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We investigated, by indirect immunofluorescence, the binding of monoclonal IgM to human peripheral nerve in 25 patients with Waldenström's macroglobulinemia and peripheral neuropathy. In 10 cases (40%), an antibody activity against the myelin sheaths was demonstrated. The reactivity was mediated by the F(ab′)2fragments of the IgM. Prior delipidation of nervous tissue was needed to allow full expression of the target antigen(s). In nine cases, the IgM reacted with both peripheral and central myelin of primates, but not mouse or rabbit nervous tissue. In one case, the IgM reacted only with human peripheral nerve. The patients, whose IgM had an antibody activity to myelin antigen(s), had some distinct hematologic and neurologic features. The peripheral neuropathy always antedated the hematologic symptoms by several years. The serum level of the monoclonal IgM was low in all cases, and overt lymphoid malignancy was frequently absent. In other patients with neuropathy, the monoclonal IgM, which lacked antimyelin antibody activity, displayed either cross-idiotypic antigenic determinants or anti-intermediate filament antibody activity. These results taken together emphasize the heterogeneity of antibody activity of the monoclonal IgM from patients with Waldenström's macroglobulinemia and peripheral neuropathy.

The potential hazards of steroids in human immunodeficiency virus (HlV)-infected patients led us to evaluate the effectiveness and safety of anti-D and anti-c Ig in 17 adults with severe HIV-related immune thrombocytopenic purpura (platelet count < 20 x 109/L). The 14 Rh+ patients received 12 to 25 μg/kg of anti-D IgG intravenously on two consecutive days. A significant platelet rise above 50 x 109/L was obtained in nine patients. Repeated boosters were performed in six cases and were effective in all cases. The 3 Rh- patients had a good response after they were given 20 mL x 2 of plasma containing potent anti-c antibodies. Therapy was well tolerated, and only one patient had significant hemolysis. These data suggest that anti-Rh IgG can be effective and safe in HIV-related thrombocytopenic purpura and that a specific interaction between the RBC antigens and the anti-Rh antibodies is required.

Multicentric Castleman's disease (MCD) is an atypical lymphoproliferative disorder defined using clinical and pathologic criteria. A characteristic of the MCD is a close association with Kaposi's sarcoma (KS), which occurs during the clinical course of most human immunodeficiency virus (HIV)-associated MCD cases and also, but less frequently, in HIV-negative patients. Recently, sequences of a putative new Herpesvirus (KSHV) have been isolated and further detected in almost all the acquired immunodeficiency syndrome (AIDS) KS and in most of the non-AIDS KS samples. In this study, we searched for these Herpesvirus-like sequences in MCD samples of 31 patients. KSHV sequences were detected in 14 of 14 cases of HIV-associated MCD, including 5 cases without detectable KS. Moreover, KSHV was detected in 7 of 17 MCD cases in HIV-negative patients, including 1 case associated with a cutaneous KS. In 34 non-MCD reactive lymph nodes (follicular and/or interfoliicuiar hyperplasia) in HIV-negative patients, KSHV was detected in only 1 case. In 1 HIV-negative case of MCD, KSHV was found in both the lymph node and peripheral blood samples. These data suggest that KSHV could play a role in the pathogenesis of MCD, especially in HIV-infected patients.

Sixty-eight patients, followed in a prospective cohort study of 185 human immunodeficiency virus (HIV)-infected patients with severe immune thrombocytopenia (platelets < 50 × 109/L), underwent splenectomy, 2 to 41 months (median: 10 months) after immune thrombocytopenic purpura (ITP) was diagnosed. The mean platelet count increased from 18×109/L to 223 × 109/L with a persistent increase in 56 (82%). It also led to a significant increase of the mean CD4 cell count from 475 × 106/L to 725 × 106/L within a mean delay of 10 months. In the whole cohort, with a mean follow-up of 63 months (range, 6 to 126), the 5-year estimated rate for progression to acquired immunodeficiency syndrome (AIDS) was 23% (95% confidence interval [Cl], 15% to 31%) and the AIDS-free survival was 69% (95% Cl, 61 % to 77%). To investigate the potential impact of splenectomy, a Cox’s multiple regression model was used; as splenectomy was not randomly assigned, it was incorporated as a time-dependent covariate. After adjustment on the CD4 cell count, no statistically significant differences were observed between the splenectomized and the nonsplenectomized patients: AIDS progression rate (P= 0,23), survival (P= 0,64) and AIDS-free survival (P= 0,72) were not influenced by splenectomy. Splenectomy is both effective and safe in the treatment of severe, refractory ITP associated with HIV infection.

Castleman's disease (CD) is a rare atypical lymphoprolifera-tive disorder that is morphologically and clinically heterogeneous and is associated with a risk of developing malignant lymphoma. We report the clonality status of CD tissues in 34 patients, including 14 patients infected by the human immunodeficiency virus (HIV). Four patients presented a localized form and 30 presented a multicentric form. Two cases were associated with B-celf lymphoma, 3 cases with Hodgkin's disease, and 9 cases (8 HIV+) with Kaposi's sarcoma. Histologically, 8 cases were of the hyaline-vascular type and 26 were of the plasma cell or mixed types. The Ig and T-cell receptor (TCR) V(D)J rearrangements were analyzed using polymerase chain reaction and Southern blot. Clonal IgH rearrangements were detected in only 4 cases, ie, 2 associated with B-cell lymphoma, 1 with Hodgkin's disease, and 1 case without malignancy. A TCRy rearrangement of restricted junctional size was amplified in 1 HIV+case. Finally, polyclonal VH-JHand Vy-Jy rearrangements were detected in the large majority of the cases, irrespective of pathologic subtypes, clinical forms, and HIV status. The lymphoid component in CD is therefore commonly reactive, and the rare occurrence of detectable monoclonal lymphoid contingents may be caused by secondary molecular events.

Marked polyclonal IgG4 hypergammaglobulinemia has exceptionally been reported. Here we report on two patients who presented an unique syndrome including a predominant and massive increase in serum levels of the IgG4 subclass. Clincal, biological and pathological data were described. Production of IgG4 by patients’ peripheral blood lymphocytes was studied, as well as the capacity of patients’ sera and T lymphocytes to induce IgG4 production by normal B cells. The possible involvement of IL4 and IL13 in the increased IgG4 production was also investigated. The two patients had anemia, lymphadenopathy, renal manifestations and a marked polyclonal IgG4 hypergammaglobulinemia leading to hyperviscosity syndrome in one case. The IgG4-producing cell percentage was significantly increased in both cases. By contrast with normal sera, both patients’ sera significantly increased the IgG4-producing cell percentagae when incubated with CD40-stimulated normal B lymphocytes. Similar effects were obtained with the culture supernatants of patients’ activated T cells. IL4 and IL13 serum concentrations were normal in the two patients. Anti-IL4 and/or anti-IL13 antibodies were unable to antagonize the IgG4 synthesis. The increased IgG4 production was found to be mediated by soluble, heat-resistant factor(s) that did not require the Stat6 signaling pathway. We described here a novel syndrome characterized by a significantly increased IgG4 production, mediated by soluble, heat-stable factor(s) most probably secreted by activated T cells, and distinct from IL4 and IL13.