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Biomedical subjects

R I Fox

Publications and source records attributed to R I Fox.

At least 37 records · Page 2Linked to original sources
PubMed1998

Mechanism of action of leflunomide in rheumatoid arthritis.

Leflunomide, a novel drug with proven efficacy in rheumatoid arthritis, is an isoxazol derivative structurally unrelated to other immunomodulatory drugs. Leflunomide is rapidly metabolized to its active form, A77 1726. Two mechanisms of action have been identified for A77 1726: inhibition of dihydroorotate dehydrogenase (DHODH) and inhibition of tyrosine kinases. DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the major mode of action. Stimulated lymphocytes must increase ribonucleotide levels from 8 to 16-fold before proceeding from the G1 into the S phase. Increased levels of ribonucleotides can only be met by de novo ribonucleotide synthesis. At low levels of ribonucleotides, p53, a "sensor" molecule, gets activated and prevents progression through the cell cycle. Therefore, an inhibitor of de novo uridine monophosphate synthesis would predictably arrest stimulated cells at the G1 phase. In support of this mechanism of action, in vitro mitogen stimulated human peripheral blood lymphocytes treated with A77 1726 undergo arrest at the G1 phase; this inhibition is reversed by uridine.

Animals↗
PubMed1997

Expression and regulation of the neural cell adhesion molecule L1 on human cells of myelomonocytic and lymphoid origin.

The neural cell adhesion molecule L1 has been implicated in a variety of neurologic processes, including neuritogenesis and cerebellar cell migration. Here we propose an expanded role for this cell adhesion molecule in the human immune system based on its expression on cells of myelomonocytic and lymphoid origin. Freshly isolated circulating monocytes had minimal L1 expression; however, activation of these effector cells by IFN-gamma, or as a result of density gradient isolation, resulted in a significant induction of L1 expression. Constitutive L1 expression was further evident on myelomonocytic cell lines but was absent on mature tissue macrophages. In further studies, positive selection with a L1-specific Ab enriched both B cells and dendritic precursor cells from peripheral blood. Significantly, L1 expression was not detected on mature dendritic cells but could be induced by treatment with LPS, PHA, and TNF-alpha. Immunohistochemical analysis further demonstrated significant L1 expression on follicular dendritic cells and on endothelial cells associated with the arterioles and red pulp of normal spleen. Based on these observations and known functions of L1, we propose that this cell adhesion molecule may contribute to cell-cell adhesion events associated with the effector function or extravasation of these immune effector cells. In support of the latter, we present evidence that L1 can be recognized by endothelial cells via the integrin alpha(v)beta3.

Cell Line↗
PubMed1997

Pathogenesis and treatment of Sjögren's syndrome.

The criteria for diagnosis of primary Sjögren's syndrome continue to be controversial, leading to confusion in clinical practice and in the research literature. Among Sjögren's syndrome patients who fulfill the European criteria, only 15% of those would fulfill the San Diego criteria. This difference in disease classification leads to difficulty in evaluating clinical trials and in elucidating pathogenetic mechanisms, because different patient populations are evaluated. As a result of the ease and safety of minor salivary gland biopsy, Sjögren's syndrome serves as a prototype model to study the immunopathogenic features of a human organ-specific autoimmune disease. Critical features of pathogenesis include: 1) failure to "delete" autoimmune T cells at the level of thymic selection; 2) "homing" of autoimmune lymphocytes to salivary and lacrimal glands via high endothelial venules; 3) clonal expansion of autoimmune T cells in the glands; 4) upregulation of major histocompatibility antigens and adhesive molecules by epithelial cells in the glands; 5) secretion of proinflammatory cytokines by both lymphocytes and epithelial cells; 6) decreased neural innervation of the glands; 7) failure of residual glandular tissue express secretory functions; and 8) failure to remove autoimmune T cells by normal mechanisms of apoptosis. Each of these steps is regulated by cell-matrix interactions, cytokine and growth factor secretion, cell membrane receptor stimulation, "second" signals in the cytoplasm, and nuclear transcription factors. Recent studies on each of these steps in Sjögren's syndrome have suggested their role in pathogenesis and, consequently, their potential as sites for therapeutic intervention.

Antibodies, Viral↗
PubMed1997

Sjögren's syndrome. Controversies and progress.

Diagnostic criteria for Sjögren's syndrome (SS) are required by both physicians and patients to (1) provide a rational basis for their symptoms, assess their prognosis, and guide therapy; (2) identify a group of patients who are most likely to share a common etiopathogenesis, in order to identify those genetic and environmental factors that are crucial in pathogenesis; (3) fill out the myriad medical insurance forms that require a diagnosis code; and (4) serve as a "shorthand" code that alerts specialists in different fields (oral medicine, ophthalmology, and a variety of specialists in internal medicine) to search for particular clinical problems found in the SS patient. The key question in this article is whether the term "Sjögren's syndrome" should apply to a rather restricted group of individuals (those with an autoimmune basis for exocrinopathy) or to a rather large group of individuals who share a similar symptom complex of dry eyes and mouth. Primary SS, as defined by San Diego criteria, is a systemic autoimmune disease that is characterized by keratoconjunctivitis sicca and xerostomia resulting from lymphocytic infiltrates of the lacrimal and salivary glands. The criteria for the diagnosis of SS continues to be controversial, leading to confusion in the clinical and research literature. It is important to distinguish SS (an idiopathic autoimmune process) from other processes including hepatitis C infection, retroviral infection, lymphoma, autonomic neuropathy, depression, primary fibromyalgia, and drug side effects that can result in sicca symptoms. Recent studies on pathogenesis of SS in human and animal models have examined the clonality of the T-cell infiltrates, the production of cytokines by lymphocytes and glandular epithelial cells, neuroendocrine and hormonal factors that affect glandular secretion, and the fine structure of antigens recognized by T cells and B cells. Studies in SS have allowed comparison of lymphocytes in blood and in the glandular tissue lesions; important differences in the gland microenvironment play an important role in the initiation and perpetuation of the autoimmune process. For example, apoptotic death depends on the balance of Fas, Fas ligand, nuclear factors (such as bcl-2, bax, and myc), cytokines, neuropeptides, and cell membrane interactions with extracellular matrix. Although increased rates of apoptosis may be present in the blood T cells of SS patients, some glandular T cells are resistant to apoptosis. Recent advances have led to improved understanding of signal transduction in response to cytokines and hormones that play a role in the local and systemic manifestations of SS.

Animals↗
PubMed1996

Clinical features, pathogenesis, and treatment of Sjögren's syndrome.

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease that is characterized by keratoconjunctivitis sicca and xerostomia resulting from lymphocytic infiltrates of the lacrimal and salivary glands. The criteria for the diagnosis of SS continue to be controversial, leading to confusion in the clinical and research literature. It is important to distinguish SS (an idiopathic autoimmune process) from other processes, including hepatitis C infection, autonomic neuropathy, and drug side effects, that can result in sicca symptoms. Recent studies on the pathogenesis of SS in humans and in animal models examine the clonality of the T cell infiltrates, cytokine production by lymphocytes and glandular epithelial cells, neuroendocrine and hormonal factors that affect glandular secretion, and the fine structure of antigens recognized by T and B cells. Studies of SS have allowed comparison of lymphocytes in blood and in the glandular tissue lesions; important differences in the gland microenvironment play an important role in the initiation and perpetuation of the autoimmune process. For example, apoptotic death depends on the balance of Fas, Fas ligand, nuclear factors (eg, bcl-2, bax, and myc), cytokines, neuropeptides, and cell membrane interactions with extracellular matrix. Although increased rates of apoptosis may be present in the blood T cells of SS patients, some glandular T cells are resistant to apoptosis. Recent advances have led to improved understanding of signal transduction in response to cytokines and hormones that play a role in the local and systemic manifestations of SS. New approaches to therapy are designed to improve the qualitative properties of corneal epithelial surface, as well as increase tear volume.

Diagnosis, Differential↗
PubMed1996

Sjögren's syndrome: immunobiology of exocrine gland dysfunction.

Sjögren's syndrome is an autoimmune disorder characterized by dryness of the eyes and mouth. The frequency of this disorder remains controversial, due to absence of a universally accepted classification system. In the San Diego and San Francisco classification systems for primary Sjögren's syndrome, evidence for an autoimmune process and focal lymphocytic infiltration of the salivary or lacrimal gland is required for diagnosis. This paper reviews the genetic and environmental factors that have been associated with the autoimmune process in Sjögren's syndrome. Key immunopathologic features include: (a) an increased prevalence of particular HLA-DR/DQ alleles; (b) induction of HLA-DR/DQ proteins on the epithelial cells in salivary and lacrimal gland biopsies; (c) infiltration of the glands by CD4+ T-cells that transcribe IL-2 and IFN-gamma; (d) induction of granzyme A and perforin in CD4+ T-cells, suggesting a mechanism of cellular destruction of the glands; (e) clonal expansion of B-cells that use a particular light chain within the salivary gland; (f) production of autoantibodies against nuclear antigens SS-A (60 and 52 kDa) and SS-B (48 kDa), indicating a failure of normal tolerance mechanisms; and (g) increased frequency of B-cell non-Hodgkin's lymphoma. Indirect evidence has suggested a potential role for viruses (especially members of the herpesvirus and retroviral family) as co-factors.

HLA Antigens↗
PubMed1996

Treatment of primary Sjögren's syndrome with hydroxychloroquine: a retrospective, open-label study.

OBJECTIVES: To determine whether patients with primary Sjögren's syndrome (SS), diagnosed according to San Diego criteria, had improvement in their laboratory or clinical features during treatment with hydroxychloroquine (6-7 mg/kg/day) for at least two years. METHODS: The study population included 50 consecutive patients with primary SS who were diagnosed according to San Diego criteria, and in whom hydroxychloroquine was suggested as treatment. This group included 10 patients who were early dropouts (side effects or desire not to take antimalarial drugs) and 40 patients who received drugs for at least two years (range 24-48 months). In a subset of SS patients, values for ESR (westergren) and quantitative immunoglobulins were available for comparison. Improvement with therapy was defined as: (a) > or = 20% improvement in variables of tear flow (Schirmer's test I) or corneal integrity (rose Bengal): (b) > or = 20% salivary function (flow rate); and (c) improvement in at least two of the following measures: physicians assessment of global disease activity by > or = 20%, patient assessment of improvement in pain or fatigue by > or = 20%, and ESR improved by > or = 20 mm/hr. RESULTS: In a retrospective study of SS patients who completed the trial, a significant improvement was noted in ocular symptoms (pain and dryness) in patients (55 and 57%) and improved corneal integrity (rose Bengal straining) in 53% of patients. The Schirmer's test was improved by > or = 2 mm/5 minutes in 50% in patients. Improvement was noted in oral symptoms (pain and dryness) in patients (57 and 60%) and salivary flow rate was increased in 82% of patients. In a subset of SS patients evaluated, the ESR improved by > or = 20 mm/hr in 17/32 patients (53%) and quantitative IgG level by > or = 20% in 8/13 patients (61%). Physician global assessment of overall patient status and patient assessment of overall status indicated improvement in over 62% of patients. CONCLUSION: In a retrospective study of patients fulfilling San Diego Criteria for SS, we found: (a) sustained improvement of local symptoms (painful eyes, painful mouth) and improvement of systemic manifestations (arthralgias and myalgias) after treatment with hydroxychloroquine 6-7 mg/kg/day over mean three-year follow-up; (b) laboratory analysis showed a significant improvement in their ESR and their quantitative IgG levels; (c) no significant late toxicity was observed in this study cohort. A prospective study of hydroxychloroquine in patients fulfilling San Diego criteria for SS is indicated.

Adolescent↗
PubMed1995

Vth International Symposium on Sjögren's syndrome. Clinical aspects and therapy.

There is increasing awareness that sicca syndrome can lead to ocular, oral and systemic complications. However, a wide variety of pathogenetic processes may lead to the same end result of diminished glandular secretion. Recognition of these different etiologies will lead to improved therapies. On the one hand, an active inflammatory/autoimmune process may respond to immunomodulatory drugs. On the other hands, processes that predominantly involve "neuroendocrine" dysfunction (unrelated to immune activity) of the gland will require a different approach.

Autoimmunity↗
PubMed1995

Sjögren's syndrome.

The literature published over the past year on Sjögren's syndrome is reviewed, including epidemiology, genetic, environmental, and clinical features. The criteria for the classification of Sjögren's syndrome remain controversial, potentially leading to confusion in clinical practice and in research publications. Dryness of the eyes and mouth can result from either interruption of the neurovascular innervation of the glands or from any infiltrative process that affects the ability of the glands to secrete. Recent studies have demonstrated that sicca symptoms also can result from autonomic neuropathy in patients with diabetes, multiple sclerosis, or systemic lupus erythematosus. It is suggested that the term Sjögren's syndrome be used to describe one subset of patients with sicca symptoms who exhibit particular major histocompatibility complex antigens, the presence of T cell lymphoid infiltrates on glandular biopsy, and specific autoantibodies in their sera. Even using these restrictive criteria for classification, no single environmental factor has been shown as necessary or sufficient for pathogenesis. Recent studies on Epstein-Barr virus have indicated a novel deleted virus in some Chinese Sjögren's syndrome patients. Other patients with sicca symptoms and autoimmune features may have infections with HIV or hepatitis C virus.

Animals↗
PubMed1994

Cytokine mRNA expression in salivary gland biopsies of Sjögren's syndrome.

Sjögren's syndrome is a human autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands, hypergammaglobulinemia, and specific autoantibodies. The accessibility of the salivary gland to biopsy provides an opportunity to study cytokine mRNA expression at the site of organ-specific immune damage. Using reverse transcriptase and a quantitative PCR to measure cytokine mRNA, we found Sjögren's syndrome: 1) salivary gland CD4+ T cells produce over 40-fold more IL-2, IFN-gamma, and IL-10 mRNA than peripheral blood CD4+ T cells from the same patient or from normal controls; 2) salivary gland CD4+ T cells produced little IL-4 and IL-5 mRNA immediately after elution from the salivary gland, although these mRNAs could be induced by mitogen stimulation of Sjögren's syndrome salivary gland lymphocytes in vitro; 3) salivary gland epithelial cells produced over 40-fold more IL-1 alpha, IL-6, and TNF-alpha mRNA than epithelial cells from individuals with histologically normal salivary glands. Increased levels of IL-1 alpha, IL-6, IL-10, TNF-alpha, and IFN-gamma cytokines were found by ELISA assay in the saliva of Sjögren's syndrome patients, indicating that the elevated mRNA levels detected in their glandular tissue by PCR correlate with local protein synthesis. Our results demonstrate that CD4+ cells in the salivary glands of Sjögren's syndrome patients exhibit mRNA expression that is distinct from previously described Th1 and Th2 lymphocytes in mice or cytokines reported in other human autoimmune or allergic diseases. Also, we found that salivary gland epithelial cells may participate in the pathogenesis of Sjögren's syndrome biopsy by producing cytokines (IL-1 alpha, IL-6, and TNF-alpha).

B-Lymphocytes↗
PubMed1994

Expression of granzyme A in salivary gland biopsies from patients with primary Sjögren's syndrome.

OBJECTIVE: To determine whether the destruction of salivary gland epithelial cells in Sjögren's syndrome (SS) could be mediated by granzyme A, a serine protease that is contained in the granules of activated lymphocytes. METHODS: We used in situ hybridization and polymerase chain reaction amplification to determine the expression of granzyme A messenger RNA (mRNA) in salivary gland biopsy samples. RESULTS: Granzyme A mRNA expression was detected in salivary glands from SS patients, but not in those from normal controls. Granzyme A mRNA content was significantly correlated (P < 0.001) with the size of lymphocytic infiltrates in the salivary glands and with the clinical activity of the disease. CONCLUSION: Cells that express granzyme A mRNA may play a role in the destruction of the target organ (i.e., the salivary gland) in patients with SS. The strong association of granzyme A mRNA expression and larger lymphoid infiltrates in the patients' salivary glands suggests that granzyme A mRNA is expressed at a relatively late stage of the local inflammatory process. Therapies designed to modulate or block granzyme A induction and action should be investigated in SS patients.

Adult↗
PubMed1994

Anti-glycosphingolipid autoantibodies in rheumatologic disorders.

Antibodies directed against ganglioside GM1 or sulfatides are frequently associated with motor or sensorimotor neuropathies. To establish the prevalence of such anti-glycosphingolipid autoantibodies in autoimmune disorders and to determine whether they contribute to neurologic symptoms in those individuals, we measured these antibodies by enzyme-linked immunosorbent assay (ELISA) in serum samples from rheumatologic patients with and without peripheral neuropathies (PN). We tested 21 patients with systemic lupus erythematosus (9 with PN), 26 with Sjögren's syndrome (12 with PN), 34 with scleroderma (28 with PN), and 14 with rheumatoid arthritis (4 with PN). Samples from 32 normal individuals were also tested. Patients with systemic lupus erythematosus and rheumatoid arthritis had elevated concentrations of GM1 antibodies and scleroderma patients had lower levels of sulfatide antibodies compared to healthy individuals. The presence of ganglioside or sulfatide antibodies did not correlate with the development of peripheral neuropathy in these patients. These findings suggest that relatively low-titer glycosphingolipid antibodies may arise as part of a nonspecific polyclonal gammopathy in rheumatologic disorders but generally without clinical manifestation.

Adult↗
PubMed1994

Sjögren's syndrome: immunologic and neuroendocrine mechanisms.

SS patients are characterized by decreased volume of lacrimal and salivary secretions. The dryness results from a combination of destroyed glandular elements as well as by interference with the neuro-endocrine innervation of the residual glands. Specific genetic factors (i.e. HLA class II alleles) have been associated with increased risk of SS in Caucasian (US), Chinese and Japanese populations. However, different class II MHC alleles are risk factors in each population. The environmental factors that precipitate SS remain unknown. Future understanding of the mechanisms of destruction of the salivary and lacrimal glands may provide a more rationale approach to therapy.

Animals↗
PubMed1994

Epidemiology, pathogenesis, animal models, and treatment of Sjögren's syndrome.

Sjögren's syndrome is characterized by dry eyes (xerophthalmia) and dry mouth (xerostomia). Although general agreement exists about the ocular features of Sjögren's syndrome, significant controversy surrounds the classification criteria for defining the oral component. This has resulted in confusion in both the clinical and the research literature. The recent litigation involving silicone breast implants has forced clinicians to evaluate critically whether the condition of a particular patient fulfills specific diagnostic criteria for Sjögren's syndrome. Research studies have focused on potential genetic and environmental factors in the pathogenesis of Sjögren's syndrome. Studies of various ethnic populations have demonstrated an association with particular HLA-DR and -DQ alleles. However, the associated alleles are different for each ethnic group. No single environmental agent has been identified as a critical cofactor. Studies have concentrated on herpesviruses (Epstein-Barr virus and human herpesvirus type 6), hepatitis C virus, and retroviruses. Epstein-Barr virus isolated from patients has altered the ability to transform and lytically infect particular types of lymphocytes. Hepatitis C can lead to sicca symptoms, even in patients with relatively normal salivary gland biopsy findings. One report of Japanese patients indicated the presence of human T cell lymphotropic virus type I-like tax genes in the salivary biopsy specimens of a subset of patients and no gag, pol, or env sequences; this finding suggested a potential infection by a defective retrovirus. Studies on the pathogenesis have indicated that cytokines produced in the salivary gland are similar to T helper type 1 lymphocytes (interferon gamma).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Criteria for diagnosis of Sjögren's syndrome.

The criteria for diagnosis of SS remain controversial, and several sets of diagnostic criteria have been proposed. On one hand, we have used a stringent set of criteria (termed the San Diego criteria) that requires evidence for an autoimmune process associated with destruction of salivary and lacrimal gland tissues. At the other extreme, several groups (including the Copenhagen and EEC Study group) have based their diagnostic criteria on clinical findings of dry eyes and mouth with no absolute requirement for gland biopsy or presence of autoantibodies. The EEC study group believe that the San Diego criteria identify only the tip of the iceberg--namely, those patients with full-blown disease--and ignore those patients with milder forms of SS. Until the underlying pathogenesis of SS is known, we suggest the continued use of the San Diego criteria for classification of SS, because it identifies a group of patients with serologic and histologic evidence for a systemic autoimmune process in association with their sicca symptoms. In patients lacking such evidence for an autoimmune process, we suggest the classification "sicca syndrome" or "dry mouth syndrome." This will allow the clinicians and clinical trials to focus on a more homogeneous group of SS patients who may share a common pathogenesis, treatment response, and prognosis. Also, patients lacking evidence of an autoimmune role in pathogenesis can be reassured, and other causes for their sicca symptoms can be investigated. Further, in the United States the particular diagnosis codes may have implications in obtaining insurance and other medical benefits. Thus, classification criteria involve not only future epidemiologic studies but also economic considerations for the individuals who are given a particular diagnostic code.

Diagnosis, Differential↗