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Biomedical subjects

L P Ryder

Publications and source records attributed to L P Ryder.

At least 19 recordsLinked to original sources
PubMed1999

Autoimmunity and extranodal lymphocytic infiltrates in lymphoproliferative disorders.

OBJECTIVE: To examine the relationship between autoimmunity and extranodal lymphocytic infiltrates in different lymphoproliferative disorders with immunoglobulin alterations. SUBJECTS AND DESIGN: A clinical review combined with a retrospective cohort study of 380 patients, 28 with monoclonal gammopathy of undetermined significance, three with common variable immunodeficiency, 147 with chronic lymphocytic leukaemia, 57 with Waldenström's macroglobulinaemia and 145 with non-Hodgkin's malignant lymphoma. SETTING: A university hospital and The State Serum Institute in Copenhagen. INTERVENTION: Clinical examination of each patient with special attention to chronic inflammatory and autoimmune manifestations. Biopsies were taken from non-infectious infiltrates, some of which were additionally tested with PCR analysis for gene rearrangements. Serological screening with a test battery for various autoantibodies was used in combination with techniques for the detection of M-components and monoclonal B-cell proliferation. MAIN OUTCOME MEASURES: Clinical and/or serological autoimmune manifestations, M-component and other immunoglobulin alterations, and inflammatory tissue changes were studied in patients with chronic inflammatory, polyclonal or oligoclonal pseudolymphomas and in monoclonal, malignant extranodal lymphomas. RESULTS: In 380 consecutive patients, 49 (12.9%) had extranodal manifestations, of whom 47 also had autoimmune manifestations. Nearly half of the 47 patients had more than one autoimmune manifestation. There was a strong correlation between clinical signs and corresponding autoantibodies such as anti-SSA and -SSB antibodies in Sjögren's syndrome (10 cases), antithyroid peroxidase antibodies in thyroiditis and Graves' disease (10 cases), and parietal cell antibodies in gastric ulcers with maltoma (12 cases). Clinical and serological signs of autoimmunity correlated strongly with female sex (34, 72% women; and 13, 28% men) and with immunoglobulin alterations. CONCLUSIONS: To our knowledge this is the first systematic review of B-lymphoproliferative and autoimmune disorders indicating that pseudolymphoma and malignant lymphomas, including maltomas, may develop in the context of a permanent autoantigenic drive.

Aged↗
PubMed1998

Costimulatory CD80 (B7-1) and CD86 (B7-2) on cerebrospinal fluid cells in multiple sclerosis.

The costimulatory CD80 and CD86 molecules were measured by flow cytometry on cerebrospinal fluid (CSF) and blood lymphocytes from patients with possible first attacks of multiple sclerosis (MS, n = 25), clinically definite MS (n = 16), and noninflammatory neurological disease control subjects (n = 30). In patients with demyelinating diseases more CSF B cells expressed CD80 than in control subjects whereas the expression of CD86 by T cells in CSF was low in patients with demyelinating disease and highly variable in the control subjects. In patients with possible first attacks of MS the expression pattern of CD80 and CD86 differed significantly between patients with or without intrathecal synthesis of IgG. Increased expression of the CD80 molecule on CSF B cells may be of importance in the pathogenesis of MS. In contrast, CSF T cell expression of CD86 may be associated with protection from MS.

Acute Disease↗
PubMed1997

HLA typing in acute optic neuritis. Relation to multiple sclerosis and magnetic resonance imaging findings.

OBJECTIVE: To study the association of brain magnetic resonance imaging (MRI) findings and HLA findings to clarify the relationship between monosymptomatic optic neuritis (ON) and ON as part of clinically definite multiple sclerosis (CDMS). DESIGN: Population-based cohort of patients with ON referred prospectively during 6 years by neurologists and ophthalmologists within 4 weeks of onset of ON. SETTING: Referral center in the general community of greater Copenhagen (Denmark) (population, 1.5 million). PATIENTS: A consecutive sample of 199 patients aged 12 to 59 years with ON (133 with idiopathic ON, 66 with ON + CDMS), ethnically matched with 192 healthy volunteers. MAIN OUTCOME MEASURES: Relation between the HLA-DR15, -DR17, -DQA-1B, and -DQB-1B polymorphisms as defined by restriction fragment length polymorphism analysis, and presence of plaques on T2-weighted brain MRI. RESULTS: The frequency of HLA-DR15 was significantly increased in patients with ON + CDMS (52%) and ON (47%) compared with control subjects (31%). The frequency of HLA-DR17 was almost equal in the ON + CDMS (18%), ON (23%), and control (23%) groups. The frequencies of HLA-DQA-1B (55% in ON + CDMS, 58% in ON) and HLA-DQB-1B (49% in ON + CDMS, 59% in ON) were significantly increased compared with control subjects (41%, HLA-DQA-1B; 37%, HLA-DQB-1B). Brain MRI was abnormal in 48 of 56 examined patients with ON + CDMS and in 64 of 120 examined patients with ON (P < .001). In contrast, the frequencies of HLA alleles did not differ between patients with and without demyelinating lesions. However, patients with ON and normal MRI findings did not show association with HLA-DR15. CONCLUSIONS: The frequencies of alleles were similar in patients with ON and ON + CDMS, confirming that they are not 2 immunogenetically distinct disease entities. The heterogeneity within the group of patients with ON suggests that the HLA-DR15 molecule is involved in susceptibility to initial demyelinating lesion formation.

Acute Disease↗
PubMed1996

The progeny of a single virgin B cell predominates the human recall B cell response to the capsular polysaccharide of Haemophilus influenzae type b.

Restricted V region diversity is a key feature of Abs to many haptens and simple polysaccharides. Two possible mechanisms exist: 1) selection of many clonally unrelated B cells using very similar or identical VDJ and VJ rearrangements; and 2) selection of a heavily expanded progeny of few virgin B cells. How many virgin B cells eventually give rise to the total Ab response to a simple Ag is a fundamental immunologic question. In this report, we address this question in human adults by analyzing the rearranged VkappaJkappa genes of B cells responding to a single dose of the capsular polysaccharide of Haemophilus influenzae type b coupled to tetanus toxoid. We combined affinity purification of circulating vaccine-induced Ab-secreting cells with PCR amplification of cDNA followed by cloning and sequencing. Forty-eight and 42 kappa VJ gene transcripts were analyzed from two adults, respectively. Both individuals used extremely restricted repertoires with >90% of the cells using a single Vkappa gene rearranged to a single Jkappa gene. Despite the fact that the Ab responses engaged high numbers of Ab-secreting cells, analysis of the many shared, somatically acquired mutations showed that the majority of the cells originated from a common virgin B cell. Kinetic considerations implied that an extremely selected population of hypermutated memory B cells must have existed in these individuals before the first systemic immunization with the Ag. A possible role for the mucosal immune system in the priming and selection of these cells is proposed.

Adult↗
PubMed1995

Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein.

Mannan-binding protein (MBP) is a serum lectin participating in the innate immune defense by opsonizing various microorganisms for phagocytosis. Opsonization defect due to MBP deficiency and low levels of the protein can partially be explained by the dominant effect of three different mutations in the structural part of the MBP gene. Large interracial differences in the frequencies of these variants have previously been described, but they cannot explain the large interindividual variation in MBP serum concentration. We describe the existence of additional polymorphisms at positions -550 (H/L variants) and -221 (X/Y variants) in the promoter region of the gene. The promoter haplotypes, HY, LY, and LX, show associations with high, medium, and low levels of MBP serum concentrations, respectively. Moreover, this represents a genetic system with additive effect of haplotypes in which a low producing LX haplotype in the homozygous state down-regulates the basal expression of MBP as effectively as a single structural variant. Populations of pure Eskimos, Caucasoids, and black Africans show marked interethnic differences in the frequencies of promoter haplotypes regulating the expression of the normal peptide, with the HY haplotype frequency varying from 0.83 in Eskimos via 0.33 in Caucasoids to 0.08 in Africans. The LY haplotype frequency varies from 0.04 in Eskimos via 0.39 in Caucasoids to 0.23 in Africans. The LX haplotype frequency varies from 0.03 in Eskimos via 0.24 in Caucasoids to 0.23 in Africans. The effect of the promoter variants can explain almost all of the ethnic differences not explainable by the structural variants alone.

Base Sequence↗
PubMed1995

Acute optic neuritis: myelin basic protein and proteolipid protein antibodies, affinity, and the HLA system.

Anti-myelin basic protein, anti-proteolipid protein, and anti-myelin basic protein peptide (amino acid residues 1-20, 63-88, and 89-101) antibody-secreting cells were studied in 20 patients with idiopathic optic neuritis, 20 with optic neuritis as part of multiple sclerosis, and 20 neurological control subjects. Antibody-secreting cells were enumerated with an immunospot assay; the relative binding affinity of the antibodies was estimated by elution with thiocyanate. Patients with optic neuritis had more anti-myelin basic protein and anti-proteolipid protein antibodies than did control subjects (both p < 0.05); there was no difference between idiopathic optic neuritis and optic neuritis as a symptom of multiple sclerosis. Presence of the multiple sclerosis-associated DRB1*1501 gene was not associated with preferential synthesis of high-affinity antibodies reactive with a single myelin basic protein peptide or with preferential synthesis of either anti-myelin basic protein or anti-proteolipid protein antibodies. The results demonstrate a potential for intrathecal synthesis of both anti-myelin basic protein and anti-proteolipid protein antibodies of high apparent affinity in patients with optic neuritis.

Adolescent↗
PubMed1994

Gamma delta T-cell fraction of peripheral blood is increased in recurrent aphthous ulceration.

Recurrent aphthous ulceration (RAU) is the most common oral mucosal disease. The etiology is unresolved but several studies have suggested a systemic immunoregulatory imbalance in the patients. The purpose of the present study was to assess possible signs of immunologic deficiency or activation of peripheral blood mononuclear cells in patients with RAU by flow cytometry using three-color immunofluorescent staining which has not previously been employed in this patient category. The population consisted of 13 and 14 otherwise healthy patients with active and inactive RAU, respectively, and 18 healthy volunteers with a negative RAU history served as controls. The most striking observation was an increased fraction of T-cell receptor (TCR)-gamma delta+ cells in patients with active RAU (median percentage 8.5) compared with controls (median percentage 2.8; P < 0.001) and patients with inactive RAU (median percentage 5.0; P < 0.01). The fraction of peripheral TCR-gamma delta cells has not previously been determined in patients with RAU but the increased figures during active disease might reflect an immunologic stimulation during exacerbation. The nature of the stimulus remains to be established, but recent studies suggest that varicella zoster virus and/or cytomegalovirus may be involved. The potential role of TCR-gamma delta cells in RAU lesions has not yet been investigated but appears to be an obvious issue for future studies.

Adolescent↗
PubMed1994

A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein.

Human mannan-binding protein (MBP) is a serum lectin participating in the innate immune defence. Low MBP concentrations are explained by the dominant action of a point mutation at codon 54 of the MBP gene in Eskimos, partially in Caucasians, but not in Africans. A previously described point mutation at codon 57 was very frequent (0.23) in East Africans, low in Caucasians (0.02), and absent in Eskimos. The African population only conformed to Hardy-Weinberg expectation when assuming the existence of an unknown allele, which was subsequently found as a point mutation at codon 52. This allele appeared with a relatively high frequency (0.05) in both Africans and Caucasians, but was absent in Eskimos. Hardy-Weinberg equilibrium is now seen in the investigated ethnic groups. All cases of MBP deficiency may be explained by these three variants.

Alleles↗
PubMed1994

Peptide specificity of anti-myelin basic protein antibodies in patients with acute optic neuritis and the HLA system.

Multiple sclerosis (MS) may be an autoimmune disease, partially caused by autoreactivity to myelin basic protein (MBP) and other central nervous system proteins. Acute optic neuritis (ON) is a frequent first symptom of MS. The role of the HLA system in anti-MBP antibody production in ON was investigated employing a restriction fragment length polymorphism system for genomic HLA-DQ and -DR typing and an immunospot assay for the detection of individual cells secreting antibodies to three different synthetic MBP peptides. Thirty-two out of 40 patients (80%) with ON had cells in cerebrospinal fluid secreting anti-MBP peptide antibodies while this occurred in 10/19 patients with other neurological diseases (53%; mainly in patients with inflammatory diseases in the central nervous system). This difference was statistically significant (P = 0.03). None of the three examined peptides were immunodominant in any patient group. It was found, however, that presence of HLA DR15, which is associated with MS, may be associated further with predominant production of antibodies to the MBP amino acids 63-88 in patients with ON (P = 0.002, corrected for multiple comparisons).

Adult↗
PubMed1994

HLA and disease associations: detecting the strongest association.

A major aim of HLA and disease association studies is to identify the causative HLA factor truly responsible for the association. This is usually difficult due to the pronounced linkage disequilibrium between most HLA determinants. The causative factor must show the strongest association compared to all other factors. Here we describe a simple analysis which can be used to identify which of two factors, say A and B, shows the strongest association. The basic data for the analysis are the entries of the two-by-four table giving the four phenotypic combinations of A and B in patients and controls, respectively. These data are analyzed in various two-by-two tables involving stratification of each of the two factors against the other. A stronger increase of factor A is established if A is significantly associated with the condition both in B-positives and in B-negatives, when this is not true for B in A-positives and A-negatives. Using simulation with control data, it is demonstrated how linkage disequilibrium may influence secondary associations. The analysis may also be used to investigate interaction between HLA factors, but linkage disequilibrium complicates the interpretation in such cases. The method is exemplified using various published data. Finally, some statistical recommendations are given. Thus, we advise that phenotype (marker) frequencies are generally used instead of gene (i.e. allele, or haplotype) frequencies. The importance of correcting p-values, the levels of significance, and the power of Fisher's exact test are discussed.

Disease Susceptibility↗
PubMed1994

MHC class II molecules regulate growth in human T cells.

MHC-class-II-positive T cells are found in tissues involved in autoimmune disorders. Stimulation of class II molecules by monoclonal antibodies (mAbs) or bacterial superantigens induces protein tyrosine phosphorylation through activation of protein tyrosine kinases in T cells, and class II signals modulate several T cell responses. Here, we studied further the role of class II molecules in the regulation of T cell growth. Costimulation of class II molecules by immobilized HLA-DR mAb significantly enhanced interleukin (IL)-2-supported T cell growth of the majority of CD4+, CD45RAlow, ROhigh T cell lines tested. Only one of three CD4+, CD45RAhigh, ROhigh T cells responded to class II costimulation. There was no correlation between T cell responsiveness to class II and the cytokine production profile of the T cell in question. Thus, T cell lines producing interferon (IFN)-gamma but not IL-4 (TH1-like) as well as T cells producing both cytokines (THO-like) responded to class II mAb. The costimulatory effect was not restricted to IL-2-driven T cell growth, since TCR/CD3-induced T cell activation was also enhanced by HLA-DR mAb. Moreover, class II costimulation potentiated CD28-mAb-induced T cell sensitivity to protein kinase C activation by phorbol 12-myristate 13-acetate. In conclusion, class II costimulation enhances T cell activation through the TCR/CD3 and IL-2 pathways and interacts with CD28 accessory signals to up-regulate growth of allospecific T cell lines.

Antibodies, Monoclonal↗
PubMed1993

[Deficiency of mannan-binding protein--a recently discovered complement defect syndrome].

Mannan-binding protein (MBP) is a newly discovered serum protein which activates the complement system by the classical pathway by binding to mannose-rich surfaces on microorganisms. MBP deficiency predisposes to infection in infancy. MBP is a C-type lectin with collagen structure, a so-called collection. The paper discusses the structure and physiological functions of MBP. MBP may be an important parameter in the investigation of immunodeficiencies in children.

Carrier Proteins↗
PubMed1993

Varicella-zoster virus DNA in recurrent aphthous ulcers.

The present study was undertaken to examine for varicella-zoster virus (VZV) constituents in recurrent aphthous ulcers (RAU). Smears and biopsies of ulcers 0-3 days old were obtained from 20 otherwise healthy minor/major RAU patients and from two patients with Behçet's syndrome. VZV could not be cultivated from any of the biopsies, all smears were negative for VZV antigen, and in situ hybridization on the five samples tested was negative for VZV nucleic acid. DNA extracted from biopsies, however, yielded positive polymerase chain reaction (PCR) products in all cases with one primer set of the protein kinase 66 (PK66). Ten control biopsies from non-RAU subjects yielded no PCR products apart from the sample from AP, who obtained the biopsies, and from HOM, who performed the PCR, suggesting that the DNA had been passed on from the patients. Other parts of the PK66 gene and of thymidine kinase 36 yielded no products. Although the consistent presence of VZV DNA in RAU might suggest a pathogenetic implication, the potential presence and possible pathogenetic importance of other herpesviruses cannot be excluded.

Adolescent↗
PubMed1993

Defective T-cell stimulatory pathways in patients after allogeneic bone marrow transplantation (BMT) in man.

Immunological reconstitution after allogeneic bone marrow transplantation in man is characterized by a decreased lymphocyte transformation response to various mitogens and antigens during a period of from months to years. One reason for the decreased proliferative capability could be an inverted CD4/CD8 ratio; however, the present investigation demonstrates that this is not the only explanation for the immunodeficiency, since the CD4 as well as the CD8 subset, when studied in isolation, have qualitative defects, as evidenced by a reduced response of both subsets to stimulation with PHA, anti-CD2 and anti-CD3 MABs. The reason for the qualitative defect is unknown but a distorted composition of the CD4+ as well as the CD8+ T-cell subsets is suggested by the present investigations. We also observed that the PHA response was almost completely reconstituted one year after BMT, while the PWM response was still severely affected. The present study suggests that T-cell subsets which differ in their capacity to respond to PHA and PWM have different kinetics of reconstitution after BMT.

Adolescent↗
PubMed1993

Rapid analysis of rearranged kappa light chain genes of circulating polysaccharide-specific B lymphocytes by means of immunomagnetic beads and the polymerase chain reaction.

Analysis of rearranged immunoglobulin genes used by B lymphocytes of known specificity is an important tool for the study of diversity and selection of B lymphocytes. Usually hybridoma cell lines are used for such analyses, but they are difficult to obtain from humans and may not be representative of the B lymphocytes activated in vivo. Here, we present a method for rapid analysis of the rearranged kappa light chain genes used by human circulating antigen-specific B lymphocytes. After vaccination with Haemophilus influenzae type b capsular polysaccharide (HibCP) conjugated with protein, the HibCP-specific B lymphocytes were isolated by antigen-coated immunomagnetic beads. After the purification, at least 98% of the immunoglobulin-secreting recovered cells were HibCP specific. The RNA was isolated and amplified by cDNA synthesis using a kappa constant region primer followed by polymerase chain reaction (PCR) using in addition a degenerate kappa light chain signal peptide region primer. The PCR product was cloned into the M13mp18 phage. The cloning efficiency was 100-600 clones/ml of blood. Of the 86 clones sequenced, 90% represented rearranged kappa light chain genes from different antibody-secreting cells. Examples of rearranged kappa genes used by HibCP-specific antibody-secreting cells from 4 adult vaccinees are given, representing the 3 largest of the 4 kappa variable region families. This method is a new tool for the investigation of vaccine-induced antibody responses with special reference to immunoglobulin gene usage and variability.

Base Sequence↗
PubMed1992

Induction of DNA repair synthesis in human monocytes/B-lymphocytes compared with T-lymphocytes after exposure to N-acetoxy-N-acetylaminofluorene and dimethylsulfate in vitro.

We have explored the induction of DNA repair synthesis in monocyte/B- and T-lymphocyte enriched cell fractions from 12 different human mononuclear blood cell populations. Unscheduled DNA synthesis was measured in monocyte/B- and T-cells after exposure to the DNA-damaging agents dimethylsulfate (DMS) and N-acetoxy-N-acetylaminofluorene in vitro. Also, the binding of DMS to DNA was measured. An increased DNA repair synthesis was measured in monocyte/B-lymphocytes after induction of the two different types of DNA lesions, whereas no induction of unscheduled DNA synthesis was observed in T-lymphocytes. A significantly higher DMS-DNA binding was also observed in monocyte/B-lymphocytes when compared with T-lymphocytes. Specific characterization of mononuclear blood cell populations used in biomonitoring of DNA adducts and repair is recommended.

Acetoxyacetylaminofluorene↗