[Intravenous immunoglobulins in autoimmune and inflammatory disorders: beyond a simple substitution]. / Immunoglobulines intraveineuses dans les maladies auto-immunes et inflammatoires: au-delà d'une simple substitution.

Despite their widespread use since many years in autoimmune and inflammatory disorders, the mechanisms of action of IVIg have not been completely understood. These mechanisms depend on Fc and/or F(ab')2. IVIg interacts with the different components of the immune system: Fc receptors, complement, cytokines, T and B lymphocytes, dendritic cells, granulocytes and NK cells. Here, we discuss the recent advances in the understanding of the mechanisms of action of IVIg, in particular the importance of the sialylated Fc fragment. These advances maybe help us conceive better therapeutic strategies against autoimmune and inflammatory disorders.

Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin.

Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over two decades. Since the early 1980s, the therapeutic efficacy of IVIg has been established in idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, dermatomyositis and Kawasaki syndrome, and the prevention of graft versus host disease in recipients of allogeneic bone marrow transplants. Its use has also been reported in a large number of other autoimmune and systemic inflammatory conditions. In this review, we discuss the mechanisms by which IVIg exerts immunomodulatory effects in immune pathologies.

Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases.

Intravenous immunoglobulins (IVIg) exert a broad range of immunoregulatory functions that provide a basis for the beneficial effects of IVIg in autoimmune and systemic inflammatory disorders. This review focuses on the effects f IVIg on humoral and cellular immunity that may be of relevance for the treatment of inflammatory neurological diseases.

Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases.

Therapeutic polyclonal intravenous immunoglobulin (IVIg) consists of normal IgG obtained from the pools of plasma of several thousand healthy blood donors. IVIg is used as substitutive treatment of primary and secondary immunodeficiences. Since the first study of Paul Imbach who demonstrated the beneficial effect in idiopathic thrombocytopenic purpura, IVIg is also used in a number of autoimmune and inflammatory diseases. The immunoregulatory effects of IVIg in autoimmune diseases depend on the interaction of Fc portion of immunoglobulins with Fc receptors and on the selection of lymphocyte repertoires of patients through variable regions of infused immunoglobulins. IVIg modulates the activation and effector functions of B and T lymphocytes, neutralizes pathogenic autoantibodies, interferes with antigen presentation and has a strong anti-inflammatory effect which depends on its interaction with the complement system, cytokines and endothelial cells. The immunomodulatory potential of IVIg in patients is thus a result of a variety of complex mechanisms that act in a synergy.

Restricted genetic defects underlie human complement C6 deficiency.

Complement C6 homozygous deficiency (C6D) has been rarely observed in Caucasians but was reported at higher prevalence among African-Americans. We report on the molecular basis of C6D in seven unrelated black individuals of North or Central Africa descent who live in France. These patients have presented Neisseria meningitidis infection (four cases), focal and segmental glomerulosclerosis with hyalinosis (one case), systemic lupus erythematosus (one case) or Still's disease (one case). All patients exhibited undetectable antigenic C6 by using a sensitive ELISA assay. An additional four cases of complete C6 deficiency with no associated disease have been characterized after family studies. Exons 6, 7 and 12 have been described recently as the location of molecular defects on the C6 gene in randomly chosen black Americans. Genomic DNA from the seven patients were subjected to direct polymerase chain reaction amplification of these three exons. Nucleotide sequencing analysis of the amplified DNA fragments revealed a homozygous single-base deletion (1936delG) in exon 12 in three cases and four compound heterozygous deletions for a single base in exon 7 (1195delC) or in exon 6 (878delA) associated with the same deletion in exon 12 (1936delG). Our observations further establish the restricted pattern of genetic defects associated with homozygous C6 complement deficiency in individuals of African descent.

Intramedullary abscess resulting from disseminated cryptococcosis despite immune restoration in a patient with AIDS.

We report on a case of cryptococcal intramedullary abscess, which occurred three years after a disseminated cryptococcosis and two years after a lymph node cryptococcal recurrence in a HIV-infected patient who exhibited a long-standing immune restoration. At the time of diagnosis, CD4(+) lymphocyte-count was 640x10(6)/l and HIV viral load was undetectable. Spinal involvement is rare during cryptococcosis of the central nervous system. As far as we are aware, there is only one case of proven intramedullary cryptococcal abscess reported in the literature and this case is then the second one. The significant and sustained increase in CD4 count following effective antiretroviral therapy was probably associated with only a partial immune restitution that did not allow to avoid the occurrence of the cryptococcal medullar abscess. Finally, this case raises the question of when to stop secondary prophylaxis of cryptococcal disease after increase in CD4 cell count under antiretroviral therapy.

Immunological and virological features of HIV-infected patients with increasing CD4 cell numbers despite virological failure during protease inhibitor-based therapy.

OBJECTIVES: To investigate the extent of functional T cell recovery and to characterize plasma virus and virus producing cells in patients with increasing CD4 cell counts despite virological failure during protease inhibitor (PI) based therapy. METHODS: The study group included 13 patients who were treated for at least 12 months with a PI based regimen and were selected on the basis of a sustained immunological response (increase of > 70 CD4 cells/microL) despite virological failure (< 1 log10 copies/mL decrease in HIV-1 RNA plasma levels). RESULTS: Compared to a historical series of 11 complete responders with less advanced disease, the proportion of memory CD4 T cells was significantly higher (67.8+/-17.8 vs. 52.8+/-11.0; P=0.045) and the proportion of naive CD4 T cells significantly lower (30.5+/-14.8 vs. 45.0+/-10.4, P=0.021) in patients who were immunological responders/virological nonresponders. In those patients, ongoing viral replication was associated with a strong activation of circulating CD8 T lymphocytes; interleukin-2 production remained decreased. CD4 T cell reactivity to cytomegalovirus proteins was observed in nine of 11 patients tested. In the study group, the proportion of infectious virus present in plasma as well as the levels of intracellular viral replication were similar to those measured in untreated patients. Virological failure in this group of patients probably resulted from pre-existing mutations in the reverse transcriptase gene. CONCLUSIONS: This study of patients with increasing CD4 cell numbers despite virological failure shows the persistence of immune activation and partial immune restoration with no evidence of specific viral dynamics in vivo.

Pathophysiology of inhibitors to factor VIII in patients with haemophilia A.

The occurrence of factor VIII (FVIII) inhibitors is one of the major complications of the treatment of haemophilia A. We present this review as a description of the major players of the antiFVIII immune response, with particular emphasis on the nature and properties of the different antiFVIII antibodies, their mechanisms of action in inhibiting FVIII activity, their potential neutralization by anti-idiotypic antibodies, and the importance of the T cell in participating in the induction of FVIII inhibitors. We briefly conclude on the avenues that remain to be explored in order to establish efficient therapeutic approaches aimed at eliminating FVIII inhibitors in patients with haemophilia A.

The concept of idiotypic vaccination against factor VIII inhibitors in haemophilia A.

Idiotypic vaccination has proven successful in several animal models and human trials. Here we suggest that the expression of cross-reactive idiotypes on factor VIII (FVIII) inhibitors of patients with haemophilia A, patients with anti-FVIII autoimmune disease and natural anti-FVIII antibodies of healthy individuals, together with the ability of anti-idiotypic reagents to neutralize anti-FVIII antibodies, provides a rationale for designing a vaccine strategy aimed at preventing the occurrence of or suppressing inhibitors, based on the induction of protective anti-idiotypes. Here we discuss the rationale supporting the concept of using idiotypic vaccination to prevent the occurrence of FVIII inhibitors in patients with haemophilia A.

Cervicovaginal secretory antibodies to human immunodeficiency virus type 1 (HIV-1) that block viral transcytosis through tight epithelial barriers in highly exposed HIV-1-seronegative African women.

Antibodies to human immunodeficiency virus (HIV) of the IgA, IgG, and IgM isotypes and high levels of the HIV suppressive beta-chemokine RANTES (regulated on activation, normally T cell expressed and secreted) were found in the cervicovaginal secretions (CVSs) of 7.5% of 342 multiply and repeatedly exposed African HIV-seronegative female sex workers. The antibodies are part of a local compartmentalized secretory immune response to HIV, since they are present in vaginal fluids that are free of contaminating semen. Cervicovaginal antibodies showed a reproducible pattern of reactivity restricted to gp160 and p24. Locally produced anti-env antibodies exhibit reactivity toward the neutralizing ELDKWA epitope of gp41. Study results show that antibodies purified from CVSs block the transcytosis of cell-associated HIV through a tight epithelial monolayer in vitro. These findings suggest that genital resistance to HIV may involve HIV-specific cervicovaginal antibody responses in a minority of highly exposed HIV-seronegative women in association with other protecting factors, such as local production of HIV-suppressive chemokines.

Broad alterations of self-reactive antibody-repertoires of plasma IgM and IgG in B-cell chronic lymphocytic leukemia (B-CLL) and B-CLL related target-restricted autoimmunity.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a malignant CD5+ B-cell clone. The leukemic clone commonly expresses IgM antibodies exhibiting reactivity toward a wide range of self-antigens. However, B-CLL associated autoimmunity is typically restricted to self-antigens expressed by blood cells, and mediated by IgG autoantibodies of polyclonal origin. In the present study, we addressed the question whether self-reactive antibody repertoires of plasma IgM and IgG are disturbed by monoclonal immunoglobulins of B-CLL patients, and whether antibody repertoires of patients exhibiting B-CLL associated target-restricted autoimmune disease (AID) differ from those of B-CLL patients without AID. We investigated antibody repertoires at a global level, using a technique of quantitative immunoblotting that allows for the quantitative screening of antibody reactivities in complex antibody mixtures toward a large panel of antigens derived from homologous tissue extracts, followed by multiparametric statistical analysis of the data. We demonstrate that self-reactive antibody repertoires of plasma IgM and IgG are broadly altered in patients with B-CLL, that alterations in self-reactive antibody repertoires are not restricted to B-CLL patients exhibiting AID, and that target-restricted autoimmunity in B-CLL patients is associated with altered antibody repertoires not restricted to the target organ. We conclude that monoclonal alterations of immunoglobulin production in B-CLL are associated with broad defects of self-reactive antibody repertoires. Our observations suggest that the application of therapeutic IVIg preparations might influence B-CLL by restoring normal self-reactive antibody repertoires in plasma.

Idiopathic membranous glomerulonephritis is associated with altered patterns of self-reactive IgM and IgG antibody repertoires.

Idiopathic membranous glomerulonephritis (MGN) is an immune complex nephropathy characterized by the subepithelial deposition of immunoglobulin (Ig)G. The pathogenesis of the disease remains largely unknown, but recent evidence suggests that human MGN may involve an autoimmune component. In the present study, we have analyzed the IgM and IgG antibody repertoires of patients with MGN towards self- and nonself-antigens using a technique of quantitative immunoblotting on a panel of whole human tissue or solubilized bacterial cell extracts as sources of antigens. Data were compared by means of multiparametric statistical analysis. We demonstrate that the antibody repertoires of self-reactive IgM and IgG in plasma of patients with MGN exhibit significantly altered patterns of reactivity, as compared with those of healthy controls. In contrast, multiparametric statistical analysis does not discriminate the reactivity patterns of IgM and IgG in plasma of patients and healthy controls towards nonself antigens. These observations indicate that a failure in the regulation of physiological self-reactivity is associated with immune complex nephropathy in MGN.

Double-blind placebo-controlled trial of oral dehydroepiandrosterone in patients with advanced HIV disease.

OBJECTIVE: Plasma levels of dehydroepiandrosterone sulphate (DHEA-S) decrease with the progression of HIV disease. Here, we report on the efficacy and safety of the oral administration of DHEA as replacement therapy, in patients with advanced HIV disease, in a trial that was primarily aimed at assessing quality of life. DESIGN: The trial was randomized and double-blind. Thirty-two patients were allocated to either DHEA 50 mg per day for 4 months (n = 14) or a matching placebo (n = 18). Clinical data, virological and immunological surrogate markers of HIV infection, plasma levels of DHEA-S and the Medical Outcomes Study HIV Health Survey (MOS-HIV) quality of life scale were recorded every month. RESULTS: The mean age of the patients was 40 +/- 11 years. The mean CD4 cell count at baseline was 32.5 +/- 32.4 x 10(6)/l. The mean DHEA-S plasma level at baseline was 5.23 +/- 0.76 micromol/l. No side-effects related to DHEA occurred during the study. A statistically significant increase in the levels of DHEA-S was observed in the treated group throughout the study (P < 0.01). A significant improvement in the Mental Health and Health Distress dimension of MOS-HIV was observed in the DHEA treated group; P = 0.001 and 0.004, respectively. No change in CD4 cell counts was seen during follow-up. CONCLUSIONS: The administration of DHEA in patients with advanced HIV infection results in improved mental function scores as assessed by the MOS-HIV quality of life scale.

Long-term efficacy of combination therapy with interferon-alpha 2b and ribavirin for severe chronic hepatitis C in HIV-infected patients.

BACKGROUND: We have assessed the long-term efficacy and safety of a combination therapy of interferon alpha-2b (IFN) and ribavirin (RBV) for the treatment of severe chronic hepatitis C in co-infected HIV-seropositive patients in an open prospective study. METHODS: Fifty-one patients were treated for 12 months. Mean baseline CD4 cell count, alanine aminotransferase and aspartate aminotransferase were 412 +/- 232 x 106/l, 113 +/- 75 IU/l and 111 +/- 84 IU/l respectively. The mean Knodell score was 11.5 +/- 2.1 with 28 patients (55%) exhibiting histological evidence of active cirrhosis. RESULTS: Fifteen (29%) patients discontinued the treatment prematurely because of adverse events. An end of treatment response (ETR) as defined by the lack of detectable hepatitis C virus (HCV) RNA in plasma at the end of treatment was achieved in 15 patients (29%). A sustained virological response (SVR), defined by the lack of detectable HCV RNA in plasma 6 months after completion of combination therapy, was achieved in 11 patients (21%). The HCV genotype 3a was associated with ETR and SVR (P = 0.002 and P = 0.003, respectively). HCV viraemia at baseline was lower in patients who achieved SVR and ETR than in those who did not (6.7 +/- 7.8 versus 24 +/- 26.7 x 10(6) genome equivalents/ml, P = 0.03 and 14.3 +/- 28.7 versus 22.5 +/- 23, P = 0.05, respectively). CONCLUSION: Our results indicate that combination therapy with IFN and RBV is effective in approximately 20% of co-infected patients with severe liver disease.

Natural autoantibodies and complement promote the uptake of a self antigen, human thyroglobulin, by B cells and the proliferation of thyroglobulin-reactive CD4(+) T cells in healthy individuals.

Serum from normal individuals contains substantial amounts of natural antibodies (NA) capable of recognizing self antigens. However, the physiological implications of this autoreactivity remain unclear. We have examined the role of self-reactive NA and complement in mediating the uptake of human thyroglobulin (Tg) by human peripheral B cells in reconstituted whole blood. Significant binding of fluorescein isothiocyanate-conjugated-Tg to B cells was observed, and absorption of Tg-reactive antibodies from serum markedly reduced this uptake, as did inactivation of serum complement or blockade of complement receptor types 1 (CR1, CD35) and 2 (CR2, CD21). T cell responsiveness to Tg was examined in a preparation of peripheral blood mononuclear cells (PBMC) cultured in the presence of autologous serum. A subset of CD4(+) T cells exhibited a dose-dependent proliferative response to Tg, which was strongly inhibited by complement inactivation and by immunoabsorption of Tg-reactive antibodies. Furthermore, this T cell response was abrogated by depletion of B cells from the PBMC culture. These data imply that uptake of complement-opsonized Tg / anti-Tg complexes and subsequent presentation of Tg by B cells are prerequisites for the proliferation of Tg-reactive CD4(+) T cells, suggesting a novel role for natural autoantibodies and complement in the regulation of autoreactivity under physiological conditions.