Term
True or False:
The majority of cases of Vasculitis are chronic, multisystem diseases that involve immune-mediated injury targeted at blood vessels? |
|
Definition
|
|
Term
| What are the 4 basic tenets of Vascular Inflammation |
|
Definition
1) PMNs leave peripheral circulation to enter tissue
2) Cyokines and chemokines attract cells, bind to endothelial cells and promote transmigration
3) PMN activation and products promote vessel injury in all wall layers
4) Vessel response (normal) leads to abnormal physiological changes in vessel |
|
|
Term
| What are 6 factors that lead to differences in the types of vasculitis? |
|
Definition
1) Patient (genetics, age, gender, ethnicity).
2) Local autoantigen/cellular receptor
3) Endothelial cells, matrix protein differences
4) Vasa vasorum in large vessels can affect immune cell and pathogen access
5) Cell-specific infections
6) Immunological response to triggering event |
|
|
Term
| What epidemiological features define GAP? |
|
Definition
1) idiopathic, chronic inflammatory condition of SMALL blood vessels
2) Triad (vasculitis of upper/lower respiratory tract, glomerulonephritis, necrotizing, granulomatous inflammation on tissue biopsy)
3) 1:30,000 (common)
4) Mainly white adults with no gender bias |
|
|
Term
| What is the "triad" of GAP? |
|
Definition
1) Vasculitis of upper/lower respiratory tract
2)Glomerulonephritis
3)Necrotizing, granulomatous inflammation |
|
|
Term
| What important clinical features should you look for to detect GAP? |
|
Definition
1) Septal perforations
2) Otitis media (ADULT)/ chronic sinusitis
3) Saddle nose
4) Orbital "pseudo tumor" consisting of fibrous tissue
5) Sub-glottal stenosis |
|
|
Term
| What is critical to remember about Ancillary testing in GAP? |
|
Definition
It is really variable!
Sometimes you see ESR, CRP, C-ANCA, PR-3 |
|
|
Term
| Explain the relationship between C-ANCA and GAP. |
|
Definition
Cytoplasmic staining pattern of neutrophils that is generally thought to involve proteinase-3.
If you have GAP, you are 90% likely to have C-ANCA + triad. However, these can be seen in other conditions, meaning they have a low PPV. |
|
|
Term
| Given that a patient has GAP restricted to the upper respiratory tract, what is the probability that you will see C-ANCA present with triad? |
|
Definition
75%!
In other words, you are less likely to have C-ANCA and the triad if the case of GAP is restricted in this way. |
|
|
Term
| What genetic factors are associated with GAP etiology? |
|
Definition
1) HLA genes
2) CD226 (CD3)
3) IL-10
4) CTAL4 |
|
|
Term
| Which environmental factor is associated with GAP? |
|
Definition
|
|
Term
| What are the PROs and CONs against the idea that ANCA has a pathogenic role in GAP? |
|
Definition
Pros- correlation with disease activity, increase titer may predict activity
Cons- high titers found in patients with clinically quiescent disease, patients who are and remain ANCA negative (PPV only 50%) |
|
|
Term
| Explain how ANCA may elicit GAP. |
|
Definition
1) Activate PMNs, which produce ROS
2) Induce production of TNF-a, IL-1, IL-8
3)Increase expression of adhesion molecules for transmigration through vessel wall.
4)Bind PR3 on neutrophils resulting in immune-complex formation that leads to complement activation
5) Promote PR3 expression on membrane of neutrophils, which promotes disease
6) PR3 deficient mice that are immunized with PR3 develop antiPR3 antibodies that lead to inflammation. |
|
|
Term
| What is "Auto-antigen complementarity"? |
|
Definition
A number of GAP patients have S. aureus infections
1) Patients generate Ab against the Staph antigens
2) These antibodies also match to the antisense (complementary) sequences of autoantigens
3) In GAP, patients have circulating antibodies that recognize PR3 though complementarity. Antibodies develop against these antibodies as an "anti-idiotypic pair." |
|
|
Term
| How does PR3-ANCA relate to GAP? |
|
Definition
| Patients with GAP express PR3 on their neutrophils, which is recognized by ANCA antibodies that are produced in response to infection. |
|
|
Term
| What is the current model of etiopathogenesis of ANCA-associated vasculitis? |
|
Definition
SHORT
1) Insult makes PMNs express PR3
2) PR3 activates DCs, which go to LN and activate CD4+ T cells and IL-18 (Th1)
3) ANCA in vessels bind PR3 and promote PMN adherence, migration, complement deposition and inflammation.
EXPLANATION
3) 1) Infection primes Neutrophils with IL-1 and IL-6 (they express PR3)
2) PR3 induces DC migration to LN, where CD4+ T cells and IL-18 promote Th1 response, with granuloma formation
3) In vessels, ANCAs produced by plasma cells bind to PR3 and promote PMN adherence and transmigration, and the production of ROS
4) Complement activation and ongoing local inflammation (granulomatous) ensues. |
|
|
Term
|
Definition
There are COMPLICATIONS with therapy
1) Corticosteroids
2) Steroid-sparing immunosuppressives (MTX, azathioprine, mycophenolate mofetil, cyclophosphamie, rituximab) |
|
|
Term
| What renal symptoms should you look for in GAP? |
|
Definition
| RBC casts in urine with proteinuria glomerulonephritis and hematuria |
|
|
Term
| What diagnosis is most commonly mistaken for GPA? |
|
Definition
Infection
Also,
Collagen vascular disorders and Cholesterol emboli |
|
|
Term
| What should you monitor a patient with primary Sjogren's for? Why? |
|
Definition
Lymphoma tends to develop!
Remember, epithelia serve as APC for T cells, which let out CXCL13 to recruit B cells, which produce BAFF and SSA/B, which leads to inflammation.
Overactivity of B cells (BAFF release and autoantibodies) and germinal center formation can lead to B-cell cancer down the line. |
|
|
