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Autoinmunidad
- 1. Autoinmunidad Fredy RS Gutierrez, MD, MsC, PhD
- 2. Origen de la autoinmunidad infections
- 4. As infecções estão resolvidas no momento do diagnóstico de doença auto-imune 152 | NOVEMBER 2003 | VOLUME 1 www.nature.com/revie
- 5. Autoimunidad inducida por infecciones Hipótesis del “terreno fértil”
- 6. De la imuno-especificidad… Paul Ehrlich : 1854-1915 ‘ Horror autotoxicus ’ Ilya Ilyich Mechnikov May 16, 1845 – 1916 Les 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"
- 7. ...a la tolerancia imunológica Sir Frank Macfarlane Burnet 1899-1985 Sel-no self hemagglutination Peter Brian Medawar 1915-1987 Tolerance Nobel Prize in Medicine in 1960 "for discovery of acquired immunological tolerance"
- 9. Criterios para reconocimiento de enfermedades autoinmunes Immunology Today 14: 426-430, 1993 The autoimmune diseases 4th ed Noel R Rose Ian R Mackay Elsevier 2006
- 10. Enfermedades autoinmunes 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
- 11. Enfermedades autoinmunes Clasificación Todos los componentes del sistema inmune participan en la patogénesis de enfermedades autoinmunes
- 13. Factores ambientales Hipótesis 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
- 14. Factores ambientales Hipótesis 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
- 15. Factores ambientales Hipótesis 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
- 16. Factores ambientales Hipótesis 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
- 17. Enfermedades autoinmunes son más frecuentes en mujeres 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.
- 18. Mecanismos propuestos para la predominancia de enfermedades autoinmunes en muejres A.Lleoetal./AutoimmunityReviews7(2008)626–630
- 21. Selección timica “ Homunculo inmunológico?” Nat. Rev. immunol vol 4 2004 sept p689
- 22. Tolerancia central NATURE|Vol 435|2 June 2005|doi:10.1038/nature03724
- 23. Tolerancia central Nanture Vol 435:2 June 2005
- 24. Mecanismos de tolerancia Regulación de la respuesta inmune 78 | jAnuAry 2008 | vOLumE 8 www.nature.com/reviews/immunol
- 26. Autoimunidad Mimetismo molecular Clin. Rev. Allergy Immunol. 2007 ISSN 1080-0549/07:111-118 Doença Auto-antígenos Patógenos Refs Febre 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
- 27. Autoimunidad Mimetismo molecular * 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 Table 10-3 Molecular mimicry between proteins of infectious organisms and human host proteins Protein* Residue + Sequence ± Human cytomegalovirus E2 HLA-DR molecule 79 60 P D P L G R P D E D V T E L G R P D A E Poliovirus VP2 acetylcholine receptor 70 176 S T T K E S R G T T T V I K E S R G T K Papilloma virus E2 Insulin receptor 76 66 S L H L E S L K D S V Y G L E S L K D L Rabies virus glycoprotein Insulin receptor 147 764 T K E S L V I I S N K E S L V I S E Klebsiella pneumoniae nitrogenase HLA – B27 molecule 186 70 S R Q T D R E D E K A Q T D R E D L Adenovirus 12 E1B α - Gliadin 384 206 L R R G M F R P S Q C N L G Q G S F R P S Q Q N Human immunodeficiency virus p24 Human IgG constant region 160 466 G V E T T T P S G V E T T T P S Measles virus P3 Corticotropin 13 18 L E C I R A L K L E C I R A C K Measles virus P3 Myelin basic protein 31 61 E I S D N L G Q E E I S F K L G Q E
- 30. Fiebre reumática Burmester, Color Atlas of Immunology © 2003 Thieme
- 31. Algumas Doenças auto-imunes causadas por infecções Fiebre reumática Burmester, Color Atlas of Immunology © 2003 Thieme
- 32. 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
- 33. Doenças auto-imunes causadas por infecções Síndrome de Guillain-Barré
- 35. Algumas Doenças auto-imunes causadas por infecções Tiroiditis auto-inmune (Hashimoto) Eur J immunol 2002 32 3435-3442
- 36. Diabetes tipo 1
- 37. Diabetes tipo 1 J.Immunol 2005 174: 7481-7486
Notas del editor
- Para responder a estas perguntas temos q entender a etiologia das DAI q não são somente provocadas por defeitos na regulação do sistema imunológico. Existe tb uma susceptibilidade genética e desencadeantes ambientais q resultam nestas doenças....
- 19/09/08 Box 1 | Difficulties in associating viruses and autoimmune diseases Hit-and-run events As the viral nucleic acid has been cleared by the time of diagnosis of autoimmune disease, a causative association is hard to prove. Persistent infections Latency can be an important problem in finding the agent unless biopsy of the target organ is a Possibility. Viral strains Different strains of the same virus vary in the immune responses they generate,which might alter their effects on ongoing autoimmunity. Timing of infection The pre-clinical autoimmune process undergoes distinct phases that can vary in their susceptibility to viral interference. Abrogation of autoimmunity by infections Viral infections can ameliorate autoimmune disease. Regulatory T cells (Tregs) Viral infections might, in certain instances, stimulate or activate lymphocytes that recognize autoantigens, but have effector functions that dampen the autoaggressive response, rather than exacerbating it.
- 19/09/08 Figure 3 | The fertile-field hypothesis. a | A diagrammatic representation of the fertile-field hypothesis. The top arrow represents gender and genetics, which are relatively constant throughout the lifetime of the host. By contrast, the factors represented by the lower arrow (age and immune history) are constantly changing. The fertile field is shown as a temporary period that follows virus infection, and which can vary depending on the type, anatomical location and duration of the virus-induced inflammatory response. b | The fertile-field hypothesis and virus-induced autoimmune disease. The fertile-field hypothesis explains how viral infections can induce and/or expand autoreactive T cells, and can cause them to become autoaggressive, leading to clinical autoimmune disease. Infection with the right virus at the right time creates a transient, localized fertile field. The autoreactive cells generated can either crossreact with viral antigens (molecular mimicry) or can react only with autoantigens (bystander activation). In the former case, virus-specific cells have the potential to become activated directly and accelerate the development of clinical disease. In the latter case, an intermediate mechanistic link that causes activation of autoaggressive bystanders in the presence of a viral infection with entirely different antigenic specificity is postulated. As described in the text, such bystander activation probably occurs through professional or non-professional ANTIGEN-PRESENTING CELLS (APC) that process and present self antigen (determinant spreading). Pro-inflammatory cytokines and chemokines also might contribute to non-antigen-specific (TCR-independent) bystander activation, although we believe the contribution of this form of bystander activation is minor. IFN, interferon; IL-12, interleukin-12; MHC, major histocompatibility complex; TCR, T-cell receptor; TNF- α, tumour necrosis factor- α.
- 19/09/08 A autoimunidade é um fenomeno que foi reconhecido por cientistas desde tempos distantes. Paul Erlich In 1905, Ehrlich and Morgenroth (1) observed that goats injected with red blood cells (RBCs) from another goat always made hemolytic antibodies directed against the immunizing cells, but these antisera never reacted against the recipient's own RBCs Furthermore, they deliberately immunized a goat with its own RBCs and also observed that no antibody response was elicited. They coined the Latin phrase horror autotoxicus to describe this situation.
- 19/09/08 A autoimunidade é um fenomeno que foi reconhecido por cientistas desde tempos distantes. Paul Erlich In 1905, Ehrlich and Morgenroth (1) observed that goats injected with red blood cells (RBCs) from another goat always made hemolytic antibodies directed against the immunizing cells, but these antisera never reacted against the recipient's own RBCs Furthermore, they deliberately immunized a goat with its own RBCs and also observed that no antibody response was elicited. They coined the Latin phrase horror autotoxicus to describe this situation.
- Doenças autoimunes podem ocorrer em qualquer parte do organismo
- Quais são os fatores que estão envolvidos no desenvolvimento de autoimunidade?
- 19/09/08 Na verdade, como demonstrado posteriormente, muitas infecções tem a capacidade de incidir de maneira negativa na indução de autoimunidade
- 19/09/08 Na verdade, como demonstrado posteriormente, muitas infecções tem a capacidade de incidir de maneira negativa na indução de autoimunidade
- 19/09/08 Na verdade, como demonstrado posteriormente, muitas infecções tem a capacidade de incidir de maneira negativa na indução de autoimunidade
- 19/09/08 Na verdade, como demonstrado posteriormente, muitas infecções tem a capacidade de incidir de maneira negativa na indução de autoimunidade
- 19/09/08 Autoimmune diseases affect approximately 8% of the population, 78% of whom are women. Figure 1. Major autoimmune diseases, comparing the incidence of disease in women (white bar) to the incidence in men (black bar) by percentage. Modified from (5). Falar de gênero e mecanismos de tolerância
- Figure 13.42. There are several ways in which infectious agents could break self-tolerance. Because some antigens are sequestered from the circulation, either behind a tissue barrier or within the cell, an infection that breaks cell and tissue barriers might expose hidden antigens (first panel). A second possibility is that infectious agents might trigger expression of co-stimulators on antigen-presenting cells that have taken up tissue antigens, thereby inducing an autoimmune response (second panel). In some cases, infectious agents might bind to self proteins. Because the infectious agent induces a helper T-cell response, any B cell that recognizes the self protein will also receive help (third panel). Such responses should be self-limiting once the infectious agent is eliminated, because at this point the T-cell help will no longer be provided. Molecular mimicry might result in infectious agents inducing either T- or B-cell responses that can cross-react with self antigens (fourth panel). Polyclonal T-cell activation by a bacterial superantigen could overcome clonal anergy, allowing an autoimmune process to begin (last panel).
- 19/09/08 HASSALL’S CORPUSCLES Small clusters or concentric whorls of stratified keratinizing epithelium in the thymic medulla. They probably represent end-stage differentiated epithelial cells either participating in negative selection of thymocytes and/or undergoing apoptosis themselves. Diverse tissues are rperesented by promiscuous gene expression in medullary thymic epithelial cells (mTECs). Genes identified as overexpressed in mouse mTECs compared with conrtical TECs using gene chip analysys were assigned to tissues according to their predominant expression (where) applicable using combined information from the public database (GNF Gene Expression Atlas) and Swissprot (see online links box) and the literature. About one quarter of all mETCs overexpressed gener could be categorized as tissue-restricted according to this approach and are shown. Note the diversity of tissues that meet these criteria. The fraction of tissue-restricted genes is probably underestimed given their low expression levels in mTECs and the limited sensitivity of the gene array method. Tools to assess in parallel the expression profile of thousands of coding and non-coding RNAs (or even the transcriptome of whole genomes) by hybridizing labelled RNA or cDNA from cells or tissues to microarrays that contain the known antisense target sequences Falar de síndrome APECED poliendrocrinopatia – candidiasis – distrofia ectodermica autoimune , em humanos
- 19/09/08
- 19/09/08 Células B podem fazer edição de receptores, principalmente na medula. A figura representa o que acontece no baço Neste processo participam varios componentes do sistema complemento (na medula principalmente). E BAFR no baço.
- 19/09/08 Deficiencia de foxp3 em humanos produce uma sindrome denominada IPEX (desregulação imune, poliendocrinopatia, enteropatia e herança ligada ao X) antes chamado XPID ou XLAAD Em camundongos "scurfy mice" Foxp3 está no cromosomo Xp 11.23-Xq13.3 Curr Op. Rheumatol 2003 15:430-435 Superexpressão de foxp3 leva a puca quantidade de celulas T, que prolifera normalmente e producem pouca IL-2 desenvolvimento timico normal hipoplasia de linfonodos Para induzir treg se necesita TGF-b via SMAD2 induzido por radicais de oxigenio (superoxido) Falaer em iNKT e CD1d Todas as resposta imunes devem pasar normalmente por uma fase de iniciaçãi, expansão e contração
- Outro exemplo: Um epitopo expresso na proteina UL6 do virus do herpes tipo1 reage cruzadamente com um antigeno da cornea. E um modelo experimental de keratite automune. Virus da encefalite murina de Theiler (TMEV) induz células reativas contra a proteina viral VP-1 , que transferidas inducem enfcefalite em camundongos normais.. Falar de epitopo patogenico e peptideos que injetados induzem EAE... Na mesma proteina alguns residuos induzem doença em hospedeiros susceptiveis de uma maneira mais rápida..p. ex. plp139-151 ou plp178-191 em contraste com plp 104-117 que induz mais lentamente e mais leve(determinante não dominante)... E as semelhanças entre resopsta antiviral e auto imune Se enghenerados para apresentarem peptideos proprios do hospedeiro, virus podem induzir diretamente autoimunidade.
- Falar de auto-imunidade induzida por vacinas, tem sido descritos casos epidemiologicamente associados mas evidencias experimentais não são facilmente obtidas. Ultimos nos aumentou vacinação e também auto-imunidade Associação com vacina de HBV, rubeola, BCG, Artrite, HLA-DR4 poucos casos e não da para generalizar...Lupus (familiar) Guillain Barre, esclerose multipla Não há dados conclusivos que ´permitam associar o uso das vacinas com apareciemtno de autoimunidade.
- Associado com vírus Epstein Bar, Citomegalovírus, HTLV, HIV, e diversos vírus respiratórios. Fig 1 Structural similarities between ganglioside GM1 in nerve cell membranes and a Campylobacter jejuni lipopolysaccharide. Adapted, with permission, from a review by Ang27
- In Graves’ disease, the antibodies do not destroy the thyroid but act as if they are TSH (i.e., they bind and activate the TSH receptor) (agonist) (compare this to the Hashimoto’s thyroiditis; previous slide) Hablar de la encefalitis de rasmussen, apesar de não ser demostrado que se produce por infecciones, es unejemplo de anticorpos agonistas, contra o RGlu3
- A morte das células da tireoides pode ser devida a lise por celulas t cd8, indução de apoptose ou ativação do sistema complemento por imuno complexos circulantes
- For insulin-dependent diabetes mellitus, CTL kill the cells (cells that make Figure 13.41. Virus infection can break tolerance to a transgenic viral protein expressed in pancreatic β cells. Mice made transgenic for the lymphocytic choriomeningitis virus (LCMV) nucleoprotein under the control of the rat insulin promoter express the nucleoprotein in their pancreatic β cells, but do not respond to this protein and therefore do not develop an autoimmune diabetes. However, if the transgenic mice are infected with LCMV, a potent antiviral cytotoxic T-cell response is elicited, and this kills the β cells, leading to diabetes. It is thought that infectious agents can sometimes elicit T-cell responses that cross-react with self peptides (a process known as molecular mimicry) and that this could cause autoimmune disease in a similar way. insulin)
- Tolerance is an Adaptive Process