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Page 4 of 10 Zierke et al. Rare Dis Orphan Drugs J 2023;2:10 https://dx.doi.org/10.20517/rdodj.2022.17

[31]
protein aggregates and ER stress appeared to be the most probable causative mechanism . Single-base-pair
deletions in the proximal part of the CEL-VNTR have been identified in a family with hereditary
[32]
pancreatitis, indicating that these variants should also be considered as a cause of hereditary pancreatitis .

Finally, mutations in the carboxypeptidase A1 (CPA1) and elastase 3B (CELA3B) genes have also been
found to be associated with hereditary pancreatitis [33,34] .

AUTOIMMUNE PANCREATITIS
Autoimmune pancreatitis (AIP) is another rare type of pancreatitis that exhibits features of both acute and
chronic pancreatitis. First described by Sarles et al. in 1961, it was termed “autoimmune pancreatitis” in
1995 by Yoshida et al. [35,36] . The exact numbers of incidence and prevalence of AIP are largely unclear;
however, they seem to differ among countries. In Germany, the incidence has been reported to be
approximately 0.29 per 100,000 people, while in Japan, there is a much higher incidence of 1.4 per 100,000
inhabitants [37,38] . AIP is classified into two subtypes: type 1, also known as lymphoplasmacytic sclerosing
pancreatitis (LPSP); and type 2, idiopathic duct-centric chronic pancreatitis (IDCP). Both are associated
[39]
with increased infiltration of immune cells into the pancreas and are responsive to steroid medication .
Each type of AIP has its own characteristics. Hallmarks of type 1 AIP are infiltration by IgG4-positive
plasma cells, increased IgG4 titer in the serum, and histological abnormalities such as storiform fibrosis and
lymphoplasmacytic infiltration of the pancreatic ducts . In addition to the manifestation in the pancreas,
[40]
other organs can be involved, including the liver, the biliary tract, the kidneys, and the lungs ,
[41]
demonstrating that type 1 AIP is one possible manifestation of the large complex of IgG4-related diseases.
Often, the onset of type 1 AIP occurs in patients over 60 years of age, with a predominance of males , and
[42]
is also related to pancreatogenic diabetes [43,44] .

In comparison, type 2 AIP is characterized by the infiltration of neutrophils into the pancreatic duct and the
surrounding tissue, especially the interlobular duct, with local destruction of the ductal epithelium at what
are called granulocytic epithelial lesions (GELs) [45,46] . In comparison to type 1 AIP, type 2 AIP is
characterized by a reduction or even complete absence of IgG4-positive plasma cells in the pancreas . No
[46]
reliable biomarker has been established thus far. Although no other organs are directly involved in the
disease, in contrast to what is seen in IgG4-related disorders, type 2 AIP is associated with inflammatory
bowel diseases . Patients suffering from type 2 AIP are generally younger, and disease distribution is more
[40]
gender-balanced . Both types of AIP are associated with different antibodies targeting the plasminogen-
[47]
binding protein of Helicobacter pylori, the ubiquitin-protein ligase E3 component n-recognin, SPINK1,
PRSS1, and PRSS2 [48,49] . Because these antibodies are also detectable in other disorders, their value in the
diagnosis of AIP is limited.

NEUTROPHIL SERINE PROTEASES IN THE PATHOGENESIS OF PANCREATITIS
Under physiological conditions, pancreatic acinar cells secrete digestive proteases, which are stored as
inactive precursors in zymogen granules, into the pancreatic duct. When reaching the duodenum, the serine
protease trypsinogen is activated by the duodenal brush border enzyme enterokinase. Active trypsin is able
to activate additional trypsinogen and can activate other zymogens secreted into the duodenum, including
chymotrypsinogen, proelastase, and procarboxypeptidase A1, A2, and B1, in a cascade-like manner .
[50]
However, activation of trypsinogen within acinar cells is also possible and is performed either by active
trypsin itself or by the lysosomal hydrolase cathepsin B (CTSB). Under normal conditions, several barriers
prevent intracellular activation of trypsinogen [51,52] , including a shift of intravesical pH to generate an acidic
milieu and the presence of inhibiting proteins. One of these proteins is SPINK1, which acts as the major