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Nutrizione, Immunità e infiammazione - Prof. Vincent Castronovo

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Presentazione del Prof. Vincent Castronovo su "Nutrizione, Immunità e Infiammazione" al Corso di medicina metabolica e funzionale di Bologna - 3-4 Luglio 2015

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Nutrizione, Immunità e infiammazione - Prof. Vincent Castronovo

  1. 1. Immunità e Infiammazione VINCENT CASTRONOVO
  2. 2. MANGIARE SENZA VENIR MANGIATI
  3. 3. Difesa LIVELLO I Le barriere LIVELLO II Immunità innata LIVELLO III Immunità specifica
  4. 4. PRIMA LINEA DI DIFESA BARRIERE
  5. 5. Le barriere Prima linea di difesa, le barriere naturali rappresentano un ostacolo contro l’invasione degli intrusi. Soltanto gli agenti patogeni sono in grado di superarle. Il non rispetto dell’integrità delle barriere provoca l’ingresso nel nostro organismo di agenti inerti cioè macromolecole che saranno considerate alla stregua di agenti patogeni e diventeranno oggetto di reazione da parte dei nostri sistemi difensivi.
  6. 6. Le barriere
  7. 7. PELLE +/- 2 m2
  8. 8. Epitelio respiratorio 2 m2
  9. 9. Alveoli polmonari 130 m2
  10. 10. BARRIERA INTESTINALE 1000 m2 5µm
  11. 11. BARRIERA INTESTINALE
  12. 12. LEAKY GUT
  13. 13. FLORA INTESTINALE
  14. 14. SECONDA LINEA DI DIFESA Il nemico è penetrato nel nostro territorio!
  15. 15. SECONDA LINEA DI DIFESA Cellule Citochine/Chemochine Fattori solubili La Guerra
  16. 16. NOZIONE DI IMPORTANZA FONDAMENTALE I sistemi di difesa innati e adattativi si sono sviluppati in base al principio per cui solo i veri nemici predatori sono in grado di attraversare le barriere.
  17. 17. L’esercito di cellule difensive…
  18. 18. Un gruppo di globuli bianchi è chiamato granulociti o leucociti polimorfonucleati (PMNs). I Granulociti sono composti da 3 tipi di cellule identificate come neutrofili, eosinofili e basofili in base alle caratteristiche di colorazione con determinati agenti. Queste cellule rivestono una particolare importanza ai fini dell’eliminazione dall’organismo di batteri e parassiti. Granulociti o leucociti polimorfonucleati (PMN)
  19. 19. MONOCITI E MACROFAGI I macrofagi vengono attivati da una varietà di stimoli diversi nel corso della risposta immunitaria. Uno dei primi segnali di attivazione viene dalle chemochine. La fagocitosi stessa è un importante stimolo di attivazione. I macrofagi sono attivati anche dalle citochine secrete dalle cellule T helper [IFN-gamma] e dai mediatori della risposta infiammatoria oltre che da diversi sottoprodotti batterici (come i LPS)
  20. 20. MASTOCITI
  21. 21. CELLULE NK Le cellule NK ("Natural killers", assassine naturali) rappresentano dal 5 al 16 % della popolazione totale dei linfociti umani. Fanno parte di una sottopopolazione di linfociti, i LGL (Large Granular Lymphocytes). Queste cellule assassine provengono dalla differenziazione delle cellule staminali linfoidi prodotte nel midollo osseo.
  22. 22. Citochine Agenti di comunicazione intercellulare
  23. 23. Immunità innata Immunità innata (naturale, aspecifica) La risposta all’invasione ha bisogno di 3 elementi: Riconoscimento Eliminazione Comunicazione
  24. 24. Riconoscimento dei microrganismi da parte del sistema immunitario innato Immunità innata
  25. 25.  Cellule dendritiche  Macrofagi  Polinucleati  Enterociti Immunità innata
  26. 26. DC MF PN Un gioco sempre uguale di recettori invariati rispetto alle molecole dei batteri Gram- Lipopolisaccaridi (LPS) Gram+ Peptidoglicani Acido lipoteicoico Funghi Mannani Immunità innata PAMPS: Pathogen Associated Molecular Patterns
  27. 27. Percezione intrinseca di ciò che è batterico, vale a dire ciò che è ostile… Immunità innata
  28. 28. La tolleranza intrinseca al self dell’immunità naturale è stata acquisita dopo centinaia di milioni di anni di evoluzione in seguito ai quali si sono selezionati dei recettori capaci di distinguere i sottoprodotti batterici e non dai sottoprodotti del self… Immunità innata
  29. 29. Limiti  Repertorio antibatterico limitato  Nessun adattamento alle mutazioni batteriche  Nessuna percezione dei batteri intracellulari Immunità innata
  30. 30. Immunità innata I PAMPS sono riconosciuti da recettori sulla superficie delle cellule del sistema immunitario innato, i PRMs e PRRs( Pattern-Recognition molecole/recettori) Recettori di endocitosi Recettori del mannosio dei macrofagi Proteine di secrezione CRP Recettore di segnalizzazione La famiglia dei recettori TOLL (TLR)
  31. 31. Recettori TOLL: Recettori dei PAMPS
  32. 32. RECETTORI TOLL
  33. 33. Ricezione del segnale
  34. 34. Chinasi Agenti di comunicazione intracellulare Enzimi che traducono l’informazione proveniente dall’esterno per coordinare una risposta cellulare appropriata.
  35. 35. Chinasi Cosa fanno?
  36. 36. Fattore trascrizionale Capo controllo dell’immunità e dell’infiammazione NF-kB
  37. 37. GENE A Start Stop Elementi di controllo Segnali A A A A A A A A RNA messagero Proteine IL FATTORE DI TRASCRIZIONE NF-kB Trascrizione Traduzione FATTORI DI TRASCRIZIONE
  38. 38. NF-kB Il maestro della guerra
  39. 39. I-kB Il maestro della pace
  40. 40. NF-kB
  41. 41. Recettori Gene A Gene B Gene C NF-kB
  42. 42. SEGNALI Recettori Vie di segnalizzazione Gene A Gene B Gene C NF-kBNF-kB
  43. 43. SEGNALI Recettori Gene A Gene B Gene C Vie di segnalizzazione NF-kB
  44. 44. SEGNALI Recettori Gene A Gene B Gene C Vie di segnalizzazione NF-kB
  45. 45. Induttori di NF-kB
  46. 46. Geni la cui trascrizione è sotto il controllo del NF-kB
  47. 47. NF-kB e infiammazione COX TNF
  48. 48. IKK Chinasi che controlla l’infiammazione
  49. 49. IKK e attivazione del NF-kB
  50. 50. NF-kB
  51. 51. - Risposta immunitaria - Infiammazioni - Sopravvivenza allo stress (ossidoriduzioni, ionizzazioni,…) - Traumi neurologici, morbo di Alzheimer, morbo di Parkinson, tumori, artrite reumatoide. NF-kB: Ruoli biologici
  52. 52. Sali d’oro Corticoidi : Aumento sintesi di Ik-B e/o antagonismo diretto di NF-kB
  53. 53. Le armi del nostro sistema di difesa
  54. 54. Difese aspecifiche I fattori solubili
  55. 55. Difese aspecifiche Umorali
  56. 56. La CRP è stata isolata da Tillett e Frances nel 1930 (Rockefeller University), nel siero di pazienti che presentavano uno stato infiammatorio acuto. Questa proteina reagiva al polisaccaride C del pneumococco. La CRP è un marcatore precoce, sensibile e specifico della reazione infiammatoria e aumenta proporzionalmente alla sua intensità. Compare nelle sei ore successive all’esordio dell’ infiammazione acuta. Il tasso aumenta ed è massimo dopo due giorni. In presenza di calcio, la CRP si lega specificamente ai residui di fosfocolina della parete dei batteri. La CRP attiva per questo tramite la via classica del complemento in assenza di anticorpi e opsonizza i leganti in previsione della loro fagocitosi. Proteina C-reattiva
  57. 57. Proteina C-reattiva
  58. 58. Difesa aspecifica La febbre
  59. 59. IL COMPLEMENTO
  60. 60. Il complemento
  61. 61. La fagocitosi
  62. 62. Fagociti
  63. 63. Oxygen Dependent Myeloperoxidase dependent reactions H2O2 + O2 -2O2 - + 2H+ Superoxide dismutase H2 O2 + Cl - myeloperoxidase OCl - + H2O H2O + O2 -2 H2 O2 catalase 2OCL - + H2O 1O2 - + Cl - + H2O Produzione di radicali liberi
  64. 64. La reazione infiammatoria è un processo fisiologico indispensabile alla sopravvivenza del nostro organismo continuamente esposto all’aggressione di organismi batterici, agenti fisici e chimici …
  65. 65. L’infiammazione è il campo di battaglia in cui le nostre difese specifiche e aspecifiche combattono il nemico.
  66. 66. Infiammazione
  67. 67. DIFESA INFIAMMAZIONE
  68. 68. LIVELLO I Le Barriere LIVELLO II Immunità innata LIVELLO III Immunità specifica Immunità adattativa
  69. 69. Immunità adattativa • Là dove ha luogo la maggior parte dell’azione evolutiva • Dipende dal contatto tra le cellule ospiti e gli antigeni (anticorps generation) • Due categorie principali di risposte : immunità umorale e immunità cellulare
  70. 70. Difesa specifica Il sistema immunitario
  71. 71. Il sistema immunitario INNATO ADATTATIVO
  72. 72. Immunità adattativa L’immunità adattativa ricorre alle stesse armi dell’immunità innata
  73. 73. Gli anticorpi
  74. 74. Antigeni Antigene : Molecola estranea che provoca una reazione immunitaria Virus dell’influenza Proteina di superficie RICONOSCIUTA dai linfociti ANTIGENE > reazione immunitaria
  75. 75. Il timo
  76. 76. Il timo: Una scuola per i linfociti
  77. 77. I linfociti T • 2 popolazioni principali CD4+: Direttore d’orchestra della risposta immunitaria adattativa CD8+: Partecipano all’ immunità cellulare (citotossicità) • Circolazione permanente tra il sangue e gli organi linfoidi secondari. • Cellula T naive prima dell’incontro con l’Ag specifico. Dopo l’incontro si parla di cellula T effettrice armata.
  78. 78. • I LT naive circolano in permanenza tra gli organi linfatici secondari all’incontro con l’Ag specifico • LT CD4+ sono programmati per diventare cellule secretrici di citochine e cellule memoria • LT CD8+ sono programmati per diventare delle cellule effettrici citotossiche (CTL CD8+) e delle cellule memoria I linfociti T
  79. 79. I linfociti B completano la maturazione diventando competenti nel midollo osseo Linfociti B
  80. 80. Figure 9-1 part 1 of 2 La risposta immunitaria umorale è mediata da molecole di anticorpi secrete dalle plasmacellule. L’antigene associato a una immunoglobulina di superficie è internalizzato, degradato in peptidi e presentato su un MHC di classe II. Questo porta all’attivazione delle cellule T, risultando nella secrezione di citochine. Linfociti B
  81. 81. Figure 9-5 part 2 of 2 Linfociti B
  82. 82. Figure 9-19 part 1 of 2 Proprietà e funzioni di diverse classi di immunoglobuline umane
  83. 83. Immunità specifica Le risposte alle cellule B si concentrano sui patogeni al di fuori delle cellula; le risposte alle cellule T si concentrano sui patogeni intracellulari
  84. 84. Mucose e immunità
  85. 85. Immunità mucosale (tonsille, adenoidi, placche di Peyer, appendice, linfonodi mesenterici) mucus no mucus here mucus Un sistema immunitario a compartimenti che è, in un certo qual modo, separato dal SI sistemico Transcytose des antigènes
  86. 86. Le cellule M facilitano l’assimilazione degli Ag
  87. 87. IgA Mucosale • 2 sottoclassi nell’uomo • IgA1- monomerica, IgA predominante nel siero • IgA2- polimerica, si riscontra soprattutto nelle secrezioni esterne. • J-chain- richiesta per la formazione dell’IgA polimerica, J-chain gko di topo- IgA monomerica ma è secreta. • La perdita di 13 aa in una zona cerniera diminuisce la suscettibilità dell’IgA2 alla divisione proteolitica.
  88. 88. L’IgA dimerico consiste in due monomeri di IgA legati da una catena J. Le cellule B individuali sono destinate alla secrezione di IgA sia monomerica sia dimerica.
  89. 89. Le IgA polimereiche rappresentano l’immunità adattativa principale presente nell’intestino
  90. 90. Sistema Immunitario Comune alle Mucose (CMIS)
  91. 91. Tolleranza mucosale • Induzione di un’assenza di risposta sistemica mediante somministrazione di antigene i.n. o orale. • L’idea: evitare lo sviluppo di allergie alimentari. • Alto dosaggio unico, basse dosi multiple. • Assenza di risposta sistemica– in presenza di risposta mucosale alle IgA
  92. 92. • Un solo recettore di struttura data su ciascuna cellula (e sulle sue cellule figlie). • Una multitudine di recettori diversi a livello della popolazione Immunità adattativa
  93. 93. TCR : T cell receptor BCR : B cell receptor « Il » recettore specializzato delle cellule dell’immunità adattativa Immunità adattativa Il suo legante : l’antigene
  94. 94. Fa fronte alla diversità dei batteri e alle loro mutazioni mediante una generazione aleatoria e continua di nuovi recettori Vantaggi Immunità adattativa
  95. 95. Immunità adattativa Percezione analitica di sequenze peptidiche ma nessuna percezione intrinseca di ciò che è batterico o meno, ostile o meno
  96. 96. Immunità adattativa Percepisce i batteri intracellulari grazie al sistema di campionamento e di presentazione da parte delle molecole del Complesso Maggiore di Istocompatibilità (CMH) Vantaggi
  97. 97. Connessione immunità innata– immunità acquisita TNF
  98. 98. Il supporto del SELF : il Complesso Maggiore di Istocompatibilità (CMH, sistema HLA nell’uomo)
  99. 99. CMH : Complexe Majeur d’Histocompatibilité = empreintes digitales des cellules Protéines servant de “présentoir” aux antigènes TUTTE le cellule del corpo: CMH di classe 1 1 1 Linfociti B e macrofagi : CMH di classe 1 E di classe 2 1 2 1 2 Antigene + CMH 1 = risposta cellulare Antigene + CMH 2 = risposta umorale Antigeni e Proteine del CMH
  100. 100. Rapporto fra CMH, tipo di linfocita e reazione immunitaria scatenata Ag presentato su CMH I Linfociti T citotossici (o CD8) RISPOSTA CELLULARE riconosce Ag presentato su CMH II Linfociti T ausiliari (o CD4) Linfociti B RISPOSTA UMORALE riconosce attiva
  101. 101. Antigeni e proteine del CMH
  102. 102. Le molecole del CMH di Classe I permettono alle cellule T CD8 di “sorvegliare” la presenza di patogeni nel citoplasma. Le molecole CMH di Classe II permettono alle cellule T CD4 di “ sorvegliare ” la presenza di patogeni negli spazi extracellulari e intravescicolari. Patogeno CD4 Patogeno CD8
  103. 103. Panoramica della Risposta Immunitaria
  104. 104. REGOLAZIONE DELLE RISPOSTE IMMUNITARIE SPECIFICHE I LINFOCITI T CD4 Th1, Th2, TH17 e Treg
  105. 105. OFFESA INFIAMMAZIONE Allergie Malattie Autoimmuni
  106. 106. MALATTIE AUTOIMMUNI Poliartrite reumatoide Psoriasi Sclerosi a placche Morbo di Crohn Lupus eritematoso Guillain-Barré Tiroiditi ...
  107. 107. Insieme di disordini immunitari che vanno da malattie molto comuni come l’artrite reumatoide, la tiroidite di Hashimoto, il morbo di Graves, l’aterosclerosi a patologie meno frequenti come la sclerosi a placche, il diabete di tipo I, il lupus eritematoso sistemico…. L’autoimmunità è la causa a monte di oltre 80 patologie croniche che colpiscono il 20% circa della popolazione dei paesi industrializzati. MALATTIE AUTOIMMUNI
  108. 108. Mimetismo antigenico
  109. 109. Artrite reumatoide
  110. 110. Tiroidite di Hashimoto
  111. 111. Diabete Di Tipo I
  112. 112. Aterosclerosi
  113. 113. Sclerosi a placche
  114. 114. ALLERGIE Riniti Congiuntiviti Eczemi Asma Diarree ...
  115. 115. Attivazione del Sistema immunitario contro molecole o organismi non patogeni ALLERGIE
  116. 116. Allergeni
  117. 117. Allergie Alimentari E contro la flora Batterica
  118. 118. Allergie cutanee
  119. 119. TRATTAMENTI CLASSICI DELLE MALATTIE INFIAMMATORIE: INIBIRE LA PRODUZIONE DI EICOSANOIDI
  120. 120. Meccanismo d’azione biochimico Influsso Na+ Cortisolo Recettore Lipocortina Fosfolipidi della membrana cellulare Prostaglandine leucotrieni Azione Antinfiammatoria
  121. 121. CLASSICI TRATTAMENTI DELLE MALATTIE INFIAMMATORIE FANS: Antinfiammatori non steroidei
  122. 122. Nutrition and immunology: from the clinic to cellular biology and back again. Chandra RK. Proc Nutr Soc. 1999 Aug;58(3):681-3. Diet and immunity have been known to be linked to each other for centuries. In the last 30 years systematic studies have confirmed that nutrient deficiencies impair immune response and lead to frequent severe infections resulting in increased mortality, especially in children. Protein-energy malnutrition results in reduced number and functions of T-cells, phagocytic cells and secretory immunoglobulin A antibody response. In addition, levels of many complement components are reduced. Similar findings have been reported for moderate deficiencies of individual nutrients such as trace minerals and vitamins, particularly Zn, Fe, Se, vitamins A, B6, C and E. For example, Zn deficiency is associated with profound impairment of cell-mediated immunity such as lymphocyte stimulation response, decreased CD4+:CD8+ cells, and decreased chemotaxis of phagocytes. In addition, the level of thymulin, which is a Zn-dependent hormone, is markedly decreased. The use of nutrient supplements, singly or in combination, stimulates immune response and may result in fewer infections, particularly in the elderly, low-birth-weight infants and malnourished critically-ill patients in hospitals. The interactions between nutrition and the immune system are of clinical, practical and public health importance.
  123. 123. Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes. Ajuwon KM, Spurlock ME. J Nutr. 2005 Aug;135(8):1841-6. Fatty acids and their metabolites regulate gene expression and immunological pathways. Furthermore, obese individuals frequently have increased circulating fatty acid concentrations, and localized inflammation in adipose tissue may facilitate the systemic inflammation associated with the insulin resistance of obesity. Although palmitate induces inflammation (i.e., activates proinflammatory pathways) in myotubes, the effects of fatty acids on inflammatory processes in adipocytes have not been established. Therefore, we examined the potential for palmitate, laurate, and docosahexaenoic acid (DHA) to modulate inflammation in 3T3-L1 adipocytes. Palmitate, but not DHA or laurate, induced nuclear factor kappaB (NF-kappaB)-driven luciferase activity and interleukin-6 (IL-6) expression (P < 0.05). Inhibition of fatty acyl Co-A synthase (FACS) with triacsin C suppressed palmitate-induced NF-kappaB activation (P < 0.05), but caused an additive increase in palmitate-induced IL-6 expression (P < 0.05). Disrupting mitogen-activated protein kinase/Erk kinase (MEK) and protein kinase C (PKC) activity with U0126 and Bisindolylmaleimide (Bis), respectively, suppressed palmitate-induced IL-6 expression (P < 0.05), but had no effect on NF-kappaB reporter gene activity (P > 0.05). However, the phosphoinositide-3 kinase (PI3K) inhibitor, wortmannin, alone and additively with palmitate, activated the NF-kappaB reporter gene and induced IL-6 expression (P < 0.05). Palmitate also induced the mRNA expression of tumor necrosis factor alpha (TNFalpha) (P < 0.05), but the increase in mRNA abundance was not reflected in a greater protein concentration in the media (P > 0.05). These data indicate that palmitate induces inflammation in adipocytes, and that this is not a generalized effect of all SFA. Furthermore, PI3K may act constitutively to suppress inflammation. Consequently, inhibition of this enzyme may promote and exacerbate the inflammation in adipose tissue that is associated with obesity and insulin resistance.
  124. 124. PRESA IN CARICO NUTRIZIONALE E FUNZIONALE DELLE MALATTIE DISIMMUNITARIE • Ridurre il rischio di ingresso di antigeni non ostili Digestione, Barriera intestinale • Ridurre l’intensità della risposta infiammatoria Equilibrio AA/EPA, Regolatori del NFKB •Impedire l’accumulo di lesioni ossidative e da carbonili inflitte ai tessuti attaccati • Antiossidanti • Aumentare l’immunotolleranza: Probiotici, Vitamina D
  125. 125. LIVELLO I Le barriere LIVELLO II Immunità innata LIVELLO III Immunità specifica
  126. 126. Medicina nutrizionale Ripristinare le barriere
  127. 127. Tight junctions, leaky intestines, and pediatric diseases. Liu Z, Li N, Neu J. Acta Paediatr. 2005 Apr;94(4):386-93. BACKGROUND: Tight junctions (TJs) represent the major barrier within the paracellular pathway between intestinal epithelial cells. Disruption of TJs leads to intestinal hyperpermeability (the so-called "leaky gut") and is implicated in the pathogenesis of several acute and chronic pediatric disease entities that are likely to have their origin during infancy. AIM: This review provides an overview of evidence for the role of TJ breakdown in diseases such as systemic inflammatory response syndrome (SIRS), inflammatory bowel disease, type 1 diabetes, allergies, asthma, and autism. CONCLUSION: A better basic understanding of this structure might lead to prevention or treatment of these diseases using nutritional or other means.
  128. 128. L-GLUTAMMINA
  129. 129. Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans. Hond ED, Peeters M, Hiele M, Bulteel V, Ghoos Y, Rutgeerts P. Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium. Aliment Pharmacol Ther. 1999 May;13(5):679-85 BACKGROUND: Long-term non-steroidal anti-inflammatory drug (NSAID) intake may induce increased intestinal permeability, eventually resulting in enteropathy. Because increased permeability might be related to cell damage resulting from energy depletion, it was hypothesized that glutamine--the major energy source of the intestinal mucosal cell--might prevent permeability changes. METHODS: The 6-h urinary excretion of 51Cr- EDTA after an oral load of 51Cr-EDTA was used in this study as a measure for intestinal permeability. Healthy volunteers underwent a series of permeability tests: (i) basal test; (ii) test following NSAID (indomethacin); (iii) test following NSAID in combination with glutamine and/or misoprostol. RESULTS: The NSAID induced increased permeability in all volunteers. Pre-treatment with glutamine (3x7 g daily, 1 week before NSAID-dosing) did not prevent the NSAID-induced increase in permeability. Multiple doses of glutamine close in time to NSAID-dosing resulted in significantly lower permeability compared to the NSAID without glutamine. Co-administration of misoprostol with the multiple-dose scheme of glutamine resulted in a further reduction in the NSAID-induced increase in permeability. CONCLUSIONS: Glutamine decreases the permeability changes caused by NSAID-dosing when it is administered close in time, and misoprostol has a synergistic effect.
  130. 130. Inflammation rather than nutritional depletion determines glutamine concentrations and intestinal permeability. Hulsewe KW, van der Hulst RW, van Acker BA, von Meyenfeldt MF, Soeters PB. Clin Nutr. 2004 Oct;23(5):1209-16. AIM: Nutritional depletion has been correlated with low plasma and mucosal glutamine concentrations and with increased intestinal permeability. Since nutritional depletion often is associated with (chronic) inflammatory stress, this study was designed to establish the influence of depletion and inflammation on glutamine concentrations and gut barrier function. METHODS: Anthropometric parameters were calculated from 26 patients who required artificial nutrition. Glutamine concentrations in plasma and gut mucosa, gut permeability and mucosal morphology were assessed. For determination of the degree of inflammation erythrocyte sedimentation rates and (pre)albumin concentrations were measured. On the basis of these parameters patients were divided into two groups having significant inflammatory stress or not. Similarly, a depleted and a non-depleted group was formed based on percentage ideal body weight, fat-free mass index (FFMI) and percentage weight loss. Glutamine concentrations, gut permeability and villus morphology were compared between the groups. RESULTS: The presence of inflammatory activity had significant negative effects on glutamine concentrations in contrast to the presence or absence of nutritional depletion. Similarly, intestinal permeability increased during active inflammation but not in depleted patients. FFMI but not inflammation was related to villus height. CONCLUSIONS: The presence of inflammation significantly affects glutamine concentrations and gut permeability, in contrast to the presence of depletion of body cell mass per se. On the other hand, villus morphology is not influenced by changes in systemic inflammatory activity whereas nutritional status possibly does affect villus height.
  131. 131. Infiammazione L-Glutammina Leaky Gut +
  132. 132. Probiotici Prebiotici
  133. 133. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Lancet 2001 Apr 7;357(9262):1076-9 BACKGROUND: Reversal of the progressive increase in frequency of atopic disease would be an important breakthrough for health care and wellbeing in western societies. In the hygiene hypothesis this increase is attributed to reduced microbial exposure in early life. Probiotics are cultures of potentially beneficial bacteria of the healthy gut microflora. We assessed the effect on atopic disease of Lactobacillus GG (which is safe at an early age and effective in treatment of allergic inflammation and food allergy). METHODS: In a double-blind, randomised placebo-controlled trial we gave Lactobacillus GG prenatally to mothers who had at least one first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma, and postnatally for 6 months to their infants. Chronic recurring atopic eczema, which is the main sign of atopic disease in the first years of life, was the primary endpoint. FINDINGS: Atopic eczema was diagnosed in 46 of 132 (35%) children aged 2 years. Asthma was diagnosed in six of these children and allergic rhinitis in one. The frequency of atopic eczema in the probiotic group was half that of the placebo group (15/64 [23%] vs31/68 [46%]; relative risk 0.51 [95% CI 0.32-0.84]). The number needed to treat was 4.5 (95% CI 2.6-15.6). INTERPRETATIONS: Lactobacillus GG was effective in prevention of early atopic disease in children at high risk. Thus, gut microflora might be a hitherto unexplored source of natural immunomodulators and probiotics, for prevention of atopic disease. Il Lactobacillus GG si è dimostrato efficace nella prevenzione dell’atopia precoce in bambini ad alto rischio. Pertanto la microflora intestinale potrebbe rappresentare una fonte finora inesplorata di immunomodulatori naturali e probiotici per la prevenzione dell’atopia.
  134. 134. Oral probiotic control skin inflammation by acting on both effector and regulatory T cells. Hacini-Rachinel F, Gheit H, Le Luduec JB, Dif F, Nancey S, Kaiserlian D. PLoS One. 2009;4(3):e4903. Probiotics are believed to alleviate allergic and inflammatory skin disorders, but their impact on pathogenic effector T cells remains poorly documented. Here we show that oral treatment with the probiotic bacteria L. casei (DN-114 001) alone alleviates antigen-specific skin inflammation mediated by either protein-specific CD4(+) T cells or hapten-specific CD8(+) T cells. In the model of CD8(+) T cell- mediated skin inflammation, which reproduces allergic contact dermatitis in human, inhibition of skin inflammation by L. casei is not due to impaired priming of hapten- specific IFNgamma-producing cytolytic CD8(+) effector T cells. Alternatively, L. casei treatment reduces the recruitment of CD8(+) effector T cells into the skin during the elicitation (i.e. symptomatic) phase of CHS. Inhibition of skin inflammation by L. casei requires MHC class II-restricted CD4(+) T cells but not CD1d-restricted NK-T cells. L casei treatment enhanced the frequency of FoxP3(+) Treg in the skin and increased the production of IL-10 by CD4(+)CD25(+) regulatory T cells in skin draining lymph nodes of hapten-sensitized mice. These data demonstrate that orally administered L. casei (DN-114 001) efficiently alleviate T cell-mediated skin inflammation without causing immune suppression, via mechanisms that include control of CD8(+) effector T cells and involve regulatory CD4(+) T cells. L. casei (DN- 114 001) may thus represent a probiotic of potential interest for immunomodulation of T cell-mediated allergic skin diseases in human.
  135. 135. Anti-inflammatory effects of bifidobacteria by inhibition of LPS-induced NF-kappaB activation. Riedel CU, Foata F, Philippe D, Adolfsson O, Eikmanns BJ, Blum S. Microbiology Department and Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. c.riedel@ucc.ie. World J Gastroenterol. 2006 AIM: Different strains of bifidobacteria were analysed for their effects on HT-29 intestinal epithelial cells (IECs) in in vitro models both of the non-inflamed and inflamed intestinal epithelium. METHODS: A reporter gene system in HT-29 cells was used to measure levels of NF-kappaB activation after challenge with bifidobacteria or after bacterial pre-treatment following LPS challenge. IL-8 protein and pro-inflammatory gene expression was investigated using normal HT-29 cells. RESULTS: None of the bifidobacteria tested induced activation of nuclear factor kappaB (NF-kappaB) indicating that bifidobacteria themselves do not induce inflammatory events in IECs. However, six out of eight bifidobacteria tested inhibited lipopolysaccharide- (LPS-) induced NF-kappaB activation in a dose- and strain-dependent manner. In contrast, NF-kappaB activation in response to challenge with tumor necrosis factor-alpha (TNF- alpha) was affected by none of the tested bifidobacteria, indicating that the inhibitory effect of bifidobacteria is specific for LPS-induced inflammation in IECs. As shown with two of the six inhibition-positive bifidobacteria, LPS- induced inhibition of NF-kappaB activation was accompanied by a dose- dependent decrease of interleukin 8 (IL-8) secretion and by lower mRNA levels for IL-8, TNF-alpha, cyclooxygenase 2 (Cox-2), and intercellular adhesion molecule 1 (ICAM-1). CONCLUSION: Some strains of bifidobacteria are effective in inhibiting LPS-induced inflammation and thus might be appropriate candidates for probiotic intervention in chronic intestinal inflammation.
  136. 136. Ripristinare gli equilibri   Medicina nutrizionale
  137. 137.   Il rapporto fra gli acidi grassi   Determina l’intensità della reazione infiammatoria
  138. 138. L’intensità della reazione infiammatoria è controllata dalle prostaglandine e dai leucotrieni
  139. 139. Acidei grassi OMEGA-3 I nutrienti antinfiammatori per eccellenza
  140. 140. The role of fish oils in the treatment of rheumatoid arthritis. Cleland LG, James MJ, Proudman SM. Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia. Drugs. 2003;63(9):845-53. Fish oils are a rich source of omega-3 long chain polyunsaturated fatty acids (n-3 LC PUFA). The specific fatty acids, eicosapentaenoic acid and docosahexaenoic acid, are homologues of the n-6 fatty acid, arachidonic acid (AA). This chemistry provides for antagonism by n-3 LC PUFA of AA metabolism to pro-inflammatory and pro-thrombotic n-6 eicosanoids, as well as production of less active n-3 eicosanoids. In addition, n-3 LC PUFA can suppress production of pro-inflammatory cytokines and cartilage degradative enzymes.In accordance with the biochemical effects, beneficial anti-inflammatory effects of dietary fish oils have been demonstrated in randomised, double-blind, placebo-controlled trials in rheumatoid arthritis (RA). Also, fish oils have protective clinical effects in occlusive cardiovascular disease, for which patients with RA are at increased risk.Implementation of the clinical use of anti-inflammatory fish oil doses has been poor. Since fish oils do not provide industry with the opportunities for substantial profit associated with patented prescription items, they have not received the marketing inputs that underpin the adoption of usual pharmacotherapies. Accordingly, many prescribers remain ignorant of their biochemistry, therapeutic effects, formulations, principles of application and complementary dietary modifications. Evidence is presented that increased uptake of this approach can be achieved using bulk fish oils. This approach has been used with good compliance in RA patients. In addition, an index of n-3 nutrition can be used to provide helpful feedback messages to patients and to monitor the attainment of target levels.Collectively, these issues highlight the challenges in advancing the use of fish oil amid the complexities of modern management of RA, with its emphasis on combination chemotherapy applied early. Conformemente agli effetti biochimici si sono dimostrati effetti antinfiammatori interessanti con gli oli di pesce alimentari in studi randomizzati in doppio cieco verso placebo nell’artrite reumatoide (RA). Gli oli di pesce dimostrano anche effetti clinici di protezione nei confronti delle patologie cardiovascolari occlusive nel gruppo di pazienti per i quali la RA rappresenta un maggior rischio. L’applicazione dell’utilizzo clinico di dosi di oli di pesce antinfiammatori è limitata. Nella misura in cui gli oli di pesce non rappresentano per l’industria possibilità di profitti sostanziali del tipo di quelli associati a prodotti brevettati e sottoposti a prescrizione, non hanno ricevuto il contributo di marketing che sostiene l’adozione delle consuete farmacoterapie. Di conseguenza molti prescrittori restano all’oscuro della loro biochimica, degli effetti terapeutici, di formulazioni, principi d’applicazione e modifiche alimentari da associarvi.
  141. 141. Vitamina D
  142. 142. Vitamina D
  143. 143. Vitamina D
  144. 144. Vitamin D: its role and uses in immunology. Deluca HF, Cantorna MT. FASEB J. 2001 Dec;15(14):2579-85. In recent years there has been an effort to understand possible noncalcemic roles of vitamin D, including its role in the immune system and, in particular, on T cell- medicated immunity. Vitamin D receptor is found in significant concentrations in the T lymphocyte and macrophage populations. However, its highest concentration is in the immature immune cells of the thymus and the mature CD-8 T lymphocytes. The significant role of vitamin D compounds as selective immunosuppressants is illustrated by their ability to either prevent or markedly suppress animal models of autoimmune disease. Results show that 1,25-dihydroxyvitamin D3 can either prevent or markedly suppress experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. In almost every case, the action of the vitamin D hormone requires that the animals be maintained on a normal or high calcium diet. Possible mechanisms of suppression of these autoimmune disorders by the vitamin D hormone have been presented. The vitamin D hormone stimulates transforming growth factor TGFbeta-1 and interleukin 4 (IL-4) production, which in turn may suppress inflammatory T cell activity. In support of this, the vitamin D hormone is unable to suppress a murine model of the human disease multiple sclerosis in IL-4-deficient mice. The results suggest an important role for vitamin D in autoimmune disorders and provide a fertile and interesting area of research that may yield important new therapies.
  145. 145. D-hormone and the immune system. Cantorna MT, Mahon BD. J Rheumatol Suppl. 2005 Sep;76:11-20. D-hormone [1,25(OH)2 D3] is an important immune system regulator that has been shown to inhibit development of autoimmune diseases including experimental inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes. Paradoxically, other immune mediated diseases (experimental asthma) and immunity to infectious organisms were not found to be affected by D- hormone treatment. The effectiveness of D-hormone treatment of autoimmune diseases is due to inhibition of the development and function of Th1 cells and the induction of other Th cells including Th2 cells. We report results of microarray analysis of colons from D-hormone treated mice with experimental IBD. Two hundred thirty-nine genes were inhibited and 298 genes were upregulated in the colon by D- hormone treatment of mice with IBD. Of interest was the D-hormone mediated inhibition of 3 tumor necrosis factor-alpha (TNF-alpha, lipopolysaccharide-induced TNF-alpha factor, and TNF receptor) related genes in the colon. It is likely that the effectiveness of D-hormone treatment of experimental autoimmunity is due in part to the inhibition of the TNF family of genes. D-hormone is a selective regulator of the immune system, and the outcome of D-hormone treatment depends on the nature (infectious disease, asthma, autoimmune disease, etc.) of the immune response.
  146. 146. Vitamin D: a natural inhibitor of multiple sclerosis. Hayes CE. Proc Nutr Soc. 2000 Nov;59(4):531-5. Inheriting genetic risk factors for multiple sclerosis (MS) is not sufficient to cause this demyelinating disease of the central nervous system; exposure to environmental risk factors is also required. MS may be preventable if these unidentified environmental factors can be avoided. MS prevalence increases with decreasing solar radiation, suggesting that sunlight may be protective in MS. Since the vitamin D endocrine system is exquisitely responsive to sunlight, and MS prevalence is highest where environmental supplies of vitamin D are lowest, we have proposed that the hormone, 1, 25- dihydroxycholecalciferol (1,25-(OH)2D3), may protect genetically-susceptible individuals from developing MS. Evidence consistent with this hypothesis comes not only from geographic studies, but also genetic and biological studies. Over-representation of the vitamin D receptor gene b allele was found in Japanese MS patients, suggesting it may confer MS susceptibility. Fish oil is an excellent vitamin D source, and diets rich in fish may lower MS prevalence or severity. Vitamin D deficiency afflicts most MS patients, as demonstrated by their low bone mass and high fracture rates. However, the clearest evidence that vitamin D may be a natural inhibitor of MS comes from experiments with experimental autoimmune encephalomyelitis (EAE), a model of MS. Treatment of mice with 1,25-(OH)2D3 completely inhibited EAE induction and progression. The hormone stimulated the synthesis of two anti-encephalitogenic cytokines, interleukin 4 and transforming growth factor beta-1, and influenced inflammatory cell trafficking or apoptosis. If vitamin D is a natural inhibitor of MS, providing supplemental vitamin D to individuals who are at risk for MS would be advisable.
  147. 147. Vitamina D
  148. 148. Ripristinare l’ambiente molecolare originale Medicina nutrizionale
  149. 149. NF-kB
  150. 150. Le spezie possono bloccare l’attivazione del NF-κB
  151. 151. Medicina nutrizionale Spegner e il fuoco
  152. 152. Valutazione
  153. 153. MALATTIE AUTOIMMUNI Valutazione nutrizionale e funzionale • Vitamina D • Microbiota intestinale (Mou) • Permeabilità intestinale ( IgG alimentare) • CRP • Profilo acidi grassi • Indicatori stress ossidativo • Difese antiossidanti

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