SummaryThe processes that govern the generation of pathogenic anti-DNA autoantibodies in human systemic lupus erythematosus (SLE) are largely unknown . Autoantibodies may arise as a consequence of polyclonal B cell activation and/or antigen-driven B cell activation and selection . The role of these processes in humoral autoimmunity may be studied by molecular genetic analysis of immunoglobulin (Ig) variable (V) regions of antibodies that are characteristic of SLE. We have analyzed the gene elements that encode a high affinity, IgG anti-double-stranded DNA autoantibody secreted by a monoclonal Epstein-Barr virus (EBV)-transformed cell line derived from a patient with active SLE. In addition, we have identified, cloned, and sequenced the germline counterparts of the VH and VL genes expressed in this autoantibody. The comparison of both sets of gene elements shows that the autoantibody VH and VL regions harbor numerous somatic mutations characteristic of an antigen-driven immune response. The light chain expressed in this autoantibody is a somatically mutated variant of the kv325 germline gene that is frequently associated with paraproteins having autoantibody activity and with Ig molecules produced by malignant B cells that express the CD5 antigen . Furthermore, the utilized DH segment has been repeatedly found in multireactive, low affinity IgM anti-DNA autoantibodies from SLE patients and healthy individuals . These results suggest that pathogenic IgG anti-DNA autoantibodies in human SLE may arise through antigen-driven selection of somatic mutations in the gene elements that frequently encode multireactive IgM autoantibodies.Systemic lupus erythematosus is an autoimmune disease characterized by the production of antibodies that react with a variety of ubiquitous autoantigens including ribonucleoproteins, cytoskeleton proteins, and nucleic acids, such as single-stranded (ss)t and double-stranded (ds) DNA (reviewed in reference 1). A direct role for IgG anti-DNA antibodies in pathogenesis has been established by the correlation of serum antibody levels with disease activity (2) and the demonstration of DNA/anti-DNA immune complexdepositions at sites of tissue damage (3) . Although human anti-DNA antibodies have been extensively characterized by immunochemical, idiotypic, and structural analyses, (e.g ., 4-7) the processes that lead to the production of these autoanti-'Abbreviations used in this paper: ds, double stranded; ss, single stranded . 461bodies in SLE are largely unknown . Two, not mutually exclusive models have been proposed to explain their origin . The first model suggests that anti-DNA autoantibodies merely arise through antigen independent, polyclonal B cell activation (8,9). This model denies a role for antigen in the autoantibody response and predicts the generation of a multiclonal population of B cells with unmutated or randomly mutated Ig V regions. The second model proposes a role for (auto)antigen in the induction and maintenance of autoantibody production . This scenario predicts the generat...

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Cardiac allograft vasculopathy (CAV) in heart trans

The immune response following vaccination with a recombinant hepatitis B vaccine was investigated in 32 patients with Type 1 diabetes mellitus and compared with the outcome in 32 healthy age- and sex-matched volunteers. Participants were vaccinated at 0, 30, and 180 days and in vivo immune response was determined at 30, 60, 90, 180, and 210 days. The number of responders (anti-HBs greater than 1 IU l-1) was significantly lower (p less than 0.05) among patients at 30 (2 vs 11), 60 (17 vs 26), 90 (20 vs 28) and 180 (22 vs 29) days. The number of patients protected (anti-HBs greater than 10 IU l-1) was lower (p less than 0.05) than the number of protected volunteers at 60 (5 vs 14), 90 (10 vs 19), 180 (15 vs 24), and 210 days (24 vs 31). After the complete course of vaccination 8 out of 32 patients were still unprotected against hepatitis B (p less than 0.05). The anti-HBs titre of responders at 210 days was 251 (20, 3162) (geometric mean (-SD, +SD] IU l-1 in patients and 1259 (126, 12589) IU l-1 in control subjects (p less than 0.05). The HLA-antigen DQw1 frequency in the diabetic low responders (anti-HBs less than 100 IU l-1) was 0.27 compared with 0.86 in diabetic adequate responders. No relation between anti-HBs production and concentration of HbA1c could be demonstrated.

Sera from patients suffering from autoimmune diseases were analyzed for the presence of antibodies that inhibit adenovirus DNA replication in vitro. DNA replication was studied in a reconstituted system containing purified viral proteins (DNA binding protein, DNA polymerase and the precursor to the terminal protein) and a crude nuclear extract from HeLa cells. About half the autoimmune sera analyzed inhibited DNA replication by more than 50% while only 2 out of 31 control sera showed strong inhibition. The inhibition was caused by the IgG fractions of the sera and was most frequently observed with sera from scleroderma patients. Several lines of evidence indicate that the inhibition is not due to anti-DNA antibodies.The mechanism of inhibition of two strongly inhibitory sera was further investigated. The IgG fractions from these sera blocked DNA chain elongation more than 80% but had no effect on the initiation step or the synthesis of the first 26 nucleotides. Using a dot blot assay and different incubation conditions, evidence was obtained that the inhibition is due to immunorecognition of a nuclear factor from HeLa cells. Two nuclear proteins are known to be required for adenovirus DNA replication, nuclear factors 1 and 11. DNA replication in the presence of purified nuclear factor I instead of a crude nuclear extract was only slightly inhibited by the antisera. In agreement with this, immunorecognition of nuclear factor 1 could not be detected using a dot blot assay. Since nuclear factor I1 is not required in our assay system, these results suggest the existence of another nuclear component involved in adenovirus DNA replication which is neutralized by these antibodies.

In two siblings with systemic lupus erythematosus (SLE), who experienced two episodes of psychosis each, a longitudinal study of autoantibodies, including antibodies to ribosomal P proteins, is described. In two of three evaluable periods of 15 weeks antedating psychosis a rise followed by a spontaneous drop in anti-P levels was recorded. In the third period antibodies to ribosomal protein P were absent. It is concluded that results with single samples are not informative, and that frequent measurement of antibodies to ribosomal protein P in patients with SLE may have limited predictive value for psychosis.

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A report is given on two male patients who showed all the main characteristics of Sézary syndrome (SS). When phototested, however, they proved to be extremely photosensitive, which suggested a diagnosis of actinic reticuloid (AR). This was supported by the predominance in blood and skin specimens of lymphoid cells with a suppressor/cytotoxic phenotype, the absence of clonal cell proliferation and a benign clinical course. Differential diagnostic problems of SS and erythrodermic AR are discussed.