Autoimmune liver and pancreatic disease

Question 1

What cells are targeted in autoimmune hepatitis (AIH) and what markers

Answer 1

Associated with hepatocellular inflammation and necrosis where hepatocytes are targeted- leads to fibrosis and scarring.

Associated with autoantibodies against smooth muscles antigens (SM) and anti-nuclear antibodies.

Question 2

what does PBC stand for and the features of this disease?

Answer 2

primary biliary cholangitis?

slow and progressive destruction of the small bile ducts- leads to cholestasis (bile duct flow blocked) and cirrhosis.

Question 3

what does PSC stand for and what features? What IBD associated with this?

Answer 3

primary sclerosing cholangitis

chronic progressive destruction of large and small bile ducts which can be intra and extrahepatic (pancreas and gall bladder)

Question 4

What is targeted in IgG4 disease?

Answer 4

intra and extra hepatic small and large bile ducts, inflammation, but less cirrhosis involved.
hepatocytes also targeted.

Question 5

what antibodies are associated with AIH?

Answer 5

smooth muscle Ab and ANAs.

Question 6

are bile ducts affected in AIH? And what gender and age groups mostly present with it?

Answer 6

Bile ducts aren’t blocked (bilirubin normal)

females more likely affected and biphasic presentation., adolescence and older age group.

Question 7

non-specific and more specific clinical symptoms of AIH?

Answer 7

non-specific: joint pain and fatigue (when diagnosed often scarring is seen).

specific: yellowing, abdominal pains, itchiness

Question 8

What are the type I and type II antibodies for AIH?

Answer 8

type 1: ANAs and SMab (against filamentous actin).

type 2: liver microsomal ab

anti-LC1 (FTCD)

anti LKM1 (CYP2D6)

Question 9

Do AIH antibodies cause disease?

Answer 9

not thought to because they are intracellular, non-specific to hepatocytes but maybe useful for type II AIH models.

Question 10

Where are necro inflammatory regions often seen in AIH?

Answer 10

In portal, periportal lesions- interface hepatitis.

Question 11

what infiltrating cells are particularly prominent in AIH?

Answer 11

CD4 T cells and CD20 B cells and CD138+ plasma cells.

Question 12

What structures do inflamed hepatocytes form in AIH?

Answer 12

rosettes in the area of interface hepatitis.

Question 13

what is emperipolesis seen in AIH?

Answer 13

Where CD8 cells are in the cytoplasm of the damaged hepatocyte.

Question 14

Are there any specific cells responsible for AIH pathogenesis?

Answer 14

Not really, basically said Th1 Th2 Th17 macrophages (TNFa IL-1) and plasma cells and even NK cell ADCC could be involved?

Question 15

What is interesting about Treg cells in AIH?

Answer 15

Tregs are reduced in number in blood and intrahepatic tissue during active disease.

With treatment Tregs increase.

Question 16

What can Il-2 deficicency within liver tissue show in an vitro liver model?

Answer 16

Tregs are suceptible to deficiency in Il-2, Treg apoptosis.

Question 17

What effects can administration of IL-2 in in vitro liver models have?

Answer 17

low doses expand and activates Tregs.

High doses will activate T effector cells.

Question 18

What Treg restoration technique is there apart from IL-2 administration?

Answer 18

Adoptive cell transfer: autologous Treg expansion and reintroduction.

Question 19

What effect does rituximab have in AIH type II murine model?

Answer 19

Doesn’t reduce IgG.
But does reduce Tfh
and reduces the pro-inflammatory profile of B cells.
Reductino in inflammatory infiltrate.

Question 20

Improvements seen in rituximab therapy in patients?

Answer 20

auto IgG ab decreased, ALT improved, inflammation grade fell in biopsies.

Question 21

Alternative B cell targets in autoimmunity to rituximab?

Answer 21

anti BAFF/APRIL or BAFFR/TACI/ BCMA receptors

and Syk (fostamatibinib) and Btk

or indirectly via T cell costimulation (CTLA-4/ CD40/40L ICOSL)..

Question 22

Non specific therapies to autoimmunity?

Answer 22

ciclospoirin, tacrolimus,
corticosteroids
mycophenolic acid
azathioprine
6- mercaptopurine.

Question 23

What does increased bilirubin and ALT, ALp and CRP imply?

Answer 23

they have a disease that is affecting the bile ducts and hepatocytes along with inflammation (ie IgG4 disease).

Question 24

What common morphological features fo IgG4 disease are there?

Answer 24

inflammatory masses and strictures.

Question 25

As well as high IgG(4) what other Ig is high in IgG4 disease?

Answer 25

Ige.

Question 26

Are inflammatory masses and strictures just seen in the pancreas and liver in IgG4 patients?

Answer 26

no, it is a multi-organ disease.

Question 27

What 4 things are characteristic of IgG4 histology?

Answer 27

lymphoplasmacytic infiltrate
obliterative phlebitis (obliteration of blood vessels)
storiform pattern of fibrosis (includes lymphocytes and fibroblasts)

high levels of IgG4+ plasma cells.

Question 28

What might initiate IgG4 disease?

Answer 28

the reaction against microbes, self or environmental antigens.

Question 29

What cells and cytokines might stimulate IgG4 B cell class switching?

Answer 29

Th2 andTreg cells producing Il-4, Il-13 and Il-20.
Induces IgG4 class switching. 

Th2 cell involvement may be why IgE and eosinophilia is see in IgG4 disease.

Question 30

What cells may contribute to the expansion of IgG4 B cells?

Answer 30

Tfh (IL-21) and basophils and monocytes (activated TLRs) provide BAFF and IL-13.

Question 31

What cytokine might induce fibroblast activation (and alternatively activated macrophages) in IgG4 disease?

Answer 31

Tregs production of TGF-B.

Question 32

Two features of IgG4 structure?

Answer 32

bispecific chains whihc can avoid crosslinking.

more flexible chains.

Question 33

What amino acid switch vs IgG1 makes Ig4 unable to cross link?

Answer 33

Proline 228 to serine.

Question 34

What do substitutions in IgG4 amino acids do for Fc binding and C1q binding?

Answer 34

reduces IgG4 Fc binding to Fc receptors

reduces ability of C1q binding and complement activation.

Question 35

How can IgG4 have an anti-inflammatory effect on other antibodies?

Answer 35

By using its constant domain to bind other Fc portion of IgG moleucels to inherit their complement action.

Question 36

what dissease is IgG4 known to be pathogenic? What disease can induce IgG4 to make it more anti-inflammatory?

Answer 36

pemphigus IgG4 complexes are pathogenic.

melanoma (IL-10) will induce IgG4 response for immune evasion.

IgG4 ab will block IgE ab against parasites.

Question 37

what would be a good antibody subclass to pick to neutralise monoclonal drugs?

Answer 37

IgG4.

Question 38

IgG4+ B cells are activation in igG4 related diseases, what ar some unusual features of their phenoytpes?

Answer 38

lower activation markers,
lowerer CR2 and CD21 (B cell dyregulation)
increased FcIgE receptors.

Lower inhibitory receptors (FcyRIIb)

Question 39

Indications IgG4 can form immune complexes that are pathogenic in IgG4 disease?

Answer 39

staining overlaps with the deposition of collagen in tissues where there is complement activation.

They exhibit increased Fab glycosylation seen only in IgG4.

Increased Fc fucosylation of IgG4 in disease too.

decreased galactosylation of all IgG in disease, seen in other autoimmune conditions.

Question 40

Is there a speicific antigen that IgG4 binds to in disease?

Answer 40

Not one, but have been found to bind Aneexin 11.
Others include laminins, probitin and galectin-3

But these are all ubiquitous proteins.

Question 41

What treatments are used for IgG4 related diseases?

Answer 41

Steroids, and also rituximab.

rituximab reduced plasmablasts, but these returned with greater SHM when therapy arrested.

reversed storiform pattern of fibrosis.