Autoinmunidad
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Transcript of Autoinmunidad
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AutoinmunidadAutoinmunidadFredy RS Gutierrez, Fredy RS Gutierrez, MD, MsC, MD, MsC,
PhDPhD
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2
infections
Origen de la autoinmunidad
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As infecções estão resolvidas no momento do diagnóstico de doença
auto-imune
152 | NOVEMBER 2003 | VOLUME 1 www.nature.com/revie
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Autoimunidad inducida por infecciones
Hipótesis del “terreno fértil”
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Paul Ehrlich:1854-1915‘Horror autotoxicus’
Ilya Ilyich MechnikovMay 16, 1845 – 1916Les anti-émolysines naturelles.
Karl Landsteiner K. Landsteiner,K 1900. The Specificity of Serological Reactions. Volume 27, p. 357-371. Harvard University Press. Cambridge, Massachusetts.
Nobel Prize in Medicine in 1908“in recognition of their work on immunity”
Nobel Prize in Medicine in 1930 "for his discovery of human blood groups"
De la imuno-especificidad…
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Sir Frank Macfarlane Burnet1899-1985Sel-no selfhemagglutination
Peter Brian Medawar1915-1987Tolerance
Nobel Prize in Medicine in 1960"for discovery of acquired immunological tolerance"
...a la tolerancia imunológica
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““Horror auto-toxicus”Horror auto-toxicus”Respuesta anafiláctica a un péptido propioRespuesta anafiláctica a un péptido propio
Nat Immunol. 2001 Mar;2(3):216-22.
•Una vez que la tolerancia se Una vez que la tolerancia se pierde no hay recuperación.pierde no hay recuperación.
•Varios procesos en Varios procesos en respuesta autoinmunerespuesta autoinmune
lung liver Heart
Thymic expression
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Criterios para reconocimiento de enfermedades autoinmunesCriterios para reconocimiento de enfermedades autoinmunes
Immunology Today 14: 426-430, 1993The autoimmune diseases 4th ed Noel R Rose Ian R Mackay Elsevier 2006
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Pénfigo
Esclerosis multiple
Síndrome deSjogren
Feibre Reumática
Hepatitis autoinmune
Colitis ulcerativa
Síndrome de Goodpasture
Diabetes
Uveitis autoinmune
Anemia hemolítica autoinmune
Enfermedad de Addison
Artritis reumatoide
Ooforitis autoinmune
Enfermedades autoinmunesEnfermedades autoinmunes
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Enfermedades autoinmunesClasificación
Todos los componentes del sistema inmune participan en la patogénesis de enfermedades autoinmunes
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AUTOINMUNIDAD
FACTORES PATOGENICOSFACTORES PATOGENICOSFatores del indivíduo
•Género•Factores Genéticos•Tolerancia/regulación inmunológicas conprometidas•Reconocimiento inmunológico conprometidos
Factores ambientales•Agentes infecciososAgentes infecciosos
•Mimetismo molecularMimetismo molecular•ContaminaciónContaminación•FármacosFármacos
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Factores ambientales
Hipótesis de Hipótesis de la higienela higiene
BMJ. 1989 November 18; 299(6710): 1259–1260. NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | FEBRUARY 2002 | 135N Engl J Med, Vol. 347, No. 12 Sept 19, 2002 p91
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Factores ambientales
Hipótesis de la higieneHipótesis de la higiene
BMJ. 1989 November 18; 299(6710): 1259–1260. NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | FEBRUARY 2002 | 135
N Engl J Med, Vol. 347, No. 12 Sept 19, 2002 p91
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Factores ambientales
Hipótesis de la higieneHipótesis de la higiene
BMJ. 1989 November 18; 299(6710): 1259–1260. NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | FEBRUARY 2002 | 135
N Engl J Med, Vol. 347, No. 12 Sept 19, 2002 p91
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Factores ambientales
Hipótesis de la higieneHipótesis de la higiene
BMJ. 1989 November 18; 299(6710): 1259–1260. NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | FEBRUARY 2002 | 135
N Engl J Med, Vol. 347, No. 12 Sept 19, 2002 p91
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Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 11, November 2004 Whitacre, CC. Sex differences in autoimmune disease. Nature Immunol. 2001;2:777–80.
Enfermedades autoinmunes son más frecuentes en mujeres
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Mecanismos propuestos para la predominancia de enfermedades autoinmunes en muejres
A.Lleoetal./AutoimmunityReviews7(2008)626–630
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Tolerancia inmunológica
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Tolerancia inmunológica
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Selección timica“Homunculo inmunológico?”
Nat. Rev. immunol vol 4 2004 sept p689
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NATURE|Vol 435|2 June 2005|doi:10.1038/nature03724
Tolerancia central
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Nanture Vol 435:2 June 2005
Tolerancia central
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Mecanismos de toleranciaRegulación de la respuesta inmune
78 | jAnuAry 2008 | vOLumE 8 www.nature.com/reviews/immunol
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Factores del hospedero que influyen en la respuesta inmune
GenéticosGenéticos• MHC• No-MHC
– Co-estimulación• CTLA-4 (Graves )• PD-1 (DM-1, AR)
– Receptores de reconocimiento patrón (PRRs)• TLR (LES)• NODLRR• INFLAMASSOMA
– CARD-Helicase
– MMP– AIRE– ...otros genes...
Enfermedades autoinmunes son poligénicasEnfermedades autoinmunes son poligénicas
Nature. 2003 May 29;423(6939):506-11Curr Biol Aug 2005; 15;15;R581
J Clin Endocrinol Metab. 2007 Aug;92(8):3162-70Neuro Endocrinol Lett. 2008 Jun;29(3):334-40
PLoS Pathog 2007 3(12): e152
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AutoimunidadMimetismo molecular
Clin. Rev. Allergy Immunol. 2007 ISSN 1080-0549/07:111-118
Doença Auto-antígenos Patógenos RefsFebre reumática Miosina cardíaca, tropomiosina, laminina,
vimentina, actina, keratina, N-acetil-glucosamina
Streptoccocus pyogenes 10,11,12
Miastenia gravis Receptor de acetilcolina, neurofilamentos Herpes virus, Hemophilus influenzae 3,13, 14
Esclerose múltipla Proteina basica da mielina Coronavirus, measles, mumps, EBV, herpes
4,15,16,17
Guillain-Barré Gangliosidos, lipo-oligossacarídeos Campylobacter jejuni 18,19
Diabetes melitus tipo 1
Antigenos das ilhotas: GAD 65, proinsulina carboxipeptidase H
Coxsackievirus B, Rotavirus, Herpes, Hepatite C, Rhino-hanta retrovirus
18,19
Espondilite anquilosante
HLA-B27, colágeno tipo I, II, IV Klebsiella pneumoniae, Chlamydia 4, 22, 23
Sindrome antifosfolipideo
B2-glicoproteina I Hemophilus influenza, Neisseria gonorrea, toxina tetanica, CMV
24,25
Lupus eritematoso sistêmico
Ro-60kD, NMDA, dsDNA EBV, polisacarideo de pneumococo 26,27,28,29
Cardiomiopatia chagasica
Proteina ribosomal 23kD, miosina, proteina B13, peptido Cha
Trypanossoma cruzi 3,4,8,9
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Table 10-3 Molecular mimicry between proteins of infectious organisms and human host proteinsTable 10-3 Molecular mimicry between proteins of infectious organisms and human host proteins
Protein* Residue+ Sequence±
Human cytomegalovirus E2HLA-DR molecule
7960
P D P L G R P D E DV T E L G R P D A E
Poliovirus VP2acetylcholine receptor
70176
S T T K E S R G T TT V I K E S R G T K
Papilloma virus E2Insulin receptor
7666
S L H L E S L K D SV Y G L E S L K D L
Rabies virus glycoproteinInsulin receptor
147764
T K E S L V I I SN K E S L V I S E
Klebsiella pneumoniae nitrogenaseHLA – B27 molecule
18670
S R Q T D R E D EK A Q T D R E D L
Adenovirus 12 E1Bα - Gliadin
384206
L R R G M F R P S Q C NL G Q G S F R P S Q Q N
Human immunodeficiency virus p24Human IgG constant region
160466
G V E T T T P SG V E T T T P S
Measles virus P3Corticotropin
1318
L E C I R A L KL E C I R A C K
Measles virus P3Myelin basic protein
3161
E I S D N L G Q EE I S F K L G Q E
* In each pair, the human protein is listed second. The proteins in each pair have been show to exhibit immunological cross-reactivity+ Each number indicates the position on the intact protein of the amino-terminal amino acid in the listed sequence.± Amino acid residues are indicated by single-letter code. Identical residues are shown in blue.SOURCE: Adapted from M.B.A. Oldstone 1987. Cell 50:819
Autoimunidad
Mimetismo molecular
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Esclerosis Esclerosis múltiplemúltiple
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Esclerosis múltiple
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Fiebre reumática
Burmester, Color Atlas of Immunology © 2003 Thieme
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Algumas Doenças auto-imunes causadas por infecções
Fiebre reumática
Burmester, Color Atlas of Immunology © 2003 Thieme
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Doenças auto-imunes causadas por infecções
Síndrome de Guillain-Barré
Trends in Immunology Volume 25, Issue 2, February 2004, Pages 61-66 PMID: 15102364
Winer, J. B BMJ 2008;337:a671
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Doenças auto-imunes causadas por infecções
Síndrome de Guillain-Barré
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Tiroidopatias autoinmunes
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Algumas Doenças auto-imunes causadas por infecções
Tiroiditis auto-inmune (Hashimoto)
Eur J immunol 2002 32 3435-3442
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Diabetes tipo 1
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Diabetes tipo 1
J.Immunol 2005 174: 7481-7486
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ConclusionesConclusiones• Enfermedades autoinmunes son poligénicas• Enfermedades autoinmunes son precipitadas por factores
ambientales• Homeostasia imunológica es garantizada a través de la
tolerancia• Es difícil atribuir o encontrar la etiologia de enfermedades
autoinmunes • Equilibrio co-evolucionario: mecanismos de evasión de
microorganismos pueden generar costos al hospedero
Fundamental Immunology, 6th Edition Paul, William E. Lippincott Williams & Wilkins 2008