Systemic Vasculitis & Alpha-1 antitrypsin Deficiency

7/29/2019 Systemic Vasculitis & Alpha-1 antitrypsin Deficiency

http://slidepdf.com/reader/full/systemic-vasculitis-alpha-1-antitrypsin-deficiency 1/27





“Vasculitis”… You what?????

AAT deficiency and natural history

Going through the pathogenic link Relevant studies

Conclusions



Non specific term

Systemic process

Non specific manifestations

Large & heterogeneous group of disorderscharacterized by

Inflammation of blood vessels












Conclusions



Genetic disorder

AATD

Liver disease

Others:

renal, vasculitis, etc

Lung disease

bronchiectasis

Airflow obstruction

Bronchial hiperresponssivenessasthmaCOPD

enphysema



There is evidence of an associationbetween AATD & systemic vasculitis.

AAT deficiency alone is not usually

enough to cause sysitemic vasculitis inthe absence of other genetic andenvironmental risk factors.






Conclusions



Neutrophil elastase is released during times

of inflammation. This action is normally

helpful and is balanced (neutralized) bythe protein a-1 antitrypsin produced in the

liver.

• One cause of damage to any tissue is that

elastase is produced by neutrophil but

there is a genetically lack of a-1 antitrypsin.



S. Stolk. Eur Respir Mon 2006; 34: 139-150

macrophage

Airwways

aneutrophils

activation

Elastase

LTB4

Neutrophile recruitment Destruction

area



• There are normal regulatory mechanismsfor control of secreted neutrophilenzymes and control pathways to limitthe enzyme action by anti-proteases.

• These are highly important for neutralization of the enzymatic activities

of the neutrophil proteases.



Anti-protease

shieldprevents degradation

of normal tissues

Then how can the neutrophil

perform its normal functions?



Subsequent to this

attack

on anti-proteases,

the neutrophil enzymes

are free to damage the

bacterial targets,

necrotic tissues, or in

pathological condition

normal tissues.






Conclusions



It’s been described that ANCA activate

primed neurophiles and possibly induce

accelerate apoptosis of tumor necrosis

factor-primed neutrophils.

Actually, the titer of ANCA is correlated with

the disease activity, and rises prior toclinical manifestations .

Savage COS et al. Lancet 1987; 1: 1389-93



The main antigenic targets for ANCA areproteinase 3 (PR3) and myeloperoxidase (MPO).

AATPR3

pANCAcANCA

MPO

Rao Nvet al. J Biol Chem 1991; 266: 9540-48



Accordingly it is likely proteases play a role inpathogenesis of systemic vasculitis

protease/antiprotease imbalance,

which may be either :

genetically determined in AATD

pathological acquire inactivation.

Rao Nvet al. J Biol Chem 1991; 266: 9540-48



In some cases the serum is negative for

ANCA, and it is apparent that other something than PR3-ANCA plays a rolein releasing PR3.



A subpopulation of AATD Pi*ZZassociated with ANCA(+) plus systemic

vasculitis has been reported,but it was demonstrated there is noevidence that a Pi*ZZ patient carryingANCA against PR3 or MPO has a greater

risk of developing systemic vasculitis thana Pi*MM patient carrying ANCA

Audrain MAP et al. Nephrol Dial Transplant 2001; 16: 31-44



Although the vasculitis associated withAATD showed a more widespread and

worse prognosis than vasculitis,in Pi*MM patients, there was nodifference in age at onset or relapsetendency.

Audrain MAP et al. Nephrol Dial Transplant 2001; 16: 31-44



Previous reports have suggested anassociation between certain ANCA(+)

vasculitis and AATD phenotypes .

Esnault Vet al. Kidney Int 1993; 43: 1329-1332



However, other small studies have given

conflicting results, so it is unclear whether this is a consistent association and, if so,whether it is of significance as regardsdisease manifestations.

Elzouki AN et al. J Intern Med 1994; 236: 543-548

O'Donaghue D et al. In: Gross WL, ed. ANCA-AssociatedVasculitides: Immunological and Clinical Aspects. Plenum Press,

NY1993; 331-335






Conclusions



ANCA neutrophil activation

releasing proteases and ROS,

which may result in systemic vasculitis.

Since vasculitis didn’t result from the

production of ANCA in some patients,the evidence suggests…

AATD may be a serious genetic factor exacerbating the vasculitis

regardless of the relation with ANCA.

Documents

Systemic Vasculitis & Alpha-1 antitrypsin Deficiency