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Biomedical subjects

R Strohal

Publications and source records attributed to R Strohal.

26 records · Page 2Linked to original sources
PubMed1990

Cyclosporin A in combination with photochemotherapy (PUVA) in the treatment of psoriasis.

Forty patients with relapsing plaque psoriasis involving more than 20% body surface were treated either with cyclosporin A (CyA) plus PUVA or the retinoid etretinate plus PUVA (RePUVA). They initially received either CyA (2 weeks) or etretinate (1 week) alone and then PUVA was given concomitantly until complete remission. The patients were monitored over a period of 6 months and any relapse recorded. With each combined treatment regimen, CyA plus PUVA and RePUVA, the patients cleared within comparable periods of time (mean treatment period of 5.3 vs. 4.7 weeks after initiation of therapy and 3.3 vs. 3.7 weeks after initiation of PUVA). However, the cumulative UVA dose required for clearance (110.9 J/cm2 vs. 62.1 J/cm2 (P less than 0.05)) and the incidence of severe and early relapses were significantly higher in the CyA cohort. Within 6 months severe relapses had occurred in 58% of CyA plus PUVA but only in 15% of RePUVA-treated patients (P less than 0.001). This suggests that the CyA plus PUVA regimen as performed in this study is less effective than RePUVA.

Adult↗
PubMed1989

Mouse Vk gene classification by nucleic acid sequence similarity.

Analyses of immunoglobulin (Ig) variable (V) region gene usage in the immune response, estimates of V gene germline complexity, and other nucleic acid hybridization-based studies depend on the extent to which such genes are related (i.e., sequence similarity) and their organization in gene families. While mouse Igh heavy chain V region (VH) gene families are relatively well-established, a corresponding systematic classification of Igk light chain V region (Vk) genes has not been reported. The present analysis, in the course of which we reviewed the known extent of the Vk germline gene repertoire and Vk gene usage in a variety of responses to foreign and self antigens, provides a classification of mouse Vk genes in gene families composed of members with greater than 80% overall nucleic acid sequence similarity. This classification differed in several aspects from that of VH genes: only some Vk gene families were as clearly separated (by greater than 25% sequence dissimilarity) as typical VH gene families; most Vk gene families were closely related and, in several instances, members from different families were very similar (greater than 80%) over large sequence portions; frequently, classification by nucleic acid sequence similarity diverged from existing classifications based on amino-terminal protein sequence similarity. Our data have implications for Vk gene analyses by nucleic acid hybridization and describe potentially important differences in sequence organization between VH and Vk genes.

Animals↗
PubMed1988

[Molecular genetic analysis of autoantibody production in systemic lupus erythematosus].

This review summarizes studies from our and other laboratories attempting to define the molecular and clonotypic origin of autoantibodies that typify systemic autoimmune diseases such as lupus and rheumatoid arthritis. Comparative restriction fragment length polymorphism (RFLP) studies investigating the immunoglobulin (Ig) germline gene organization in lupus-prone strains of mice suggested that the disease can develop in different Ig heavy (H) and light (L) chain haplotypes, and that the Ig germline genes in lupus mice are probably normal. Analysis of the Ig gene segments expressed in monoclonal autoantibodies from autoimmune mice revealed that similar, and in some instances even identical, gene segments are expressed in autoantibodies and in antibodies to exogenous antigens, and that anti-self and anti-non-self responses are encoded by the same, or at least an overlapping germline gene repertoire. A large variety of Ig variable (V), diversity (D), and joining (J) gene segments can encode autoantibodies with different specificities, and both germline genes and somatically-mutated genes can be expressed in such antibodies.

Animals↗
PubMed1988

Immunoglobulin kappa light chain variable region gene complex organization and immunoglobulin genes encoding anti-DNA autoantibodies in lupus mice.

We have investigated the genetic origin of autoantibody production in several strains of mice that spontaneously develop a systemic lupus erythematosus-like disease. Restriction fragment length polymorphism analyses of gene loci encoding kappa light chain variable regions (Igk-V) demonstrated, as shown previously for the Ig heavy chain locus, that autoantibody production and disease occur in different Igk-V haplotypes. Moreover, autoimmune mice with known genetic derivation inherited their Igk-V loci essentially unaltered from their nonautoimmune ancestors. New Zealand black lupus mice, with unknown genetic derivation, had a possibly recombinant Igk-V haplotype, composed of V kappa loci that were primarily indistinguishable from those of nonautoimmune strains from either of the two potential donor haplotypes. The heavy and light chain gene segments (variable, diversity, joining) encoding anti-DNA antibodies were diverse and often closely related, or even identical, to those found in antibodies to foreign antigens in normal mice. Only 1 of 11 sequenced variable region genes could not be assigned to existing variable region gene families; however, corresponding germline genes were present in the genome of normal mice as well. These data argue against abnormalities in the genes and mechanisms generating antibody diversity in lupus mice and suggest a remarkable genetic and structural diversity in the generation of anti-DNA binding sites.

Amino Acid Sequence↗
PubMed1987

Molecular analysis of the murine lupus-associated anti-self response: involvement of a large number of heavy and light chain variable region genes.

The mRNA encoding heavy and light chains of a hybridoma-derived monoclonal IgM, kappa anti-immunoglobulin (rheumatoid factor) and an IgG3, kappa anti-histone autoantibody from systemic lupus erythematosus and arthritis-prone MRL/Mp-lpr/lpr mice have been molecularly cloned, and the nucleotide sequences corresponding to their variable regions have been determined. To investigate whether autoantibodies with specificities frequently observed in lupus disease might share common structural components, the sequences obtained in this study have been compared with those of a monoclonal MRL/Mp-lpr/lpr IgM, kappa anti-DNA autoantibody previously analyzed in our laboratory (J. Exp. Med. 1985. 161: 805). The 3 immunoglobulins employed different heavy chain variable region (VH) genes belonging to the large J588 VH gene family, kappa light chain variable region (V kappa) genes from 3 different V kappa groups, and different diversity and joining segments. Our findings suggest that murine lupus-associated autoantibodies of different specificities do not have genetic components in common to signal their self-reactive nature and are encoded by a large number of immunoglobulin gene elements.

Animals↗
PubMed1987

The genetic origin of murine lupus-associated autoantibodies.

Systemic lupus erythematosus and rheumatoid arthritis in human and murine systems are characterized by circulating autoantibodies and immune complex deposition in various organs causing tissue damage and disease. To define the molecular and clonotypic origin of these anti-self responses, and to determine whether abnormalities in Ig genes or somatic mechanisms generating autoantibody diversity may contribute to lupus etiology, we performed molecular analyses of the Ig germline gene organization and the Ig gene segments expressed in monoclonal autoantibodies from autoimmune mice. Comparative restriction fragment length polymorphism analysis of a large number of Ig gene loci from autoimmune and normal mice indicated that (a) lupus can develop in different Ig heavy and kappa light chain variable region gene haplotypes, and (b) the Ig germline genes in lupus mice might be normal. To determine whether autoantibodies are encoded by unique Ig gene segments present in the normal germline repertoire, but not expressed in exogenous responses, we compared nucleic acid sequences encoding lupus autoantibodies and antibodies against foreign antigens. Similar, and in some instances even identical, gene segments were expressed in both types of antibodies, indicating that anti-self and anti-foreign responses use the same, or at least an overlapping, germline gene repertoire. A large variety of Ig variable, diversity, and joining gene segments encoded these autoantibodies with different specificities. Hence, the overall murine lupus-associated anti-self response may be essentially unrestricted. Furthermore, limited evidence has been obtained that both germline genes and somatically mutated genes encode autospecificity, making gross abnormalities in mechanisms for somatic mutation of Ig variable genes unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Evidence for a new murine immunoglobulin heavy chain variable region gene family.

In the course of a previous study addressing autoantibody generation in murine models for generalized autoimmune disorders, we observed a nonfunctional immunoglobulin heavy chain transcript in a B cell hybridoma from lupus-prone MRL-Mp-lpr/lpr mice. This transcript, the cDNA sequence of which is presented here, is of general interest for murine immunoglobulin genetics as it cannot be ascribed to any known heavy chain variable region gene (Vh) family by nucleic acid sequence homology criteria and, hence, may represent a new Vh gene family. The sequence showed about equal nucleotide similarity (70-73%) to 3 other Vh gene families (S107, J606, 7183) and less than 65% similarity to members of the remaining 6 Vh gene families. Nucleic acid sequence comparisons with unpublished immunoglobulin sequences uncovered a highly homologous (greater than 95%) functional Vh transcript indicating that the suggested Vh gene family also encodes expressed antibody molecules.

Animals↗