Immune Computation and COVID-19 Mortality: A Rationale for IVIg.

COVID-19 infection tends to be more lethal in older persons than in the young; death results from an overactive inflammatory response, leading to cytokine storm and organ failure. Here we describe immune regulation of the inflammatory response phenotype as emerging from a process that is analogous to machine-learning algorithms used in computers. We briefly describe some strategic similarities between immune learning and computer machine learning. We reason that a balanced response to COVID-19 infection might be induced by treating the elderly patient with a wellness repertoire of antibodies obtained from healthy young people. We propose that a beneficial training set of such antibodies might be administered in the form of intravenous immunoglobulin (IVIg).

T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial.

BACKGROUND: T-cell vaccination (TCV) for multiple sclerosis (MS) refers to treatment with autologous anti-myelin T-cells, attenuated by irradiation. Previously published clinical trials have been all open-labeled. AIM: To evaluate the safety and efficacy of TCV in progressive MS, in a double-blind, controlled clinical trial. METHODOLOGY: Twenty-six patients with relapsing-progressive MS were enrolled in the study (mean age: 39±9.8 years; mean EDSS: 4.4±1.7). T-cell lines reactive to 9 different peptides of the myelin antigens, MBP, MOG and PLP were raised from the patients' peripheral blood. The patients were randomized into two groups: 19 were treated with TCV (four subcutaneous injections of 10-30×10(6) T-cells, attenuated by irradiation, on days 1, 30, 90 and 180) and 7 patients were treated with sham injections. Twenty-four patients (17 in the TCV group and 7 in the placebo) were eligible for per-protocol analysis. RESULTS: At one year following the inclusion, an increase in the EDSS (+0.50) and an increase in 10-meter walking time (+0.18 sec), were observed in the placebo group; in the TCV group there was a decrease in the EDSS (-0.44; p<0.01) and in the 10-meter walking time (0.84 sec; p<0.005). Sixteen of the 17 patients (94.1%) in the TCV group remained relapse-free during the year of the study, as compared to 42.9% in the placebo group (p = 0.01 and p = 0.03 with adjustment). The proportion of patients with any relapse during the year of the study in the TCV-group, was reduced by 89.6%., as compared to the placebo-treated group. MRI parameters did not change significantly. CONCLUSIONS: This is the first controlled, double-blind trial with TCV in progressive MS. The results demonstrate the feasibility and safety of the procedure, and provide significant indications of clinical efficacy. Further studies with larger groups of subjects are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01448252.

Stem cell research: from what stage may a cell or cellular artifact be qualified as an embryo?

Until recently, the answer to that question was obvious: from fertilization. The discovery that artificial cellular constructs, by nuclear transfer from adult cells and by other techniques, can produce blastocyst-like structures, which under some conditions may develop into embryos upon uterine implantation, with no fertilization, leads us to consider successful uterine implantation as necessary for the qualification of what is an embryo. This implies replacement of essentialist definitions by evolutionary ones. In addition, the concept of potentiality must not be restricted to genome formation but extended to subsequent epigenetic events in embryonic development.

Major CD4 epitopes involved in anti-CD4 T-cell autoimmunity in HIV-1 patients.

We studied HIV-positive and -negative subjects for T-cell reactivity to rCD4, and found that 80% of 25 tested HIV-infected patients and 25% of controls manifested T-cell proliferation responses to rCD4. We mapped the major CD4 immunogenic epitopes among the CD4+ responders of both groups by testing T-cell proliferation responses to 31 synthetic overlapping peptides from the human CD4 molecule. Such responses to p1, p4, p14, p21, p28 and p29 were significantly higher in the eight infected patients and, with the exception of p14, these peptides differed from those found in three HIV-negative controls (p11, p14 and p27). Peptides p1, p28 and p29 are major immunogenic epitopes. Our findings suggest: (1) that HIV infection is associated with T-cell reactivity to CD4; and (2) that the use of synthetic CD4 peptides to replace the complete CD4 molecule may therefore lead to a cost-effective T-cell vaccination for HIV-positive patients exhibiting anti-CD4 autoimmunity, as well as to the development of complimentary TCR peptides for future peptide vaccinations.

The emergence of goals in a self-organizing network: a non-mentalist model of intentional actions.

A model of intentional actions is presented through the operation of two connected neural networks. A deterministic causal recurrent network relates a random initial state to an ordered final state. A perceptron-like, feed-forward network provides a memory mechanism that links the final states to the original initial states. A non-supervised learning mechanism that selects which final states are defined as goals to be retrieved together with initial states leading to them. Causal sequences of states are transformed into procedures directed towards the achievements of goals. We propose a mechanism through which goals and their achievement in goal-directed actions can be emerging properties of self-organizing networks, not initially endowed with intentionality. This allows for a monist, non-mentalist description which does not need to resort to intentional mental states as causes of intentional actions. Cognitive, neurophysiological and philosophical implications are discussed.

Na+/K+/Cl- cotransporter activates MAP-kinase cascade downstream to protein kinase C, and upstream to MEK.

In this study, we demonstrated that the specific inhibitors of the Na+/K+/Cl- cotransporter (NKCC1), bumetanide and furosemide, inhibited extracellular regulated kinase (ERK) phosphorylation in Balb/c 3T3 fibroblasts, stimulated with a variety of mitogens. In addition to fibroblast growth factor (FGF) shown before, the various mitogens tested in the present study (endothelial growth factor (EGF), platelet-derived growth factor (PDGF), insulin, thrombin, and the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA)). Enter, the Ras/Raf/MEK/ERK cascade via different growth factors receptors and through one of the two main routes. The results of the present study provide evidence that have led us to conclude that the target protein which is controlled by the Na+/K+/Cl- cotransporter, is downstream of tyrosine kinase receptors, as well as of the G-protein-coupled receptor (GPCR). Several additional lines of evidence supported the above conclusion: (i) furosemide inhibits phosphorylation of MAPK kinase (MEK) induced by receptor tyrosine kinase (RTK) ligands, such as PDGF, FGF, and EGF. (ii) Furosemide also inhibited ERK phosphorylation, induced by thrombin, a GPCR. (iii) Furosemide inhibited MEK and ERK phosphorylation even when ERK phosphorylation was induced by direct activation of protein kinase C (PKC) by TPA, which bypasses early steps of the mitogenic cascade. In addition, we found that furosemide did not affect PKC phosphorylation induced directly by TPA. Taken together, the results of the present study indicate that the signal transduction protein, controlled by the Na+/K+/Cl- cotransporter, must be downstream of the PKC, and at/or upstream to MEK in the Ras/Raf/MEK/ERK cascade.

O útero artificial

Médico, biofísico, filósofo e exmembro do Comité nacional de ética para os ciências da vida, Henri Atlan oferece, na sua última publicação o Útero Artificial (2005), as suas reflexões sobre os progressos de a embriologia e da genética em matéria de procriação medicamente assistida. com palavras simples, mostra como science-fiction de ontem torn-se-ar, num futuro mais ou menos próximo, a ciência de amanhã, como os perturbações provocadas pelo aparecimento da contracepção hormonal e os fécondations in vitro parece-nos -rem anodins ao lado deos procedentes do desenvolvimento o ectogenese (ou útero artificial), a clonagem reprodutiva, o reprodução por estaca e o parthénogenèse. Atlan assegura que hoje as finalidades terapêuticas justificam o financiamento destas investigações: salvar grandes os prematuros ou os fetos procedentes de abortos espontâneos e não desejados por transferência num Útero Artificial. Mas, previne Henri Atlan, quando estes técnicos estiverem à ponto, pedidos extramédicos adicionar-se-á aos tratamentos terapêuticos. As mulheres poderão, e algumas quererão, dissociar procriação e gravidez. Ser mãe sem gravidez seria à alcance de mão, da mesma maneira que é-o hoje épanouissement de uma sexualidade sem criança. Estas perturbações provocarão consequências sociais, culturais, económicas, políticos, religiosos e mesmas metafísicas pouco previsíveis sobre o conjunto da sociedade. Os sexos serão por último à igualdade perante a procriação, estruturas familiares novas antes genéticas e sociais que biológicos aparecerão, o sentimento materno alterar-se-á. Só ponto de interrogação em ausência de experimentação: o que será de a criança, soncorps, os seus sentimentos e aptidões mentais sem a simbiose que oferece o gravidez? num espírito especulativo, Henri Atlan mede estas mudanças em relação mythologie, a filosofia, a literatura e da história, navega entre o totalitarismo eugénique e o liberalismo individualista para fazer-nos tomar consciência dos desafios subjacentes à estas inovações

O útero artificial / The artificial uterus

Médico, biofísico, filósofo e ex-membro do Comité Nacional de Ética para as Ciências da Vida, Henri Atlan oferece, na sua última publicação de O Útero Artificial (2005), as suas reflexões sobre os progressos da embriologia e da genética em matéria de procriação medicamente assistida. Com palavras simples, mostra como a science-fiction de ontem tornar-se-á, num futuro mais ou menos próximo, a ciência de amanhã, como as perturbações provocadas pelo aparecimento da contracepção hormonal e as fertilizações in vitro parece-nos -rem anodins- ao lado de os procedentes do desenvolvimento o ectogenese (ou útero artificial), a clonagem reprodutiva, a reprodução por estaca e o parthénogenèse. Atlan assegura que hoje as finalidades terapêuticas justificam o financiamento destas investigações: salvar grandes os prematuros ou os fetos procedentes de abortos espontâneos e não desejados por transferência num Útero Artificial. Mas, previne Henri Atlan, quando estes técnicos estiverem à ponto, pedidos extramédicos adicionar-se-á aos tratamentos terapêuticos. As mulheres poderão, e algumas quererão, dissociar procriação e gravidez. Ser mãe sem gravidez seria à alcance de mão, da mesma maneira que é-o hoje épanouissement de uma sexualidade sem criança. Estas perturbações provocarão consequências sociais, culturais, economicas, políticos, religiosos e mesmas metafísicas pouco previsíveis sobre o conjunto da sociedade. Os sexos serão por último à igualdade perante a procriação, estruturas familiares novas antes genéticas e sociais que biológicos aparecerão, o sentimento materno alterar-se-á. Só ponto de interrogação em ausência de experimentação: o que será de a criança, soncorps, os seus sentimentos e aptidões mentais sem a simbiose que oferece o gravidez? Num espírito especulativo, Henri Atlan mede estas mudanças em relação mythologie, a filosofia, a literatura e da história, navega entre o totalitarismo eugénique e o liberalismo individualista para fazer-nos tomar consciência dos desafios subjacentes à estas inovações.

T-cell vaccination against anti-CD4 autoimmunity in HIV-1 subtypes B and C-infected patients--an extended open trial.

This study is an extended clinical trial of the one initiated and reported in the Journal of Clinical Virology 2004;31S:S48-54. Thirteen HIV-1 patients (eight subtype B and five subtype C) that manifested T-cell autoimmunity to recombinant human CD4 (rCD4) were treated with T-cell vaccine composed of glutaraldehyde-treated autologous anti-CD4 reactive T-cells and compared to historical seven non-vaccinated HIV-1-infected subjects. This study proved to be feasible and safe. Follow-up study revealed that 7/8 subtype B and 2/4 subtype C patients (one has just received the first TCV injection) responded with a persistent increase in their blood CD4 T-cell levels and four subtype B patients manifested decreased anti-CD4 autoimmunity. Despite highly active antiretroviral therapy (HAART), the persistence of CD4 T-cell lymphopenia may be associated with anti-CD4 autoimmunity. T-cell vaccination (TCV) may decrease such autoimmunity and elevate CD4 T-cell numbers.

T-cell vaccination against anti-CD4 autoimmunity in HIV-1 infected patients.

BACKGROUND: Highly active antiretroviral therapy (HAART) is frequently associated with only partial restoration of CD4 T-cell levels. Autoimmunity to CD4 T-cells may account for the persistence of the CD4 T-cell lymphopenia in such cases. OBJECTIVE: To document T-cell autoimmunity to CD4 in HIV-infected patients and to determine if T-cell vaccination against CD4 autoimmunity is feasible and safe. STUDY DESIGN: Seven out of 20 HIV-infected patients undergoing HAART who manifested T- cell reactivity to rCD4, gp120 and to recall antigens (Tetanus toxoid and Candida) were treated with T-cell vaccines composed of glutaraldehyde treated autologous, activated T-cells, and enriched in anti CD4-reactive T-cells. The response of the seven vaccinated patients was compared to seven non-vaccinated HIV-1 infected subjects. RESULTS: Five out of seven responded with a decrease in anti-CD4 autoimmunity, associated with a persistent increase in their CD4 T-cell levels; just one of the control patients showed increased CD4 levels. No change in HIV plasma viral loads and no adverse effects were detected in any of the T-cell vaccinated patients. CONCLUSIONS: The persistence of CD4 T-cell lymphopenia despite effective anti-retroviral treatment may be associated with anti-CD4 autoimmunity. T-cell vaccination with autologous autoimmune CD8 T-cells may decrease such autoimmunity and increase CD4 T-cell numbers.

Both raft- and non-raft proteins associate with CHAPS-insoluble complexes: some APP in large complexes.

Components of caveolae and lipid rafts are characterized by their buoyancy after detergent extraction. Using flotations in density gradients, we now show that non-raft membrane molecules are also associated with detergent-insoluble, buoyant assemblies. When Triton X-100 cellular extracts were spun to equilibrium in Nycodenz, only components of classical rafts floated. In contrast, with the zwitterionic detergent CHAPS, non-raft residents such as calnexin and APP also buoyed. When CHAPS extracts were spun in non-equilibrium (velocity) conditions, some raft components rapidly exited the input fractions while other raft markers and non-raft molecules remained relatively immobile. This pointed to size heterogeneities of CHAPS-insoluble complexes. Combined velocity/equilibrium gradients broadly divided CHAPS-insoluble membrane complexes into three size categories, which all contained cholesterol and the glycosphingolipid GM1. Large complexes were enriched in caveolin and ESA. Medium size complexes were enriched in PrP, whereas small complexes contained non-raft proteins, PrP, and some ESA. While Alzheimer's APP was primarily confined to small assemblies, a portion of its glycosylated form did buoy with large complexes. Large CHAPS-insoluble complexes resemble, but are not equal to, classical rafts. These findings extend considerably the range of detergent-insoluble membranal domains.

T cells and autoantibodies to human HSP70 in type 1 diabetes in children.

We studied T-cell proliferative responses (stimulation index: SI) and autoantibodies to human HSP60, HSP70 and HSP90 proteins in 25 children (mean age 10.1+/-3.8 years) newly diagnosed with Type 1 diabetes. The control group for T cells included 25 adults and three pediatric donors without Type 1 diabetes. Controls for antibodies included 10 pediatric subjects. The T-cell responses to HSP70 of the test group (mean SI=4.5+/-3.1) were significantly greater than those of the control group (meanSI=1.4+/-0.6; p<0.0001); the incidence of HSP70 responders was (85%) compared to 14% in the control group. All but three of the Type 1 children who responded to HSP70 also responded to HSP60 (85%). The T-cell responses of the Type 1 group to HSP90 (mean SI=1.7+/-1.1) were similar to those of the control group (mean SI=1.5+/-0.7). We mapped HSP70 epitopes recognized by T cells in seven subjects using overlapping peptides of the molecule. Among the Type 1 subjects, IgG seropositivity was 45% to HSP60, 30% to HSP70, and 15% to HSP90. Thus, we conclude that children with newly diagnosed Type 1 diabetes manifest heightened T-cell autoimmunity to HSP70 and HSP60, but not to HSP90.

Proliferation and competition in discrete biological systems.

We study the emergence of collective spatio-temporal objects in biological systems by representing individually the elementary interactions between their microscopic components. We use the immune system as a prototype for such interactions. The results of this detailed explicit analysis are compared with the traditional procedure of representing the collective dynamics in terms of densities that obey partial differential equations. The simulations show even for very simple elementary reactions the spontaneous emergence of localized complex structures, from microscopic noise. In turn the effective dynamics of these structures affects the average behaviour of the system in a very decisive way: systems which would according to the differential equations approximation die, display in reality a very lively behaviour. As the optimal modelling method we propose a mixture of microscopic simulation systems describing each reaction separately, and continuous methods describing the average behaviour of the agents.

Na(+)/K(+)/Cl(-) cotransporter activates mitogen-activated protein kinase in fibroblasts and lymphocytes.

In a previous work, we have shown that overexpression of the Na(+)/K(+)/Cl(-) cotransporter (NKCC1) induces cell proliferation and transformation. We investigate in the present study the role of the NKCC1 in the mitogenic signal transduction. We show that overexpression of the cotransporter gene (NKCC1) in stablely transfected cells (Balb/c-NKCC1), resulted in enhanced phosphorylation of the extracellular regulated kinase (ERK) to produce double phosphorylated ERK (DP-ERK). Furthermore, the level of DP-ERK was reduced by 50-80% following the addition of bumetanide, a specific inhibitor of the Na(+)/K(+)/Cl(-) cotransporter, in quiescent as well as in proliferating cultures of the Balb/c-NKCC1 clone. In order to explore further the role of the Na(+)/K(+)/Cl(-) cotransporter in mitogenic signal transduction, we measured the effect of the two specific inhibitors of the cotransporter; bumetanide and furosemide, on DP-ERK level in immortalized non-transformed cells. In Balb/c 3T3 fibroblasts stimulated with FGF, bumetanide, and furosemide inhibited 50-60% of the ERK 1/2 phosphorylation. The inhibitor concentration needed for maximal inhibition of ERK 1/2 phosphorylation was similar to the concentration needed to block the K(+) influx mediated by the Na(+)/K(+)/Cl(-) cotransporter in these cells. To analyze whether the Na(+)/K(+)/Cl(-) cotransporter has a role in the mitogenic signal of normal cells, we measured the effect of bumetanide on ERK phosphorylation in human peripheral blood lymphocytes. The phosphorylation of ERK 1/2 in resting human lymphocytes, as well as in lymphocytes stimulated with phytohemagglutinin (PHA) was inhibited by bumetanide. The effect of bumetanide on ERK 2 phosphorylation was much lower than that of ERK 1 phosphorylation. The finding that the Na(+)/K(+)/Cl(-) cotransporter controls the ERK/MAPK (mitogen-activated protein kinase) signal transduction pathway, support our hypothesis that Na(+) and K(+) influxes mediated by this transporter plays a central role in the control of normal cell proliferation. Exploring the cellular ionic currents and levels, mediated by the Na(+)/K(+)/Cl(-) cotransporter, should lead to a better comprehension of cell proliferation and transformation machinery.