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The spectrum of renal diseases associated with proliferations of the B cell lineage is continuously expanding. Most of them are caused by deposition of a monoclonal Ig or a fragment thereof, whereas others include neoplastic cell infiltration, nephrocalcinosis, and infection-related complications. Solomon et al. (1) first demonstrated that human renal lesions associated with deposition of monoclonal lights chains (LC) could be reproduced in mice by intraperitoneal injection. Subsequent studies have shown that the pattern of renal lesions associated with the deposition of monoclonal Ig mostly depends on biochemical and structural abnormalities of Ig (2). Most renal complications occur in patients who produce free LC with or without complete IgG molecules. Renal complications of malignant IgM-secreting proliferations are rare. Their incidence seems to have decreased, mostly because of improved therapy of Waldenstrom macroglobulinemia (WM), the major cause of those nephropathies. First reviewed by Morel-Maroger et al. (3), WM-related nephropathies include characteristic intracapillary deposits of IgM with or without cryoglobulinemia, AL-amyloidosis, and infiltration of the interstitium by neoplastic lymphoplasmacytic cells. Subsequent case reports included immunotactoid and nonamyloid fibrillary glomerulopathy (4,5), cryoglobulinemia-related glomerulonephritis (6), and crescentic glomerulonephritis (7,8). Cases of cast nephropathy (9), Fanconi syndrome (10), and LC deposition disease (11) as a result of free LC toxicity have also been reported in patients who presented with a circulating monoclonal IgM. In this study, we retrospectively analyzed 14 patients with renal lesions associated with an IgM-secreting proliferation with the aims of reappraising the relative prevalence of the various renal lesions and underlying hematologic disorders, the characteristics of the nephropathies, and the patients’ outcome. We included both renal lesions that were caused by cell infiltration and those that were caused by the deposition of the monoclonal component (complete IgM and/or isolated LC) to cover the full disease spectrum.

International audience; Marked polyclonal immunoglobulin (Ig)G4 hypergammaglobulinemia has exceptionally been reported. Here we report on two Algerian patients who presented a syndrome characterized by anemia, plasmacytic lymphadenopathy, renal manifestations, and a marked polyclonal IgG4 hypergammaglobulinemia leading to a hyperviscosity syndrome in one case. The IgG4-expressing cell percentage was significantly increased in the peripheral blood lymphocytes collected from the two patients upon diagnosis. Moreover, in contrast with normal sera, both patients' sera significantly increased the percentage of IgG4-expressing cells when incubated with CD40-stimulated normal B lymphocytes. Similar effects were obtained with the culture supernatants of the patients' activated T cells. Anti-interleukin (IL) 4 and/or anti-IL-13 antibodies were unable to antagonize the IgG4 production. IL-4 and IL-13 serum concentrations were found to be normal in the two patients. The increased IgG4 production was found to be mediated by soluble factor(s), most probably secreted by activated T cells, which did not require the signal transducer and activator of transcription 6 signaling pathway.

Numerous studies have shown that several red blood cell polymorphisms protect against severe malaria. Such a relation is much less clear for mild malaria attacks and for the asymptomatic carriage of Plasmodium falciparum. The impact of red blood cell polymorphisms on the level of parasite density was assessed in a group of 464 Senegalese children from the Sereer ethnic group, studied for 18 months. These genetic factors were also related to the malarial morbidity, investigated during 2 successive transmission seasons among 169 of these children. The frequencies of the host genetic factors in the whole group were 0.52 for blood group O, 0.13 for hemoglobin S, 0.16 for the G6PD A-deficient variant and 0.24 for alpha(+)-thalassemia (-alpha(3.7) deletion). Hemoglobin S was associated with protection against mild malaria attacks. None of the genetic factors was implicated in a better control of parasite densities. These associations may be particular to this ethnic group due to the specificities of malaria endemicity in this area. The pressure exerted in the area by other non-malarial infectious diseases as well as the genetic heterogeneity of circulating parasites may also contribute to these observations. (c) 2006 Elsevier SAS. All rights reserved.

The six Brucella species are gram-negative bacteria that cause brucellosis in human and animals, a disease also known as Malta fever. Brucella spp. are facultative intracellular pathogens and infect a variety of cells including “professional” and “nonprofessional” phagocytes (14, 19, 22). Many aspects of the pathophysiology of the disease are still unclear (establishment of chronicity, for example), but it is assumed that the intracellular location is essential for bacterial multiplication and virulence (22). After penetration inside the macrophages, Brucella-containing vacuoles traffic in a complex manner (8) to become the replicative niche of the pathogen: the brucellosome (18). Attachment to the host membrane and phagocytosis are the first steps leading to the intracellular stages, but little is known about the molecular mechanisms involved. The use of inhibitors or antibodies against putative receptors has led only to incomplete inhibition. For instance, bacterial entry into bovine macrophages was partially inhibited by the peptide RGDS, the outer membrane-peptidoglycan complex from Brucella abortus strain RB51, anti-lymphocyte function-associated antigen-1 monoclonal antibody, anti-C3 antiserum, fibronectin, purified O antigen from B. abortus lipopolysaccharide (LPS), and mannan- and heat-aggregated immunoglobulin G (5). On the other hand, recent studies have presented data suggesting that the adherence mechanism of Brucella to macrophages is mediated by cellular receptors containing sialic acid and sulfated residues, explaining the affinity for proteins of the cellular matrix (6). Recent advances in cellular biology have attracted the attention of microbiologists to the importance of membrane cellular structures, namely, lipid rafts that exhibit many specific functions, the ability to concentrate signaling molecules in particular. An increasing number of bacteria and their products have been shown to interact with lipid rafts to promote infection (20). Brucella needs functional lipid rafts to enter macrophages (24, 36), as the disruption of lipid rafts markedly inhibits internalization and intracellular replication, indicating that the path of entry into macrophages determines the intracellular fate of the bacteria and shapes phagosome maturation (24). In particular, it was suggested that raft elements incorporated into the phagosomes containing Brucella modulate their maturation into replicative vesicles, probably by the initiation of a signaling transduction cascade (36). Some of these raft elements determining intracellular fate of the bacteria have been identified as cholesterol, gangliosides (e.g., GM1), glycosphingolipids, and glycosylphosphatidylinositol (GPI)-anchored proteins. Nevertheless, it can be supposed that bacterial phagocytosis involves many other interactions between bacterial membrane and cellular partners that are still undefined. However, because penetration needs functional rafts, it has been suggested that the cellular receptor for Brucella would be a GPI-anchored protein known to be localized inside these cholesterol-rich structures. This point of view was recently adopted by Watarai et al. (35), who concluded that the cellular prion protein (PrPC) promotes infection and could thus be one receptor for the bacteria on the membrane of macrophages. PrPC is a 231-amino-acid GPI protein anchored on the outer leaflet of the plasma membrane of many cell types (17). It was remarkably conserved during mammalian evolution and is ubiquitously expressed in organisms, predominantly in the central nervous system. PrPC is the cellular, nonpathogenic homologue of PrPSc (for prion protein scrapie), which is suspected according to Prusiner's hypothesis (30) to be the unconventional agent responsible of transmissible spongiform encephalopathies. The two proteins share a common primary structure but differ in their tertiary structure: PrPSc exhibits a majority of β-sheets that aggregate into β-amyloid fibrils. On the contrary, PrPC exhibits mainly α-helix conformation (37). The physiological functions of PrPC are still poorly understood, and the protein has been implicated in many functions such as protection from oxidative insults, apoptosis, cellular signaling, membrane excitability and synaptic transmission, neuritogenesis, and copper(II) transport or metabolism (17, 21, 29). But how all these functions are achieved by the same protein is still enigmatic. PrPC is located in rafts of the plasmic membrane to which it is attached by its GPI anchor. This localization is compatible with a role as a membrane receptor and with cellular signaling. The use of PrPC by B. abortus (35) could be an interesting opportunity to better understand the function of this protein. In consequence, we decided to further analyze the mechanisms involving cellular prion protein during infection of macrophages by Brucella. Surprisingly, we were not able to find any evidence of the participation of cellular prion protein during infection process, even with different species of Brucella.

Recent reports suggest that immunity against the prion protein (PrP) retards transmissible spongiform encephalopathies progression in infected mice. A major obstacle to the development of vaccines comes from the fact that PrP is poorly immunogenic, as it is seen as self by the host immune system. Additional questions concern the immune mechanisms involved in protection and the risk of eliciting adverse reactions in the central nervous system of treated patients. Peptide-based vaccines offer an attractive strategy to overcome these difficulties. We have undertaken the identification of the immunogenic regions of PrP, which trigger helper T cells (Th) associated with antibody production. Our results identify two main regions, one between the structured and flexible portion of PrP (98–127) and a second between α 1 and α 2 helix (143–187). Peptides (30-mer) corresponding to these regions elicit class II-restricted Th cells and antibody production against native PrP and could therefore be of potential interest for a peptide-based vaccination.