Organization and evolution of synthetic idiotypic networks

We introduce a class of weighted graphs whose properties are meant to mimic the topological features of idiotypic networks, namely the interaction networks involving the B-core of the immune system. Each node is endowed with a bit-string representing the idiotypic specificity of the corresponding B cell and a proper distance between any couple of bit-strings provides the coupling strength between the two nodes. We show that a biased distribution of the entries in bit-strings can yield fringes in the (weighted) degree distribution, small-worlds features, and scaling laws, in agreement with experimental findings. We also investigate the role of ageing, thought of as a progressive increase in the degree of bias in bit-strings, and we show that it can possibly induce mild percolation phenomena, which are investigated too.Comment: 13 page

Anergy in self-directed B lymphocytes from a statistical mechanics perspective

The ability of the adaptive immune system to discriminate between self and non-self mainly stems from the ontogenic clonal-deletion of lymphocytes expressing strong binding affinity with self-peptides. However, some self-directed lymphocytes may evade selection and still be harmless due to a mechanism called clonal anergy. As for B lymphocytes, two major explanations for anergy developed over three decades: according to "Varela theory", it stems from a proper orchestration of the whole B-repertoire, in such a way that self-reactive clones, due to intensive interactions and feed-back from other clones, display more inertia to mount a response. On the other hand, according to the `two-signal model", which has prevailed nowadays, self-reacting cells are not stimulated by helper lymphocytes and the absence of such signaling yields anergy. The first result we present, achieved through disordered statistical mechanics, shows that helper cells do not prompt the activation and proliferation of a certain sub-group of B cells, which turn out to be just those broadly interacting, hence it merges the two approaches as a whole (in particular, Varela theory is then contained into the two-signal model). As a second result, we outline a minimal topological architecture for the B-world, where highly connected clones are self-directed as a natural consequence of an ontogenetic learning; this provides a mathematical framework to Varela perspective. As a consequence of these two achievements, clonal deletion and clonal anergy can be seen as two inter-playing aspects of the same phenomenon too

A statistical mechanics approach to autopoietic immune networks

The aim of this work is to try to bridge over theoretical immunology and disordered statistical mechanics. Our long term hope is to contribute to the development of a quantitative theoretical immunology from which practical applications may stem. In order to make theoretical immunology appealing to the statistical physicist audience we are going to work out a research article which, from one side, may hopefully act as a benchmark for future improvements and developments, from the other side, it is written in a very pedagogical way both from a theoretical physics viewpoint as well as from the theoretical immunology one. Furthermore, we have chosen to test our model describing a wide range of features of the adaptive immune response in only a paper: this has been necessary in order to emphasize the benefit available when using disordered statistical mechanics as a tool for the investigation. However, as a consequence, each section is not at all exhaustive and would deserve deep investigation: for the sake of completeness, we restricted details in the analysis of each feature with the aim of introducing a self-consistent model.Comment: 22 pages, 14 figur

Glycosylation of glycolipids in cancer: basis for development of novel therapeutic approaches

Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described.Fil: Daniotti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Vilcaes, Aldo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Torres Demichelis, Vanina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Ruggiero, Fernando Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Rodríguez Walker, Macarena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentin

P3 mAb: An Immunogenic Anti-NeuGcGM3 Antibody with Unusual Immunoregulatory Properties

P3 is a murine IgM mAb that recognize N-glycosylated gangliosides, sulfatides, and antigens expressed in melanoma, breast, and lung human tumors. This antibody has the ability to trigger an IgG antibody response in the syngeneic BALB/c model, even when it is administered in the absence of adjuvant or carrier protein. The mechanism by which the P3 mAb, a self-immunoglobulin, induce this immune response in the absence of co-stimulatory or classical danger signals is still unknown. In the present paper we show that the high immunogenicity of P3 mAb depends not only on CD4 but also on CD8+ T cells, since the depletion of CD8+ or CD4+ T cells led to the loss of P3 mAb immunogenicity in the syngeneic model. Furthermore, the immunization with P3 mAb enhanced the recovery of the CD8+ T cell population in mice treated with an anti-CD8a antibody. Additionally, the immunization with P3 mAb restored the capacity of immunosuppressed mice to reject allogeneic tumors, a mechanism mediated by the action of CD8+ T cells. Finally, in mice with cyclophosphamide induced lymphopenia, the administration of P3 mAb accelerated the recovery of both CD4+ and CD8+ T cells. These results show new possibilities for B and CD8+ T cells interactions during the immune response elicited by a self-protein. Furthermore they point to P3 mAb as a potential interesting candidate for the treatment of immunosuppressed patients

A human CD5+ B cell clone that secretes an idiotype-specific high affinity IgM monoclonal antibody.

We previously demonstrated the occurrence of a naturally arisen human anti-idiotypic B cell clone, that we transformed with EBV (EBV383). We show evidence that EBV383 not only expresses the CD5 surface Ag, but also contains the 2.7-kb mRNA transcript encoding this protein. In addition, we show the presence of the 3.6-kb mRNA precursor. Most Ig produced by CD5+ B cells are polyreactive natural IgM antibodies encoded by unmutated copies of germline VH genes. However, in this study we present data demonstrating the monoreactive high affinity character of the anti-idiotypic antibody (mAb383) produced by EBV383. These data are in agreement with our previous observations, showing that the VH chain of mAb383 is encoded by an extensive somatically mutated VHV gene in a way that is consistent with an Ag-driven immune response. A possible role for this remarkable anti-idiotypic antibody in the maintenance of B cell memory is discussed