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Systemic Vasculitis & Alpha-1 Antitrypsin Deficiency

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Vasculitis You what?????

AAT deficiency and natural history Going through the pathogenic link Relevant studies Conclusions

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 disorders characterized by

Inflammation of blood vessels

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

COPD enphysema

Airflow obstruction asthma Bronchial hiperresponssiveness

bronchiectasis Others: renal, vasculitis, etc Lung disease

Liver disease

Genetic disorder AATD

There is evidence of an association between AATD & systemic vasculitis. AAT deficiency alone is not usually enough to cause sysitemic vasculitis in the absence of other genetic and environmental risk factors.

Vasculitis You what????? AAT deficiency and natural history Going 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 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.

macrophage Airwways aneutrophils activation

Elastase

LTB4

Neutrophile recruitment

Destruction area

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

There are normal regulatory mechanisms for control of secreted neutrophil enzymes and control pathways to limit the enzyme action by anti-proteases. These are highly important for neutralization of the enzymatic activities of the neutrophil proteases.

Anti-protease shield prevents 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.

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

Its 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: 1389-93

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

MPO

AAT

PR3

cANCA

pANCA

Rao 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 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 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: 31-44

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: 31-44

Previous reports have suggested an association 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 regards disease manifestations.
Elzouki AN et al. J Intern Med 1994; 236: 543-548 O'Donaghue D et al. In: Gross WL, ed. ANCA-Associated Vasculitides: Immunological and Clinical Aspects. Plenum Press, NY1993; 331-335

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

ANCA neutrophil activation releasing proteases and ROS, which may result in systemic vasculitis. Since vasculitis didnt 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.

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