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M C Sneller

Publications and source records attributed to M C Sneller.

At least 19 recordsLinked to original sources
PubMed1999

Regulation of immunoglobulin production in hyper-IgE (Job's) syndrome.

BACKGROUND: The hyper-IgE (HIE), or Job's, syndrome is a rare, complex disorder characterized by high levels of serum IgE in childhood and chronic dermatitis with recurrent, often severe sinopulmonary and skin infections. Although the etiology of HIE syndrome is unknown, there is evidence that patients with HIE have abnormalities in cellular immune responses, as well as in the production of polyclonal and antigen-specific antibodies. Furthermore, there appears to be a common (but still undefined) mechanism underlying the regulation of IgE and IgG4 in this condition. OBJECTIVE: We sought to assess the role of cytokines or cytokine receptor blockade in regulating IgE and IgG4 production in HIE. METHODS: PBMCs were isolated from patients with HIE (n = 9) and normal individuals (n = 8), and IgE and IgG4 production was assessed spontaneously, in the presence of recombinant IL-4, IL-13, IL-6, IL-8, IL-12, and IFN-gamma, under conditions in which the IL-4R was blocked or when these cytokines were neutralized by specific monoclonal or polyclonal antibodies. RESULTS: In PBMCs from patients with HIE, a significant (P <.01) reduction in the spontaneously produced IgE (and IgG4) was induced by either IFN-gamma or IL-12, although neither cytokine could totally abrogate the immunoglobulin production. Whereas spontaneous IgE (and IgG4) production was not affected by exogenous IL-4 and IL-13, neutralizing antibodies to IL-4 and IL-13 also significantly (P <.01) reduced the production of IgE and IgG4, a finding supported by the observation of increased expression of IgE germline transcripts in these patients. In contrast to the neutralization of IL-4 and IL-13 protein, anti-IL-4R antibodies or soluble IL-4R completely suppressed IgE and IgG4 production in HIE. Similarly, IL-8 or antibodies to IL-6 and TNF-alpha, cytokines known to affect IL-4-dependent IgE production, completely inhibited both IgE and IgG4 production. CONCLUSION: These data show that overproduction of IgE and IgG4 can be regulated by a number of cytokines affecting the IL-4-dependent pathway of IgE/IgG4 production in HIE and suggest new targets for therapeutic intervention.

Cytokines↗
PubMed1999

Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS.

Alleles↗
PubMed1999

Pituitary involvement by Wegener's granulomatosis: a report of two cases.

We describe two cases of pituitary involvement by Wegener's granulomatosis. At initial presentation, or during subsequent disease "flares," a pattern of pituitary abnormality was suggested. During periods of remission, we found the pituitary returned to a nearly normal appearance. Loss of the normal posterior pituitary T1 hyper-intensity matched a clinical persistence of diabetes insipidus, suggesting there is permanent damage to this structure by the initial disease process.

Adolescent↗
PubMed1998

Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease. Part 2: Inflammatory bowel disease, systemic vasculitis, and therapeutic toxicity.

When cytotoxic agents were introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease. During the course of this use, however, it became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward the treatment of non-neoplastic diseases in which autoimmune mechanisms were considered important to pathogenesis. As a result of these investigations, cytotoxic agents and, more recently, cyclosporine have emerged to become an important part of the therapeutic regimen for many autoimmune diseases. Nonetheless, these medications may still cause treatment-induced illness or even death. It is therefore particularly important to weigh the benefits and risks of cytotoxic therapy when treating a non-neoplastic disease. This two-part Clinical Staff Conference reviews data on the efficacy and toxicity of cytotoxic drugs and cyclosporine in selected autoimmune diseases. In part 2, we focus on the role of these agents in treating inflammatory bowel disease and systemic vasculitis and review the toxic effects of these agents.

Cyclosporine↗
PubMed1998

Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease. Part 1: rheumatologic and renal diseases.

When cytotoxic agents were initially introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease. During the course of this use, however, it became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward the treatment of non-neoplastic diseases in which autoimmune mechanisms were considered important to pathogenesis. As a result of these investigations, cytotoxic agents and, more recently, cyclosporine have emerged to become an important part of the therapeutic regimen for many autoimmune diseases. Nonetheless, these medications may still cause treatment-induced illness or even death. It is therefore particularly important to weigh the benefits and risks of cytotoxic therapy when treating a non-neoplastic disease. This two-part Clinical Staff Conference reviews data on the efficacy and toxicity of cytotoxic drugs and cyclosporine in selected autoimmune diseases. Part 1 examines the manner in which these agents have been used to treat rheumatologic and renal diseases.

Autoimmune Diseases↗
PubMed1998

Active Wegener's granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10.

Wegener's granulomatosis (WG) is a granulomatous vasculitis that affects the upper respiratory tract, lung, and kidney. Since T cells make up a significant proportion of cells infiltrating granulomatous lesions in WG, we investigated the proliferative response and cytokine profile of T cells from these patients. PBMCs were isolated from 12 patients with active WG, 7 patients with inactive disease, and 12 healthy normal donors. PBMCs from clinically active WG patients exhibited increased proliferation following stimulation with either PMA/ionomycin or anti-CD2 and anti-CD28, when compared with normal donors. In addition, these PBMCs exhibited increased secretion of IFN-gamma, but not of IL-4, IL-5, or IL-10. Furthermore, TNF-alpha production from PBMCs and CD4+ T cells isolated from patients with WG was elevated, when compared with healthy donors. In further studies, we investigated the ability of WG patients' monocytes to produce IL-12 and showed that both inactive and active patients produced increased amounts of IL-12. Finally, the in vitro IFN-gamma production by WG PBMC is inhibited in a dose-dependent manner by exogenous IL-10. These data suggest that T cells from WG patients overproduce IFN-gamma and TNF-alpha, probably due to dysregulated IL-12 secretion, and that IL-10 may therefore have therapeutic implications for this disease.

Adult↗
PubMed1998

Pathological findings in human autoimmune lymphoproliferative syndrome.

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).

Apoptosis↗
PubMed1998

Evaluation, treatment, and prophylaxis of infections complicating systemic vasculitis.

Infection continues to be a major cause of morbidity and mortality in patients with systemic vasculitis. The recognition and treatment of infections in these patients is a particularly difficult task because the spectrum of potential pathogens is broad and the clinical manifestations of infection often mimic those of the underlying disease. This article provides 1) a general overview of the immunosuppressive properties of agents commonly used in the treatment of systemic vasculitis, and 2) a framework for the diagnostic evaluation and treatment of various infectious syndromes in patients with systemic vasculitis.

Evaluation Studies as Topic↗
PubMed1998

Polypoid lesions of airways: early experience with computer-assisted detection by using virtual bronchoscopy and surface curvature.

PURPOSE: To test the application of a technique developed by the authors for the computer-assisted diagnosis of polypoid airway lesions from surface rendered virtual bronchoscopic reconstructions. MATERIALS AND METHODS: A computer algorithm was developed to detect polypoid airway lesions by means of segmentation of the bronchial surface with curvature classification. This method was tested with a bronchial phantom, five cadaveric lung specimens, and virtual bronchoscopic studies in 16 patients. RESULTS: For the patient studies, the sensitivity and specificity of the method were 47%-88% and 58%-89%, respectively, depending on the value of an adjustable parameter (the mean curvature threshold). The sensitivity increased (by 20% to 34%) when only lesions larger than 5 mm in diameter were considered. CONCLUSION: With this method, polypoid airway lesions can be detected automatically, although false-positive diagnoses present an important limitation.

Adult↗
PubMed1997

Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.

Anemia, Hemolytic, Autoimmune↗
PubMed1997

ALPS: an autoimmune human lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.

Apoptosis of activated lymphocytes is critical to immune homeostasis. The cell surface receptor Fas is an important mediator of lymphocyte apoptosis; defective Fas expression causes accumulation of lymphocytes and autoimmune disease in mice. Apoptosis defects due to mutations of Fas have also been found in a rare human autoimmune lymphoproliferative syndrome (ALPS). Nine unrelated children with ALPS had lymphadenopathy, autoimmunity and expansion of a normally infrequent population of CD4-CD8-T cells. All nine exhibited impaired lymphocyte apoptosis in vitro, and eight had heterozygous Fas gene mutations. Thus genetic defects in apoptosis pathways are implicated in the pathogenesis of at least one human autoimmune disorder.

Apoptosis↗
PubMed1997

Pathogenesis of vasculitis syndromes.

The pathogenesis of vasculitis is complex and involves a variety of mechanisms acting in concert to bring about necrotizing inflammation of blood vessel walls. In recent years, there has been considerable progress in dissecting the immunologic abnormalities present in specific vasculitis syndromes. The primary immunopathogenic events that initiate the process of vascular inflammation and blood vessel damage, however, are still largely unknown. Although the cause of most vasculitis syndromes remains a mystery, advances in molecular and cellular immunology have defined many of the effector mechanisms that mediate inflammatory vascular damage. In this regard, modulation of the inflammatory response by specific cytokine and adhesion molecule antagonists is now possible and may prove beneficial in the treatment of vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1997

Infectious complications of immunosuppressive therapy in patients with rheumatic diseases.

Infection continues to be a significant cause of morbidity and mortality in patients with rheumatic diseases, and, consequently, early diagnosis and treatment of infection is critical to the successful medical management of these patients. The intensity of immunosuppressive therapy is the dominant risk factor for infection in this patient population. Because the manifestations of infection in patients with rheumatic diseases are highly variable, the clinician must always be vigilant about the possibility of infection even if the clinical presentation is highly suggestive of an exacerbation of the underlying disease. We have stressed a systematic and individualized approach in the diagnostic evaluation of suspected infection in these patients. The first part of the evaluation involves forming a list of the most likely pathogens based on a detailed history and physical examination and the intensity and type of immunosuppressive therapy the patient is receiving. The physician must then formulate a plan designed to establish a diagnosis expeditiously and with the least morbidity.

Communicable Diseases↗
PubMed1997

Methotrexate use in systemic vasculitis.

Although GS and CYC have been important agents in improving the outcome and survival of patients with systemic vasculitis, they carry their own risk of drug-induced morbidity and mortality. It has also become apparent that these medications are not the final answer in disease management because some forms of vasculitis have the potential to relapse or be treatment resistant. For these reasons, the pursuit of effective, less toxic therapeutic alternatives is critical. Initial results from the use of MTX in systemic vasculitis have been encouraging. Although drug-related toxicity and disease relapse have still been found to occur, MTX appears to be a valuable addition in the treatment of vasculitis. Further studies will be necessary to determine the optimal way that this agent may be used to safely and effectively manage vasculitic disease.

Antirheumatic Agents↗
PubMed1997

HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies.

Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.

CD4-Positive T-Lymphocytes↗
PubMed1997

New developments in the treatment of Wegener's granulomatosis, polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome.

With the opportunity for long-term follow-up, it has been appreciated that disease severity may vary considerably in patients with Wegener's granulomatosis, polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Although combined therapy with cyclophosphamide and glucocorticoids continues to be the foundation of treatment, concerns have increased about the toxicities of this regimen. As illustrated by studies on Wegener's-related subglottic stenosis and endobronchial involvement, it has also become apparent that some disease manifestations may not respond to this therapy. Recent therapeutic investigations have therefore focused on identifying approaches that are less toxic and that are based on anatomic involvement and disease severity. The study of polyarteritis nodosa has additionally been affected by proposed changes in classification that would make this condition a separate entity from microscopic polyangiitis. As progress is made in defining the clinical significance of this nomenclature, the prognostic factors in these patients have also been examined, which may be helpful in guiding therapeutic decisions.

Churg-Strauss Syndrome↗
PubMed1997

Management of neutralizing antibody to Ceredase in a patient with type 3 Gaucher disease.

OBJECTIVES: The beneficial effects of macrophage-targeted glucocerebrosidase (Ceredase) in patients with Gaucher disease are well established. A minority of recipients develop transient nonneutralizing antibodies to the exogenous enzyme. A 7-year-old patient with type 3 Gaucher disease whose clinical course began to deteriorate while receiving Ceredase developed a progressively increasing titer of IgG antibody that blocked the catalytic activity of Ceredase. We sought to develop a strategy that would restore the benefit of enzyme replacement therapy in this patient. METHODS: The patient was treated with two courses of a combination of plasma exchange, cyclophosphamide, intravenous IgG, and large doses of Ceredase. RESULTS: After the second course of this regimen, the titer of the neutralizing antibody in the blood gradually declined to negligible levels. Clinical parameters that had been deteriorating (reduction of hemoglobin level, increased serum acid phosphates activity, repeated skeletal infarctions, progressive enlargement and infarction of the spleen) all improved. There has been no recurrence of the neutralizing antibody in this patient. CONCLUSIONS: Very few patients with Gaucher disease who are treated with Ceredase develop a neutralizing antibody to the exogenous enzyme. In the rare instances where this phenomenon occurs, it is likely that the strategy we have used (plasma exchange, cyclophosphamide, intravenous IgG, and large doses of enzyme) may provide benefit to such individuals. It is also likely that this technique may be helpful when enzyme replacement therapy is attempted in patients with other disorders in which the genetic mutation abrogates the production of the protein (CRIM-negative individuals).

Antibody Formation↗