“Vasculitis”… You what????? AAT deficiency and natural history Going through the pathogenic link Relevant studies Conclusions

““VasculitisVasculitis””… You what?????… You what????? AAT deficiency and natural history Going through the pathogenic link Relevant studies Conclusions

Non specific termNon specific term

Systemic processSystemic process

Non specific manifestationsNon specific manifestations

Large & heterogeneous group of disorders Large & heterogeneous group of disorders characterized bycharacterized by

Inflammation of blood vesselsInflammation of blood vessels

“Vasculitis”… You what????? AAT deficiency and natural historyAAT deficiency and natural history Going through the pathogenic link Relevant studies Conclusions

Genetic disorderGenetic disorderAATDAATD

Liver disease

Others:renal, vasculitis, etc

Lung disease

bronchiectasis

Airflow obstructionBronchial hiperresponssivenessasthmaCOPD

enphysema

There is evidence of an association There is evidence of an association between AATD & systemic vasculitis.between AATD & systemic vasculitis.

AAT deficiency alone is not usually AAT deficiency alone is not usually enough to cause sysitemic vasculitis in enough to cause sysitemic vasculitis in the absence of other genetic and the absence of other genetic and environmental risk factors.environmental risk factors.

“Vasculitis”… You what????? AAT deficiency and natural history Going through the pathogenic linkGoing through the pathogenic link Relevant studies Conclusions

Neutrophil elastase is released during times of inflammation. This action is normally helpful and is balanced (neutralized) by the protein -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 -1 antitrypsin.

S. Stolk. S. Stolk. Eur Respir Mon Eur Respir Mon 2006; 34: 139-1502006; 34: 139-150

macrophage

Airwways aneutrophils activation

Elastase

LTB4

Neutrophile recruitment Destruction area

• There are normal regulatory There are normal regulatory mechanisms for control of secreted mechanisms for control of secreted neutrophil enzymes and control neutrophil enzymes and control pathways to limit the enzyme action by pathways to limit the enzyme action by anti-proteases.anti-proteases.

• These are highly important for These are highly important for neutralization of the enzymatic neutralization of the enzymatic activities of the neutrophil proteases.activities of the neutrophil proteases.

Anti-proteaseshield prevents degradationof normal tissues

Then how can the neutrophilThen how can the neutrophilperform its normal functions?perform its normal functions?

Subsequent to this attack

on anti-proteases, the neutrophil enzymesare free to damage the

bacterial targets, necrotic tissues, or in

pathological conditionnormal tissues.

“Vasculitis”… You what????? AAT deficiency and natural history Going through the pathogenic link Relevant studiesRelevant studies 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 to clinical manifestations .

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

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

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

Accordingly it is likely proteases play a role in pathogenesis of systemic vasculitis protease/antiprotease imbalance, which may be either :

genetically determined in AATD genetically determined in AATD pathological acquire inactivation. pathological acquire inactivation.

Rao Nvet al. J Biol Chem 1991; 266: 9540-48Rao 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 role in releasing PR3.

A subpopulation of AATD Pi*ZZ associated with ANCA(+) plus systemic vasculitis has been reported, but it was demonstrated there is no evidence that a Pi*ZZ patient carrying ANCA against PR3 or MPO has a greater risk of developing systemic vasculitis than a Pi*MM patient carrying ANCA

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

Although the vasculitis associated with AATD showed a more widespread and worse prognosis than vasculitis, in Pi*MM patients, there was no difference in age at onset or relapse tendency.

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

Previous reports have suggested an association between certain ANCA(+) vasculitis and AATD phenotypes .

Esnault VEsnault Vet al. Kidney Int et al. Kidney Int 1993; 43: 1329-13321993; 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 regards disease manifestations.

Elzouki AN et al. Elzouki AN et al. J Intern Med J Intern Med 1994; 236: 543-5481994; 236: 543-548 O'Donaghue D et al. In: Gross WL, ed. O'Donaghue D et al. In: Gross WL, ed. ANCA-Associated ANCA-Associated

Vasculitides: Immunological and Clinical Aspects. PVasculitides: Immunological and Clinical Aspects. Plenum Press, lenum Press, NY1993; 331-335NY1993; 331-335

“Vasculitis”… You what????? AAT deficiency and natural history Going through the pathogenic link Relevant studies ConclusionsConclusions

ANCAANCA neutrophilneutrophil activation activation

releasing proteases and ROS, releasing proteases and ROS,

which which may result may result in systemic in systemic vasculitis. vasculitis.

Since vasculitis didn’t result from the Since vasculitis didn’t result from the production of ANCA in some patients, production of ANCA in some patients, the evidence suggests… the evidence suggests…

AATD may be a serious genetic factor AATD may be a serious genetic factor exacerbating the vasculitis exacerbating the vasculitis regardless of the relation with ANCA.regardless of the relation with ANCA.