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International audience; Monoclonal gammopathies of renal significance (MGRS) encompass a remarkable variety of kidney diseases that result from intrinsic nephrotoxic properties of certain monoclonal Igs or their subunits. Effective disease-modifying treatments rely on the targeting of a malignant B-cell clone that may be demonstrable but often is quite hypothetical. Hence, convincing arguments for the genuine monoclonal character of the causative mono-isotypic Ig tissue deposits is needed for design of appropriate treatment strategies. The purpose of this article was to critically analyze distinct situations of suspected MGRS that occur in the practice of pathologists, nephrologists, hematologists, and immunologists. A particular focus of interest is the group of conditions known as proliferative glomerulonephritis with mono-isotypic immunoglobulin deposits (PGNMIDs), which illustrates the difficulties and ambiguities surrounding a definitive assignment of MGRS status.

Recent Advancements in Hematology: Knowledge, Methods and Dissemination is a series of editorials which is published on a biannual basis by the editorial board of the journal Bloods [...]

IgG4-Related Disease (IgG4-RD) results from tissue infiltration by IgG4-expressing plasma cells and lymphocytes, leading to fibrosis and organomegaly. Clinical presentation is remarkably variable according to organ involvement, and high IgG4 serum concentration, initially considered a diagnostic hallmark of IgG4-RD, tends to be forgone as an indispensable criterion for its diagnosis; it can indeed be absent in some patients, highlighting the diversity of presentation of this dysimmune condition. Nevertheless, elevation of IgG4 serum concentration in suggestive settings remains an argument in favour of IgG4-RD, and while other IgG subclasses can be elevated, this biological feature lacks any diagnostic value. We retrospectively studied 9 patients (5 females, 4 males, 31-81 years old) for whom a diagnosis of IgG4-RD had been considered, based on clinical, imaging or histological criteria, but appeared to display abnormally high serum IgG2 while IgG4 levels were normal. Increased serum IgG1 in one case and increased IgG3 in another one were also noticed. Immunohistochemical analyses of intracellular immunoglobulins could be performed on tissue lymph node biopsies from 2 patients, which demonstrated strong infiltration with IgG2-expressing plasma cells. Thus, overexpression of IgG2 subclass may highlight cases of dysimmune disorders resembling IgG4-RD, although the disease trigger might be different, notably infectious. We suggest measuring all serum IgG subclass levels in patients with features consistent with IgG4-RD.

International audience; No abstract available

The mechanical obstruction of cerebrospinal fluid (CSF) flow can lead to very high hyperproteinorachia. In myeloma, tumoral clivus obstruction can cause such high proteinorachia, associated with paraprotein detection in the CSF in absence of intrathecal synthesis.

International audience; PURPOSE:To better characterize IgG4-related disease (RD) in the setting of idiopathic orbital inflammation syndrome (IOIS).METHODS:National, multicentre, prospective, observational cohort study. Among the patients consecutively included in the French multicentre SIOI cohort, we selected those who underwent orbital and/or adnexal biopsy. Clinical, morphological and pathological findings at diagnosis were blindly analysed. Serum IgG4 levels at inclusion were measured and all available biopsy specimens were immunostained for IgG4 and IgG. Biopsy samples with more than 10 IgG4-positive plasma cells per high-power field and a IgG4+/IgG+ plasma cell ratio above 40% were scored as positive. IgG4-positive patients were then screened for comprehensive diagnostic criteria for IgG4-RD.RESULTS:Of the 87 patients included, 35 had histologically documented IOIS. Thirteen patients (37%) with a mean age at onset of 27 years (range 21-78) had IgG4-positive biopsies, among which 10 patients (77%) and 3 (23%, with IgG4 serum levels >1.35 g/L) were considered as having probable and definite IgG4-RD, respectively. The latter 13 patients more frequently fulfilled histological criteria for IgG4-RD (including plasmacytic infiltrate (p = 0.006), fibrosis (p = 0.0025) and periphlebitis (p = 0.075)) than IgG4-negative patients. Storiform fibrosis was exclusively found in orbital tissues from IgG4-positive patients (n = 3, 23%). Eosinophilia associated with recurrent sinusitis or asthma was a prominent feature in patients with definite IgG4-RD.CONCLUSIONS:More than one-third of patients with biopsy-proven IOIS satisfied criteria for IgG4-RD, but only a few had a definite type.

International audience; Background: Scleromyxedema (SME) is a rare mucinosis associated with monoclonal gammopathy. Several biochemical peculiarities of monoclonal immunoglobulins (Ig) in SME patients were reported in case reports or short series, such as IgGλ over-representation, cationic migration, and partial deletion. Methods: Monoclonal immunoglobulins (Ig) from the serum of 12 consecutive patients diagnosed with scleromyxedema (SME) were analyzed using electrophoretic and immunoblotting techniques. Results: All monoclonal Ig from 12 SME were of IgG1 subclass, with an overrepresentation of the lambda-type light chain and a cationic mobility on standard zone electrophoresis, as compared with 21 cases of monoclonal gammopathy of undetermined significance (MGUS) of IgG1 subclass. Reactivity with specific monoclonal antibodies demonstrated no evident deletion of the heavy chain constant domains, which was also confirmed by analysis of Ig heavy chain molecular weight on a purified monoclonal component from one case. Conclusions: Significant isotype restriction of both heavy and light chains, and peculiar biochemical properties suggest that monoclonal Ig might be involved in pathophysiological events of SME.

International audience; Systemic lupus erythematosus (SLE) patients are at risk for pneumococcal infection. Twenty-one consecutive SLE patients (40[25-75] years) received the sequential PCV13/PPSV23 vaccine and factors associated with long-term protection were analyzed. Immune protection, defined by an antigen-specific IgG concentration ≥1.3 µg/mL for at least 70% of 7 pneumococcal serotypes was assessed at baseline, 2, 6, 12 and 36 months defining long-term protection. Only 10 patients showed pneumococcal immune protection 36 months after vaccination. Eleven (52.4%) patients had no long-term protection with a seroconversion that never or only transiently occurred. SLE disease features, treatment received and immunological characteristics did not differ between protected and unprotected patients except for the pre-vaccination IgG2 serum levels. Serum IgG2 level >2.125 µg/ml showed a sensitivity of 100% and a specificity of 90.9% for long-term protection. Sequential pneumococcal vaccination conferred poor immune protection in SLE. Baseline IgG2 serum level identified patients able to benefit from pneumococcal vaccination.

ObjectiveTo study blood anti-Aβ antibodies in the context of spontaneous inflammatory or hemorrhagic CAA manifestations, which are similar to complications occurring after monoclonal anti-Aβ antibody immunotherapies.MethodsIn this case-control study, serum anti-Aβ antibody isotype, concentration, avidity, and reactivity toward soluble or fibrillary Aβ1-40 and Aβ1-42 isoforms were assessed using an ELISA-based multiplex analysis. Anti-Aβ serologic patterns were defined in CAA and CAA subgroups using multivariable logistic regression analyses.ResultsFourty-one healthy aged controls and 64 CAA patients were recruited: 46 with hemorrhagic features (CAA-he) and 18 with CAA-related inflammation (CAA-ri). As compared to controls, the most striking features of CAA-related serological profiles were the following: i) both CAA-he and CAA-ri patients displayed lower binding diversity of anti-soluble Aβ1-40 IgM; ii) CAA-he patients displayed higher anti-soluble Aβ1-40 / fibrillary Aβ1-42 IgG4 concentrations ratio and higher anti-soluble Aβ1-42 IgG4 and IgA avidity; iii) CAA-ri patients displayed higher binding diversity of anti-soluble Aβ1-40 IgG3 and higher anti-fibrillary/soluble Aβ1-42 IgG4 dilution curve steepness ratio.ConclusionThis proof-of-concept study revealed anti-Aβ antibody variations in CAA patients, some of which were associated to CAA clinical phenotypes, unveiling pathophysiological insights regarding CAA-hemorrhagic and inflammatory related events.

International audience; Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French, multicenter, retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an IgG isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4/33 patients (12%) (smoldering myeloma, n=2; chronic lymphoid leukemia, n=1; and refractory cytopenia with multilineage dysplasia n=1). Carpal tunnel syndrome (33%), arthralgia (25%) and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. Intravenous immunoglobulin (HDIVig) treatment alone or in combination with steroids appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig-refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4/5 patients. Quantitative reverse transcriptase-PCR (RT-PCR) analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor β (TGFβ) and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management.

Objective Recent studies have underlined the effect of systemic inflammation on the pathophysiology of Alzheimer's disease (AD). Neutrophils are key components of early innate immunity and contribute to uncontrolled systemic inflammation if not tightly regulated. The aim of our study was to fully characterize human circulating neutrophils at different disease stages in AD. Methods We analyzed neutrophil phenotypes and functions in 42 patients with AD (16 with mild cognitive impairment and 26 with dementia), and compared them to 22 age-matched healthy subjects. This study was performed directly in whole blood to avoid issues with data interpretation related to cell isolation procedures. Results Blood samples from AD patients with dementia revealed neutrophil hyperactivation associated with increased reactive oxygen species production and increased levels of intravascular neutrophil extravascular traps. The homeostasis of circulating neutrophils in these patients also changed: The ratio between the harmful hyperreactive CXCR4high /CD62Llow senescent and the CD16bright /CD62Ldim immunosuppressive neutrophil subsets rose in the later stage of the disease. These abnormalities were greater in fast-decliner than in slow-decliner patients. Interpretation Our results indicate that the inflammatory properties of circulating neutrophils shift as the percentage of aged neutrophils expands in patients with AD-changes that may play an instrumental role in establishing systemic chronic inflammation. Most important, our data strongly suggest that the neutrophil phenotype may be associated with the rate of cognitive decline and may thus constitute an innovative and prognostic blood biomarker in patients with AD. Ann Neurol 2018;83:387-405.

Introduction Les patients atteints de lupus systemique sont a haut risque d’infection invasive a pneumocoque. La vaccination anti-pneumococcique sequentiel (i.e. vaccin conjugue 13-valents (VPC13) puis vaccin polysaccharidique 23-valents (VPP23)) est recommandee chez ces patients. L’objectif de ce travail etait d’analyser le taux de protection anti-pneumococcique induite a long terme par cette strategie vaccinale et d’identifier les facteurs associes a la protection. Patients et methodes Conformement aux recommandations la vaccination anti-pneumococcique etait proposee a tous les patients suivis pour un lupus systemique admis de facon consecutive dans notre unite d’hospitalisation de jour (HDJ) entre avril et decembre 2015. Les patients recevaient le vaccin VPC13 puis le vaccin VPP23 8 semaines apres. La protection immune anti-pneumocoque, definie par un titre d’IgG specifique ≥ 1.3 μg/ml pour au moins 70 % des 7 serotypes pneumococciques (4, 6B, 9 V, 14, 18 C, 19F, 23F), etait evaluee avant la premiere injection vaccinale puis a 2 mois, 6 mois, 12 mois, et 36 mois, definissant la protection a long terme. Resultats La vaccination anti-pneumococcique etait proposee a 37 patients suivis pour un lupus. Parmi ceux-ci, 8 ont refuse la vaccination, 7 ont accepte la vaccination mais ont refuse le monitoring de la reponse immune et 1 etait deja vaccine. Vingt et-un patients lupiques (40 [25–75] ans ; 85,7 % femmes) ont finalement recu les vaccins VPC13/VPP23 dans le cadre de cette etude. Seulement 10 (47,6 %) patients avaient une protection immune anti-pneumococcique persistante 36 mois apres la vaccination (protection a long terme, LTP). Onze patients n’avaient pas de protection a long terme (NLTP), avec une seroconversion qui n’apparaissait jamais (n = 6) ou transitoirement (n = 5). Les caracteristiques cliniques et immunologiques ainsi que les traitements recus n’etaient pas differents entre les patients proteges et non proteges a la seule exception des taux d’IgG2 seriques avant la premiere injection vaccinale qui etaient significativement plus bas dans le groupe NLTP (1,45 [1,30–1,82] vs 3,30 [2,92–4,44] g/L, p Conclusion Le benefice de la vaccination anti-pneumococcique sequentielle VPC13/VPP23 dans le lupus systemique est limite. Les taux seriques d’IgG2 avant la vaccination identifient les patients beneficiant ou non d’une protection post vaccinale a long terme.

Background:Systemic lupus erythematosus (SLE) patients are at increased risk forStreptococcus pneumoniaeinfection. Although pneumococcal vaccination is an attractive method to prevent invasive pneumococcal infection, vaccination coverage remains dramatically low in SLE. Moreover, the efficacy of vaccination may be reduced in SLE patients and sequential pneumococcal vaccination using new conjugated pneumococcal vaccines in combination with 23-valent pneumococcal polysaccharide vaccine (PPV23) is now advocated. However, limited study directly addressed the immune efficacy of such prime-and-boost strategy in SLEObjectives:We aimed to measure the immunological efficacy of the sequential pneumococcal vaccination using PCV13 in combination with PPV23 and identify factors associated with long-term immune protection following vaccination in SLE.Methods:SLE patients received PCV13 vaccine followed by PPSV23 vaccine 8 weeks later. Immune protection, defined by an antigen-specific IgG concentration ≥ 1.3 µg/mL for at least 70% of 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F), was assessed at baseline, 2 months, 12 months, and 36 months, defining very long-term protection.Results:21 (40[25-75] years; 85.7% female) SLE patients received the sequential PCV13/PPV23 vaccines. Only 10 (47.6%) showed a sustained immune protection against pneumococcal infection 36 months after PCV13 shot (very long-term protected, VLTP). Eleven patients had no long-term protection (NLTP) with a seroconversion that never (n=6) or only transiently (n=5) occurred. SLE disease features, treatment received and immunological characteristic did not differ between VLTP and NLTP patients except for a lower serum IgG2 levels in NLTP (1.45 [1.30, 1.82] vs 3.30 [2.92, 4.44] g/L, pConclusion:The benefit of sequential PCV13/PPV23 vaccination in SLE is limited. Baseline IgG2 serum level before vaccination is strongly indicative of very long term protection following vaccinationDisclosure of Interests:None declared

BACKGROUND: While different clinical manifestations of IgM and IgG monoclonal cryoglobulins have been demonstrated, little is known about the roles of IgG subclasses in the pathophysiology of these conditions. METHODS: In two cases of myeloma-associated monoclonal (type I) cryoglobulinemia with quite distinct clinical and biological features, serum samples were analyzed using an original IgG subclass-specific immunoblotting technique. RESULTS: The first case had painful arthritis of hands and feet, with skin purpura and a sharp decrease of complement C4 level, and the cryoglobulin was of IgG1 subclass. The second case displayed mostly thrombotic lesions of the limb extremities, C3 and C4 serum levels were normal, and the cryoglobulin belonged to the IgG2 subclass. CONCLUSIONS: Type I cryoglobulins of distinct IgG subclasses may result in different syndromes. In both cases, the treatment relies on eradication of the underlying plasma cell dyscrasia.

Although patients with systemic lupus erythematosus (SLE) are at increased risk for Streptococcus pneumoniae infection,1 2 vaccination coverage remains dramatically low in SLE,3 and efficacy of the now recommended prime-and-boost strategy using 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) is not known. Consecutive patients with SLE admitted in our daycare hospital unit were prospectively enrolled to receive PCV13 followed by PPSV23 8 weeks later. Immune protection, defined by an antigen-specific IgG concentration ≥1.3 µg/mL for at least 70% of seven pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F and 23F), was assessed at baseline, 2 and 12 months. Patients were defined as ‘long-term protected (LTP)’ when seroconversion was observed 2 months and 12 months after PCV13 shot. Patients were considered ‘short-term protected (STP)’ when seroconversion was observed 2 months but no more at 12 months after PCV13 shot. Patients were ‘not protected (NP)’ when seroconversion occurred neither 2 months nor 12 months after PCV13 shot. Laboratory tests included the analysis of blood …

Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by tissue deposition of a truncated monoclonal immunoglobulin heavy chain lacking the first constant domain. Pathophysiological mechanisms are unclear and management remains to be defined. Here we retrospectively studied 15 patients with biopsy-proven HCDD of whom 14 presented with stage 3 or higher chronic kidney disease, with nephrotic syndrome in 9. Renal lesions were characterized by nodular glomerulosclerosis, with linear peritubular and glomerular deposits of γ-heavy chain in 12 patients or α-heavy chain in 3 patients, without concurrent light chain staining. Only 2 patients had symptomatic myeloma. By serum protein electrophoresis/immunofixation, 13 patients had detectable monoclonal gammopathy. However, none of these techniques allowed detection of the nephrotoxic truncated heavy chain, which was achieved by immunoblot and/or bone marrow heavy chain sequencing in 14 of 15 patients. Serum-free kappa to lambda light chain ratio was abnormal in 11 of 11 patients so examined. Immunofluorescence studies of bone marrow plasma cells showed coexpression of the pathogenic heavy chain with light chain matching the abnormal serum-free light chain in all 3 tested patients. Heavy chain sequencing showed first constant domain deletion in 11 of 11 patients, with high isoelectric point values of the variable domain in 10 of 11 patients. All patients received chemotherapy, including bortezomib in 10 cases. Renal parameters improved in 11 patients who achieved a hematological response, as assessed by normalization of the free light chain ratio in 8 cases. Tissue deposition in HCDD relates to physicochemical peculiarities of both variable and constant heavy chain domains. Early diagnosis and treatment with bortezomib-based combinations appear important to preserve renal prognosis. Thus, monitoring of serum-free light chain is an indirect but useful method to evaluate the hematological response.

Introduction Depuis 2013, le Haut Conseil de la Sante publique recommande que les patients traites par immunosuppresseur, biotherapie et/ou corticotherapie pour un lupus systemique (LS) soient systematiquement vaccines contre le pneumocoque. Le schema vaccinal propose est une dose de vaccin conjugue 13-valent (PCV13-PREVENAR) suivie, deux mois plus tard, d’une dose de vaccin non conjugue polysaccharidique 23-valent (PPV23-PNEUMO 23). Il n’y a toutefois aucune donnee publiee sur l’immunogenicite de ce schema dans cette population. L’objectif de cette etude est de mesurer la reponse vaccinale 2 et 12 mois apres une vaccination sequentielle par PCV13/PPV23 et analyser les determinants cliniques et immunologiques associes a la protection vaccinale anti-pneumococcique chez les sujets lupiques. Patients et methodes Cette etude monocentrique observationnelle non controlee a ete realisee d’avril a decembre 2015 dans 1 service de medecine interne (Paris). La vaccination anti-pneumococcique et le suivi de la reponse immune sur 12 mois ont ete proposes a tous les patients lupiques admis en hopital de jour (HDJ) pour le suivi de leur maladie et candidats a la vaccination. Les donnees cliniques et biologiques etaient collectees et le taux d’anticorps anti-pneumococcique (Elisa) etait mesure a m0, m2 et m12. Etait exclu tout patient en poussee de LS, ayant recu une injection de rituximab durant l’annee precedente ou ayant ete deja vaccine contre le pneumocoque. La protection vaccinale etait definie par une concentration d’IgG ≥ 1,3 μg/mL pour au moins 70 % des 7 serotypes pneumococciques (4, 6B, 9V, 14, 18C, 19F, 23F) testes. Les patients etaient dit « proteges a long terme » (PLT) si la protection vaccinale etait observee a m2 et m12, « proteges a court terme » (PCT) si la protection etait observee a m2 mais perdue a m12, et « non proteges » (NP) si aucune protection vaccinale n’etait observee a m2 et m12. Resultats Au total, 37 patients lupiques candidats a la vaccination anti-pneumococcique conformement aux recommandations ont ete admis en HDJ pour le suivi habituel de leur maladie sur la periode consideree. Parmi eux, 8 patients ont refuse la vaccination, 7 ont accepte la vaccination mais, ont refuse le suivi immunologique et 1 etait deja vaccine contre le pneumocoque. Vingt et un patients (40 [25–75] ans ; 85,7 % femme ; SELENA-SLEDAI score a 1 [0–4]) ont ete inclus. La duree mediane du LS etait de 11 [1–32] ans. Tous les patients avaient recu une corticotherapie pendant une duree mediane de 2 ans [0,5–13] et 12 (57,1 %) etaient toujours sous corticoides a la dose quotidienne de 10 mg [7–15] a l’inclusion. Quinze patients (71,4 %) avaient recu un immunosuppresseur pendant 3 ans [1–14] et 9 (42,9 %) etaient toujours traites. Trois (14,3 %) patients avaient presente une infection a pneumocoque documentee. A m0, aucun patient n’etait protege contre le pneumocoque. La protection etait retrouvee chez 17 (81 %) patients deux mois apres l’injection de PCV13 (M2), mais n’etait plus presente que chez 12 (57,1 %) patients a m12 (PLT, n = 12 et PCT, n = 5). Chez 4 patients, aucune protection n’etait observee a m2 et m12 (NP, n = 4). Les criteres cliniques consideres (âge, duree de la maladie, traitement, duree cumulee des traitements, SLENA-SLEDAI) ne permettaient pas de differencier les patients PLT, PCT et NP. Un taux faible de lymphocytes B naifs, memoires et memoires switches, un taux faible de lymphocytes T CD4+ et une hypogammaglobulinemie Conclusion Pres de la moitie des patients lupiques vaccines contre le pneumocoque conformement aux recommandations (PCV13/PPV23) n’ont pas de reponse protectrice a m12. Un taux faible de lymphocytes B et T CD4+, une hypogammaglobulinemie profonde et un faible titre d’IgG dirigee contre le serotype 19F a m2 de la 1re injection vaccinale (PCV13) sont associes a l’absence de protection.

International audience; Results of Phase III studies involving a large number of Alzheimer's disease (AD) patients treated by passive immunotherapy with humanized anti-amyloid β monoclonal antibodies have recently been released. These approaches failed to show a significant clinical benefit in patients with mild to moderate AD. The most considered explanation is that the patients have been treated too late. Whereas targeting patients at asymptomatic stages of the disease is a critical step in the goal of improving the efficacy of such antibody-based strategies, several other important factors should be considered in the development and clinical evaluation of anti-amyloid β immunotherapies, including the as yet poorly understood relationship of AD with the immune system and the importance of cerebral amyloid angiopathy. Better understanding the role of immune responses in AD and their impact on immunotherapy appears essential in the design of alternative or combinatorial immunotherapy approaches in AD, which may imply effectors other than antibodies and even additional antigenic targets.

Ig-related renal diseases occurring in lymphoplasmacytic disorders (LPD) cover a wide spectrum of renal lesions. Except for cast nephropathy, which is almost specific for multiple myeloma, similar renal lesions caused by deposition or precipitation of monoclonal Ig-related material may occur in the various types of LPD. Because the secreted Ig provides the link between the LPD and the kidney disease, the renal outcome is linked to efficacy of chemotherapy. In the past 10 years, considerable advances have occurred in chemotherapy regimens with the advent of new classes of drugs, which already result in markedly improved renal and vital survival.

Prion diseases are caused by the transconformation of a normal cellular protein, PrPc, into an infectious isoform, PrPsc, which ultimately triggers neuronal death. They are always fatal and, after transmission, they feature long incubation periods, during which prions accumulate in lymphoid tissues, infect nerves and progress to the central nervous system. In lymphoid organs, prions replicate and accumulate in follicular dendritic cells. Suppressing these cells slows down the neuro-invasion but does not totally abrogate it. This review examines the current knowledge in the roles of hematopoietic dendritic cells at different steps of the pathogenesis of prion diseases. Dendritic cells endocytose inoculated prions, permit their crossing of the intestinal epithelium and then migrate and transport them to lymphoid organs. They can carry prions to sites of neuroinvasion, and establish contacts with axons in peripheral lymph nodes or even after passage of the blood-brain barrier. However, results in the literature on the role of dendritic cells differ according to the host or the prion strain.

A 62-year-old woman presented with nephrotic syndrome, monoclonal gammopathy, and membranous-like nephropathy with nonorganized deposits composed of monoisotypic immunoglobulin G1 lambda protein. Nephrotic syndrome remitted after a brief course of treatment with melphalan despite ongoing production of the monoclonal protein. The circulating monoclonal immunoglobulin G1 lambda showed unusual in vitro aggregation properties, including dependence on low ionic strength and neutral pH, suggesting that electrostatic interactions had a role in the precipitation process. This case illustrates the importance of looking for monoclonal immunoglobulin deposits when kidney biopsy findings are suggestive of membranous nephropathy. In addition, our in vitro demonstrations of the role of physicochemical factors in immunoglobulin precipitation help elucidate the pathogenesis of immunoglobulin deposition disorders. Although binding to podocyte antigens is a well-recognized determinant of subepithelial immunoglobulin deposition, proneness to aggregation as described in this case also might be nephritogenic.

There is to date no effective way of preventing or curing neurodegenerative diseases such as Alzheimer disease or transmissible spongiform encephalopathies. The idea of treating those conditions by immunological approaches has progressively emerged over the last ten years. Encouraging results have been reported in Alzheimer disease and in peripheral forms of mouse prion diseases following passive injection of Abs or active immunization against the peptides or proteins presumably at the origin of those disorders. Still, major difficulties persist due to some characteristics of those conditions such as slow evolution, brain location, uncertainties regarding precise pathogenic pathways, and, above all, the fact that the target Ag is self, meaning that it is poorly immunogenic and potentially harmful if tolerance was transgressed. To analyze some of those difficulties, we are developing adoptive cell transfer approaches. In this study, lymphocytes sensitized against the prion protein in nontolerant Prnp−/− mice were transferred into histocompatible wild-type recipients which were partly or totally devoid of their own lymphocytes. Under such conditions, we found that the engrafted T lymphocytes resisted peripheral tolerance, remained reactive for several months against epitopes of the prion protein, and significantly attenuated the progression of prions in secondary lymphoid organs with subsequent delay in the evolution of the neurological disease. Interestingly, those protective T lymphocytes secreted lymphokines and migrated more readily into the host CNS but did not appear to be engaged in cooperation with host B cells for Ab production.

Following oral exposure, some transmissible spongiform encephalopathy (TSE) agents accumulate first upon follicular dendritic cells (DCs) in the GALT. Studies in mice have shown that TSE agent accumulation in the GALT, in particular the Peyer’s patches, is obligatory for the efficient transmission of disease to the brain. However, the mechanism through which TSE agents are initially conveyed from the gut lumen to the GALT is not known. Studies have implicated migratory hemopoietic DCs in this process, but direct demonstration of their involvement in vivo is lacking. In this study, we have investigated the contribution of CD11c+ DCs in scrapie agent neuroinvasion through use of CD11c-diptheria toxin receptor-transgenic mice in which CD11c+ DCs can be specifically and transiently depleted. Using two distinct scrapie agent strains (ME7 and 139A scrapie agents), we show that when CD11c+ DCs were transiently depleted in the GALT and spleen before oral exposure, early agent accumulation in these tissues was blocked. In addition, CD11c+ cell depletion reduced susceptibility to oral scrapie challenge indicating that TSE agent neuroinvasion from the GALT was impaired. In conclusion, these data demonstrate that migratory CD11c+ DCs play a key role in the translocation of the scrapie agent from the gut lumen to the GALT from which neuroinvasion subsequently occurs.

Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloid-β peptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+) T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease.

8 pages; Light-, light- and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light- and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly kappa, and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression.

Expression of the physiological cellular prion protein (PrPC) is remarkably regulated during differentiation and activation of cells of the immune system. Among these, dendritic cells (DCs) display particularly high levels of membrane PrPC, which increase upon maturation, in parallel with that of molecules involved in Ag presentation to T cells. Freshly isolated mouse Langerhans cells, dermal DCs, and DCs from thymus, spleen, and mesenteric lymph nodes expressed low to intermediate levels of PrPC. Highest levels of both PrPC and MHC class II molecules were displayed by lymph node CD8αint DCs, which represent fully mature cells having migrated from peripheral tissues. Maturation induced by overnight culture resulted in increased levels of surface PrPC, as did in vivo DC activation by bacterial LPS. Studies on Fms-like tyrosine kinase 3 ligand bone marrow-differentiated B220− DCs confirmed that PrPC expression followed that of MHC class II and costimulatory molecules, and correlated with IL-12 production in response to TLR-9 engagement by CpG. However, at variance with conventional DCs, B220+ plasmacytoid DCs isolated from the spleen, or in vitro differentiated, did not significantly express PrPC, both before and after activation by TLR-9 engagement. PrP knockout mice displayed higher numbers of spleen CD8α+ DCs, but no significant differences in their maturation response to stimulation through TLR-4 and TLR-9 were noticed. Results are discussed in relation to the functional relevance of PrPC expression by DCs in the induction of T cell responses, and to the pathophysiology of prion diseases.

Macrophages and dendritic cells (DCs) are crucial for immune and inflammatory responses and belong to a network of cells that has been termed the mononuclear phagocyte system (MPS). However, the origin and lineage of these cells remain poorly understood. Here, we describe the isolation and clonal analysis of a mouse bone marrow progenitor that is specific for monocytes, several macrophage subsets, and resident spleen DCs in vivo. It was also possible to recapitulate this differentiation in vitro by using treatment with the cytokines macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Thus, macrophages and DCs appear to renew from a common progenitor, providing a cellular and molecular basis for the concept of the MPS.

International audience; BACKGROUND: Fibrillary glomerulonephritis (GN) is a rare disorder with poor renal prognosis. Therapeutic strategies, particularly the use of immunosuppressive drugs, are debated. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 27 adults with fibrillary GN referred to 15 nephrology departments in France between 1990 and 2011 were included. All patients were given renin-angiotensin system blockers and 13 received immunosuppressive therapy, including rituximab (7 patients) and cyclophosphamide (3 patients). OUTCOMES & MEASUREMENTS: Clinical and histologic features of patients and kidney disease outcome. Renal response was defined as a >50% decrease in 24-hour proteinuria with

Light chain deposition disease (LCDD) and light chain amyloidosis (AL) are disorders of monoclonal immunoglobulin deposition in which normally soluble serum precursors form insoluble deposits in tissues. A common feature in both is the clonal proliferation of B-cells that produce pathogenic light chains. However, the deposits in LCDD differ from those in AL in that they are ultrastructurally granular rather than fibrillar and do not bind Congo red or colocalize with amyloid P component or apolipoprotein E. The reason(s) for their differences are unknown but are likely multifactorial and related to their protein conformation and their interaction with other molecules and tissue factors in the microenvironment. Knowledge of the primary structure of the light chains in LCDD is very limited. In the present study two new κ 1 light chains from patients with LCDD are described and compared to seven other reported κ-LCDD proteins. The N-terminal amino acid sequences of light chain GLA extracted from the renal biopsy and light chain CHO from myocardial tissue were each identical to the respective light chains isolated from the urines and to the V-region amino acid sequences translated from the cloned cDNAs obtained from bone marrow cells. The germline V-region sequences, determined from the genomic DNA in both and in MCM, a previously reported κ 1 LCDD light chain, were identical and related to the L12a germline gene. The expressed light chains in all three exhibit amino acid substitutions that arise from somatic mutation and result in increased hydrophobicity with the potential for protein destabilization and disordered conformation.

A 45-year-old white woman was found to have microscopic hematuria during her annual physical examination. After a negative urologic workup, she returned 5 months later with nephrotic syndrome, renal insufficiency, and hypocomplementemia. Renal biopsy showed a nodular sclerosing glomerulopathy that could not be further characterized because of inadequate tissue for immunofluorescence. The patient returned 8 months later with chronic renal failure. A repeat renal biopsy showed deposits composed of immunoglobulin G (IgG) heavy chain and complement components C3 and C1 along glomerular, tubular, and vascular basement membranes, with negativity for kappa and lambda light chains, findings consistent with heavy chain deposition disease (HCDD). The heavy chain subclass was exclusively IgG3. Staining with monoclonal antibodies to epitopes of the constant domains of IgG heavy chain showed a CH1 deletion, indicating a truncated heavy chain. On review of the previously reported cases of HCDD, common clinical presentations include nephrotic syndrome, renal insufficiency, hematuria, and, in some cases, hypocomplementemia. In most patients, the hematologic disorder is mild, without overt myeloma. Light microscopy shows a nodular sclerosing glomerulopathy, and heavy chain deposits are detectable within basement membranes throughout the kidney by immunofluorescence and electron microscopy. There is no effective treatment for this condition, and virtually all patients progress to chronic renal failure.

The objective of this study was to further characterize the clinical and immunopathologic features of heavy chain deposition disease (HCDD), a recently described entity. Four patients were diagnosed as having HCDD on a kidney biopsy. All presented with nodular glomerulosclerosis with deposition of gamma1 heavy chains lacking CH1 epitopes, but without light chains. Two different patterns were observed in the serum. First, patients 1 and 2 had a circulating monoclonal IgGlambda containing a short gamma1 heavy chain lacking CH1 epitopes, with an apparent molecular weight of 40 kD consistent with a complete CH1 deletion. Biosynthetic experiments also showed that the deleted heavy chain was produced in excess compared with light chains, and was secreted in vitro together with half Ig molecules, although these abnormal components were not detected by Western blot analysis of whole serum. Second, patients 3 and 4 had a circulating monoclonal IgG1lambda with an apparently normal, nondeleted heavy chain subunit, but serum fractionation followed by immunoblotting revealed an isolated monoclonal gamma1 chain lacking CH1 epitopes. These data strongly suggest that renal deposition of a CH1-deleted heavy chain circulating in low amounts in the serum as a free unassembled subunit is a major feature of HCDD. The CH1 deletion is most likely responsible for the premature secretion in blood of the heavy chain by a clone of plasma cells.

Introduction Le syndrome de Fanconi (SF) correspond a une dysfonction du tube proximal. Dans sa forme acquise il est souvent secondaire a une gammapathie monoclonale. Il est classiquement lie a une chaine legere (CL) vkappa 1 resistante a la proteolyse. En ME, on observe une accumulation de la CL sous forme de cristaux au sein des lysosomes des TP. Le mecanisme de toxicite est inconnu. Nous avons voulu evaluer le spectre des SF : les aspects des CL en ME, l’atteinte mitochondriale, mais aussi evaluer l’impact des nouvelles therapeutiques (bortezomib) sur la fonction renale et la tubulopathie. Patients et methodes Nous avons analyse de facon prospective les donnees de 10 patients ayant eu une PBR entre 2010 et 2014 dans 5 centres de nephrologie pour une TP secondaire a une gammapathie monoclonale. Nous avons collige les donnees biologiques au moment du diagnostic et apres traitement. L’etude anatomopathologique comprenait une etude en MO, en IF standard et apres traitement par pronase en paraffine, en ME (± immunogold). La CL a pu etre sequencee dans 2/3 des cas et sa sensibilite aux cathepsines etudiee. Resultats Une hypouricemie etait presente chez tous les patients mais le SF etait le plus souvent incomplet. Des cristaux de CL ont pu etre vus dans les urines chez une patiente. Sur l’etude anatomopathologique, 4 patients avaient une histiocytose cristalline de surcharge associee. Les depots monotypiques n’ont pas pu etre prouves en IF standard dans la moitie des cas. La ME retrouvait une accumulation de CL intracytoplasmique sous forme de cristaux ou de depots pseudofibrillaires. Des anomalies mitochondriales ont souvent ete observees. Les CL legeres incriminees derivaient du segment de gene vkappa1 ou vkappa3. La resistance de la CL aux cathepsines n’a pas toujours etait observee. Le traitement a parfois permis une amelioration de la fonction renale et de la tubulopathie. Discussion Dans notre serie de SF secondaire a une gammapathie monoclonale, l’aspect en ME etait plus heterogene que celui initialement rapporte. La toxicite de la CL n’est pas univoque : par defaut de degradation, toxicite mitochondriale… Conclusion Les therapeutiques actuelles ameliorent notablement le pronostic renal.

The basic pathogenesis of numerous neurodegenerative disorders is now thought to be related to abnormal protein conformation. The common theme in all these diseases is the conversion of a normal cellular and/or circulating protein into an insoluble, aggregated, beta-sheet rich form which is deposited in the brain, sometimes in the form of amyloid. These deposits are toxic and produce neuronal dysfunction and death. The most common of these illnesses is Alzheimer's disease (AD), in which a central event is the conversion of the normal soluble amyloid beta (sA beta) peptide to amyloid beta (A beta) within neuritic plaques and cerebral vessels. A unique category of the conformational conditions are prion related diseases (or prionoses), where the etiology is thought to be related to conversion of the normal prion protein, PrPC, into an infectious and pathogenic form, PrPSc. In the case of AD and the prionoses, the conformational change can be influenced by the presence of mutations in various gene products, as well as by chaperone proteins. Apolipoprotein E is thought to act as such a chaperone protein in AD; however, among the prionoses such a protein has been hypothesized to exist only by indirect evidence and is called "protein X". Our growing understanding of the mechanisms involved in this category of diseases, raises the possibility of therapeutic approaches based directly on the prevention and reversal of pathologic protein conformation.

Light chain deposition disease is a severe complication of certain immunoproliferative disorders, due to the secretion of a monoclonal light chain which precipitates close to basement membranes of several tissues. A kappa isotype restriction and an unusual frequency of a variable region subgroup (VkappaIV) suggest that precise structural features govern the propensity of pathogenic light chains to precipitate in extracellular spaces. We studied primary structures of light chains from six patients with light chain deposition disease in comparison with light chains from other pathological conditions. Sequence alignment revealed the presence of certain amino acids only in light chain deposition disease, in particular non-polar replacing hydrophilic residues. To determine the role of these residues, structures of the variable domain from four kappa chains belonging to VkappaI and VkappaIV subgroups responsible for deposition disease were modeled using known immunoglobulins as templates. The most evident structural features shared by all pathogenic light chains were hydrophobic residues exposed to the solvent in complementarity determining regions 1 or 3. In contrast to immunoglobulin light chain-related amyloidosis, where deposition of organized material might be due to electrostatic interactions between light chain dimers, hydrophobic interactions could enhance amorphous precipitation in non-amyloid light chain deposition disease.

Identification of disease-specific diagnostic and prognostic biomarkers allowing for an early characterization and accurate clinical follow-up of Alzheimer's disease (AD) patients is a major clinical objective. Increasing evidences implicate both humoral and cellular adaptive immune responses in the pathophysiology of AD. Such disease-related B- and T-cell responses constitute a promising source of potential specific early biomarkers. Among them, levels of anti-Aβ antibodies in the serum and/or cerebrospinal fluid of patients may correlate with AD progression, clinical presentation of the disease, and occurrence of associated pathologies related to cerebral amyloid angiopathy. In the same line, Aβ-specific T cell responses and immune regulatory populations implicated in their modulation appear to play a role in the pathophysiology of AD and cerebral amyloid angiopathy. Further characterization of both autoantibodies and T cell responses specific for disease-related proteins, i.e. Aβ and hyperphosphorylated Tau, will allow better deciphering their interest as early diagnostic and prognostic markers in AD. Biomarkers of adaptive immune responses specific for other pathological proteins may also apply to other neurological disorders associated with abnormal protein deposition.

Immunoglobulin free light chains are produced in excess during normal antibody synthesis. Their evaluation is commonly used in case of a monoclonal gammopathy. In polyclonal hypergammaglobulinemia related to the Sjögren syndrome or systemic lupus, erythematosus serum free light chain levels are increased and could correlate with disease activity. We show here that theκ() andλ() free light chains and theκ : λratio () are increased in sixteen patients with IgG4-related disease when compared to healthy controls. The increase ofκandλfree light chains probably reflects the marked polyclonal B cell activation of the disease. We could not assess in this small cohort of patients a significative correlation of serum free light chain levels and disease activity or extension.