Revisiting the tuberculosis and leprosy cross-immunity hypothesis: Expanding the dialogue between immunology and paleopathology.

OBJECTIVE: Our primary objective is to re-visit the tuberculosis and leprosy cross-immunity. hypothesis through the careful integration of immunology and paleopathology. METHODS: Using an integrated theoretical analysis that evaluates clinical literature on human innate immunological responses, paleomicrobiology, bioarchaeology, and paleopathology, we develop a multifactorial model. RESULTS: Past populations do not represent homogeneous immunological landscapes, and therefore it is likely that leprosy in Medieval Europe did not uniformly decline due to cross-immunity. CONCLUSIONS: We recommend that bioarchaeological reconstructions of past disease experience take into consideration models that include variation in immune function based on past environments and social contexts. This provides a unique opportunity to conduct comprehensive analyses on complex immunological processes. SIGNIFICANCE: Extrapolating results from experimental immunology to larger populations elucidates complexities of disease cross-immunity and highlights the importance of synthesizing archaeological, social, paleopathological and biological data as a means of understanding disease in the past. LIMITATIONS: All extrapolations from data produced from in vitro studies to past populations, using living donors, pose significant limitations where, among other factors, the full reconstruction of past environmental and social contexts can frequently be sparse or incomplete. SUGGESTIONS FOR FUTURE RESEARCH: To reduce the limitations of integrating experimental immunology with bioarchaeological reconstructions (i.e. how to use skeletal samples to reconstruct inflammatory phenotypes), we propose that osteoimmunology, or the study of the interplay between immune cells and bone cells, should be considered a vital discipline and perhaps the foundation for the expansion of paleoimmunology.

Do leprosy and tuberculosis generate a systemic inflammatory shift? Setting the ground for a new dialogue between experimental immunology and bioarchaeology.

It is possible that during long lasting chronic infections such as tuberculosis (TB) and leprosy individuals who generate a stronger immune response will produce a chronic shift in the systemic levels of inflammatory proteins. Consequently, the systemic immunological shift could affect inflammatory responses against other persistent pathogens such as Porphyromonas gingivalis associated with periodontal disease (PD). OBJECTIVE: To determine if in vitro exposure to Mycobacterium tuberculosis or M. leprae lysates impacts subsequent immune responses to P. gingivalis; and to propose a new dialogue between experimental immunology and paleopathology. MATERIAL AND METHODS: We sequentially (2 days protocol) exposed peripheral blood mononuclear cells (PBMCs) from healthy donors to bacterial lysates either from M. tuberculosis, or M. leprae, or P. gingivalis. After collecting all supernatants, we measured the expression of immune proteins TNFα and IFNγ using an enzyme-linked immunosorbent assay. RESULTS: Early exposure (day 1) of PBMCs to M. leprae or M. tuberculosis lysates induces an inflammatory shift detected by the increase of TNFα and IFNγ when the same cells are subsequently (day 2) exposed to oral pathogen P. gingivalis. DISCUSSION: By extrapolating these results, we suggest that chronic infections, such as TB and leprosy, could generate a systemic immunological shift that can affect other inflammatory processes such the one present in PD. We propose that the presence and severity of PD should be explored as a proxy for inflammatory status or competence when reconstructing the health profile in past populations.

Cytokine expression and microglial activation in progressive supranuclear palsy.

Although little is known about the etiology of progressive supranuclear palsy (PSP), genetic and epigenetic factors, oxidative injury and inflammation are thought to contribute to its development and/or progression. Evidence for activated glia involvement in PSP has raised the possibility that neuroinflammation may contribute to its pathogenesis. To investigate the correlation between neuroinflammation and PSP, a comparative study was conducted on the patterns of cytokine expression in different regions of the brains of PSP, Alzheimer's disease (AD) patients and normal controls. Our results show different patterns of cytokine expression in each disease, with the expression of IL-1ß transcripts being significantly higher in the substantia nigra of PSP than in AD and controls, while AD brains had significantly higher IL-1ß expression in the parietal cortex compared to PSP and controls. In addition, expression of TGFß was significantly higher in the cortical areas (particularly frontal and parietal lobes) of AD compared to PSP and controls. These results show a disease-specific topographical relationship among the expression of certain cytokines (IL-1ß and TGFß), microglial activation and neurodegenerative changes, suggesting that these cytokines may contribute to the pathologic process. If so, the use of cytokine-inhibitors and/or other anti-inflammatory agents may be able to slow disease progression in PSP.

Digoxin-like immunoreactive factors induce apoptosis in human acute T-cell lymphoblastic leukemia.

BACKGROUND: Plant-derived cardenolides reportedly possess anticancer properties in human leukemic cells via selective induction of apoptosis, cell cycle arrest, and differentiation. Selective induction of apoptosis with mammalian-derived digoxin-like immunoreactive factor (DLIF) could provide new strategies for anticancer drug development or the identification of biomarkers for cancer. We investigated whether DLIFs selectively induce apoptosis in human lymphoblastic leukemic cells. METHODS: We compared the relative potencies of digoxin, ouabain, and DLIF on induction of programmed cell death in Jurkat cells (an acute T-leukemic cell line), K-562 (a myelogenous leukemia cell line), and nonpathologic human peripheral blood mononuclear cells (PBMCs). Apoptosis was measured by flow cytometry with the annexin V/propidium iodide method. RESULTS: Digoxin and ouabain induced apoptosis in Jurkat cells [digoxin 50% inhibitory concentration (IC(50)), 24 nmol/L; ouabain IC(50), 26 nmol/L]. Neither digoxin nor ouabain induced apoptosis in K-562 cells or PBMCs. DLIF was more potent (IC(50), 1.9 nmol/L) and >2-fold more effective than digoxin or ouabain at inducing maximum apoptosis in Jurkat cells. The IC(50) values in the apoptosis assays were >100-fold lower (DLIF) and 20-fold lower (digoxin and ouabain) than the IC(50) required for Na(+)- and K(+)-dependent ATPase (DLIF, 200 nmol/L; digoxin, 910 nmol/L; ouabain, 600 nmol/L). CONCLUSION: DLIF selectively induces apoptosis in a human acute T-cell lymphoblastic leukemia cell line but not in K-562 cells or PBMCs. These data suggest a new physiological role for these endogenous hormone-like factors.

The immunoregulatory effects of gangliosides involve immune deviation favoring type-2 T cell responses.

Gangliosides, sialic acid-containing glycosphingolipids present in most cell membranes, are thought to participate in the maintenance of immune privilege and tumor-induced immunosuppression. However, the mechanisms responsible for their immunomodulatory activity remain poorly understood. The purpose of this study was to investigate whether gangliosides are able to modulate the balance of type-1/type-2 T cell responses and to characterize the cellular mechanisms involved. The effects of different gangliosides on anti-CD3-stimulated murine splenocytes and purified T cells were studied. The presence of gangliosides during T cell activation reduced the expression of interferon-gamma (IFN-gamma) and enhanced that of interleukin (IL)-4, suggesting a shift toward a type-2 response. Intracellular cytokine staining demonstrated that gangliosides inhibited IFN-gamma production in CD4+, CD8+, and natural killer (NK)1.1+ cell populations and enhanced IL-4 in CD4+ T cells. The ganglioside-mediated enhancement in IL-4 production was independent of changes in endogenous IFN-gamma, did not occur with cells from CD1d-deficient mice, and was partially inhibited by anti-CD1d antibodies. The inhibitory effects on IFN-gamma were independent of endogenous IL-4 or the presence of NKT cells and were unaffected by anti-CD1d antibodies. These results suggest that gangliosides may modify the immunological environment by promoting immune deviation in favor of type-2 T cell responses.

Modulation of acute inflammation by targeting glycosaminoglycan-cytokine interactions.

Glycosaminoglycans (GAGs) located on cellular membranes and the extracellular matrix (ECM) are able to interact with chemokines and pro-inflammatory cytokines, leading to local cytokine/chemokine accumulation. The tissue-bound cytokines/chemokines function in promoting leukocyte migration and activation, contributing to local inflammation. Hence, targeting of GAG-cytokine interactions may provide an avenue for the attenuation of inflammatory responses. A cationic peptide (MC2) derived from the heparin-binding sequence of mouse IFN-gamma was previously shown by our laboratory to delay allograft rejection in an animal model. In order to further investigate potential anti-inflammatory properties of the MC2 peptide, we have studied its activity in an acute peritoneal inflammation model. Groups of C57Bl/6 mice were injected intraperitoneally with either ConA or thioglycollate and treated with saline (control), the MC2 peptide or two control cationic peptides, poly-l-lysine (PLL) and poly-l-arginine (PLA). Treatment with the MC2 peptide, but not PLA or PLL, resulted in statistically significant reductions in total cell numbers, concentration of total proteins and concentrations of pro-inflammatory cytokines (TNFalpha, IL-6 or IL-1 beta) in peritoneal lavage fluids, without alterations to the qualitative cellular composition of the exudate. These results suggest that targeting GAG-cytokine interaction is a viable approach to reduce inflammation.

Failure to deplete anti-Galalpha1-3Gal antibodies after pig-to-baboon organ xenotransplantation by immunoaffinity columns containing multiple Galalpha1-3Gal oligosaccharides.

BACKGROUND: The impact of anti-Galalpha1-3Gal (alphaGal) antibodies on the acute humoral xenograft rejection (AHXR) of pig organs transplanted in baboons is unclear. METHODS: Twenty-three baboons underwent heterotopic pig heart transplantation (Tx). Groups A (n = 5) and B (n = 6) received non-transgenic and human decay accelerating factor (hDAF) pig hearts, respectively, without any treatment. Groups C (n = 5) and D (n = 7) were transplanted with non-transgenic and hDAF organs, respectively, and the exclusive treatment was repeated extracorporeal immunoadsorptions (EIA) before and after Tx with an alphaGal column containing disaccharide (DI), trisaccharide (TRI) 2 and pentasaccharide (PENTA) oligosaccharides. RESULTS: In group A, 3 of 5 xenografts underwent hyperacute rejection (HAR). No xenograft from groups B, C and D experienced HAR, most of them failing from AHXR. Immediately after Tx and up to day 2, the level of immunoglobulin (Ig)M and IgG anti-alphaGal DI, TRI2 and TRI6, and anti-pig hemolytic antibody (APHA) antibodies decreased in all the groups by 80 to 96% compared with the concentration present before Tx. From day 3 to AHXR, a sustained increase of anti-alphaGal IgM DI, TRI2 and TRI6, and APHA occurred in all groups. EIA depleted anti-alphaGal IgM and APHA before Tx, but it did not modify the increase of these antibodies after Tx. Baboon serum samples before Tx, pre-incubated in vitro with 1 mg/ml of DI, TRI2 and TRI6, had an average of 93% reduction of anti-alphaGal IgM antibodies specific against each one of these alphaGal oligosaccharides. In contrast, at AHXR, the average reduction after in vitro pre-incubation with either 1 or 5 mg/ml of DI, TRI2 and TRI6 was 40%. CONCLUSIONS: The EIA reduces anti-alphaGal and APHA antibodies, preventing the HAR of non-transgenic pig hearts transplanted in baboons, as does hDAF expression. However, EIA does not modify the level of anti-alphaGal IgM and APHA antibodies after Tx nor the AHXR of either non-transgenic or hDAF pig organs. The increase in anti-alphaGal IgM after Tx was similar for the different antibodies of the anti-alphaGal polymorphism, and was only partially neutralized in vitro with the specific alphaGal oligosaccharide.

Targeting of glycosaminoglycan-cytokine interactions as a novel therapeutic approach in allotransplantation.

BACKGROUND: Glycosaminoglycans (GAGs) are heteropolysaccharides present as integral components of the extracellular matrix (ECM), cell and basement membranes. GAGs play an important role in immune and inflammatory responses because of their ability to interact with cytokines and chemokines, promoting the localization of these molecules onto the ECM or cell membranes at specific anatomical sites. The main goal of these studies was to test the hypothesis that interference with the binding of cytokines/chemokines to GAGs will interfere with a graft rejection response. METHODS: MC-2, a cationic peptide derived from the sequence of the heparin-binding domain of mouse interferon gamma, was used as an inhibitor of the binding of cytokines/chemokines to GAGs. The effects of this peptide were studied in an allogeneic transplantation model involving vascularized rat skin flaps. RESULTS: The MC-2 peptide was found to inhibit binding of interferon-gamma, as well as that of the chemokines, interleukin-8, interferon gamma inducible protein-10, and regulated on activation normal T cell expressed and secreted (RANTES), to GAGs in vitro. Direct administration of MC-2 in an allogeneic skin flap transplantation model resulted in a significantly delayed time of rejection, from 5.4 +/- 0.5 days (control; n=6) to 12.6 +/- 1.6 days (treated animals; n=10). Histopathologic analysis of the skin biopsies was consistent with the delayed rejection process in those animals receiving the peptide, showing only mild signs of rejection up to day 11 (in contrast, all control animals had rejected their flaps by day 6). CONCLUSIONS: These results are consistent with the idea that GAG-cytokine interactions constitute valid therapeutic targets and suggest the potential applicability of such an approach in the prevention of graft rejection.

Soluble cytokine receptors in biological therapy.

Due to their fundamental involvement in the pathogenesis of many diseases, cytokines constitute key targets for biotherapeutic approaches. The discovery that soluble forms of cytokine receptors are involved in the endogenous regulation of cytokine activity has prompted substantial interest in their potential application as immunotherapeutic agents. As such, soluble cytokine receptors have many advantages, including specificity, low immunogenicity and high affinity. Potential disadvantages, such as low avidity and short in vivo half-lifes, have been addressed by the use of genetically-designed receptors, hybrid proteins or chemical modifications. The ability of many soluble cytokine receptors to inhibit the binding and biological activity of their ligands makes them very specific cytokine antagonists. Several pharmaceutical companies have generated a number of therapeutic agents based on soluble cytokine receptors and many of them are undergoing clinical trials. The most advanced in terms of clinical development is etanercept (Enbrel, Immunex), a fusion protein between soluble TNF receptor Type II and the Fc region of human IgG1. This TNF-alpha; antagonist was the first soluble cytokine receptor to receive approval for use in humans. In general, most agents based on soluble cytokine receptors have been safe, well-tolerated and have shown only minor side effects in the majority of patients. Soluble cytokine receptors constitute a new generation of therapeutic agents with tremendous potential for applications in a wide variety of human diseases. Two current areas of research are the identification of their most promising applications and characterisation of their long-term effects.

Revascularización miocárdica arterial completa con ambas arterias mamarias sin circulación extracorpórea / Off-Pump total arterial revascularization with both internal thoracic arteries without extracorporeal circulation

Introducción. Tector ha descrito la técnica de revascularización arterial completa usando múltiples anastomosis con ambas arterias mamarias internas. Para reducir la morbimortalidad quirúrgica nos hemos propuesto realizar esta técnica sin circulación extracorpórea. Pacientes y métodos. Desde abril de 1998 hemos realizado revascularización 'tipo Tector' sin circulación extracorpórea en 92 pacientes, 74 varones (80 por ciento) y 18 mujeres (20 por ciento), con una edad media de 64,9 ñ 8,1 años (rango, 42-78). La angiografía preoperativa puso de manifiesto que diecinueve (20,5 por ciento) pacientes tenían lesión significativa de tronco común y 58 (63 por ciento) triple vaso. Cuarenta pacientes (43,5 por ciento) presentaban angina inestable, 24 (26 por ciento) enfermedad vascular periférica significativa y 26 (28 por ciento) diabetes. Ambas mamarias fueron disecadas sin pedículo, y anastomosadas como injerto en 'Y' o 'T'. La permeabilidad de las anastomosis se evaluó con Doppler intraoperatorio en 24 (26 por ciento) pacientes mediante estudio angiográfico. Resultados. Se han realizado 274 anastomosis distales, 122 (45 por ciento) en la cara lateral y/o inferior del corazón y 69 (25 por ciento) de tipo secuencial, con una media de 2,98 bypass por paciente. En el 59,8 por ciento de los pacientes se realizó bypass triple, en el 22 por ciento bypass doble, en el 17 por ciento bypass cuádruple, y en un paciente bypass quíntuple. El 64,9 por ciento de los pacientes fue extubado en las primeras 6 h. Sólo un paciente (1,1 por ciento) precisó balón intraaórtico, y 3 (3,2 por ciento) inotrópicos durante el período postoperatorio. La mortalidad hospitalaria fue de 3 (3,2 por ciento) pacientes. Un paciente (1,1 por ciento) fue reoperado por sangrado, y el 78,3 por ciento no se transfundieron. Tres pacientes (3,2 por ciento) sufrieron mediastinitis. No se presentaron eventos neurológicos. Tras 7,77 ñ 2,8 meses de seguimiento, todos los pacientes se encuentran asintomáticos y la tasa de permeabilidad global es del 94 por ciento. Conclusiones. Esta técnica posibilita una revascularización arterial completa y una reducción en la morbimortalidad quirúrgica (AU)

Chlamydia pneumoniae, enfermedades cardiovasculares y asma / Chlamydia pneumoniae, cardiovascular diseases and asthma

Como patógeno respiratorio, C. pneumoniae ha sido asociada con crisis de asma bronquial como uno de varios factores desencadenantes. Las evidencias seroepidemiológicas, histopatológicas y de biología molecular que relacionan además la infección por C. penumonaie con la producción de angiopatía coronaria van en aumento. Se revisan los antecedentes que han permitido encontrar esta relación, incluyendo nuestra propia experiencia, aunque se desconoce el grado de responsabilidad atribuible a la infección en esta afección degenerativa

Cardiomioplastia dinámica: resultados / Dynamic cardiomyoplasty: results

El objetivo del presente trabajo fue evaluar los resultados inmediatos y a los 17 (5-40) meses promedio, de la Cardiomioplastia en pacientes con miocardiopatía dilatada en insuficiencia cardíaca con capacidad funcional III - IV (New York Heart Association), a pesar del tratamiento médico. Fueron intervenidos 10 pacientes con una edad promedio de 60,7 ñ 5,5 años. En 5 de ellos el origen de su afección fue idiopático y en los otros 5 isquémico necrótico; con valores promedio de fracción de eyección del ventrículo izquierdo: 22,2 ñ 5,3 por ciento, diámetro diastólico del ventrículo izquierdo: 74 ñ 6 mm, aurícula izquierda: 59 ñ 7 mm, y fracción de acortamiento: 13,9 ñ 3,4 por ciento. Para tener una mejor prueba de la capacidad funcional se les hizo una prueba de caminata de 6 minutos desarrollando un promedio de 332 ñ 134 m. Se produjo 1 muerte en el postoperatorio temprano y 2 durante el seguimiento alejado. En 6 pacientes que completaron los 6 meses del postoperatorio se han encontrado los siguientes resultados promedio: clase funcional: 1,7 ñ 0,5, fracción de eyección del ventrículo izquierdo: 32 ñ 0,3 por ciento, diámetro diastólico del ventrículo izquierdo: 72 ñ 9 mm, fracción de acortamiento: 19 ñ 7 por ciento, caminata a los 6 minutos: 391 ñ 28 m. La cardiomioplastia ha revelado a los 6 meses de seguimiento mejoría en la capacidad funcional y en la función sistólica del ventrículo izquierdo

Cardiomioplastia dinámica: resultados / Dynamic cardiomyoplasty: results

El objetivo del presente trabajo fue evaluar los resultados inmediatos y a los 17 (5-40) meses promedio, de la Cardiomioplastia en pacientes con miocardiopatía dilatada en insuficiencia cardíaca con capacidad funcional III - IV (New York Heart Association), a pesar del tratamiento médico. Fueron intervenidos 10 pacientes con una edad promedio de 60,7 ñ 5,5 años. En 5 de ellos el origen de su afección fue idiopático y en los otros 5 isquémico necrótico; con valores promedio de fracción de eyección del ventrículo izquierdo: 22,2 ñ 5,3 por ciento, diámetro diastólico del ventrículo izquierdo: 74 ñ 6 mm, aurícula izquierda: 59 ñ 7 mm, y fracción de acortamiento: 13,9 ñ 3,4 por ciento. Para tener una mejor prueba de la capacidad funcional se les hizo una prueba de caminata de 6 minutos desarrollando un promedio de 332 ñ 134 m. Se produjo 1 muerte en el postoperatorio temprano y 2 durante el seguimiento alejado. En 6 pacientes que completaron los 6 meses del postoperatorio se han encontrado los siguientes resultados promedio: clase funcional: 1,7 ñ 0,5, fracción de eyección del ventrículo izquierdo: 32 ñ 0,3 por ciento, diámetro diastólico del ventrículo izquierdo: 72 ñ 9 mm, fracción de acortamiento: 19 ñ 7 por ciento, caminata a los 6 minutos: 391 ñ 28 m. La cardiomioplastia ha revelado a los 6 meses de seguimiento mejoría en la capacidad funcional y en la función sistólica del ventrículo izquierdo (AU)

Complicaciones vasculares en el síndrome del opérculo torácico / Vascular complications in thoracic outlet compression syndrome

Se presentan cuatro pacientes con complicaciones vasculares en miembros superiores provocadas por síndrome comprensivo del opérculo torácico que fueron sometidos a tratamiento quirúrgico. Se realizó una revisión histórica del tema así como de los temas controvertidos referidos a su diagnóstico, tratamiento y en el caso que éste sea quirúrgico los distintos procedimientos efectuados sobre elementos blamdos, óseos, cartilaginosos y musculo-tendinosos. Referente al diagnóstico se promueve la utilización de los nuevos métodos incruentes como el Ecodoppler. Con respecto al tratamiento quirúrgico creemos que los mejores resultados se obtienen con la resección de la primera costilla. La evolución de cuatro pacientes fue satisfactoria incluso en uno de ellos que requirió reiteradas intervenciones

Complicaciones vasculares en el síndrome del opérculo torácico / Vascular complications in thoracic outlet compression syndrome

Se presentan cuatro pacientes con complicaciones vasculares en miembros superiores provocadas por síndrome comprensivo del opérculo torácico que fueron sometidos a tratamiento quirúrgico. Se realizó una revisión histórica del tema así como de los temas controvertidos referidos a su diagnóstico, tratamiento y en el caso que éste sea quirúrgico los distintos procedimientos efectuados sobre elementos blamdos, óseos, cartilaginosos y musculo-tendinosos. Referente al diagnóstico se promueve la utilización de los nuevos métodos incruentes como el Ecodoppler. Con respecto al tratamiento quirúrgico creemos que los mejores resultados se obtienen con la resección de la primera costilla. La evolución de cuatro pacientes fue satisfactoria incluso en uno de ellos que requirió reiteradas intervenciones (AU)

El sistema respiratorio en Arctocephalus australis (Pinnipedia, Otariidae) I - Macroanatomia y microanatomia de traquea y vias aereas extrapulmonares / The respiratory system in Arctocephalus australis (Pinnipedia, Otariidae) I- Macroanatomy and microanatomy of trachea and extrapulmonary airways

Este trabajo apresenta os resultados da organizaçäo histológica e histoquímica da traquéia e brônquios primários. A presença de uma lâmina subepitelial e uma camada de músculo liso no córion superficial, provavelmente relacionada com um mecanismo funcional respiratório, säo definidos. A estrutura das glândulas da traquéia e brônquios, bem como o modo e tipo de secreçäo säo também descritos