Maladies auto-immunes



Maladies auto-immunes
Maladies auto‐immunes
• Hypersensitivity diseases : disorders caused by immune response
• Pathologic immune responses – Autoimmune : against self antigens
– Uncontrolled and excessive responses to foreign antigens
• Mecanisms – Circulating immune complexes
– Ab that binds to cells in tissues
– T lymphocytes reactive with antigens in tissues
• Effector mecanisms
– Antibody : complement, FC receptor‐mediated inflammation
– T cells : DTH and cell lysis by CTL
Maladies induites par anticorps Ac‐Ag (cellules, extracellulaires) ou complexes immuns dans la circulation
• Tranfert adoptif d’Ac chez un animal => provoquer la maladie
• Passage Ac par le placenta : manifestations foetus – Nouveau né
• Mise en évidence des Ac ou des complexes immuns chez l’homme
Figure 18-1 Types of antibody-mediated diseases. Antibodies may bind specifically to tissue antigens
(A), or they may be deposited as immune complexes that are formed in the circulation (B). In both cases, the
deposited antibodies induce inflammation, leading to tissue injury.
Anticorps contre cellules et antigènes tissulaires
• Atteintes non systémiques
• Parfois réactions croisées
• 3 grands mécanismes physiopathologiques
– Opsonisation et phagocytose
– Inflammation médiée par complément et Fc
– Réponse physiologique anormale sans lésion
Effector mechanisms of
antibody-mediated disease
Maladies / complexes immuns
• Antigènes du soi ou étrangers
• Manifestations pathologiques liées au site de dépôt
des complexes et non la source cellulaire de l’antigène
=> Systémique
• 1911 : Clemens von Piquet : maladie sérique
• Ag‐Ac – phagocytose rate et foie
– Si trop abondant : dépôts vaculaires, activation complément, recrutement cellules infl (PNN+++) : vascularite, néphrite, arthrite…….poumon
Maladies / complexes immuns
Maladies Antigène
Manifestations cliniques Systemic lupus erythematosus
DNA, nucleoproteins, others
Nephritis, arthritis, vasculitis
Polyarteritis nodosa
Hepatitis B virus surface antigen
Streptococcal cell wall antigen(s); may be "planted" in glomerular basement membrane
Serum sickness
Various proteins
Arthritis, vasculitis, nephritis
Immune complex glomerulonephritis
•poststreptococcal glomerulonephritis,
•lupus nephritis,
•IgA nephropathy with crescents
experimental acute serum sickness
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Goodpasture's syndrome
© 2005 Elsevier
Figure 18-5 Mechanisms of T cell-mediated diseases. A. In delayed-type
hypersensitivity reactions, CD4+ T cells (and sometimes CD8+ cells) respond to
tissue antigens by secreting cytokines that stimulate inflammation and activate
phagocytes, leading to tissue injury. APC, antigen-presenting cell. B. In some
diseases, CD8+ CTLs directly kill tissue cells.
Maladies immunes / lympho T
Disease Specificity of pathogenic T cells
Human disease
Animal models
Type I (insulin‐
dependent) diabetes
Islet cell antigens Yes; specificity of T (insulin, glutamic acid cells not established
decarboxylase, others) NOD mouse, BB rat, transgenic mouse models
Rheumatoid arthritis
Immunité humorale ?
Unknown antigen in joint synovium
Yes; specificity of T cells and role of antibody not established
Collagen‐induced arthritis, others
Multiple sclerosis, experimental autoimmune encephalomyelitis
Myelin basic protein, proteolipid protein
Yes; T cells recognize myelin antigens
EAE induced by immunization with CNS myelin antigens; TCR transgenic models
Inflammatory bowel disease (Crohn's, ulcerative colitis)
Colitis induced by depletion of regulatory T cells, knockout of IL‐10
Peripheral neuritis
Guillain‐Barre syndrome
P2 protein of peripheral nerve myelin
Yes Induced by immunization with peripheral nerve myelin antigens
Autoimmune myocarditis
Myocardial proteins
Yes (post‐viral myocarditis); specificity of T cells not established
Induced by immunization with
myosin or infection by Coxsackie virus
Polyarthrite rhumatoïde
Synovite : destruction cartilage‐os
CD4, B, plasmocytes, macrophages… follicules lymphoïdes
IL‐1, 8, TNF, INFg dans le liquide synovial
Complications systémiques : arthrite, vasculites, lésions pulmonaires : complexes immuns
• Adultes : Ac circulants = IgM ou IgG anti‐Fc, (rarement Fab) de leur propre IgG = facteurs rhumatoïd => complexes immuns (rôle ?)
• Spécificité et rôle pathogène des Ac produits • Anti‐TNF efficace
Polyarthrite rhumatoïde
• Défaillance de la “tolérence du soi” des B et/ou T
– Sélection anormale ourégulation des lymphocytes auto‐réactifs
– Présentation des antigènes du soi au système immunitaire
• Rôle des lympho T
– Régulateurs de toutes les réponses immunes contre les protéines
– Lien avec HLA : fonction présentation des peptides antigéniques aux T
– Anomalies des T helper : production auto‐Ac
• Maladies systémique ou spécifiques d’organes
• Mécanismes effecteurs variés : CI, auto‐Ac circulants, T auto‐réactifs
• Epitope spreading
Figure 18-6 Postulated mechanisms of autoimmunity. In this proposed model of an organ-specific T cell-mediated
autoimmune disease, various genetic loci may confer susceptibility to autoimmunity, in part by influencing the
maintenance of self-tolerance. Environmental triggers, such as infections and other inflammatory stimuli, promote
the influx of lymphocytes into tissues and the activation of self-reactive T cells, resulting in tissue injury.
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© 2005 Elsevier
Infection et autoimmunité
• Développement et exacerbation
• Lésions non induites / agents pathogènes, mais par le déclenchement et la dérégulation de la réaction immune de l’hôte
– Réaction immune anti‐infectieuse spécifique => activation des T non spécifique “bystander activation”, expression aberrante des costimulateurs
– Molecular mimicry
– TLR ?
• Mais : Infections peuvent Ð l’autoimmunité : Diabète 1, SEP
Figure 18-8 Role of infections in the development of autoimmunity. A. Normally, encounter of a mature self-reactive T cell
with a self antigen presented by a costimulator-deficient resting tissue antigen-presenting cell (APC) results in peripheral
tolerance by anergy. (Other possible mechanisms of self-tolerance are not shown.) B. Microbes may activate the APCs to
express costimulators, and when these APCs present self antigens, the self-reactive T cells are activated rather than
rendered tolerant. C. Some microbial antigens may cross-react with self antigens (molecular mimicry). Therefore, immune
responses initiated by the microbes may activate T cells specific for self antigens.
Figure 18-7 Susceptibility loci for autoimmune diseases. The chromosomal loci associated with some autoimmune
diseases are shown. The location of candidate genes of immunologic interest are indicated as ovals on the left of
the chromosomes. These ovals are color coded to indicate the diseases to which the genes are linked. SLE,
systemic lupus erythematosus; AITD, autoimmune thyroid disease; RA, rheumatoid arthritis; T1D, type 1
diabetes. (Modified from Yamada R and K Ymamoto. Recent findings on genes associated with inflammatory
diseases. Mutation Research 573:136-151, Copyright 2005 with permission from Elsevier.)
Anticorps antinucléaires
20% environ de la population
37% à 65 ans !
titre anticorps
Aspect de fluo sur culture oriente le diagnostic
Sjogren: 40‐60% AAN, SSA 90%
Sclérodermie : 60‐90% AAN
Raynaud, PR, DM, SHARP…
Si AAN ‐ : LED peu probable
Antagonistes TNF‐α AAN positive et sd lupus‐like AAN
ANA patterns by IIF on HEp-2 cell substrate.
(A) Fine-speckled nucleoplasmic stain with additional occasional bright dots.
(B) Fine-speckled nucleoplasmic stain with additional occasional bright dots
accompanied by punctate (speckled) nucleolar staining
(C) Fine-speckled nucleoplasmic stain: anti-Ro.
(D) Clumpy nucleolar stain: AFA.
(E) Homogenous (very fine speckled) nucleoplasmic with homogenous nucleolar stain
Syndrome de Sjögren
• maladie chronique, autoimmune, systémique, inflammatoire, cause inconnue • Sécheresse : yeux, bouche et autres glandes exocrines / infiltration lymphocytaire des glandes exocrines et endocrines et dysfonctionnement glandulaire secondaire
• Femme, âge moyen
• Primaire : pas d’autre maladie associée. associations génétiques (HLA‐DR3 chez caucasiens)
• 30% des patients avec maladies autoimmunes développent un SS « secondaire » : PR, LED, sclérodermie, SHARP, Hashimoto, CBP, hépatite autoimmune
Pathophysiology SS
• exocrine glands become infiltrated with CD4+ T cells and with some
B cells. The T cells produce inflammatory cytokines (eg, IL‐2, interferon‐γ). Salivary duct cells also produce cytokines, eventually
damaging the secretory ducts. Atrophy of the secretory epithelium
of the lacrimal glands causes desiccation of the cornea and conjunctiva (keratoconjunctivitis sicca—see Corneal Disorders: Keratoconjunctivitis Sicca). • Lymphocytic infiltration and intraductal cellular proliferation in the parotid gland cause luminal narrowing and in some cases formation of compact cellular structures termed myoepithelial islands; atrophy of the gland can result. Dryness and GI mucosal or submucosal atrophy and diffuse infiltration by plasma cells and lymphocytes may cause symptoms (eg, dysphagia).
SS: Symptomes
Glandulaires •
sécheresse oculaire => kératite
Xérostomie : dysphagie, dents, candidose, calcul salivaire, gôut et odorat
Peau, muqueuses nasale, gorge, larynx, bronche, voies génitales, Alopécie
Arthralgies 50%, Arthrites 33% distribution identique au PR mais non érosive
Vascularite : nerfs périphérique ou SNC, peau (purpura), glomérulonéphrites
Rein : acidose tubulaire, calcul, nephrite inerstitielle
Hématologique : Lymphadénopathie, LMNH (x 40), pseudolymphome, Waldenström
Maladies hépatobiliaires chroniques et pancréatite
American‐European classification criteria for SS; 2002 •
Eye symptoms are ≥ 3 mo of either dry eyes or use of tear substitutes ≥ 3 times/day; slit‐lamp examination may also confirm dry eyes.
Oral symptoms are > 3 mo of daily dry mouth sensation, daily use of liquids to aid in swallowing, or swollen salivary glands.
Most common causes of dry eyes and dry mouth (sicca symptoms) are aging and drugs, but when parotid enlargement occurs in addition to sicca symptoms, diseases such as hepatitis C, HIV, bulimia, and sarcoidosis should be differentiated from SS.
Eye signs include evaluation – Schirmer's test
– Ocular staining with rose bengal or lissamine green solution is highly specific. – Slit‐lamp examination: fluorescein tear breakup in < 10 sec is also suggestive.
Salivary gland involvement: abnormally low saliva production (≤ 1.5 mL/15 min)
Autoantibodies (serologic criteria): limited sensitivity and specificity
Ro (SS‐A autoantibodies)
nuclear antigens (La or SS‐B autoantibodies), antinuclear antibodies, or antibodies against γ‐globulin. Rheumatoid factor is present in > 70% of patients. ESR is elevated in 70%, 33% have anemia, and up to 25% have leukopenia.
Lupus ED
• Complexes immuns
• Complément
• Apoptose
LED : articulations • Arthralgies, polyarthrites : 90%, non destructrices
• Maladies au long cours : déformations sans destruction = Maladie de Jaccoud
LED Atteintes Hématologiques
• Anémie hémolytique
• Leucopénie
• Thrombopénie
• Thromboses Ac anti‐antiphospholipide
LED : peau
Lésions cutanées
Vasculite : érythème mains, péri‐unguéale, urticaire, purpura
• Pétéchie / thrombocytopenie
LED : poumon, coeur
• Atteinte pleuro‐pulmonaire, hémorragie pulmonaire, HTAP, syndrome restrictif
• Péricardite, épanchement péricardique, myocardite, vascularite coronaire, atteinte valvulaire, Libman‐Sacks endocardite, athérosclérose évolutive
• Bloque cardiaque congénitale
• Adénopathies, splénomégalie 10%
• Neurologique : SNC, SNP, méninges •
Troubles cognitifs, psychose, épilepsie
Hémorragie méningée
Myélite transverse
Atteinte cérébelleuse
• Rein : glomerulite focale (souvent bénigne) ou glomerulonephrites membranoproliferative (grave)
• Obstetrique
• Perte foetale : prévoir grossesse lors des rémissions
• Ac antiphospholipides risque MFIU récurrente augmente
• Gastro‐intestinale
• Vasculite, constipation, pancréatite (corticosteroides
or azathioprine), perforation, pseudoobstruction
• Diagnostic : Autres connectivites ?
• Infections opportunistes ++++ (immunosuppression)
Criteria for the Classification of SLE*
At least 4 of the following are required to classify patients as having SLE in reports of clinical research.
• Malar rash
• Discoid rash
• Photosensitivity
• Oral ulcers
• Arthritis
• Serositis
• Renal disorder
• Leukopenia (< 4000/μL), lymphopenia (< 1500/μL), hemolytic anemia, or thrombocytopenia (< 100,000/μL)
• Neurologic disorder
• Positive anti‐DNA or anti‐Smith antibody, or positive test for antiphospholipid
antibodiesAntinuclear antibodies in high titers
*These 11 criteria are from the American College of Rheumatology and are also often
used as aids in diagnosis. Although at least 4 criteria are not needed to make a diagnosis of SLE, the criteria help in recognizing manifestations of SLE.
Maladie de Wegener
• Vascularite nécrosante associant une inflammation de la paroi vasculaire et une granulomatose, péri‐ et extravasculaire
Wegener Nécrose carte géographique : PNN, L, CGM
Vascularite :
Petit > moyen calibre, capillaire, parfois veinules
Granulomes non spécifiques : existe des CGM
Glomérulonéphrite extracapillaire à croissant, IF-
Endocardite, tuberculose : ANCA+
WG diangostics différentiels
• Vascularites petit et moyens calibres
• PAN peu probable quand atteinte pulmonaire préominante et glomérulonéphrite
• Infections : mycose, mycobactéries
• PR : FR présent chez ½ des patients avec Wegener
Syndrome de Churg et Strauss
1951 à partir d’une série autopsique, tableau anatomo‐clinique voisin de PAN.
<1 pour 1 million d’habitants,
Syndrome de Churg et Strauss : poumon
Asthme en premier +- manifestations « allergiques », vascularite plus tardive
Hémorragie alvéolaire : hémoptysie, infiltrat pulmonaire, anémie
Infiltrats pulmonaires labiles : éosinophiles ou hémorragie alvéolaire
Churg : ANATOMIE PATHOLOGIQUE 3 types de lésions élémentaires, coexistence rare : • vascularite nécrosante, artères et veines de petit calibre avec des lésions segmentaires et un infiltrat riche en éosinophiles • infiltration éosinophilique tissulaire • granulomes extravasculaires contenant une nécrose centrale entourée de cellules épithélioïdes. Churg et Strauss : autres atteintes
• Neuro : mulitnévrite, nerfs crâniens, vascularite SNC (AVC, hémorragie, hém méningée), troubles cognitifs, épilepsie
• Peau : vascularite ou granulome, raynaud, urticaire…
• Gastro‐intestinale
• Cardiaque
• Ostéo‐articulaire • Musculaire • Rein
• ORL : peut ressembler à Wegener +++, mais non destructive
Figure 2-2 Mammalian TLRs: specificities, basic signaling mechanisms, and cellular responses. Ligands for TLRs are shown together with dimers of the TLRs that
specially bind them. Note that some TLRs are expressed in endosomes and some on the cell surface (see Fig. 2-7). The basic steps in TLR signaling, illustrated only for
TLR3 and TLR4, are applicable to all TLRs. Further details about the signaling pathways are described in Box 2-1.
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Figure 2-5
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Antinuclear antibodies
• Fluorescent ANA: The fluorescent test for ANA is the best screen for SLE; positive ANA tests (usually in high titer: > 1:80) occur in > 98%. However, positive ANA tests can also
occur in RA, other connective tissue diseases, cancers, and even in the general population. The false‐positive rate varies from about 3% for ANA titers of 1:320 to about 30% for ANA titers of 1:40 among healthy controls. Drugs such
as , procainamide and tumor necrosis factor (TNF)‐α
antagonists can produce positive ANA results as well as a lupus‐like syndrome; the ANA eventually becomes negative
if the drug is stopped. Positive ANA should prompt more specific testing such as anti–double‐stranded DNA antibodies; high titers are highly specific for SLE but occur
in only 25 to 30% of people with SLE.
Other ANA and anticytoplasmic
antibodies: • The ANA test is very sensitive, but it is not specific for SLE, thus the need for other autoantibodies to establish the diagnosis. These include Ro [SSA], La [SSB], Smith [Sm], ribonucleoprotein [RNP], and double‐stranded DNA. Ro is predominantly
cytoplasmic; anti‐Ro antibodies are occasionally
present in ANA‐negative SLE patients presenting with
chronic cutaneous lupus. Anti‐Ro is the causal antibody
for neonatal lupus and congenital heart block. Anti‐Sm
is highly specific for SLE but, like anti–double‐stranded
DNA, is not sensitive. Anti‐RNP occurs in patients with
SLE, mixed connective tissue disease,