Beneficial Effect Of Intravenous Immunoglobulin Research Articles

Immunoglobulin for multifocal motor neuropathy.

Immunoglobulin for multifocal motor neuropathy.

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

Beneficial effects of intravenous immunoglobulin as an add-on therapy to azathioprine for NMO-IgG-seropositive neuromyelitis optica spectrum disorders

BackgroundThe efficacy of intravenous immunoglobulin (IVIG) in neuromyelitis optica spectrum disorders (NMOSD) has rarely been investigated, despite it being a conceivable therapeutic strategy based on its mode of action. We aimed to evaluate the efficacy of IVIG as an add-on therapy to azathioprine in the prevention of NMOSD relapse. MethodsWe retrospectively reviewed the medical records of NMO-IgG-positive NMOSD patients treated with IVIG infusions (0.4 g/kg/day) every one to three months as a part of combination therapy with azathioprine for more than six months. Treatment efficacy and safety were assessed based on the changes in the pre-IVIG and post-IVIG treatment annualized relapse rates (ARR), and on the proportion of relapse-free and progression-free patients and adverse events. ResultsThis study was performed on 20 patients (19 women; median age 52 years). After add-on therapy with IVIG, 19 patients (95%) showed a significant reduction in the median ARR from 1.1 [interquartile range, 0.6‒1.4] to 0.3 [interquartile range, 0‒0.6] (p < 0.001). Seven patients (35%) were relapse-free during 43.5 months (median) of treatment. The median Expanded Disability Status Scale (EDSS) score remained stable at 4.0. In addition, 80% of the patients showed no disability progression, and 25% of the patients experienced an improvement in EDSS. The median NMO-IgG titer decreased from 1:480 (n = 19) to 1:120 (n = 13) after treatment (p = 0.006) and was found to be negative in three patients. Six patients (30%) stopped IVIG due to relapses after 27.5 months (median; interquartile range, 15.3‒43.3) of IVIG initiation. There were no severe side effects that led to discontinuation of IVIG. ConclusionIVIG as add-on therapy may be associated with beneficial effects in preventing relapse and disability progression in NMO-IgG-positive NMOSD patients who have breakthrough disease activity despite immunosuppressive treatment with azathioprine. Further randomized controlled trials are necessary to validate the efficacy of IVIG in NMOSD.

Intravenous Immunoglobulin Therapy Eliminates Candida albicans and Maintains Intestinal Homeostasis in a Murine Model of Dextran Sulfate Sodium-Induced Colitis.

Intravenous immunoglobulin (IVIg) therapy has diverse anti-inflammatory and immunomodulatory effects and has been employed successfully in autoimmune and inflammatory diseases. The role of IVIg therapy in the modulation of intestinal inflammation and fungal elimination has not been yet investigated. We studied IVIg therapy in a murine model of dextran sulfate sodium (DSS)-induced colitis. Mice received a single oral inoculum of Candida albicans and were exposed to DSS treatment for 2 weeks to induce colitis. All mice received daily IVIg therapy starting on day 1 for 7 days. IVIg therapy not only prevented a loss of body weight caused by the development of colitis but also reduced the severity of intestinal inflammation, as determined by clinical and histological scores. IVIg treatment significantly reduced the Escherichia coli, Enterococcus faecalis, and C. albicans populations in mice. The beneficial effects of IVIg were associated with the suppression of inflammatory cytokine interleukin (IL)-6 and enhancement of IL-10 in the gut. IVIg therapy also led to an increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), while toll-like receptor 4 (TLR-4) expression was reduced. IVIg treatment reduces intestinal inflammation in mice and eliminates C. albicans overgrowth from the gut in association with down-regulation of pro-inflammatory mediators combined with up-regulation of anti-inflammatory cytokines.

Pivotal Role of Preexisting Pathogen-Specific Antibodies in the Development of Necrotizing Soft-Tissue Infections.

Necrotizing soft-tissue infections (NSTI) are the most severe form of bacterial-induced tissue pathology. Their unpredictable onset and rapid development into life-threatening conditions considerably complicate patient treatment. Understanding the risk factors for NSTI in individual patients is necessary for selecting the appropriate therapeutic option. We investigated the role of pathogen-specific antibodies in the manifestation of NSTI by performing a comparative serologic approach, using plasma samples and bacterial isolates from patients with clinical NSTIs or nonnecrotizing STIs caused by Streptococcus pyogenes. We also evaluated the potential beneficial effect of intravenous immunoglobulin (IVIG) treatment. We identified a hitherto overlooked state of serologic susceptibility in patients with NSTIs during the earliest stages of the infection that is potentially linked to disease progression. Thus, all patients with NSTIs included in this study exhibited a deficiency in specific antibodies directed against the causative S. pyogenes strains and the majority of their exotoxins during the initial stage of the infection. We also showed that the clinical use of IVIG during the course of infection compensates the observed antibody deficiency but is unable to halt the disease progression, once tissue necrosis has developed. These observations emphasize the requirement of preexisting pathogen-specific antibodies to prevent the irreversible progression of tissue infections into severely spreading NSTIs and urge further investigations on the beneficial effect of IVIG-based early phase intervention strategies to prevent the severe effects of this devastating bacterial infection.

IVIG activates Fc\u03b3RIIB-SHIP1-PIP3 Pathway to stabilize mast cells and suppress inflammation after ICH in mice

Following intracerebral hemorrhage (ICH), the activation of mast cell contributes to brain inflammation and brain injury. The mast cell activation is negatively regulated by an inhibitory IgG-receptor. It’s signals are mediated by SHIP (Src homology 2-containing inositol 5′ phosphatase), in particular SHIP1, which activation leads to hydrolyzation of PIP3 (Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3, leading to the inhibition of calcium mobilization and to the attenuation of mast cell activation. Intravenous immunoglobulin (IVIG) is a FDA-approved drug containing IgG. We hypothesized that IVIG will attenuate the ICH-induced mast cell activation via FcγRIIB/SHIP1 pathway, resulting in a decrease of brain inflammation, protection of the blood-brain-barrier, and improvement of neurological functions after ICH. To prove this hypothesis we employed the ICH collagenase mouse model. We demonstrated that while ICH induced mast cell activation/degranulation, IVIG attenuated post-ICH mast cell activation. Mast cell deactivation resulted in reduced inflammation, consequently attenuating brain edema and improving of neurological functions after ICH. Furthermore using siRNA-induced in vivo knockdown approach we demonstrated that beneficial effects of IVIG were mediated, at least partly, via SHIP1/PIP3 pathway. We conclude that IVIG treatment represents a promising therapeutic approach potentially able to decrease mortality and morbidity after ICH in experimental models.

A Review of the Active Treatments for Toxic Epidermal Necrolysis.

Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction associated with the separation of skin and mucous membranes at the dermal-epidermal junction. Although it is rare, many treatments have been trialed because of its high mortality rate. Active interventions performed to date include the use of systemic corticosteroids, intravenous immunoglobulins (IVIg), cyclosporine, plasmapheresis, anti-tumor necrosis factor drugs and N-acetylcysteine, but none has been established as the most effective therapy. IVIg and short-term high-dose corticosteroids were regarded as the most promising treatments for TEN in a comprehensive review of all reported TEN cases from 1975-2003. When used with an appropriate dose and timing, the beneficial effects of IVIg can be maximized. Although no randomized controlled trials have been conducted, cyclosporine and plasmapheresis are considered to be beneficial. As no gold standard for active intervention for TEN has been established, the choice of treatment relies partly on the available guidelines and the experience of the dermatologist. There is still much to be investigated regarding the pathogenesis of TEN, and new findings may contribute to the identification of an effective active intervention strategy.

Anti-HLA sensitization after kidney allograft nephrectomy: changes one year post-surgery and beneficial effect of intravenous immunoglobulin.

The analysis of anti-HLA sensitization at the time of and following allograft nephrectomy may help clinicians to define better both the indications for nephrectomy and preventive therapeutic strategies. We carried out a retrospective analysis of anti-HLA antibodies in 63 clinically indicated nephrectomies (baseline and three and 12 months after) according to the time elapsed since transplantation (six months) and clinical background. An intervention study included 10 patients without donor-specific antibodies (DSA) at the time of nephrectomy treated with high-dose intravenous immunoglobulin (IVIG) (1.5 g/kg). Early nephrectomies were performed in 15 patients (24%). Among the late nephrectomies, 14 patients (22%) were asymptomatic and 34 (54%) had graft intolerance syndrome (GIS). At baseline, anti-HLA sensitization was significantly lower in the early and late asymptomatic groups than in the GIS group, but increased considerably within the three months following surgery. In the group of 10 patients treated with IVIG, only the number of class I non-DSA increased in the three months after surgery, whereas in the control group (N = 13), all anti-HLA variables increased significantly. All patients undergoing a clinically indicated allograft nephrectomy become highly sensitized within the 12 months after surgery. In patients without DSA before nephrectomy, high doses of IVIG may prevent anti-HLA sensitization.

7thInternational Immunoglobulin Conference: Mechanisms of Action

Although intravenous immunoglobulin (IVIg) is widely used for replacement therapy in immunodeficiencies and to treat autoimmune and inflammatory diseases, its mechanisms of action are not fully understood. Examination of immunoglobulin (Ig) receptors, including the Fc-gamma receptors (FCγRs) and the neonatal Fc receptor, have revealed genetic variations that are linked to autoimmune diseases and to the efficacy of IVIg treatment. However, the beneficial effect of IVIg encompasses multiple mechanisms of action. One of these is scavenging of activated complement fragments, such as C3a, C5a, C3b and C4b, by infused Ig molecules. This interaction prevents binding of complement fragments to their receptors on target cells, thus attenuating the immune damage. Additionally, anti-inflammatory effects may be facilitated by IgA via specific receptors and/or complement scavenging. Glycosylation of both the Fc- and Fab-fragments has also been implicated in the anti-inflammatory action of IVIg. Although there is evidence to support a role for sialylated IgG glycovariants in mediating the effect of IVIg, evidence from animal models of inflammatory disease suggest that sialylation may not be a critical factor. However, an increase in IgG glycosylation has been observed following IVIg treatment in Guillain-Barré syndrome patients, and this has been associated with improved clinical outcomes.

Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin

Several mechanisms account for the beneficial effect of intravenous immunoglobulin (IVIg) in autoimmune and inflammatory diseases. These mechanisms include effects on the cellular compartment and on the humoral compartment. Thus, IVIg impacts on dendritic cells, macrophages, neutrophils, basophils, NK cells, and B and T lymphocytes. Several studies have emphasized that the antiinflammatory effect of IVIg is dependent on α2,6-sialylation of the N-linked glycan on asparagine-297 of the Fc portion of IgG. However, recent reports have questioned the necessity of sialylated Fc and the role of FcγRIIB in IVIg-mediated antiinflammatory effects. In view of the critical role played by Th17 cells in several autoimmune pathologies and the increasing use of IVIg in several of these conditions, by using neuraminidase-treated, desialylated IVIg, we addressed whether the α2,6-sialylation of IgG is essential for the beneficial effect of IVIg in experimental autoimmune encephalomyelitis (EAE), a Th17-driven condition, and for the reciprocal modulation of helper T-cell subsets. We observed no difference in the ability of IVIg to ameliorate EAE irrespective of its sialylation. Our findings thus show that sialylation of IVIg is not necessary for IVIg-mediated amelioration of EAE or for downregulation of Th17 cells and upregulation of regulatory T cells.

Natural Autoantibodies to Fcγ Receptors in Intravenous Immunoglobulins

A considerable progress has been achieved in the comprehension of the cellular and molecular mechanisms that account for the therapeutic benefit of intravenous immunoglobulin (IVIg) in several autoimmune and inflammatory conditions. However, the precise mechanisms responsible for such a wide range of biological activities have not been proven unambiguously. A wide range of specificities have been identified within IVIg including idiotypes of immunoglobulins, T cell receptor, HLA molecules, several cell surface molecules of immunological importance such as CD4, CD5, Fas, BAFF, cytokines and cytokine receptors, chemokine receptors, CD40 among others. Here we identify and characterize the natural autoantibodies of IgG isotype directed against the human Fc receptors. We show that the F(ab')2 of IVIg recognize the FcγRIII (CD16) and FcγRII (CD32). Interestingly, the immunopurified anti-FcγIII and anti-FcγII antibodies isolated from IVIg bind soluble and membrane-bound FcR and inhibit rosette formation. Altogether, these results along with previous reports provide pointers on the existence of functionally relevant natural autoantibodies towards a wide range of self-motifs that may participate in regulation of the immune response. Their presence in the therapeutic immunoglobulin preparations may explain at least in part, the beneficial effect of IVIg in autoimmune diseases.

High-dose intravenous immunoglobulin therapy for eosinophilic granulomatosis with polyangiitis.

BackgroundRegulatory T (Treg) cells are implicated in the development and progression of eosinophilic granulomatosis with polyangiitis (EGPA). We previously showed beneficial effects of intravenous immunoglobulin (IVIG) therapy combined with corticosteroid and immunosuppressant treatment on clinical symptoms, including mononeuritis multiplex and cardiac dysfunction, and Treg cell frequency, during EGPA. Whether the timing of administration (during initial treatment or at relapse after remission) or previous treatment affects the clinical and immunologic efficacy of IVIG is unknown. We evaluated whether the frequency of Treg cells varied depending on when IVIG was provided relative to the start of conventional therapy for EGPA.MethodsThe patient population for this retrospective analysis comprised 17 patients with severe mononeuritis multiplex or heart failure whose EGPA did not respond to corticosteroids combined with immunosuppressant therapy. Ten patients first received IVIG during initial treatment, whereas the remaining 7 patients first received IVIG on relapse after remission. We measured the percentage of Treg cells, defined as FOXP3+CD4+ T cells, present before the first round of IVIG and at 1 month after the last IVIG treatment.ResultsFOXP3+CD4+ T cells were increased in patients who required only a single course of IVIG to achieve remission compared with those who needed two or more courses. The dosage of prednisolone at initial IVIG was inversely correlated with the ratio of the number of FOXP3+CD4+ T cells before IVIG and that at 1 month thereafter.ConclusionPatients with severe EGPA who receive IVIG after nonresponse to high-dose prednisolone during initial treatment may need multiple courses of IVIG to achieve remission. An increase in the frequency of Treg cells after IVIG may predict the need for additional IVIG in EGPA.

Specific Antibody in IV Immunoglobulin for Postsplenectomy Sepsis

Overwhelming postsplenectomy infection progresses rapidly and shows unacceptably high mortality even when treated with optimal antibiotics. Recent reports have described beneficial effects of intravenous immunoglobulin in sepsis. However, the underlying mechanisms, especially the roles of the pathogen-specific antibody fraction in intravenous immunoglobulin, remain unclear. We investigated the effects of intravenous immunoglobulin on overwhelming postsplenectomy infection and the role of pathogen-specific antibody. Prospective, controlled, and randomized animal study. University laboratory. Male C57BL/6JJcl mice. Mice underwent splenectomy or a sham operation at 8 weeks old. At 4 weeks after the operation, mice were injected intravenously with 106 colony-forming units pneumococcus. Intraperitoneal injection of 300 mg/kg IV immunoglobulins was conducted simultaneously with infection. Specific antibody-depleted IV immunoglobulin prepared using immunoprecipitation was also injected into the animals. IV immunoglobulin markedly improved splenectomized mice survival. Removal of pneumococcus-specific antibody canceled it completely. Fluorescence microscopy results indicated significantly increased phagocytosis of antibody-bound bacteria in the livers of splenectomized mice treated with intact IV immunoglobulins. Immunomodulation, including suppression of marginal zone B-cell activation, was induced by IV immunoglobulin. IV immunoglobulin showed a significantly protective effect on overwhelming postsplenectomy infection via enhancement of specific antibody-mediated phagocytosis in the liver. Specific antibody, more than immunological modulation, is crucial for effects of IV immunoglobulin on overwhelming postsplenectomy infection.

Intravenous Immunoglobulin Treatment Increased Live Birth Rate in a Spanish Cohort of Women with Recurrent Reproductive Failure and Expanded CD56+ Cells

Natural killer (NK, CD3(-)CD56(+)/CD16(+)) and NKT-like cells (CD3(+)CD56(+)/CD16(+)) activity is considered among the key factors for reproductive success. In the absence of immunological screening, beneficial effects of intravenous immunoglobulin (IVIG) in preventing recurrent reproductive failure (RRF) have not been reported. Here, we analyse the IVIG influence on pregnancy success in women with RRF and circulating NK or/and NKT-like cells expansion. One hundred fifty-seven women with previous recurrent miscarriage and/or recurrent implantation failure after in vitro fertilization were consecutively studied. Sixty-four patients with CD56(+) cell expansion, no apparent underlying disease and who maintained their desire to conceive were selected. Forty of them received IVIG during pregnancy. Overall, the clinical pregnancy rate for the women under IVIG therapy was 92.5% and the live birth rate was 82.5%. Significantly lower pregnancy and live birth rates (25% and 12.5%, respectively) were observed for the patients with recurrent pregnancy loss and NK/NKT-like cells expansion without IVIG. After three cycles of IVIG, NK cell percentages decreased significantly and these values persisted throughout gestation. Intravenous immunoglobulin therapy for women with RRF and NK or NKT-like cell expansion was a safe and beneficial therapeutic strategy that associated with high clinical pregnancy and live birth rates.

Complement‐derived anaphylatoxin, C5a‐mediated signaling pathway is a novel pharmacological target for IVIG‐regulated humoral immunotherapy in Alzheimer's Disease

Human intravenous immunoglobulin (IVIG) has been found to benefit patients with Alzheimer's disease (AD) and other neurodegenerative diseases. According to a common hypothesis, IVIG contains naturally occurring auto antibodies that block the toxic effects of β‐amyloid (Aβ) and promote brain Aβ clearance. However, with the discrepancy between Aβ pathology in postmortem AD brains and the severity of clinical dementia in the elderly, the beneficial effects of IVIG may extend beyond Aβ clearance. We hypothesized that elevated brain levels of complement C5‐derived C5a anaphylatoxins play a crucial role in the regulation of signaling pathways related to learning and memory functions, which contribute to successful aging, and that human intravenous immunoglobulin may have beneficial effects on cognitive function in age‐related dementia by modulating C5a expression in the brain. Our studies show that the levels of C5a are decreased in C57BL6 mice (24–28 month old), and that reduced brain C5a content is correlated with a decline in cognitive function. Most importantly, four weeks of treatment with IVIG in TG2576 mice significantly increased the level of C5a in the brain and improved synaptic plasticity. Given the high safety of IVIG in clinical practice over the past decade and the lack of effective AD therapy, our study would provide novel mechanisms in AD treatment for the elderly.Supported by unrestricted grant to GMP

Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systematic literature review

The objectives of this study are to review and summarize published information on the use, effectiveness, and adverse effects of intravenous immunoglobulin (IVIG) in patients with polymyositis (PM) or dermatomyositis (DM) and to search MEDLINE and CNKI (Chinese) databases from 1985 to 2011 to retrieve clinical research articles concerning IVIG in adult patients with PM/DM. Of the 14 articles selected, two were randomized controlled trials, nine prospective open studies, and three retrospective studies with a total of 308 adult patients. IVIG has been used successfully in the treatment of PM/DM. The standard dose is 2 g/kg, given in two to five individual daily doses. The course of IVIG treatment is usually 3~6 months. IVIG therapy seemed rarely employed as first-line therapy in PM/DM. In a double-blind study conducted in patients with refractory DM, IVIG combined with corticosteroid significantly improved muscle strength and decreased serum creatine kinase level, compared with placebo. The beneficial effect of IVIG in refractory, flare-up, rapidly progressive, or severe PM/DM has been documented in many open-label trials. IVIG was shown to be effective in most of PM/DM patients with lung involvement and esophageal involvement. In some patients, IVIG can lower the corticosteroid dose required for maintenance, demonstrating the most effective steroid-sparing effect. Adverse effects were generally tolerable. IVIG is effective in the treatment of adult patients with PM/DM and appears to be relatively well tolerated and safe. IVIG may be a good choice especially in patients with refractory, flare-up, rapidly progressive, or severe PM/DM, and can be tried in patients with a contraindication for corticosteroid.

Intravenous immunoglobulin suppresses IL-10 production by activated B cells in vitro

A therapeutic preparation of polyclonal human IgG, i.e., intravenous immunoglobulin (IVIg), has been employed to treat several inflammatory and autoimmune disorders. B cells are supposed to be a target of IVIg, but the molecular mechanism is elusive because of the lack of a suitable experimental system. To gain an insight into the beneficial effect of IVIg on B cells, we first established an experimental setting in which IVIg modulates a murine B cell function in vitro, and then aimed at identifying the mechanistic features at the molecular level. Here we show that IVIg down-regulates IL-10 production by CpG-activated B cells in vitro. The responsible component of IVIg was identified as the F(ab’)2 portion, whose polyclonality is mandatory for the suppressive effect. IVIg, bound to the surface of activated B cells, was found to be co-localized with intracellular SHP-1 on confocal laser microscopy, suggesting that B cell-surface immunoreceptor tyrosine-based inhibitory motif-harboring receptors that recruit SHP-1 are target molecules for IVIg in our experimental setting. Overall, we postulate a scenario in which IVIg attenuates B cells by suppressing IL-10 production, a B cell growth factor, and thus down-regulates the production of pathogenic antibodies.

A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage

To estimate whether intravenous immunoglobulin (IVIG) improves the probability of a live birth in women with unexplained recurrent miscarriage (RM). A computerized search in Medline, Embase, Central, Ovid Medline In-Process, and Other Non-Indexed Citations Databases and randomized controlled trial (RCT) registries was performed. Abstracts of the American Society of Reproductive Medicine and European Society of Human Reproduction and Embryology annual meetings and reference lists of identified reports were searched. None. Women with unexplained primary (without a prior live birth) or secondary (subsequent to a live birth) RM. IVIG or placebo control intervention. Live birth rate per randomized woman. Six relevant RCTs were identified including 272 women with unexplained RM. The overall odds ratio for live birth is 0.92, with a 95% confidence interval of 0.55-1.54, indicating a lack of a treatment effect with IVIG. Similarly, IVIG was not found to be beneficial when women with primary and secondary RM were analyzed separately. A beneficial effect of IVIG in treatment of RM was not observed. Given the absence of a proven mechanism of action, and the lack of a diagnostic algorithm to identify patients who are likely to benefit from such treatment, IVIG administration for treatment of recurrent miscarriage is not justified outside the context of properly designed RCTs.

Plasma exchange and intravenous immunoglobulins: Mechanism of action in immune-mediated neuropathies

Immune-mediated neuropathies are a heterogeneous group of peripheral nerve disorders, which are classified by time course, clinical pattern, affected nerves and pathological features. Plasma exchange (PE) and intravenous immunoglobulins (IVIg) are mainstays in the treatment of immune-mediated neuropathies. Of all treatments currently used, IVIg has probably the widest application range in immune-mediated neuropathies and efficacy has been well documented in several randomized controlled trials for Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). Beneficial effects of IVIg have also been proven for multifocal motor neuropathy (MMN). Likewise, PE is an established treatment for GBS and CIDP, whereas it is considered to be ineffective in MMN. Different mechanisms of action are sought to be responsible for the immunemodulatory effect of PE and IVIg in autoimmune disorders. Some of those might be important for immune-mediated neuropathies, while others are probably negligible. The aim of this review is to summarize the recent advances in elucidating disease-specific mechanisms of actions of PE and IVIg in the treatment of immune-mediated neuropathies.

IVIg inhibits classical pathway activity and anti-GM1 IgM-mediated complement deposition in MMN

The effects of intravenous immunoglobulins (IVIg) on anti-GM1 IgM titer and function, classical complement pathway activity, and antibody–complement interaction were investigated in 62 patients with multifocal motor neuropathy (MMN). In vitro, IVIg decreased complement deposition by anti-GM1 IgM antibodies. First IVIg treatment (2 g/kg) decreased C1q and C4 concentrations and classical pathway activity in serum. In sera from patients receiving IVIg maintenance therapy (0.4 g/kg) C4 concentrations and classical pathway activity were generally lower at higher IgG concentrations. The beneficial effects of IVIg in MMN may be explained by reduced antibody-mediated complement deposition in nerves amplified by a systemically attenuated classical pathway.