients and showed atypical granulomata in two; chromosome studies in seven patients were normal. Clonal T-cell receptor gene rearrangement was not found in any of 12 patients evaluated. At presentation, seven patients (44%) had no clinical symptoms or signs and the others had vasculitic skin lesions (three patients), non-neutropenic fever (three patients), recurrent neutropenic infection (two patients), musculoskeletal symptoms (two patients), peripheral neuropathy (two patients), aphthous ulcers (one patient), and splenomegaly (one patient). Five patients had anaemia, five had neutropenia, and two had thrombocytopenia. After a median follow-up of 5.1 years (range 0-10.2) from immunophenotypic diagnosis or 5.7 years (range 0.1-14.1) from documentation of absolute lymphocytosis, vasculitic glomerulonephritis developed in one patient, accelerated splenomegaly developed in a patient receiving myeloid growth factor treatment, and severe aplastic anaemia developed in one patient. Treatment with nonsteroidal anti-inflammatory drugs or immunosuppressive agents was variably successful.
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PMID:A long-term study of patients with chronic natural killer cell lymphocytosis. 1051 98

MRL/lpr mouse is an established animal model which develops autoimmune diseases including glomerulonephritis, sialoadenitis, hepatitis and inflammatory lung disease. Additionally, it has been reported that lpr strains uniquely accumulate CD3+ CD4- CD8- B220+ (double negative, DN) T cells in lymphoid organs leading to lymphadenopathy and splenomegaly. To investigate the role of CD28/CTLA4-B7 pathway in the development of lymphadenopathy and splenomegaly, MRL/lpr mice were treated with soluble form of CTLA4 molecules, CTLA4IgG, which efficiently blocks this pathway. It was demonstrated that (i) the development of DN T cells was independent of the CD28/CTLA4-B7 pathway, (ii) the CD28/CTLA4-B7 pathway was required for the development of lymphadenopathy and splenomegaly, (iii) the CD28/CTLA4-B7 pathway was important for the accumulation of various cell populations in the lymph node and spleen, (iv) composition of the accumulating cell populations was not altered by CTLA4IgG treatment, and (v) activation of conventional T cells and IL-4 production from conventional T cells were the CD28/CTLA4-B7 pathway dependent. Thus, we concluded that the CD28/CTLA4-B7 pathway was required for the development of full-blown lymphadenopathy and splenomegaly in MRL/lpr mice.
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PMID:Involvement of CD28/CTLA4-B7 costimulatory pathway in the development of lymphadenopathy and splenomegaly in MRL/lpr mice. 1067 86

Many patients with type II mixed cryoglobulinemia have been shown to be infected with hapatitis C virus (HCV). Therefore, interferon-alfa has become the first choice of treatment for patients with HCV-associated cryoglobulinemia. However, the disease often relapses after the discontinuation of interferon therapy. The long-term effect of interferon therapy is controversial. Therefore, a more effective therapy needs to be developed. A 62-year-old Japanese woman was admitted to our hospital for the examination of abnormal liver function tests, severe edema, and purpura in her lower extremities. Glomerulopathy secondary to HCV-related cryoglobulinemia was suspected. Her serum creatinine was increased to 2.1 mg/dL. Interferon therapy was considered initially. However, because of pancytopenia caused by liver cirrhosis and splenomegaly, splenectomy was performed in February 1997, before the start of interferon therapy. Renal biopsy specimen taken at the time of the splenectomy showed typical cryoglobulinemic glomerulonephritis. Gradually, after surgery, the patient's thrombocytopenia and anemia improved, her proteinuria and hematuria were decreased, her cryocrit dropped from 15% to 5%, the Ccr increased from 21.1 mL/min to 48.8 mL/min, and the purpura in her lower extremities disappeared. A repeat renal biopsy performed in May 1998 showed marked histological improvement. Splenectomy is not widely accepted as a treatment for cryoglobulinemia. Our case suggests the possibility that the monoclonal-IgM component of the type II cryoglobulin may be formed in the spleen. In conclusion, splenectomy may be an effective therapy for cryoglobulinemia in patients with HCV-positive liver cirrhosis and pancytopenia secondary to splenomegaly.
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PMID:Splenectomy may improve the glomerulopathy of type II mixed cryoglobulinemia. 1084 34

Systemic lupus erythematosus (SLE) is characterized by immune abnormalities explained by the overproduction of Th(2)cytokines such as autoantibody production and polyclonal B cell activation. We examined the effect of administering a DNA plasmid encoding IL-12 on the lupus-like disease of MRL/MP-lpr/lpr (MRL/lpr) mice. Treatments were delivered intramuscularly every 4 weeks, starting at 4 weeks of age. This intervention significantly inhibited the accumulation of CD4(-)CD8(-)T cells, and reduced lymphadenopathy and splenomegaly. A significant decrease in serum IgG anti-DNA autoantibody titers was observed, and plasmid IL-12 therapy was also associated with a reduction in the proteinuria and glomerulonephritis characteristic of this disease. Serum IFN-gamma level was increased by inoculating IL-12 encoding plasmid, suggesting that the cytokine balance was skewed towards Th(1). The clinical implications of this suppression of autoimmune disease are also discussed.
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PMID:IL-12-encoding plasmid has a beneficial effect on spontaneous autoimmune disease in MRL/MP-lpr/lpr mice. 1088 Feb 49

The literature on the assessment of morbidity due to Schistosoma mansoni infection is updated. Imaging techniques such as ultrasonography, echodoppler cardiography, computerized tomography (CT scan) and magnetic resonance imaging (MRI) introduced a new perspective, and expanded our knowledge on morbidity. Three well-defined syndromes caused by schistosomiasis mansoni have been described: the stage of invasion, acute schistosomiasis (Katayama fever), and chronic schistosomiasis. Complications of the acute and chronic syndromes have also been reported: pulmonary hypertension, neuroschistosomiasis, association with Salmonella, association with Staphylococci, viral hepatitis B, glomerulonephritis. In most individuals with hepatosplenic schistosomiasis the spleen is increased in size. Hepatosplenic schistosomiasis can, however, occur without splenomegaly. The definition of hepatosplenic schistosomiasis in endemic areas as the finding of S. mansoni eggs in the stools in an individual with hepatosplenomegaly is not satisfactory anymore. Many aspects of morbidity are expected to change after schistosomiasis control. Some are expected to change quickly (worm burden, Salmonella bacteremia, hepatosplenic schistosomiasis in children) whereas others shall remain for years (pulmonary hypertension, glomerulonephritis, neuroschistosomiasis). Intestinal schistosomiasis in individuals with low worm burdens is very difficult to diagnose and therefore laborious to control.
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PMID:Schistosoma mansoni: assessment of morbidity before and after control. 1099 26

The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4(-/)- mice. This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2(-)(/)- mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4(-)(/)- but not Cr2(-)(/)- mice. C4(-)(/)-, but not Cr2(-)(/)-, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.
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PMID:Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. 1106 82

Emk is a serine/threonine protein kinase implicated in regulating polarity, cell cycle progression, and microtubule dynamics. To delineate the role of Emk in development and adult tissues, mice lacking Emk were generated by targeted gene disruption. Emk(-/-) mice displayed growth retardation and immune cell dysfunction. Although B- and T-cell development were normal, CD4(+)T cells lacking Emk exhibited a marked upregulation of the memory marker CD44/pgp-1 and produced more gamma interferon and interleukin-4 on stimulation through the T-cell receptor in vitro. In addition, B-cell responses to T-cell-dependent and -independent antigen challenge were altered in vivo. As Emk(-/-) animals aged, they developed splenomegaly, lymphadenopathy, membranoproliferative glomerulonephritis, and lymphocytic infiltrates in the lungs, parotid glands and kidneys. Taken together, these results demonstrate that the Emk protein kinase is essential for maintaining immune system homeostasis and that loss of Emk may contribute to autoimmune disease in mammals.
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PMID:Immune system dysfunction and autoimmune disease in mice lacking Emk (Par-1) protein kinase. 1128 24

The Fas ligand (FasL)/Fas pathway is crucial for the maintenance of homeostasis of the peripheral immune system. Its importance is illustrated by the spontaneous mouse mutants gld andlpr which lack functional FasL and Fas receptor, respectively. These animals develop lymphadenopathy, splenomegaly, increased serum Ig and autoantibodies, leading to an autoimmune syndromeand premature death. The Rel/NF-kappaB family of transcription factors plays an important role in peripheral lymphocyte proliferation and survival. In this report, we studied the consequences of T cell-specific inhibition of NF-kappaB on the development of the gld phenotype. Transgenic gld/gld mice expressing a non-degradable form of IkappaBalpha under the control of T cell-specific regulatory elements show dramatically reduced lymphadenopathy, splenomegaly, and an almost complete elimination of Thy-1(+)B220(+)CD4(-)CD8(-) abnormal T cells, correlating with reduced proliferative responses and increased apoptosis of peripheral T cells upon TCR triggering. Interestingly, the B cell abnormalities that are characteristic of gld/gld mice, such as the production of autoantibodies, high levels of serum Ig, and the development of glomerulonephritis, are partially corrected. These results suggest that the T cell-specific inhibition of NF-kappaB opens apoptotic pathways distinct from FasL/Fas which, along with a diminished proliferative response, blocks splenomegaly and lymphadenopathy and partially rescues autoimmune disease in gld/gld mice.
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PMID:Inhibition of NF-kappaB in T cells blocks lymphoproliferation and partially rescues autoimmune disease in gld/gld mice. 1153 59

Costimulatory molecules on antigen-presenting cells (APCs) play an important role in T cell activation and expansion. However, little is known about the surface molecules involved in direct T-T cell interaction required for their activation and expansion. LIGHT, a newly discovered TNF superfamily member (TNFSF14), is expressed on activated T cells and immature dendritic cells. Here we demonstrate that blockade of LIGHT activity can reduce anti-CD3-mediated proliferation of purified T cells, suggesting that T cell-T cell interaction is essential for this proliferation. To test the in vivo activity of T cell-derived LIGHT in immune homeostasis and function, transgenic (Tg) mice expressing LIGHT in the T cell lineage were generated. LIGHT Tg mice have a significantly enlarged T cell compartment and a hyperactivated peripheral T cell population. LIGHT Tg mice spontaneously develop severe autoimmune disease manifested by splenomegaly, lymphadenopathy, glomerulonephritis, elevated autoantibodies, and severe infiltration of various peripheral tissues. Furthermore, the blockade of LIGHT activity ameliorates the severity of T cell-mediated diseases. Collectively, these findings establish a crucial role for this T cell-derived costimulatory ligand in T cell activation and expansion; moreover, the dysregulation of T cell-derived LIGHT leads to altered T cell homeostasis and autoimmune disease.
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PMID:The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT. 1174 55


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