ANCA Prepared by Dr. Anees Al-SaadiApril 2008

Clinical immunology principles and practice RICH, 2nd editionMethodological update ANCA.mhtwww.medicinenet.com › emedicine.medscape.com/,www.youtube.com

Methodological update ANCA.mht

History ANCA auto antibodies related to

inflammatory disorders. 

van der Woude et al. in 1985 showed ANCA related to Wegener's granulomatosis. 

Methodological update ANCA.mht

Antigens Enzymes used in the defense

against bacteria found in WBCs granules.

Most reactivities were found molecular weights ≈29kD & l4OkD. 

Methodological update ANCA.mht

Antigens

Two main enzymes in ANCA take part in the killing of bacteria by:

Proteinase 3 (PR3) showing cANCA pattern.

Myeloperoxidase (MPO) showing pANCA pattern.

Methodological update ANCA.mht

Proteinase 3 (PR3)

Molecular weight of 29kD antigen:  Which is proteinase . PR3 is a single protein chain that is

glycosylated.  Is very similar to other serine proteases

like elastase and cathepsin G.

Methodological update ANCA.mht

Myeloperoxidase (MPO)

Myeloperoxidase (MPO)  

MPO is a dimer molecular weight of l4OkD consisting of one heavy & light chain .

It is glycosylated with mannose oligosaccharide chains. 

Is cleaved by heating and has a green color .

Methodological update ANCA.mht

Myeloperoxidase (MPO)

Many other antigens have been described to be associated with ANCA, i.e. elastase, lactoferrin cathepsin G, BPI defensins, HMG1/2, catalase etc.

Methodological update ANCA.mht

Antigens associated with ANCA

Methodological update ANCA.mht

Development of ANCA

It is poorly understood how ANCA are developed.

Two possible mechanisms of ANCA development are postulated:

Theory of molecular mimicry. Theory of defective apoptosis.

Methodological update ANCA.mht

Development of ANCA

Theory of molecular mimicry.

Superantigens have the power to stimulate a strong immune response . THEY have regions that resemble self-antigens – this is the theory of molecular mimicry.

classical example in post group A streptococcal rheumatic heart disease, where there is similarity between M proteins of Streptococcus pyogenes to cardiac myosin and laminin.

Theory of defective apoptosis.

ANCA may be developed either via ineffective apoptosis or ineffective removal of apoptotic cell fragments, leading to the exposure of the immune system to molecules normally sequestered inside the cells. This theory solves the paradox of how it could be possible for antibodies to be raised against the intracellular antigenic targets of ANCA.[4]

Methodological update ANCA.mht

Three patterns of ANCA

p-ANCA, show a perinuclear staining pattern

c-ANCAs, show a diffusely granular, cytoplasmic staining pattern

Atypical that develop against antigens other than MPO or PR3 will occasionally result in patchy staining

Methodological update ANCA.mht

pANCA disease association :

• Primary vasculitisMicroscopic polyangitis Churg-Strauss syndrome Polyarteritis nodosa

• CollagenosisFelty's syndromeSLERheumatiod arthritisSjögren's syndrome 

• Chronic inflammatory bowel disease

 • Chronic liver disease

Primary sclerosing cholangitis

cANCA disease : association

• Primary vasculitis

• Wegener's granulomatosis

• Microscopic polyangitis

• Churg-Strauss syndrome.

Atypical

• Primary sclerosing cholangitis

• Primary biliary cirrhosis

• Autoimmune hepatitis

• SLE

• RA

Wegener's granulomatosis

Definition

ClinicalPicture

Treatment

Wegener's granulomatosis is a uncommon type of (vasculitis). It classically involves the lungs, the nasal passages (sinuses), and the kidneys.

Nasal or oral inflammation: Lungs: abnormal chest X-ray .Kidneys: with microhematuria or red cell casts Biopsy: granulomatous inflammation Initial treatment is corticosteroids and oral CYC.On remission treatment is changed to azathioprine or methotrexate.Duration of therapy should be at least one year.

Methodological update ANCA.mht

Microscopic polyangitis

Definition • Microscopic

polyangiitis (MPA) is vasculitis of small vessels.

Features• Renal GN

79%.• May progress

to irreversible rapid progressive renal damage If not treated .

• Weight loss 73%.

• Fever 55%.

• Pulmonary: alveolar hemorrha

ge.

Treatment• daily/

intermittent I.v cyclophosphamide 6-12months .

• Methotraxate or azathioprine in remission stage of the disease.

Methodological update ANCA.mht

Churg-Strauss syndrome .

Definition

• An eosinophil-rich form of granulomatous inflammation mainly involving respiratory tract

• Asthma and eosinophilia.

Features

• 1. A prodromal phase• Allergic

disease.

• 2. Eosinophilia-tissue infiltration phase:• Eosinophilia.

• 3. Vasculitic phase : • Systemic

necrotizing vasculitis .

Treatment

• Treatment is prednisone for mild cases , systemic involvement cyclophosphamide to be added.

• Clinical remission seen in 90% of the cases and recurrences seen in 25%

Applications of Antineutrophil Cytoplasmic Antibody.mht

Applications of ANCA

The application of ANCA useful in both the diagnosis and monitoring of disease activity .

Methodological update ANCA.mht

Applications of ANCA Churg-Strauss Syndrome

Wegener's Granulomatosis

Microscopic Polyangiitis ANCA

10% 80% 40 % PR3-ANCA

60% 20% 50% MPO-ANCA

30% 5% 10% Negative

Applications of ANCA Prevalence of ANCA in renal

vasculitis ANCA test positivity (%) Type of renal

vasculitis C-ANCA P-ANCA

10-20% 10-20% Polyarteritis nodosa

10-20% 50-80% Microscopic polyangitis

80-90% 10-20% Wegener`s granulomatosis

10-20% 50-80% Necrotizing and crescentic GN

Clinical immunology principles and practice RICH, 2nd edition .

Applications of ANCA

In Juvenile rheumatoid arthritis : Occur in 10-20% of active conditions. Showing atypical pattern. Does not correlate with clinical

parameters.

Clinical immunology principles and practice RICH, 2nd edition pr

Applications of ANCA

Autoimmune hepatitis : Showing p-ANCA pattern. Seen in 65%-96% in AIH-1 not in AIH-

2. Not correlated with disease activity and

liver function test.

Clinical immunology principles and practice RICH, 2nd edition pr

Applications of ANCA

Inflammatory bowel disease: Showing p-ANCA pattern more seen

in UC than CD. Not been used for distinguishing the 2

diseases .

Clinical immunology principles and practice RICH, 2nd edition pr

AccessMedicine - ANCA induced by drugs.mht

Applications of ANCA Drug-induced ANCA:

Picture of ANCA-associated vasculitis (AAV).

Propylthiouracil is a well-documented cause of drug-induced AAV.

Other drugs:▪ Hydralazine,sulfasalazine.▪ minocycline, D-penicillamine.▪ ciprofloxacin, phenytoin.▪ clozapine, allopurinol, and pantoprazole.

AccessMedicine - ANCA induced by drugs.mht

Applications of ANCA

Usually of p-ANCA pattern.

Slow resolving condition.

Good responding to low dose of immunosuppressive agents.

Applications of ANCA

Prognostic significance of ANCAs:

Increasing ANCA titers do not reliably predict relapse.

Nevertheless, many clinicians assume that ANCA titers are reliable indicators of disease activity !.

ANCA\Clinical Applications of Antineutrophil Cytoplasmic Antibody.mht

Thank You!

www.youtube.com

Histopathology Lung --Wegener granulomatosis - icyou health videos.flv

Mark Lesko's Story - Wegener's Granulomatosis.flv