immunopathogenesis of vasculitis in cellular & subcellular ... · • tolerance to self...
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ا ت ل ک ا ژنز ات ن ايمونوپاتوژنز واسکوليتھااi iVasclitides:
Th I th g iThe Immunopathogenesis
دکتر محمدمھدی محمدیLMD PhD MPH
The 7th International 12th National Congress on Quality
LMD, PhD, MPH([email protected])
The 7th International 12th National Congress on Quality Improvement in Clinical Laboratories
28 Farvardin 1393 / 17April 2014 , Tehran, Iran
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A small spoonful of Terminology• path·o·gen·e·sis, n. – بيماريزايی) in Farsi)
– the production and development of disease (events and reactions and p p (other pathologic mechanisms) . Also, pa·thog·e·ny
• path·o·ge·nic·i·ty, n. _ (بيماريزايی in Farsi) !?!the disease producing capacity of a pathogen [PATHOGENIC + ITY]– the disease-producing capacity of a pathogen. [PATHOGENIC + -ITY]
• vir·u·lence, n.– the relative ability of a microorganism to cause disease; degree of
pathogenicity.
• Vasculitis, n. (vasculitides, plural)– a general term for vessel wall inflammation systemic or localized– a general term for vessel wall inflammation, systemic or localized,
immune-mediated or directly invaded by microbes.• Infections may indirectly generate vasculitis, e.g. through IC formation or by
X_reaction. Note that immunosuppressive therapy is only appropriate for --?– type!
• WHAT R the IMMUNE MECHANISMS in VASCULITIS?
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تعادل تفريطافراط
Defence AllergyImmunodeficiency Defence Allergy(& Infection)
AutoimmunitySurveillanceImmunodeficiency(& Malignancy)
Homostasis ?!
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Some Inter-related Concepts
Immunological Vasculitis
Some Inter related Concepts
Immunological VasculitisHypersensitivityHypersensitivity
AuoimmunityAuoimmunityTolerance
EDUCATION?
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Tolerancein different classic Txtbks of Immunology
(Abbas, Benjamini, Janeway, Kuby, Roitt, Stites …)
• Tolerance (by C&M Immunology): Unresponsiveness of the adaptive immune system to antigens as a– Unresponsiveness of the adaptive immune system to antigens, as a result of inactivation or death of antigen-specific lymphocytes, induced by exposure to the antigens.
– (Active) Unresponsiveness of the (HEALTHY) adaptive immune system ( ) p ( ) p yto (selected) antigens, as a result of (i.e. MECHANISMS:) inactivation or death of antigen-specific lymphocytes, induced by exposure to those antigens.
• Tolerance to self antigens is a normal feature of the adaptive immune system, but tolerance to foreign antigens may be induced
d t i diti f tiunder certain conditions of antigen exposure.
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Tolerance Induction
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Non responsivenessNon-responsiveness•Immunocompromised State•Immunocompromised State
•Sequestration
•Tolerance •Central (by N&P selection / edition)•Peripheral, through -Deletion (AICD)p , g ( )
-Anergy (Functional)
-Suppression
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Autoimmunity: an imbalancey
Activating signalsActivating signals•MHC-II peptide•Cytokines (IFN-g)CD40/CD40L
DownregulatingDownregulating signalssignals•Cytokines (IL-10,TGFβ)
•CD40/CD40L•CD28/CD80,86
•CD80,86/CTLA-4 (CD152)
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D l i BT T BDeletion BT TH BNegative Selectionegat e Se ect oCentral ToleranceUnresponsiveness
Anergy
InhibitoryCytokines BTy BT
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Autoimmune responses resemble h iti it tihypersensitivity reactions
IgE سيتو كمپلكسT cell تحريكي ممانعتي•Type I: IgE mediated•Type I: IgE mediated
•Type II:Antibodies against cell surfaces / extracellular matrixType II:Antibodies against cell surfaces / extracellular matrix
•Type III:Immune complexes
•Type IV:Effector T cells
•Type V: Cell stimulating Antibodies
•Type VI: Cell Inhibitory Antibodies
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Coombs and Gell’s Classification of Hypersensitivity
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Allergic reactions or hypersensitivity cause tissue damage. Janeway, ed8, 2012
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Vascular Damage by Type-II Hypersensitivity
IgG reacts with epitopes on the host cell membrane.Phagocytes then bind to the Fc portion of the IgG and discharge their lysosomesPhagocytes then bind to the Fc portion of the IgG and discharge their lysosomes
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Endothelial Injury by MAC Lysis During Type II HypersensitivityType-II Hypersensitivity
IgG or IgM reacts with epitopes on, in, near to the host cell membrane and activates the classical complement pathway, aggravating the inflammation. Membrane attack complex (MAC) then causes lysis of the cellMembrane attack complex (MAC) then causes lysis of the cell.
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Autoimmune responses resemble h iti it tihypersensitivity reactions
• Type II: Antibodies (Abs) against cellsurfaces/extracellular matrix
• Type III: Insoluble immune complexesdeposited in tissuesdeposited in tissues
• Type IV: Effector T cellsType IV Effector T cells
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Type II HypersensitivityType II HypersensitivityAutoimmunityAutoimmunityAutoimmunityAutoimmunity
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Figure 13-27 part 1 of 3Figure 13 27 part 1 of 3
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Type III HypersensitivityType III HypersensitivityAutoimmunityAutoimmunityAutoimmunityAutoimmunity
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Figure 13-27 part 2 of 2Figure 13 27 part 2 of 2
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Type IV HypersensitivityType IV Hypersensitivity
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Figure 13-27 part 3 of 3Figure 13 27 part 3 of 3
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PPernnicioous Aneem
iaa
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Figure 13-6Figure 13 6
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Grandmother's Gift
هديه مادر بزرگRh+Gift Rh+
Rh-
Rh+
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INTRODUCTION!• Vasculitis is a clinicopathologic process
characterized by inflammation of andcharacterized by inflammation of and damage to blood vessels.
• The vessel lumen is usually compromised, and this is associated with ischemia of the tissues supplied by the involved vessel.
• A broad and heterogeneous group of syndromes may result from this process, since any type, size, and location of blood vessel may be involved.
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Potential Mechanisms of Vessel Damage in Vasculitis SyndromesVasculitis Syndromes
Pathogenic immune complex formation and/or deposition• Henoch-Schönlein purpura • Vasculitis associated with collagen vascular diseases• Serum sickness and cutaneous vasculitis syndromes• Hepatitis C associated essential mixed cryoglobulinemia• Hepatitis C–associated essential mixed cryoglobulinemia• Hepatitis B–associated polyarteritis nodosa Production of antineutrophilic cytoplasmic antibodies• Wegener's granulomatosisg g• Churg-Strauss syndrome• Microscopic polyangiitisPathogenic T lymphocyte responses and granuloma formation• Giant cell arteritis• Takayasu's arteritis• Wegener's granulomatosis• Churg Strauss syndrome• Churg-Strauss syndrome
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Pathophysiology and Pathogenesis• Generally, most of the vasculitic syndromes are assumed
to be mediated at least in part by immunopathogenic mechanisms that occur in response to certain antigenicmechanisms that occur in response to certain antigenic stimuli.
• However, evidence supporting this hypothesis is for the pp g ypmost part indirect and may reflect epiphenomena as opposed to true causality.
• It is unknown why some individuals might develop• It is unknown why some individuals might develop vasculitis in response to certain antigenic stimuli, whereas others do not. It is likely that a number of factors are involved in the ultimate expression of a vasculitic syndrome. These include the genetic predisposition, environmental exposures, and the regulatory mechanismsenvironmental exposures, and the regulatory mechanisms associated with immune response to certain antigens.
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Pathogenic Immune-Complex F tiFormation
• Vasculitis is generally considered withinVasculitis is generally considered within the broader category of immune-complex diseases that include serum sickness anddiseases that include serum sickness and certain of the connective tissue diseases, of which systemic lupus erythematosusof which systemic lupus erythematosus (Chap. 313) is the prototype.
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Production of antineutrophilic t l i tib di
• ANCA are antibodies directed against certain
cytoplasmic antibodies
ANCA are antibodies directed against certain proteins in the cytoplasmic granules of neutrophils and monocytes. These autoantibodies are present in a high percentage of patients with certain systemic vasculitis
d ti l l W 'syndromes, particularly Wegener's granulomatosis and microscopic polyangiitis, and in patients with necrotizing and crescenticand in patients with necrotizing and crescentic glomerulonephritis. There are two major categories of ANCA based on different targets g gfor the antibodies.
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Production of antineutrophilic t l i tib dicytoplasmic antibodies
• Proteinase-3 and myeloperoxidase reside in the y pazurophilic granules and lysosomes of resting neutrophils and monocytes, where they are apparently inaccessible to serum antibodies However wheninaccessible to serum antibodies. However, when neutrophils or monocytes are primed by tumor necrosis factor (TNF) or interleukin (IL) 1, proteinase-3 and myeloperoxidase translocate to the cell membrane where they can interact with extracellular ANCA. The neutrophils then degranulate and produce reactive p g poxygen species that can cause tissue damage. Furthermore, ANCA-activated neutrophils can adhere to and kill endothelial cells in vitro Activation of neutrophilsand kill endothelial cells in vitro. Activation of neutrophils and monocytes by ANCA also induces the release of proinflammatory cytokines such as IL-1 and IL-8.
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delayed hypersensitivity and cell-di t d i i jmediated immune injury
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Pathogenesis of Granulomatous I fl ti (i W G l t i )Inflammation (in Wegener Granulomatosis)
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Other mechanisms such as:• Other mechanisms such as:• direct cellular cytotoxicity,• antibody directed against vessel components, • antibody-dependent cellular cytotoxicity have y p y y
been suggested in certain types of vessel damage.g
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Figure 13-13Figure 13 13
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These SitesThese Sites Sequester Self Antigens, ButAntigens, But
Few Autoimmune Diseases Are Due
Of Releaseto Hidden Self
A tiAntigens
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م:بازخوانی چند مفھوم چ یAntigenAntigen
--+محرک سيستم ايمنی
++واکنشگربا محصوالت آن
ImmunogenHapten ImmunogenHapten
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THANKYOU FOR YOUR ATTENTIONTHANKYOU FOR YOUR ATTENTIONTHANKYOU FOR YOUR ATTENTIONTHANKYOU FOR YOUR ATTENTION