Autoinmunidad*
Origen de la autoinmunidad
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....
As infecções estão resolvidas no momento do diagnóstico de doença auto-imune
152 | NOVEMBER 2003 | VOLUME 1 www.nature.com/revie
19/09/08
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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.
Autoimunidad inducida por infecciones
Hipótesis del “terreno fértil”
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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.
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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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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
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...a la tolerancia imunológica
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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
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Nat Immunol. 2001 Mar;2(3):216-22.
Una vez que la tolerancia se pierde no hay recuperación.
Varios procesos en respuesta autoinmune
lung
liver
Heart
Thymic
expression
Immunology Today 14: 426-430, 1993
The autoimmune diseases 4th ed Noel R Rose Ian R Mackay Elsevier 2006
Enfermedades autoinmunes
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Clasificación
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Contaminación
Fármacos
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NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | FEBRUARY 2002 | 135
N Engl J Med, Vol. 347, No. 12 Sept 19, 2002 p91
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Na verdade, como demonstrado posteriormente, muitas infecções tem a capacidade de incidir de maneira negativa na indução de autoimunidade
Factores ambientales
NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | FEBRUARY 2002 | 135
N Engl J Med, Vol. 347, No. 12 Sept 19, 2002 p91
19/09/08
Na verdade, como demonstrado posteriormente, muitas infecções tem a capacidade de incidir de maneira negativa na indução de autoimunidade
Factores ambientales
NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | FEBRUARY 2002 | 135
N Engl J Med, Vol. 347, No. 12 Sept 19, 2002 p91
19/09/08
Na verdade, como demonstrado posteriormente, muitas infecções tem a capacidade de incidir de maneira negativa na indução de autoimunidade
Factores ambientales
NATURE REVIEWS | IMMUNOLOGY VOLUME 2 | FEBRUARY 2002 | 135
N Engl J Med, Vol. 347, No. 12 Sept 19, 2002 p91
19/09/08
Na verdade, como demonstrado posteriormente, muitas infecções tem a capacidade de incidir de maneira negativa na indução de autoimunidade
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
19/09/08
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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
Mecanismos propuestos para la predominancia de enfermedades autoinmunes en muejres
A.Lleoetal./AutoimmunityReviews7(2008)626–630
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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
NATURE|Vol 435|2 June 2005|doi:10.1038/nature03724
Tolerancia central
Tolerancia central
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.
Mecanismos de tolerancia
78 | jAnuAry 2008 | vOLumE 8 www.nature.com/reviews/immunol
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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
Factores del hospedero que influyen en la respuesta inmune
Genéticos
MHC
No-MHC
Co-estimulación
TLR (LES)
J Clin Endocrinol Metab. 2007 Aug;92(8):3162-70
Neuro Endocrinol Lett. 2008 Jun;29(3):334-40
PLoS Pathog 2007 3(12): e152
Autoimunidad
Doença
Auto-antígenos
Patógenos
Refs
Streptoccocus pyogenes
4,15,16,17
Guillain-Barré
18,19
Klebsiella pneumoniae, Chlamydia
4, 22, 23
24,25
Trypanossoma cruzi
3,4,8,9
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
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* 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
Table 10-3 Molecular mimicry between proteins of infectious organisms and human host proteins
Protein*
Residue+
Sequence±
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
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
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Algumas Doenças auto-imunes causadas por infecções
Fiebre reumática
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
Associado com vírus Epstein Bar, Citomegalovírus, HTLV, HIV, e diversos vírus respiratórios.
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Síndrome de Guillain-Barré
Tiroidopatias autoinmunes
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)
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Tiroiditis auto-inmune (Hashimoto)
Eur J immunol 2002 32 3435-3442
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J.Immunol 2005 174: 7481-7486
For insulin-dependent diabetes mellitus, CTL kill the b cells (cells that make
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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
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