pathogenesis anca associated vasculitis.pptx final

7/29/2019 Pathogenesis ANCA Associated Vasculitis.pptx FINAL

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Pathogenesis of ANCA associated

vasculitis


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Outline

Introduction

Pathogenesis: Role of

ANCAs

Mode of action

Expanding subtypes

Complement system

T cells

Tertiary lymphoid tissue

Correlation of pathogenesis with targeted therapy

Conclusions


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Introduction

The antineutrophil cytoplasm antibody (ANCA)associated vasculitides are a

Spectrum of heterogeneous autoimmune diseasescharacterized by necrotizing small vessel vasculitisand

Presence of ANCA

Reactive to either proteinase-3 (PR3-ANCA) ormyeloperoxidase (MPO-ANCA), which areconstituents of neutrophil granules and monocytelysosomes

Therapeutics and Clinical Risk Management 2010:6 253264


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Introduction

AAV are

Idiopathic multisystem vasculitides which causedestructive inflammation of mainly small caliberarterial vessels and comprise several clinically andpathologically defined disease entities..

Wegeners granulomatosis (WG),

Microscopic polyangiitis (MPA),

Renal-limited vasculitis (RLV) and

ChurgStrauss syndrome (CSS)



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Introduction

AAV cause

Considerable morbidity and mortality, with

End-stage renal failure developing in over 20% ofpatients at five years



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Pathogenesis

The pathophysiology of AAV is

Complex and the humoral as well as the cellularimmune system are involved

We shall see simplified view on diseasemechanisms and subsequently discuss refinedand detailed recent findings

Kidney International 2011;79, 599612


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Pathogenesis: Simplified view

ANCAs

Themselves are thought to be pathogenic

Promote degranulation of neutrophils andmonocytes facilitating endothelial damage

The initial damage leads to a cascade of events,resulting in

leukocyte tissue infiltration, T-cell-driven granulomaformation, and further damage



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Pathogenesis

Recent findings on

ANCAs, complement, neutrophils, lymphocytes,and dendritic cells (DCs) demand to confine newroles for old players in AAV

Thus, we discuss and illustrate novel insights andthe role in the current concept of disease

will also highlight and further explain implications

for treatment modalityKidney International 2011;79, 599612


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ANCAs: MODE OF ACTION

ANCAs

Bind to membrane-bound PR3/MPO onneutrophils, results in

Activation and finally in release of cytotoxicsuperoxide and serine proteases (such as PR3)

Thus, degranulation occurs in close contact with thevascular endothelium, resulting in vasculitic damage



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Two pathways (a) The classic neutrophil pathwaycauses

necrotizing vasculitis.

(b) additional T-cell pathway that mainlycauses granulomatous inflammation andpromotes necrotizing vasculitis.


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Infections are the starting point of

both pathways

infections trigger priming of neutrophils

upregulation of adhesion molecules onendothelial cells, and expansion of circulatingeffector T cells

Primed neutrophils show increased surface

expression of ANCA antigens and adhesionmolecules


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Kidney International 2011;79, 599612Explanation of figure next slide


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ANCA binding activates the neutrophil in thefollowing ways:

(1) enhancing vessel wall adherence andtransmigration capacity;

(2) production and release of oxygen radicals,

and (3) degranulation and release of enzymes

including myeloperoxidase (MPO) andproteinase-3 (PR3)


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Transient immune complexes are formed locallyby binding of ANCA to PR3/ MPO sticking to

endothelial cells.

complement is activated, which furtherpromotes neutrophil degranulation.

the development of necrotizing vasculitis.


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expanded effector memory T cells(Tems) The expanded effector memory T cells (Tems)

are not sufficiently regulated by regulatory T

cells (Tregs, b).

This leads to dysbalance in the homeostasis ofTregs and Tems, resulting in further release of

proinflammatory cytokines promotingneutrophil priming

ANCA production is enhanced by further T-cell/B-cell interaction.


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Granulomas

Expanded circulating Tems migrate into targetorgans such as the lungs or the kidney.

Tems drive granuloma formation, executionerof tissue destruction.

Granulomas are composed of numerous cell

types such as T cells, B cells, giant cells, anddendritic cells (DCs).

ANCA production occurs in granulomas.


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tertiary lymphoid organs (TLOs)

tertiary lymphoid organs (TLOs) are localcontrollers of tissue inflammation, as induction

of Tregs is thought to take place in TLOs.


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Neutrophil extracellular trap (NET)

Neutrophil extracellular trap (NET) formationoccurs in lesions as a consequence of neutrophil

apoptosis and degranulation.

DNA and serine proteases are deployed in theseNETs.

NET-derived products activate DCs and B cellsby sensing via Toll-like receptors (TLRs).

Interferon (IFN-a) production by DCs mighthave impair Tregs in function.


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The origin of ANCA is unexplained so far. If andhow genetic background, microbial agents,and/or T-cell dysregulation finally lead to thedevelopment of ANCA needs to be investigated

further.


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ANCAs

There is ongoing discussion about the role of

cytotoxic mediators in endothelial damage

A recent study confirmed that serine proteases(like PR3 and elastase) are more important thansuperoxide radicals in mediating cytotoxic damage

injury was not prevented by blocking superoxiderelease.

However, inhibition of serine proteases led to lessendothelial cell injury



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ANCAs

ANCA-induced release ofproteases seems to be

the most important factor for vasculitic damage

Nevertheless, release ofreactive oxygen speciesenhances the activity of serine proteases byinactivating 1-anti-trypsin, which is a potent PR3inhibitor



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Apart from in vitro experiments, ANCApathogenicity has been investigated in animalmodels

In summary, there is convincing evidence fromboth in vitro and in vivo experiments thatANCAs are pathogenic



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ANCAs: EXPANDING RANGE OF SUBTYPES?

In the late 1980s, it was discovered that

PR3 was the main antigen for cytoplasmic-ANCA,

MPO was shown to be the antigenic target ofperinuclear-ANCA in patients with vasculitis

The range of ANCA subtypes expanded andadditional autoantigens recognized by ANCAswere found



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Recent findings bring up a new hypothesis onthe induction of ANCAs by

Immune responses against Gram-positive orGram-negative bacteria

Pendergraft et alinvestigated the role ofcomplementary peptides in WG

The authors hypothesized that Initial immune response in WG is directed against

the complementary protein PR3 (cPR3) and thatanti-PR3 antibodies evolve during a secondary anti-idiotypic immune response



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According to this hypothesis, antibodies formingthe humoral immune response against cPR3

would serve as antigenic target for a secondaryimmune response (antiidiotypic response)

Anti-idiotypic antibodies not only react to anti-cPR3-antibodies but also to the sense proteinPR3



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Pathogens likeStaphylococcus aureusbeargenetic sequences that are complementary to the

human PR3 gene, pointing to an exogenousorigin of cPR3 transcripts Indeed, chronic nasal carriage of S. aureus has

been demonstrated to increase the risk for disease

relapse Moreover, WG patients treated with cotrimoxazoleare less prone to relapse, and in some cases evenremission can be induced by applyingcotrimoxazole as monotherapy



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The mechanism proposed by Pendergraft et al.defines a pivotal, novel role for a specific ANCA

subtype but Needs further confirmation

In addition, the clinical relevance andimportance to disease pathogenesis needs to bedefined and remains unclear



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Recently, Kain et al. reported the discovery ofautoantibodies against lysosomal membrane

protein-2 (LAMP-2) in patients with AAV-associated NCGN

They provided in vitro and in vivo evidence for therelevance of these antibodies to diseasepathogenesis and linked them with infectiouspathogens



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Anti-LAMP-2 antibodies were only found inpatients with active ANCA-associated NCGN.

Interestingly, anti-LAMP-2 antibodies were alsodetectable in several patients with NCGN lacking

PR3-ANCA or MPOANCA.


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Anti-LAMP-2 crossreacted with FimH, which ispart of the fimbriae of Gram-negative pathogens.

immunization with FimH led to development ofcrescentic glomerulonephritis in rats.

The findings by Kain et al need to be confirmed

in other patient cohorts


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HNE (human neutrophil elastase)

Belongs to the chymotrypsin family of serine

proteases

ANCAs with specificity to HNE are rarely andinfrequently detected in patients with vasculitis

Importantly, HNE-ANCA might be of use fordiagnosing

Cocaine-induced midline destructive disease and/or

Drug-induced AAV



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HNE (human neutrophil elastase)

Dolman et aldetected Anti-HNE antibodies

frequently in patients developing vasculitisduring treatment with propylthiouracil

These findings were confirmed by others showingan association of ANCA with the administration ofantithyroid drugs



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THE COMPLEMENT SYSTEM AND ITS ROLE IN AAV

Pauci-immunity is a hallmark of ANCA-associated vasculitis, and deposition of immune

complexes or complement factors is consideredto be absent

However, accumulating evidence suggests that

the complement pathway is involved in diseasepathogenesis

The complement system has a pivotal role in hostdefense as well as clearance of immune complexes



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Overview oncomplement

system


ExplanationNext slide.


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The complement system seems to be an importantplayer in AAV

Complement activation and the resulting productsmight promote inflammation and enhance tissuedamage

Although the exact mechanisms are not known yet,the neutrophilcomplement axis might be crucial

Neutrophils become activated by complementproducts and complement is activated by neutrophils



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Hence, dysregulation of this axis might lead tosustained, self-perpetuating inflammation and

contribute in this way to AAV (Figure 1) Finally, complement activation might also account

for increased risk of venous thromboembolismobserved in active AAV, as activated complement

factors trigger coagulation



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T CELLS IN AAV

T cells are usually found within granulomas aswell as in other lesions present in AAV

In accordance with these findings, Elevated levels of markers of T-cell activity such as

soluble interleukin-2 (IL-2) receptor, neopterin,and soluble CD30 as measured in the circulationhave been shown to be associated with diseaseactivity


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T CELLS IN AAV

Furthermore, ANCA IgG subclasses suggest thata T-cell-mediated subclass switch has taken

place

Specific T-cell-targeted therapy is occasionally

used in refractory cases and has beendemonstrated to be beneficial



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T CELLS IN AAV

In patients with active disease and duringremission, T cells are in a persistent state of

activation

Furthermore, memory T cells are expanded,

whereas naive T cells are decreased



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T CELLS IN AAV

Studies demonstrated that a specific subset ofeffector memory T cells (Tems) expressing

CD134 and GITR (glucocorticoid-induced TNF-receptor-related protein) is especially expandedin WG patients



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T CELLS IN AAV Tems

Powerful immune cells that initiate and sustain

immune responses Long lived and responds quickly to adequate

triggers

Granuloma formation is driven by these T cells

Tems have a major pathophysiological role in AAV



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T CELLS IN AAV IL-17-producing Th17 effector T cells were

shown to be of major importance in

autoimmunity

As the influx of neutrophils is a hallmark of AAV,

IL-17 might also have a pivotal pathophysiologicalrole in AAV



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T CELLS IN AAV Regulatory T cells (Tregs) limit immune

responses

In some autoimmune diseases, Treg defects havebeen described

Limited data on Tregs in AAV

Defective Treg function might account for theTem expansion and the persistent T-cellactivation observed in AAV



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TERTIARY LYMPHOID TISSUE IN AAV At present, it is unknown whether local

activation or control of the immune response

within the affected tissue itself occurs in AAV Local control of immune responses is linked to the

development of tertiary lymphoid organs (TLOs),also known as lymphoid neogenesis

In AAV, so far, granulomas are regarded as someform of TLOs where immune responses aremodified



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Summarizing Pathogenesis Disease pathogenesis of AAV is complex with a

number of overlapping effector limbs

It is clear thatANCAs are of major importancefor disease and cause vasculitis, interacting withneutrophils upon specific triggers like infections

At the same time, Tems escaping immuneregulation enhance autoantibody productionand drive tissue inflammation



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Application in therapy Understanding the pathogenesis of anti-

neutrophil cytoplasmic antibody (ANCA)-

associated vasculitis (AAV) allows application oftargeted therapy.



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Conclusions AAV is an autoimmune disease with complex

pathophysiology

Anti-neutrophil cytoplasmic antibodies (ANCAs)with specificity for proteinase-3 (PR3) or

myeloperoxidase (MPO) are hallmarks of AAVand have a pivotal role in disease development


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Conclusions In addition to ANCA, the cellular immune

system contributes to the pathogenesis of the

disease

ANCA-mediated degranulation of neutrophilscauses vasculitic damage;

T cells drive granuloma formation, promotevasculitic damage by several different pathways,and enhance autoantibody production by B cells


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Conclusions Recently, complementary PR3 and lysosomal

membrane protein-2 were suggested as novel

autoantigens in AAV New findings also indicate the importance of

complement, danger-associated molecularpatterns, and dendritic cells in AAV

Understanding the pathogenesis ANCA -associated vasculitis (AAV) allows application oftargeted therapy


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pathogenesis anca associated vasculitis.pptx final

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