Download malattie autoimmuni d`organo: mao

Sezioni Regionali del Veneto, Friuli Venezia Giulia e Trentino Alto Adige
Programma di Formazione Permanente
Corso Residenziale
La Diagnostica di Laboratorio
delle Malattie Autoimmuni Organo-Specifiche
Bassano del Grappa (VI)
7-9 ottobre 2009
Epidemiologia e fisiopatologia delle
malattie autoimmuni d’organo
Marcello Bagnasco e Giampaola Pesce
Di.M.I. Università degli Studi di Genova
Dipartimento di Patologie Immunoendocrinologiche,
A.O.U. San Martino Genova
LA REAZIONE AUTOIMMUNITARIA
E’ INDOTTA DALLA
ROTTURA DELLA TOLLERANZA
IMMUNOLOGICA
NEI CONFRONTI DEL “SELF”
“horror
autotoxicus”
Paul Ehrlich
CHE COSA PUO’ SUCCEDERE
QUANDO UN ANTIGENE VIENE A CONTATTO
CON IL NOSTRO SISTEMA IMMUNITARIO ?
•Risposta immunitaria
Antigene immunogenico
• Tolleranza immunologica
Antigene tollerogenico
MALATTIE
AUTOIMMUNI
D’ORGANO: MAO
…In certe situazioni il sistema immunitario può perdere
il controllo della discriminazione tra self e non-self,
divenendo “intollerante” verso i propri costituenti e
dando origine ad un processo autoimmune ….
produrrà un danno circoscritto ad un organo o ad un
tessuto generando un’alterazione anatomo-funzionale
del distretto colpito che si esprime a livello clinico con
una sintomatologia connessa all’alterata funzione…
Corrado Betterle, Fabio Presotto, Renato Zanchetta
1
The management of the patient with unexpected
autoantibody positivity.
M.Bagnasco, L.Grassia, G.Pesce Autoimmunity Reviews, 2007
SLE
T1D
SS
OTHERS
RA
APS
CD
AITD
Corrado Betterle, Fabio Presotto, Renato Zanchetta
MAO: La presentazione clinica si caratterizza per un danno
d‘organo, le cui conseguenze sono qualitativamente e
quantitativamente differenti in rapporto all’organo
interessato….
Giampaola Pesce, Irene Bossert, Marcello Bagnasco
Relative frequencies of different
autoimmune diseases
QuickTime™ e un
decompressore
sono necessari per visualizzare quest'immagine.
EPIDEMIOLOGIA delle MAO
I dati epidemiologici dipendono da:
~diverse strategie degli studi epidemiologici
~ conoscenza della malattia da parte dei
medici di base
~ esistenza o meno di marcatori specifici
~ affinamento dei metodi diagnostici
Esempi di MAO con bruschi cambiamenti nella loro storia
epidemiologica:
Celiachia :
• 1980 anticorpi anti-gliadina.
• 2006 Catassi et all Coeliac
disease epidemiology is alive and
kicking, especially in the developing
word.
• 2009 prevalenza tra 1:100-1:200
nel mondo
Cirrosi Biliare
Primitiva:
• 1970 anticorpi
anti mitocondrio
Ipofisite
autoimmune:
2007 ?
CONCLUSIONS:
The prevalence of CD in the study group was 1:100 ….
2006 Dec; 41(12):14141(12):141-420
Population screening for coeliac
disease in a low prevalence area in
Italy
G Menardo; R Brizzolara; S Bonassi; A Marchetti; G Dante; C
Pistone; Marenco; V Rabellino; S Buscaglia; R Scarso; M
Murialdo; E Venturino; C Marino; D Descalzi; F Minetti; M
Bagnasco; G Pesce
2
MALATTIE AUTOIMMUNI D’ORGANO
J. Endocrinol. Invest. 31: 1063-1068, 2008
Prevalence of post-partum thyroiditis in Liguria (Italy): An
observational study
U. Filippi, R. Brizzolara, D. Venuti, A. Cesarone, V.A. Maritati, M. Podestà, W.F.
Yung, L.C. Bottaro, A. Orselli, A. Chiappori, M. Schiavo, M. Caputo, S. Bonassi, and M.
Bagnasco
Conclusions: An overall PPT prevalence of about 18% may be
estimated. PPT was also observed in autoantibody-negative
women. Differences with other surveys may be related to both
study protocol and characteristics of the population studied.
1
• Fattori genetici / Familiarità
• Fattori ambientali / esogeni
• Alterazioni dell’immunoregolazione
• Danno immuno-mediato conseguente a reazioni
autoimmunitarie
• Presenza di autoanticorpi circolanti (valore diagnostico)
• Modelli animali di malattia (spontanea / indotta)
sistemiche
Caratteristiche Comuni
Caratteristiche Distintive
2
• Sintomi / Segni generali – Interessamento di più organi e
apparati – Frequente interessamento articolare
• Fondamentalmente (ma non esclusivamente) danno
immunopatologico mediato da anticorpi
• Autoanticorpi verso antigeni ubiquitari (ridotta clearance?)
• Differente ruolo dei fattori esogeni scatenanti?
• Differente ruolo degli steroidi sessuali?
d’organo
Malattie Autoimmuni Sistemiche e
Organo-Specifiche
•Danno d’organo
•Fondamentalmente autoanticorpi organo-specifici
•Molteplici meccanismi effettori sia cellulari che umorali
3
Corrado Betterle, Fabio Presotto, Renato Zanchetta
The autoinflammatory diseases are characterized by
seemingly unprovoked episodes of inflammation, without hightiter autoantibodies or antigen-specific T cells.
…… these illnesses derive from genetic variants of the innate
immune system.
….we define six categories of autoinflammatory diseases…
AUTOIMMUNITÀ
Infiammazione diretta contro il “Self” con ruolo predominante
giocato dalla risposta immunitaria adattiva
AUTOINFIAMMAZIONE
Infiammazione diretta contro il “Self” con ruolo predominante
giocato dalla risposta immunitaria innata
4
PRR: recettori cellulari
che riconoscono i PAMP
e i DAMP
PRR si dividono in base all
diversa funzione,
localizzazione e expressione
in:
•TLR
•NLR
•TREM
•CLR
•ALTRI
PAMP (pathogen associated
molecular pattern): strutture
molecolari conservati espressi
da microbi (LPS, flagelina,
dsRNA, ecc)
DAMP (damaged
associated molecular
patterns): molecole
rilasciate da tessuti
danneggiati
How do Regulatory T Cells Work?
Nature 453, 1051-1057 (19 June 2008)
Corthay, Scandinavian Journal of Immunology 70, 2009
Induction and effector functions of TH17 cells
Estelle Bettelli1, Thomas Korn1,2, Mohamed Oukka1 & Vijay K. Kuchroo1
5
THE ROLE OF T HELPER SUBSETS IN
AUTOIMMUNITY AND ALLERGY MarcVeldhoen
Current Opinion in Immunology 2009, 21:1–6
THE ROLE OF T HELPER SUBSETS IN
AUTOIMMUNITY AND ALLERGY MarcVeldhoen
Current Opinion in Immunology 2009, 21:1–6
Journal of Autoimmunity 29(2007) 310-318
B cell autonomous TLR signaling
and autoimmunity
Almut Meyer-Bahlburg
, David J. Rawlings
QuickTime™ e un
decompressore
e un
sono necessari per QuickTime™
visualizzare quest'immagine.
decompressore
sono necessari per visualizzare quest'immagine.
8 (2009) 400–404
The role of innate immune responses in
autoimmune disease development.
Waldner H et al.
Take-home messages
…..
• Responses of specific DC subsets play a critical role in the
induction and regulation of various autoimmune diseases in
mice.
• TLR-activated BMDCs from EAE-susceptible SJL mice
induce higher frequencies of pro-inflammatory PLP-specific
T cells than those from B10.S mice.
• Strain-specific innate immune responses may control
differential development of spontaneous EAE in PLP TCR
transgenic SJL and B10.S mice.
Prevention of autoimmune disease by induction of
tolerance to Toll-like receptor 7
2007 Aug;27(2):321-33.
Toll-like Receptor 2 Senses b-Cell Death and Contributes to the
Initiation of Autoimmune Diabetes
…..The development of autoimmune diabetes was markedly
inhibited in TLR2- mice but not in TLR4- mice, showing that
TLR2 plays an important role in the initiation of the disease.
Apoptotic b-cell injury could stimulate the priming of
diabetogenic T cells through a TLR2-dependent, but TLR4independent, activation of antigen- presenting cells. These
findings suggest that b-cell death and its sensing via TLR2 may
be an initial event for the stimulation of antigen- presenting cells
and development of autoimmune diabetes.
Hun Sik Kim, et all
T. Hayashia, C. S. Graya, M. Chana, R. I. Tawataoa, L.
Ronacherb, M. A. McGargillc, S. K. Dattad, D. A. Carsona, and M.
Corrb.
PNAS, February 24, 2009 vol 106 no 8
Activation of Toll-like receptors (TLR) contributes to the initiation and
maintenance of chronic inflammation in autoimmune diseases, yet
repeated exposure to a TLR agonist can induce hyporesponsiveness to
subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist,
9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136)
to study TLR7 induced attenuation of inflammatory responses and its
application to autoimmune diseases. Repeated low dose administration
of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2,
-7, and -9 activators and limited the course of neural inflammation in an
experimental allergic encephalomyelitis model. …TLR7 tolerance did
not cause global immunosuppression, because susceptibility to Listeria
monocytogenes infection was not altered. …
6
Regulatory T Cells Prevent Transfer of Type 1 Diabetes in
NOD Mice Only When Their Antigen Is Present In Vivo
2008, 181, 4516 -4522
Regulatory T cells (Tregs) can potentially be used as tools to
suppress pathogenic T cells in autoimmune diseases such as type 1
diabetes…. Current reports in the NOD mouse model of type 1
diabetes are in conflict as to whether suppression of disease by
Tregs is Ag-dependent. …Our data show that Treg numbers in
pancreas are reduced in the absence of Ag and that there are Agdependent differences in the effects of Tregs on pathogenic T cells
in the pancreas. By examining protection from diabetes induced by
T cell transfer, we have clearly demonstrated that Tregs suppress
only in the presence of their Ag and not in mice in which the islets
lack the Treg Ag. …
Norikazu Harii, Christopher J. Lewis, Vasilly Vasko, Kelly McCall,
Uruguaysito Benavides-Peralta, Xiaolu Sun, Matthew D. Ringel, Motoyasu
Saji, Cesidio Giuliani, Giorgio Napolitano, Douglas J. Goetz and Leonard D.
Kohn
Thyrocytes Express a Functional Toll-Like Receptor 3:
Overexpression Can Be Induced by Viral Infection and
Reversed by Phenylmethimazole and Is Associated with
Hashimoto’s Autoimmune Thyroiditis
Molecular Endocrinology 19 (5): 1231-1250 (2005)
Daniel R. Tonkin et al
“Aberrant expression of HLA...”
Aberrant expression of HLA-DR antigen on thyrocytes in Graves'
disease: relevance for autoimmunity.
Hanafusa T, Chiovato L et al. Lancet. 1983 Nov 12;2(8359):1111-5.
8 (2009) 659–662
Regulatory T cells in diabetes
and gastritis
Núria Alonso et all.
Expression of intercellular adhesion molecule-1 (ICAM-1) on
thyroid epithelial cells in Hashimoto's thyroiditis but not in Graves'
disease or papillary thyroid cancer.
Bagnasco M, Caretto A et al. Clin Exp Immunol. 1991 Feb;83(2):309-13.
B7.1 costimulatory molecule is expressed on thyroid follicular cells
in Hashimoto's thyroiditis, but not in Graves' disease.
Battifora M., Pesce G. et al- J Clin Endocrinol Metab. 1998 Nov;83(11):4130-9.
Marazuela M., et all
Regulatory T Cells in Human Autoimmune Thyroid Disease
The Journal of Clinical Endocrinology & Metabolism 91 ( 9): 3639-3646 (2006)
Conclusions:
Although T regulatory cells
are abundant in inflamed
thyroid tissue, they are
apparently unable, in most
cases, to downmodulate the
autoimmune response and the
tissue damage seen in AITD.
Tireopatie autoimmuni
Aspetti fisiopatologici
Tiroidite autoimmune “classica”:
• abbondante infiltrato linfocitario (Th1 > Th2)
• morte dei tireociti per apoptosi
• importanza patogenetica di citochine Th1 – derivate, APC – derivate
• ruolo patogenetico di autoanticorpi ridotto
Tiroidite atrofica (alcune forme):
• ruolo patogenetico di autoanticorpi anti – recettore TSH “bloccanti”
Thyroid. 2001;11(3):233-44. Giordano C,
Richiusa P, Bagnasco M, et all
Science. 1997:14;275(5302):960-3.
Giordano C, Stassi G, De Maria R,
Todaro M, Richiusa P, Papoff G, Ruberti
G, Bagnasco M, Testi R, Galluzzo A.
Hashimoto’s T
Cytokeratin/tunnel
7
Infiltrato linfocitario della tiroide
Nature 453, 1051-1057 (19 June 2008)
Induction and effector functions of TH17 cells
- Tipico reperto della tiroidite
autoimmune
Estelle Bettelli1, Thomas Korn1,2, Mohamed Oukka1 & Vijay K. Kuchroo
- Correlazione tra TPO Ab e infiltrato
linfocitario nella tiroidite autoimmune
…the concept that autoimmune diseases were exclusively mediated
by TH1 cells has been challenged, and the idea that TH17 cells are
an important part of the autoimmune reaction has emerged in light of
the following observations:
1) mice deficient for the TH1 effector cytokine IFNγ develop
enhanced experimental autoimmune encephalomyelitis (EAE)
2) deficiency in the IL-12p35 subunit (specific for IL-12) does not
alter the progression of EAE, but deficiency in either p40 or p19,
which form IL-23, results in a decreased number of TH17 cells and
protection from EAE…
3) the transfer of myelin-reactive IL-17-producing T cells expanded
with IL-23 in vitro induces severe EAE
4) IL-17 has profound pro-inflammatory effects and induces tissue
damage during the course of various autoimmune diseases
- Prevalenza elevata (>40%) di
infiltrati focali negli anziani, specie
nelle donne caucasiche
- Infiltrato presente anche in altre
patologie oltre alla tiroidite
autoimmune
Okayasu et al,
1994
Roth et al,
1997
Lindbergh et
al, 2001
Nature 453, 1051-1057 (19 June 2008)
Induction and effector functions of TH17 cells
Estelle Bettelli1, Thomas Korn1,2, Mohamed Oukka1 & Vijay K. Kuchroo
… Despite the recent major interest in TH17 cells, these cells
may not be the only TH cells that can induce autoimmunity
because TH1 cells can readily transfer organ-specific
autoimmune disease.
It is therefore possible that there is a sequential involvement
and different functions of TH17 and TH1 subsets rather than an
exclusive role of these subsets during the development of
autoimmune diseases and other tissue inflammation. In this
scenario, TH17 cells might facilitate the migration of other TH
cells (such as TH1 cells) into the target tissue, which could
further propagate and modulate inflammation and tissue
damage….
Predicting and Preventing Autoimmunity
Complement
abnormality
A1-B8-DR3
DQ3-DR4
DQ3-DR9
DQ5-DR1
DQ5-DR10
The patient
with already
one AI disease
C1q def.
C4 def.
C2 def.
Family
History
Female
Gender
FcGR2A, FcGR3A,
IL-10, CTLA-4,
PDCD-1, TNFα,
TNFß, C4, MBL,
FASL, FAS, Bcl-2
Infection
Autoantigen-specific signal
Non-antigen-specific signal
HLA
Candidate genes
Selective IgA
deficiency
Autoimmune-prone
individual
Environmental Factors
Disease
Type
Approximated time
until clinical
appearance of disease
Appearance of
Autoantibodies
• anti-Islet cell Abs -> DM
• RF, anti-CCP -> RA
• anti-PL, anti-Ro, anti-La,
anti-dsDNA, anti-nuclear
ribonucleoprotein, anti-HS,
anti-nucleosome, anti-Histone,
anti-rP protein -> SLE
• anti-Ro, anti-La -> Sjorgren’s
• anti-gp120, anti-PDC -> PBC
• ASCA -> crohn’s disease
• Infections (EBV, CMV, HCV, Helicobacter
pylori, Streptococcus pyogenes)
• UV light
• Vaccines (Diphtheria, Tetanus toxoid, Polio and
measles vaccines -> GBS, MMR vaccines -> ITP-like
thrombocytopenia, Rubella vaccine -> Arthritis)
• Drugs (Hydralazine, Quinidine, Procainamide)
• Toxins (Silica dust, aromatic hydrocarbons, aliphatic
chlorinated hydrocarbons, phthalate)
• Silicone implants (?)
• Hormones (pregnancy, ERT, OC, prolactin)
• Smoking
• Stress
Treatment/Prevention
•
•
•
•
Overt autoimmune
disease
Ursodeoxycholic acid tx for PBC
Dietary enrichment with PUFA for SLE
Avoiding UV light and OC for SLE
Aspirin tx for APS
• Vitamin D receptor agonist
• Synthetic peptides
• Molecular mimicry
° Inflammation
•T cell degeneracy
• Aberrant expression
°Adjuvant effect
• Altered self
• Epitope spreading
• anti-PL, anti-Ro, anti-La – 3.4 yrs prior
to SLE
• anti-dsDNA – 2.2 yrs prior to SLE
• anti-Sm, anti-nuclear ribonucleoprotein
– 1.2 yrs prior to SLE
The adjuvant effect in infection in autoimmunty
N.R.Rose Clinic. Rev. Allerg. Immunol. 2007
Yehuda Shoenfeld, M.D
8
Fattori socioeconomici e
autoimmunità
autoimmunità tiroidea
Kondrashova A., et al.
Serological Evidence of Thyroid
Autoimmunity among
Schoolchildren in Two Different
Socioeconomic Environments
The Journal of Clinical Endocrinology & Metabolism
93 ( 3): 729-734 (2008)
The prevalence of thyroid autoimmunity is
lower in Russian Karelia than in Finland.
This difference was not related to ethnic
background or HLA-DQ alleles. The results
support the idea that the Russian Karelian
environment, which is characterized by
inferior prosperity and standard of hygiene,
may provide protection against thyroid
autoimmunity.
Trends in Immunology Vol 30 No 8; 2009
Infections and autoimmunity – friends or foes?
S Kivity, N Agmon-Levin, M Blank and Y Shoenfeld
QuickTime™ e un
decompressore
sono necessari per visualizzare quest'immagine.
Fattori socioeconomici
Seiskari T., et al. Clin Exp Immunol 148:47–52, 2007
The EPIVIR Study Group Allergic sensitization and
microbial load–a comparison between Finland and
Russian Karelia.
Kondrashova A., et al. Ann Med 37:67–72, 2005
A six-fold gradient in the incidence of type 1 diabetes at
the eastern border of Finland.
Kondrashova A., et al. Ann Med 40 (3) 223-31, 2008
The EPIVIR Study Group Lower economic status and
inferior hygienic environment may protect against celiac
disease.
Trends in Immunology Vol 30 No 8; 2009
Infections and autoimmunity – friends or foes?
S Kivity, N Agmon-Levin, M Blank and Y Shoenfeld
Ten principles that summarize the relationship between infection and autoimmunity
1. Infections can cause autoimmune diseases.
2. Different infectious agents can trigger autoimmunity.
3. An infection can trigger an individual with an underlying immune dysregulation to
express an overt autoimmune disease.
4. Infectious agents can determine the presence of disease-specific autoantibodies and clinical manifestations.
5. In many cases, it is not a single infection, but rather the ‘burden of infections’
during life that is responsible for induction of autoimmunity.
6. Infections during childhood can be implicated in the development of autoimmune
diseases in adulthood.
7. Infections can protect individuals from some autoimmune diseases.
8. The same infectious agent can induce one specific autoimmune disease and
protect from another autoimmune disease.
9. Molecular mimicry, epitope spreading, bystander activation and polyclonal
activation can induce autoimmunity after infections via innate and adaptive immune
responses.
10. Genetic susceptibility might explain why only a subgroup of individuals will
develop autoimmunity after infections.
APECED (SPA tipo I)
difetto genetico della tolleranza
centrale attribuita a mutazioni del
gene AIRE
SINDROME DI CANALE SMITH
difetto dell’apoptosi dovuto alla
mutazione del gene Fas e del gene
della caspasi
9
Journal of Autoimmunity 32 (2009) 231–239
The etiology of autoimmune thyroid disease: A
story of genes and environment
Yaron Tomer, Amanda Huber
Soluble CTLA-4 in autoimmune thyroid diseases: Relationship
with clinical status and possible role in the immune response
dysregulation
Daniele Saverino, Renata Brizzolara, Rita Simone, Alessandra Chiappori,
Francesca Milintenda-Floriani, Giampaola Pesce, Marcello Bagnasco
… Autoimmune thyroid diseases arise due to complex interactions
between environmental and genetic factors. Significant progress
has been made in our understanding of the genetic and
environmental triggers contributing to AITD. However, the
interactions between genes and environment are yet to be defined.
Among the major AITD susceptibility genes that have been
identified and characterized is the HLA-DR gene locus, as well as
non-MHC genes including the CTLA-4, CD40, PTPN22,
thyroglobulin and TSH receptor genes. …
Clin Immunol. 2007 May;123(2):190-8.
A functional soluble form of CTLA-4 is present in the
serum of celiac patients and correlates with mucosal
injury
R Simone, R Brizzolara, A Chiappori, F Milintenda-Floriani1, C.
Natale3, L Greco, M Schiavo, M Bagnasco, G Pesce, D Saverino
International Immunology 2009 21(9):1037-1045
The New England Journal of Medicine 360; 16, 2009
Mechanisms of Disease
Genetics of Type 1A Diabetes
Patrick Concannon, Stephen S. Rich, and Gerald T. Nepom, M.D.
Celiac disease (CD) is a multifactorial disorder influenced by environmental, genetic and immunological
factors. Increasing evidence showed CTLA-4 gene as an important susceptibility locus for autoimmune
disorders. A native soluble cytotoxic T-lymphocyte-associated protein-4 (sCTLA-4), lacking of
transmembrane sequence, has been described in several autoimmune diseases. We aimed to evaluate
the presence of increased sCTLA-4 concentration in the serum of patients with CD and the possible
immunoregulatory function. Blood samples were collected from 160 CD patients; sCTLA-4 levels were
evaluated by ELISA, western blot and reverse transcription–PCR. The capability of serum sCTLA-4 to
modulate T-lymphocyte proliferation in vitro was evaluated by two-way mixed leukocyte reaction assay.
We demonstrated high levels of sCTLA-4 in serum of untreated celiac patients. Additionally, we
observed that sCTLA-4 concentrations are related to gluten intake and that a correlation between
autoantibodies to tissue transglutaminase and sCTLA-4 concentration exists. Moreover, sCTLA-4 levels
correlate with the degree of mucosal damage. Conversely, no correlation between sCTLA4 levels and
the HLA-related risk was observed. Finally, we show that sCTLA-4 from sera of CD patients displays
functional activities. These results strongly suggest a regulation of sCTLA-4 synthesis depending on the
presence or absence of dietary gluten and imply a possible immunomodulatory effect on cytotoxic T
lymphocyte functions. In gluten-exposed patients, serum sCTLA-4 levels might provide insight about
mucosal injury.
The New England Journal of Medicine 360; 16, 2009
Mechanisms of Disease
Genetics of Type 1A Diabetes
M. M. A. Fernando,et al.
PLoS Genet. 2008 April; 4(4)
Defining the Role of the MHC in Autoimmunity:
A Review and Pooled Analysis
Patrick Concannon, Stephen S. Rich, and Gerald T. Nepom, M.D
10
NATURAL HISTORY OF AUTOIMMUNE
DISEASES
AUTOANTICORPI PATOGENETICI
correlano significativamente
con la malattia
in grado di indurre le
alterazioni tipiche sia in vivo
che in vitro
correlano con l’andamento
della malattia
Rare monogenic Autoinflammatory Diseases:
FMF, TRAPS, HIDS, PAPA
Blau’s Syndrome (Uveitis)
Polygenic Autoinflammatory Diseases:
Crohn’s Disease, Ulcerative Colitis
Self-limiting inflammatory arthritis including diseases clinically presenting as RA
Storage diseases/Congenital diseases with associated tissue inflammation
Non-antibody associated vasculitis including Giant Cell and Takayasu’s arteritis
Idiopathic Uveitis
Acne and Acneform associated diseases
Some neurological diseases eg. Acute disseminated encephalomyelitis
Erythema Nodosum associated disease, including Sarcoidosis
Mixed Pattern Diseases with evidence of acquired component (MHCI associations) and
autoinflammatory components:
Ankylosing Spondylitis
Reactive Arthritis
Psoriasis
Behcet’s Syndrome
Uveitis (HLA-B27 associated)
Classic Polygenic Autoimmune Diseases (Organ Specific and Non Specific):
Rheumatoid Arthritis
Autoimmune Uveitis (Sympathetic Ophthalmia)
Coeliac disease
Primary biliary Cirrhosis
Autoimmune gastrittis/pernicious anaemia
Autoimmune Thyroid Disease, Addison’s Disease,
Pemphigus, Pemphigoid, Vitiligo
Myasthenia Gravis, Dermatomyositis/polymyositis/scleroderma
Goodpasture’s Syndrome
ANCA associated Vasculitis
Type 1 diabetes
Cogan’s Syndrome
Sjogren’s Syndrome
Systemic Lupus Erythematosus
Rare Monogenic Autoimmune Disease: ALPs,Ipex, APECED
autoimmunità
M.S.Longhe et all J Autoimmun. 2009 Sep 17
autoinfiammazione
Aetiopathogenesis of autoimmune hepatitis
AUTOANTICORPI
NON PATOGENETICI
correlano significativamente con
la malattia
ma non in grado di riprodurla
né in vivo né in vitro
titolo e andamento indipendente
dall’andamento della malattia
EPIFENOMENI
possono formarsi in corso di patologia non autoimmune
come conseguenza di necrosi tessutale
sono per lo più transitori
si riscontrano in malattie che non rispondono ad altri
criteri di autoimmunità
Take-home messages
~ Le MAO sono globalmente le malattie
autoimmuni a più elevato impatto
epidemiologico
~ La distinzione tra malattie autoimmuni
d’organo e sistemiche è probabilmente
tuttora utile sul piano pratico
~ La classificazione di molte malattie con
caratteristiche “intermedie” è complessa
( fattori organo specifici/fattori sistemici,
autoimmunità/autinfiammazione)
Genetic predisposition
Triggering (environmental) factor(s)
Pathogenic immunological factor(s)
Precipitating event(s)
S p e c i f i c
A u t o a n t i b o d i e s
Normal function(s)
Homeostatic mechanism(s) Abnormal function(s)
Potential phase
Subclinical phase
Clinical phase
Time
Take-home messages
~ Il coinvolgimento dell’immunità naturale
accanto a quella adattiva e la loro
interazione nella patogenesi delle malattie
autoimmuni è sempre più evidente
~ L’interazione immunità naturale/immunità
adattiva contribuisce a chiarire il ruolo dei
fattori genetici e ambientali nella malattia
autoimmune
~ Tali acquisizioni hanno importanza pratica
potenziale: la strategia diagnostica delle
MAO resta legata al dosaggio degli
autoanticorpi
11
...namque alid ex alio clarescet nec tibi caeca
nox iter eripiet quin ultima naturai
pervideas: ita res accendent lumina rebus.
..e infatti ogni cosa da altra
troverà la sua luce né te
cieca
notte strapperà dal cammino,
sì che tu non possa tutti
vedere
i confini della natura: Sì, le
cose riempiranno di luce le
cose.
Lucrezio, De Rerum Natura, I,1114-17
(traduzione G. Milanese)
12