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Biomedical subjects

R I Fox

Publications and source records attributed to R I Fox.

At least 55 records · Page 3Linked to original sources
PubMed1993

Lymphoproliferative disease in SCID mice reconstituted with human Sjögren's syndrome lymphocytes.

Patients with Sjögren's syndrome (SS) have increased frequency of non-Hodgkin's B-cell lymphoma. These lymphomas frequently use a specific subclass of kappa light chain (encoded by variable region gene segment Hum KV325) and exhibit bcl-2 protooncogene translocation t(14;18). In order to determine whether expansion of this B-cell subset could be reproduced in an animal model, immunodeficient SCID (CB-17) mice were reconstituted with lymphocytes from 4 different SS patients at high risk of the development of lymphoma. Tumor-like nodules developed in all 11 SCID mice that received at least 5 x 10(5) lymphocytes from SS salivary glands or peripheral blood samples. However, the tumor-like nodules in the SCID mice differed from SS lymphomas in vivo in that they (1) exhibited multiple immunoglobulin gene rearrangements; (2) did not have expansion of B-cells expressing the Hum KV325 K-light chain; and (3) lacked detectable t(14;18) translocations. Characterization of the SCID tumor-like nodules revealed a high level of Epstein-Barr virus (EBV) DNA, EBV-associated antigens (EA-R, EBNA-2, AND LMP), and the EBV-encoded cytokine BCRF-1 that is structurally similar to IL-10. These results demonstrate that the lymphoproliferation occurring in the salivary glands of SS patients is not reproduced in the SCID/hu chimeric mouse. It is likely that specific factors in the human salivary gland are required for development of lymphoma in SS patients and that such factors are not present in the SCID/hu chimeric mouse. Furthermore, EBV-induced lymphoproliferation, as seen in the SCID/hu chimera, does not lead to expansion of the same lymphoid subsets that occurs in vivo.

Animals↗
PubMed1993

Mechanism of action of hydroxychloroquine as an antirheumatic drug.

The antimalarial agents chloroquine and hydroxychloroquine have been used widely for the treatment of rheumatoid arthritis and systemic lupus erythematosus. These compounds lead to improvement of clinical and laboratory parameters, but their slow onset of action distinguishes them from glucocorticoids and nonsteroidal antiinflammatory agents. Chloroquine and hydroxychloroquine increase pH within intracellular vacuoles and alter processes such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes, and posttranslation modification of proteins in the Golgi apparatus. It is proposed that the antirheumatic properties of these compounds results from their interference with "antigen processing" in macrophages and other antigen-presenting cells. Acidic cytoplasmic compartments are required for the antigenic protein to be digested and for the peptides to assemble with the alpha and beta chains of MHC class II proteins. As a result, antimalarials diminish the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells and result in down-regulation of the immune response against autoantigenic peptides. Because this mechanism differs from other antirheumatic drugs, antimalarials are well suited to complement these other compounds in combination drug therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation.

Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) alpha, beta, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of alpha-Ii and beta-Ii chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, alpha-Ii and beta-Ii; (e) the displacement of Ii chains by peptides to form alpha-beta-peptide complexes in the endosome; and (f) the migration of alpha-beta-peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the alpha-beta-peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Epstein-Barr virus induced lymphoproliferative tumors in severe combined immunodeficient mice are oligoclonal.

Severe combined immunodeficient (SCID) mice reconstituted with lymphocytes from Epstein-Barr virus (EBV) negative human donors develop aggressive tumors after the chimeric mice are infected with EBV. The tumors were composed of human B cells that expressed EBV encoded antigens (latent membrane protein and EBV nuclear antigen2). Southern blot analysis of DNA from 16 SCID/hu tumors with human Ig gene probes showed that each tumor contained multiple heavy and light chain gene rearrangements. Ig kappa gene rearrangements were frequent, while clonal lambda gene rearrangements were infrequent. Analysis of EBV terminal repeat sequences indicated two or more fused termini in each tumor, consistent with a multiclonal origin. Linear terminal repeat segments and viral antigens (EA-D and EA-R) associated with EBV replication were not detected in the tumors. High levels of human Igs in the SCID/hu serum were oligoclonal and primarily contained kappa light chains. Before the appearance of overt tumors, circulating cells with human and EBV DNA could be detected in the SCID/hu mice by the polymerase chain reaction. We conclude that EBV infection in SCID/hu chimeric mice produces a limited number of transformation events, which give rise to oligoclonal tumors resembling EBV-associated lymphoproliferative disorders in some immune-deficient patients.

Animals↗
PubMed1992

Immunotactoid-like endoneurial deposits in a patient with monoclonal gammopathy of undetermined significance and neuropathy.

An 85-year-old man with a 2-year history of progressive lower limb weakness and paresthesia was found to have an IgG kappa monoclonal gammopathy of undetermined significance (mgus). Clinical and electrophysiological studies revealed a severe distal bilateral symmetrical polyneuropathy. A sural nerve biopsy showed extensive nerve fibre loss with the deposition of large amounts of amorphous material throughout the endoneurium. Electron microscopy showed the deposits to be composed of microtubular structures which were located diffusely throughout the endoneurium. The deposits were also located within the lumina of the vasa nervorum, some of which were undergoing disintegration and rupture with release of the proteinaceous material into the endoneurium. The regions of the nerve in which they appeared most numerous showed more severe nerve fibre damage than other areas. These microtubular structures were also observed in disintegrating vessels and adjacent endoneurium. On immunohistochemistry they stained with antibody to IgG. Identical deposits were found in the dermis in which there was a leucocytoclastic vasculitis. Located in linear arrays within the axons of myelinated and unmyelinated fibres were highly organised tubular structures resembling immunotactoids. Identification of immunotactoid-like structures within the nerve is unique and may be another mechanism by which monoclonal proteins can induce nerve fibre injury.

Aged↗
PubMed1992

Laboratory evaluation of patients with Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocytic infiltration of the lacrymal and salivary glands, leading to severe dryness of eyes (keratoconjunctivitis sicca) and mouth (xerostomia). SS may exist as a primary disorder (1 degree-SS) or in association with other autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus or progressive systemic sclerosis (scleroderma). Diagnosis of 1 degree-SS is confirmed by minor salivary gland biopsy and the presence of circulating autoantibodies. Minor salivary gland biopsies exhibit focal lymphocytic infiltrates that are present in the majority of lobules. Incorrect methods of biopsy and failure to determine the average focus score are common causes for false-positive and false-negative biopsies. SS patients frequently have a positive antinuclear antibody test due to presence of SS-A (Ro) and SS-B (La) autoantibodies. Molecular analysis has revealed multiple "SS-A" proteins (60 kd, 54 kd, 52 kd) that react with sera from SS patients, as well as a 48 kd SS-B protein. Rheumatoid factor (anti-IgG Fc antibody) in 1 degree-SS patients exhibits restriction in its light chain-associated idiotype, in contrast to RA patients where no restriction of idiotype was detected. Other autoantibodies found in a subpopulation of SS patients include anti-ADP ribose polymerase, anti-cardiolipin, anti-mitochondrial, anti-mitotic spindle apparatus, anti-parietal cell, and anti-thyroid associated antibodies. Due to the high frequency of dryness syndromes in patients due to other causes (ranging from drug side effects to normal aging processes), the use of strict criteria for diagnosis of SS will lead to improved cost-efficient medical care avoiding needless anxiety in the patient.

Animals↗
PubMed1992

Antiphospholipid antibodies and HLA associations in primary Sjögren's syndrome.

Blood samples from 65 patients with primary Sjögren's syndrome were evaluated for the presence of antiphospholipid antibodies. Increased levels of antiphospholipid antibodies were found in 13 of 65 (20%) of patients. These antiphospholipid antibodies were predominantly of the IgA isotype, in contrast with the IgG isotype antiphospholipid antibodies found in patients with systemic lupus erythematosus (SLE). The presence of IgA antiphospholipid antibodies in the patients with primary Sjögren's syndrome was not significantly associated with arterial or vascular thrombosis, nor peripheral or central nervous system vasculitis. There was no association with laboratory determined features such as lupus anticoagulant or false positive results of the Venereal Disease Research Laboratory (VDRL) test. Oligonucleotide specific DNA amplification and hybridisation with allele specific probes was used to examine the HLA-D antigens occurring in this group of patients with primary Sjögren's syndrome. Of 13 patients with antiphospholipid antibodies, seven had the genotype HLA-DR2/DR3. However, compared with the whole group of 65 patients with Sjögren's syndrome, no increased occurrence of haplotype DR2 or DR3 was noted. These results suggest that gene interaction between DR2 and DR3 may play a part in the production of antiphospholipid antibodies in patients with Sjögren's syndrome. In contrast with patients with SLE, the IgA antiphospholipid antibodies in patients with Sjögren's syndrome are not risk factors for thrombosis or vasculitis. The presence of IgA antiphospholipid antibodies in patients with Sjögren's syndrome probably reflects its production at mucosal sites of inflammation and the absence of vasculopathy may be due to the inability of IgA antibodies to activate complement.

Female↗
PubMed1992

Potential role of Epstein-Barr virus in Sjögren's syndrome and rheumatoid arthritis.

In the pathogenesis of Sjögren's syndrome (SS), a role for Epstein-Barr virus (EBV) has been suggested because; (a) EBV is present in salivary gland epithelial cells of healthy individuals, and exaggerated immune responses against EBV could play a role in the destruction of salivary glands in SS; (b) SS salivary gland biopsies contain increased levels of EBV DNA compared to normal salivary glands, indicating viral reactivation and inability of lymphoid infiltrates to control EBV replication in patients with SS; and (c) salivary gland epithelial cells in patients with SS express high levels of HLA-DR antigens and may present EBV associated antigens to immune T cells in patients with SS. Therefore, SS may represent a situation where genetically predisposed individuals (i.e., HLA-DR3-DQA4-DQB2) have a persistent but ineffectual T cell immune response against EBV at its site of latency. In the case of rheumatoid arthritis (RA), evidence for a potential role of EBV includes the following: (a) EBV encoded proteins share antigenic and sequence similarity to proteins found in the synovial tissues. These crossreactive proteins include EBV protein gp110 (BALF-4) and the beta chain of HLA-DR4. Also, the human and mycobacterial 65 kDa heat shock proteins have a sequence similar to that of EBV encoded proteins; (b) patients with RA have increased frequency and levels of antibodies against specific epitopes on EBV encoded EBNA-1 (BKRF-1) and EBNA-3 (BERF-1) antigens; and (c) lymphocytes from patients with RA have decreased ability to limit outgrowth of autologous EBV infected lymphocytes, probably due to defects in release of interferon gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Pathogenesis of Sjögren's syndrome.

Sjögren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltrations of lacrimal and salivary glands. SS patients produce a variety of autoantibodies, including RF and ANA. Genetic factors, including HLA-DR3, predispose to primary SS. In contrast to normal SGs, the SS SG epithelial cells express high levels of HLA-DR antigens. This class II gene expression on the target organ may represent the structural basis for HLA-associated disease susceptibility. The glands are infiltrated with CD4+ T cells that can produce cytokines, including IL-2 and interferon-gamma. B cells within the SG produce autoantibodies, including RF. These SG B cells frequently use the VKIIIb subgroup of kappa light chain, a feature that SS patients share with Waldenstrom's macroglobulinemia patients. B cells undergo small clonal expansions that can be detected on Southern blot as immunoglobulin gene rearrangements, and SS patients have a markedly increased risk of developing non-Hodgkin's B-cell lymphoma involving the SGs and cervical lymph nodes. Due to accessibility of the SG for biopsy and the characteristic patterns of autoantibody production, SS provides an opportunity to study the target organ for autoimmune destruction and the transition from autoimmunity to lymphoma.

Amino Acid Sequence↗
PubMed1992

Genetic and environmental factors in systemic sclerosis.

The occurrence of autoantibodies in patients with systemic sclerosis has suggested a role for immune dysregulation in this disease. Recent genetic studies have concentrated on the major histocompatibility complex-encoded antigens and found an association of particular HLA-DQ alleles with anticentromere antibodies. Although the role of major histocompatibility complex antigens and autoantibodies in the pathogenesis of systemic sclerosis remains unclear, determination of major histocompatibility complex alleles may have clinical value in identifying patients who are at increased risk for development of pulmonary fibrosis or rapidly advancing skin disease. A variety of environmental factors have been associated with systemic sclerosis-like skin diseases, including silica, vinyl chloride, paraffin, adulterated L-tryptophan, and "toxic" rapeseed oil. It has been suggested that silicone used during breast augmentation may be a risk factor for development of systemic sclerosis, but ascertainment bias in case reporting makes interpretation of these studies difficult. The heterogeneity of clinical features, major histocompatibility complex status, and autoantibody profiles in systemic sclerosis suggest that this disorder may actually be a group of distinct disorders, each of which has its own characteristic genetic and environmental predisposing risk factors.

Environment↗
PubMed1992

Treatment of the patient with Sjögren's syndrome.

SS is a systemic autoimmune disease characterized by lymphocytic infiltrations of lacrimal and salivary glands. Extraglandular organs including skin, nerve, lung, and kidney may be involved. At the present time, there remains a great deal of confusion regarding the precise definition of SS. As a result, both patients and clinicians frequently have a difficult time in making a specific diagnosis and instituting a specific plan of therapy. Regardless of the diagnostic label, all patients with significant eye and mouth dryness should receive conservative therapy of tear replacement and intensive oral hygiene. Based on the presence or absence of clinical or laboratory features of systemic autoimmunity, additional therapies may prove beneficial in controlling the symptoms and progression of SS.

Humans↗
PubMed1991

High frequency of t(14;18) translocation in salivary gland lymphomas from Sjögren's syndrome patients.

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocytic infiltration of the salivary and lacrimal glands. These patients have a markedly increased frequency of developing non-Hodgkin's lymphoma in their salivary glands and cervical lymph nodes. Translocations of proto-oncogene bcl-2 t(14;18) were observed in five of seven SS-associated lymphomas by Southern blot analysis. Using primers specific for chromosomes 14 and 18, translocation of the proto-oncogene bcl-2 was detected by polymerase chain reaction (PCR) in all five lymphomas positive by Southern blot analysis. Among SS patients lacking clinical evidence of coexistent lymphoma, no bcl-2 translocations were detected in 50 consecutive salivary gland biopsies. Of particular interest, pre-lymphoma biopsies were available from the seven SS patients who subsequently developed lymphoma and these DNA samples lacked detectable t(14;18) translocations even though they exhibited oligoclonal rearrangements of their immunoglobulin genes. We conclude that the great sensitivity of PCR can help us in detecting early onset of lymphoma in SS patients and aid in understanding the transition from autoimmunity to lymphoma.

Chromosomes, Human, Pair 14↗
PubMed1991

T-lymphocytic leukemia expresses complex, branched O-linked oligosaccharides on a major sialoglycoprotein, leukosialin.

Leukocytes express a major sialoglycoprotein, leukosialin, of which the apparent molecular weight (mol wt) can be variable according to the differences in O-glycans attached to this molecule. In the present study, we analyzed the structures of O-glycans attached to leukosialin present in various T-lymphocytic leukemia cells. T-lymphoid cells from patients with acute T-lymphocytic leukemia express a large amount of the branched hexasaccharides, NeuNAc alpha 2----3Gal beta 1----3(NeuNAc alpha 2----3Gal beta 1----4GlcNAc beta 1----6)GalNAc, which are also expressed in activated normal T lymphocytes, but that are almost absent in resting normal T lymphocytes. T-lymphoid cells from patients with chronic T-lymphocytic leukemia, on the other hand, mainly express the tetrasaccharides NeuNAc alpha 2----3Gal beta 1----3(NeuNAc alpha 2----6)GalNAc on leukosialin, but they also express a small significant amount of the hexasaccharides. The same hexasaccharides can be detected in thymocytes. The increased amount of the hexasaccharides in acute leukemia is associated with increased activity of beta 1----6 GlcNAc-transferase, a key enzyme in forming the hexasaccharides. Immunoblot analysis of cell lysates showed that monoclonal antibody (MoAb) T-305 reacts preferentially with leukosialin of high mol wt containing the hexasaccharides. These findings indicate that T-lymphocytic leukemia cells reexpress the oligosaccharides present in immature cells.

Antibodies, Monoclonal↗
PubMed1991

Reactivation of Epstein-Barr virus in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by severe dryness of the eyes and mouth, resulting from lymphocytic infiltration of the lacrimal and salivary glands. SS may exist as a primary condition (primary SS, 1.SS) or as a secondary condition (2.SS) in association with rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis. In some 1.SS patients, there may be involvement of the extraglandular organs, including skin, kidney, liver, lung and nervous system. Furthermore, these patients may develop a lymphoproliferative syndrome that includes lymphadenopathy and increased risk of lymphoma. In the pathogenesis of SS, a role for Epstein-Barr virus (EBV) has been suggested because: (a) EBV is present in salivary gland epithelial cells of normal individuals and exaggerated immune responses against EBV could play a role in the destruction of salivary glands in SS; (b) SS salivary gland biopsies contain increased levels of EBV DNA in comparison to normal salivary glands, indicating viral reactivation and inability of lymphoid infiltrates to control EBV replication in SS patients; and (c) salivary gland epithelial cells in SS patients express high levels of HLA-DR antigens and may present EBV-associated antigens to immune T cells in SS patients. Therefore, SS may represent a situation in which genetically predisposed individuals (i.e., HLA-DR3-DQA4-DQB2) have a persistent but ineffectual T cell immune response against EBV at its site of latency. Among 14 non-Hodgkin's lymphomas that developed in SS patients, EBV DNA was detected in increased amounts in the tumor tissue of one patient. Characterization of this tumor DNA revealed: (a) polyclonal immunoglobulin gene rearrangements; (b) EBV DNA with an unusual restriction fragment length polymorphism pattern involving the Bam M fragment; and (c) EBV terminal repeat sequences suggestive of viral replication, similar to those reported in EBV lymphomas occurring in other immunocompromised individuals. Early recognition of this clinical problem may allow beneficial use of antiviral agents.

Autoantibodies↗
PubMed1991

Detection of Epstein-Barr virus and human herpes virus type 6 in saliva from patients with lymphoproliferative diseases by the polymerase chain reaction.

Direct detection of these viruses was made by using the PCR for amplifying viral DNA. In virtually all adults low levels of the herpesvirus can be detected. Therefore it is necessary to quantitate the amount of viral DNA, and a method to compare the plasmid containing the cloned target gene was used here. After 35 cycles of amplification, 10 copies of the viral DNA per 100 microliters saliva were detected. The PCR was used to detect increased levels of EBV and HHV-6 in saliva from patients with lymphoproliferative diseases, suggesting that these viruses may play a part in their pathogenesis. Viral detection by such highly sensitive methods as PCR may allow better monitoring of medication, as well as early detection of EBV- and HHV-6 related diseases that may arise in these patients. The great sensitivity of PCR and its ability to analyse very small samples make this technique most suitable for clinical diagnosis.

Adult↗
PubMed1990

Dissociation of immune responses to the SS-A (Ro) 52-kd and 60-kd polypeptides in systemic lupus erythematosus and Sjögren's syndrome.

The cellular RNA particle SS-A (Ro) is a target of autoimmune response in many patients with Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). Recent immunologic, biochemical, and DNA cloning studies have shown that the SS-A particle consists of at least 2 polypeptide components, of 52 kd and 60 kd. Immunodiffusion analysis of 60 sera from patients with primary SS revealed 47 (78%) to be SS-A precipitin positive. Western blotting studies of the sera showed 3 groups of reactivities: 22 (47%) possessed autoantibodies against both the 60-kd and the 52-kd polypeptides, 19 (40%) reacted only with the 52-kd protein, and 6 (13%) were nonreactive in Western blots although positive in immunodiffusion. Fifty-one of 90 SLE sera (57%) were SS-A precipitin positive by immunodiffusion. In Western blots, 24 (47%) possessed antibodies against both the 60-kd and the 52-kd antigens, while 9 (18%) reacted only with the 60-kd protein. Eighteen (35%) were nonreactive by Western blot, although positive by immunodiffusion. Antibody to the 52-kd antigen without concomitant antibody to the 60-kd antigen was seen only in patients with primary SS, whereas antibody to the 60-kd antigen without concomitant antibody to the 52-kd antigen was seen only in SLE patients. Although antibodies to SS-A are detected in both SS and SLE, our findings show that there is dissociation of immune responses to the 2 component antigens of the particle, which may be evidence of different events initiating the autoimmune process in these diseases.

Antibody Formation↗