Biomedical subjects
Publications and source records attributed to V Agnello.
HCV appears to cause chiefly an asymptomatic chronic infection, which is nonetheless linked to a heightened prevalence of "essential" mixed cryoglobulinemia. The monoclonal rheumatoid factor occurring in the disease may result from chronic stimulation of the immune system, perhaps by the virus directly.
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A strong association of hepatitis C infection (HCV) with 'essential' mixed cryoglobulinaemia has been established. The demonstration of HCV in Type II mixed cryoglobulins with monoclonal rheumatoid factors (mRF) that bear the WA crossidiotype has lead to the hypothesis that mixed cryoglobulins result from chronic stimulation by HCV-lipoprotein of a population of XId WA+B-1a cells. The reactivity of WA IgM initially produced is with the HCV-self antigen complex with RF activity resulting secondarily from the pausi-mutational process accompanying the T cell independent process. This benign proliferation progresses by multi step mutations to malignancy in a minority of patients. The implications of the hypothesis for understanding the physiology of certain natural auto antibodies and for therapeutic intervention in this disease are discussed.
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Membranoproliferative glomerulonephritis (MPGN) is associated with hepatitis C virus infection predominantly in patients with mixed cryoglobulinemia. Viral-like particles reported in cryoglobulins and in glomerular deposits may be artifacts; in situ identification of viral genome or antigens is required to establish validity of such observations. Although the precise role for hepatitis C virus in the pathogenesis of MPGN remains to be determined, recent evidence suggests that chronic infection with hepatitis C virus may stimulate the production of the monoclonal rheumatoid factor in type II cryoglobulins that are deposited in the glomerular lesions. Interferon-alpha now appears to be the drug of choice in treating MPGN associated with hepatitis C virus infection. The association of hepatitis B virus infection with MPGN has not been convincingly established nor has its role in the pathogenesis of MPGN been demonstrated.
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The WA cross-idiotype (XId) is the major XId among human monoclonal rheumatoid factors (mRF) and is almost always associated with the light (L) chain XId, 17.109, and the heavy (H) chain XId, G6. A cell line, 35G6, was cloned that bears the WA XId, but shows no reactivity with immunoglobulin G (IgG) and is negative for the 17.109 and G6 XIds. The 35G6 L chain appears to be derived from the same VKIII-JKI genes as most WA mRFs L chains. In contrast to the WA mRFs H chains in which VH1 genes are used, the 35G6 IgM expresses a VH3 gene. Sequence comparisons with other WA XId-positive mRF suggested several common structural features that may be related to the WA XId and differences that may relate to lack of IgG reactivity. Cells similar to 35G6 have previously been described in pokeweed mitogen-stimulated cell lines of peripheral blood lymphocytes from normal individuals and patients with rheumatoid arthritis and type II mixed cryoglobulinemia. These observations were confirmed, and in addition, it was shown that the majority of WA XId-positive cells in these cultures were negative for the 17.109 and G6 XIds. The presence of the WA XId in the absence of IgG reactivity suggests that the WA XId is more directly associated with an antigen specificity other than IgG, and its association with RF activity may be incidental. It is postulated that these WA XId-positive RF-negative antibodies may serve a physiologic role as natural antibodies to a pervasive pathogen, and that IgG reactivity is a consequence of somatic diversification accompanying proliferation of the WA XId-positive RF-negative cell.
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BACKGROUND: Type II cryoglobulinemia is a vasculitis characterized by cryoglobulins consisting of complexes of polyclonal IgG and monoclonal IgM rheumatoid factors. The cause of these immune complexes is unknown, though both the hepatitis B (HBV) and C (HCV) viruses have been suspected. METHODS: We studied 19 patients with Type II cryoglobulinemia for markers of HCV and HBV infection. Quantitative HCV antibody and RNA studies were performed on whole serum, cryoprecipitates, and supernatants. RESULTS: Eight patients (42 percent) had HCV antibodies, and 16 (84 percent) had HCV RNA: Of the 19 patients, 5 (26 percent) had HBV markers, but only 1 had evidence of active HBV infection. Control serum samples from nine patients with Type I cryoglobulinemia were negative for HCV antibody and HCV RNA: There was a close, although not exclusive, association of one type of rheumatoid factor (WA) with HCV RNA: HCV antibody and HCV RNA were concentrated approximately 10-fold and 1000-fold, respectively, in the Type II cryoglobulins examined. CONCLUSIONS: Type II cryoglobulinemia is strongly associated with concomitant HCV infection and a high rate of false negative serologic tests. HCV virions and HCV antigen-antibody complexes are concentrated in the cryoprecipitates, most commonly in association with the WA type of rheumatoid factor, suggesting a role for HCV in the pathogenesis of mixed cryoglobulinemia.
We describe the case of a 19-year-old woman who died of overwhelming aspergillosis 3 months after receiving intravenous (IV) cyclophosphamide for progressive lupus nephritis. Her history is instructive because it illustrates the wisdom of strict adherence to the National Institutes of Health protocol for this treatment, specifically, the contraindication to use of IV cyclophosphamide when other immunosuppressive therapy has recently been employed.
The BLA cross-idiotype (XId) is present on a unique subset of rheumatoid factors (RF) that cross-react with DNA-histone. In this study, prototype Bla monoclonal RF was shown from serologic investigations and N-terminal amino acid sequence analysis to have distinct kappa chains related to the V kappa III subgroup and VH4 heavy chains. The amino terminus of the heavy chain was cyclized, rendering the protein resistant to Edman degradation and providing a possible investigator bias to the published Ig sequence data to date. This appears to be the first definitive report of a serum IgM that expresses the VH4 gene. RF with DNA cross-reactivity have been reported to be produced by human and mouse cloned cells that have the VH4 or homologous mouse Vh36-60 gene.
The sera from three C8 alpha-gamma deficient patients previously reported to have a selective C8 alpha-gamma defect were analyzed by SDS-PAGE and Western blot using two polyclonal antisera to C8 alpha-gamma and a monoclonal antibody to C8 alpha. All three sera exhibited C8 alpha-gamma bands that dissociated into alpha and gamma chains under reducing conditions. Quantitation of the alpha-gamma subunit in these sera by a sensitive ELISA revealed an amount approximately 1% of that found in normal human serum. A similar assay performed with a specific antiserum to C8 beta showed unexpectedly low levels of C8 beta in these sera, which were confirmed by hemolytic titration of C8 beta. The remarkable differences between C8 alpha-gamma and C8 beta in the C8 alpha-gamma deficient sera was that in spite of their comparable immunochemical levels, C8 beta still exhibited functional activity whereas C8 alpha-gamma was totally inactive. That the residual C8 alpha-gamma was inactive was also proved by its inability to show lytic bands in an overlay system after SDS-PAGE and subsequent removal of SDS. The implications of these findings for a novel concept of C8 deficiency are discussed.
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The prevalence of autoantibodies of immunoglobulin G (IgG) and immunoglobulin M (IgM) classes directed against myeloma immunoglobulin E (IgE) were determined in distinct subsets of urticaria, using an enzyme immunoassay. IgG anti-IgE antibodies were found in five of nine patients (55%) with cold urticaria, four of eight patients (50%) with urticarial vasculitis, and three of six patients (50%) with chronic urticaria. IgM anti-IgE antibodies were found exclusively in cold urticaria (two of nine patients, 22%). Heating of these sera increased the binding to IgE, suggesting immune complex formation. Several positive sera were capable of inducing histamine release from normal peripheral basophils and caused a wheal-flare response upon intradermal injection. Sera containing such autoantibodies from three cold urticaria patients were studied for passive transfer of cold sensitivity. One serum containing IgG anti-IgE gave a strongly positive transfer test at 5 h but not 48 h, suggesting a pathogenic role for the IgG.
The amino acid sequence of the L-CDR2 (complementarity-determining region) of Bla mRF (monoclonal rheumatoid factor) is identical to that of the Wa mRFs. The PSL2-CRI (crossreactive idiotype), as determined by anti-PSL2, which has been shown to be present on all Wa mRFs, is also present on the Bla mRF and other monoclonal autoantibodies. PSL2-CRI is, therefore, not unique to Wa mRFs and may be present on most IgM kappa monoclonal autoantibodies. Whether PSL2-CRI is a crossidiotype (XId) that is selectively present on autoantibodies or represents an allotypic marker for a V kappa III gene is undetermined.
Three immune complex assays, the monoclonal rheumatoid factor inhibition (mRF), the C1q solid phase (C1q-SP), and the C1q fluid phase binding (C1q-BA) assays, were compared with native DNA antibody (nDNA Ab) titers and serum hemolytic complement (CH50) levels in serial analyses of patients with systemic lupus erythematosus (SLE). No correlation was evident among the immune complex assays. A positive correlation was observed between the C1q-SP and nDNA Ab assays, and a negative correlation was observed between the C1q-SP and CH50 assays. Evidence is presented that these correlations are related to the presence of complement-fixing nDNA Ab. The C1q-SP may be useful in delineating the basis for the unexplained association of nDNA Ab and hypocomplementemia.
Fewer than 20 patients with lymphocytic adenohypophysitis have been reported, all of them women, and it usually occurs during pregnancy or the postpartum period. We report the recognition of lymphocytic adenohypophysitis in a man. The patient presented with anterior hypopituitarism and an intrasellar mass on computed tomography. Antipituitary antibodies, found in only one of the previous patients, were not present in this man, although low titer antinuclear antibodies were found. The implications of this latter finding are unclear. The patient's histocompatibility antigen (HLA) types were A2, B8, Bw58, DR1, and DR5. The degree of pituitary failure seemed out of proportion to the size of the mass seen on computed tomographic scan.
Evidence was obtained that both the WA and BLA crossidiotype (XId) groups are conformational antigens requiring both L and H chains and that with heat denaturation the antigens that define the XIds and antigen-binding activity are lost in parallel. In contrast, the primary structure-dependent crossreactive idiotype (CRI), PSL2, which is only weakly detected on native Wa and Bla monoclonal rheumatoid factors (mRFs), became prominently detected on the heated Wa and Bla mRFs. Heat denaturation may provide a simple method for distinguishing Ids determined by conformational antigen from primary structure-dependent Ids. In addition to heat denaturation, some acid conditions commonly used for preparation of RFs were also found to cause marked loss of Id antigen. The finding of PSL2-CRI on Bla mRF indicates that this Id is not unique to the WA XId.