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reported to have strong localization on the apical surface of BEC from patients with
PBC [155]. It was proposed that this surface stain was comprised of a modied form
of PDC-E2 or a molecule that cross reacted with the antibody, acting as a molecular
mimic [164], and generating a self-perpetuating attraction of inammatory cells
that result in the CNSDC of PBC [155]. The epitope specicity of several anti-PDC-
E2 monoclonal antibodies that recognize a certain protein in BEC of patients with
PBC and not in control liver tissue has been shown to differ; however, this nding
has been interpreted to suggest that the recognized epitopes form part of PDC-E2
and include the lipoyl domain, which, localized at the apical domain of the BEC
itself, contributes to the pathogenesis of the CNSDC of PBC [155]. In this regard,
immune complexes were reported to exist within the bile ducts; as the dimeric form
of immunoglobulin A (IgA) can traverse from the basal to the apical domain of the
BEC by transcytosis [165], it has been proposed that IgA may bind a relevant anti-
gen in the lumen prior to transcytosis and take it into the cell. In this context, IgA
from serum in patients with PBC was reported to colocalize with PDC-E2 within
the cytoplasm and on the apical side of the BEC [166], which may contribute to the
staining in the luminal domain of BEC, as described above [155]. These ndings
have been interpreted to suggest that the IgG binding of a complex formed by IgA
bound to its epitope may exert an inammatory response around the bile duct area,
in spite of the noninammatory regulatory role of IgA [167, 168].
Non-protein and protein antigens can generate antibody production; however,
antibodies to protein antigens require that the antigen be internalized by B cells and
be presented to T cells of the CD4+ type of helper T cells[169]. The humoral
immune response is initiated by the recognition of antigens that bind to IgM (and to
IgD) on the surface of mature, naïve B cells; this recognition results in activation of
B cells with the proliferation of antigen-specic cells, which differentiate and gen-
erate memory B cells and plasma cells that secrete antibodies in large quantities to
keep up with the rapidity with which microbes multiply themselves [169]. The rst
antibody response to a specic protein or non-protein antigen is mostly of the IgM
class; the second response is induced by the stimulation of memory B cells by a
formerly encountered protein antigen, mainly of the IgG class. Characteristically,
patients with PBC have high levels of serum IgM [19]. In the context of the humoral
response, it has been recognized that the lack of methylation of CpG dinucleotides
in bacterial DNA, in contrast to the mammalian methylated form, allows its recogni-
tion by toll-like receptor (TLR) 9, which is associated with a robust immunogenic
responseCD27+ memory B cells were reported to produce IgM via the stimulation
of the TLR9 receptor signaling in studies of peripheral mononuclear cells from
patients with PBC invitro, in contrast to the absence of a response from cells from
control subjects [170]. In addition, the stimulation of peripheral mononuclear cells
from patients with PBC with CpG-B was reported to be associated with phenotypi-
cal changes that include an increased expression of TLR9, and of CD86, a co-
stimulator of T cells, on B cells, and also with enhanced production of AMA [171].
These ndings have been interpreted to suggest that CpG-B [170] may be a poten-
tial endogenous trigger of B cells to produce IgM and AMA and have further sug-
gested an involvement of the innate immune system in the pathogenesis of PBC.In
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this regard, BEC express IL-17 receptors; in response to IL-17, they secrete chemo-
kines and cytokines, including IL-6, IL-1B, and IL-23p19, which are associated
with responses to PAMPs (see above) [172].
The genesis of AMA and their potential role in the pathogenesis of the CNSDC
of PBC may be associated with the characteristic response to apoptosis by bile ducts
[173–175]. In addition to PDC-E2, which can be recognized by T cells, apoptotic
bile ducts retain the three 2-oxoacid dehydrogenase enzymes immunologically
intact [176] within apoptotic bodies, termed apotopes [177, 178]. In a controlled
invitro system, macrophages from patients with PBC co-cultured with apoptotic
bodies from intrahepatic BEC and AMA were reported to produce robust amounts
of cytokines [178]. Macrophage stimulation was through the classic (M1) pathway,
as suggested by decreased cytokine production in association with the addition of
anti-CD16 to the system. Anti-CD16 blocks the fragment crystallizable receptor for
immunoglobulin (FcgR). FcgR is expressed on macrophages’ surface and is acti-
vated by microbial products and cytokines, especially interferon gamma. FcgR rec-
ognizes antibody coated cells, which are subsequently killed by macrophages [179].
Stimulated macrophages in the presence of apoptotic bodies from intrahepatic BEC
and AMA demonstrated the ability to phagocytize apoptotic bodies, as studied by
confocal microscopy methodology; however, the calculated index of phagocytosis
by activated mononuclear cells from patients with PBC was signicantly lower than
that of control stimulated mononuclear cells [178]. Phagocytosis was not blocked
by anti-CD16 [178], suggesting that, as measured in an invitro system, phagocyto-
sis and cytokine secretion by activated macrophages are conducted via independent
pathways. In addition, the expression of the messenger RNA of tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL) in macrophages from patients
with PBC that had been cocultured with apoptotic bodies from intrahepatic BEC
and AMA was reported as markedly increased, suggesting a role of TRAIL in the
inammatory injury of BEC.
These ndings add to the developing consensus of an active role of the innate
immune system and apoptosis of BEC in the pathogenesis of the CNSDC of PBC,
and it may shed light on the question of the remarkable selection of small intrahe-
patic bile ducts as targets of the inammatory destruction in this disease [178]. The
term dry gland syndrome has been used in reference to PBC because of its associa-
tion with the decreased ow of tears, saliva, and pancreatic juice [103, 180–183], in
addition to impaired bile secretion, as a result of the CNSDC, and ductopenia.
Histological studies have conrmed inammatory changes in the ducts of glandular
structures other than BEC [103, 180–183], as well as the immunoreactivity against
PDC-E2 monoclonal antibody [184]; however, studies of apoptosis of the epithe-
lium of those glandular ducts in the context of PBC have not been published.
Antinuclear antibodies (ANAs) with various patterns of expression including
speckled, multiple nuclear dots, rim-like and membranous, centromeric, and homo-
geneous are detected in approximately half of the patients with PBC, their presence
reported to be more common in patients in whom serum AMA are not detected than
in patients with AMA [185]. ANAs displaying multiple nuclear dots and rim-like/
membranous are infrequently found (1.3%). When found, they are highly
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suggestive of the diagnosis of PBC, independent of the AMA status of the patients
[186]. The elements recognized by the ANAs of patients with PBC are reported in
Table3.2 [187–190, 193–197]. The presence of antibodies against the nuclear pore
protein gp210 was reported in association with severe cholestasis and impaired liver
function [185, 198] and anticentromere antibody with the development of portal
hypertension [198].
As described previously in this chapter, other autoantibodies can also be detected
in the serum of patients with PBC.Still, their presence does not contribute signi-
cantly to diagnosing and managing a patient with this disease.
Histology
The Scheuer’s histological classication of PBC is comprised of four stages; the
characterization of which are I: chronic nonsuppurative destructive cholangitis
(CNSDC) or orid bile duct lesion, II: bile ductular proliferation, III: biliary bro-
sis, IV: biliary cirrhosis [17]. The orid bile duct lesion, i.e., nonsuppurative destruc-
tive cholangitis, is considered the primordial lesion of PBC [17] (Fig. 3.1).
Cholangiolitis, comprised of polymorphonuclear leukocytes in the inammatory
inltrate and pseudoxanthomatous changes, a “bubbly” appearance of periportal
hepatocytes resulting from cholate stasis (accumulation of bile acids), characterize
Table 3.2 Features of the most common types of antinuclear antibodies in the serum of patients
with PBC
ANA patterns on
immunouorescence
Recognized
cellular
element Nature of antigen References
Multiple nuclear dots SP 100 proteins Transcription activating proteins [187]
Multiple nuclear dots PML Transformation and cell growth
suppressing protein aberrantly
expressed in promyelocytic leukemia
cells
[
188]
sp 140 Promyelocytic leukemia protein
nuclear body
[186]
Rim like/membranous gp 210 Integral glycoprotein of the nuclear
envelope pore membrane
[
189]
Rim like/membranous np62 A functional protein of the nuclear
pore complex
[
190]
Rim like/membranous LBR Integral membrane protein of the
nuclear envelope
[
191]
Granules in cells in
mitosis (i.e. interphase)
CENP-B Polyprotein that interacts with
centromeric heterochromatin in
human chromosomes
[192]
ANA antinuclear antibodies; sp speckled protein; PML promyelocytic leukemia protein; gp glyco-
protein; np nucleoporin; LBR lamin B receptor; CENP-B centromere protein B
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the histological ndings of nonsuppurative destructive cholangitis, leading to duc-
topenia, a decrease in the number of intrahepatic bile ducts [17]. Granulomata tend
to be appreciated in early disease. As a result of cholestasis, there is an accumula-
tion of copper in the liver and other organs.
The cellular inltrate of the CNSDC of PBC is composed of plasma cells, eosin-
ophils, B and natural killer cells, and T lymphocytes, the latter being the majority
[199–206]. The Ludwig classication consists of stage 1, characterized by portal
hepatitis, stage 2 by periportal hepatitis, stage 3 by bridging brosis or necrosis, and
stage 4 by cirrhosis [207].
Cellular Immunology
Studies to identify cellular immunological phenotypes have characterized the lym-
phocytes of the CNSDC as being of the CD4+ and CD8+ types [177, 208, 209]. It
may be that the predominance of a particular phenotype may depend on the stage of
the disease [159]. A marked increase in PDC-E2 specic CD4+ cells in the peripor-
tal lymph nodes, and the liver of patients with PBC compared with peripheral
mononuclear cells was reported [159]. In addition, compared to the blood compart-
ment, there is an important increase in the frequency of PDC-E2 specic CD8+ in
the liver of patients with PBC [210], particularly in the inammatory inltrate in the
portal areas [211]. The predominance of interferon gamma mRNA in the inamma-
tory inltrate of livers of patients with PBC suggests that the most prominent T cell
subset in the CNSDC lesion is the Th1 [212].
The presence of autoreactive T cells in the CNSDCof PBC suggests that this
type of cell is attracted to the biliary epithelium, where they participate in the gen-
esis of the lesion. Most of the T lymphocytes found in the CNSDC of PBC are
TCRalphabeta, which are MCH restricted, meaning that they can only recognize
antigens in association with MHC molecules [199, 213, 214]. A small proportion of
gamma delta T cells has also been reported in the CNSDC lesion of PBC [215].
Loss of self tolerance is considered to be a fundamental pathophysiological pro-
cess in autoimmunity [216]. CD4+CD25high regulatory T cells (Tregs) are consid-
ered to play an important role in self-tolerance. Studies of this population of cells in
PBC have revealed Tregs’ normal function; however, alterations in the proportion of
Tregs in the CD4+TCR-alpha-beta and FoxP3+ T cell pool in the periphery and
liver tissue have been reported [217, 218]. These data have been interpreted to sug-
gest that Tregs are involved in the pathogenesis of PBC [217, 218]. In this regard,
the proportion of CD4+CD25+ and CD8+ and CD28− T cell subpopulations in the
circulation is not signicantly different between patients with PBC and control sub-
jects; however, the characteristic surface features of CD8 Tregs, including increased
expression of CD127 and decreased expression of CD39, and the reduced induction
of CD8 Tregs in response to stimulation of IL10 invitro, have suggested resistance
from CD8Treg cells to commit to their regulatory functions [219], which has been
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interpreted to suggest substantial alterations in this cell compartment in patients
with PBC, as reported in other autoimmune diseases [219].
Antigen presentation is a fundamental process in recognition of antigens by T
cell receptors (TCRs). Antigen presenting cells (APCs) present antigenic peptides
associated with major histocompatibility complex (MHC) class II to T cells; they
must also express on their surface B 7, a co-stimulatory protein that interacts with
the CD28 molecule expressed on the TCRs, to generate signals for T cell activation.
Professional APCs constitutively express MHC class II and include dendritic cells,
macrophages, and B cells [220]; immunological studies have reported markers for
dendritic cells in the cellular component of this histological ndings, including den-
dritic cell CD11c. A role of double-negative (DN)-T cells as contributors to the
break of tolerance in PBC was suggested by a study that documented a signicantly
decreased number of cells in the periphery and the liver of patients with PBC, with
their presence negatively correlating with advanced disease stages and positively
correlating with response to treatment with UDCA. DN-T cells demonstrated
decreased capacity to stimulate proliferation of CD4, effectors, and CD8 cytotoxic
cells, nding interpreted to suggest that the DN-T cells’ impaired function may
contribute to the pathogenesis of PBC [221].
B cells and plasma cells expressing IgM were reported to abound in the liver’s
granulomata of PBC [222]. Langerhans cells (LCs), which mature into dendritic
cells in the lymph nodes, have been found inltrating the bile ducts in the lesion of
CNSDC [223]. BEC in culture produce LC-attracting chemokines in response to
certain cytokines and pathogen associated molecular patterns; thus, the presence of
LC in the lesion of CNSDC has been interpreted to suggest that the cytokine milieu
of the liver in PBC perpetuates the inammatory process by the production of che-
mokines that attract APC, and also, that innate immunity processes inherent to bile
ducts contribute to the pathogenesis of the CNSDC of PBC [223, 224]. Innate
immunity is an endogenous defense mechanism against bacterial and viral infec-
tions that consistently reacts rapidly to microbes upon reexposure. The innate
immune system is comprised of epithelial barriers, natural killer (NK) cells, phago-
cytic cells (neutrophils and macrophages), cytokines, and the complement system
[224]. BEC are reported to secrete antimicrobial agents, including immunoglobulin
A, cytokines, and chemokines that recognize pathogen associated molecular pat-
terns (PAMP), to ght infection. PAMPs induce inammatory reactions; as they
have been found in BEC overtaken by CNSDC, they have been proposed to contrib-
ute to this cholangiopathy [31].
A contribution of the biliary epithelial cell itself to the lesion of CNSDC by its
possible ability to express class II MHC antigen when activated by inammatory
processes, consistent with features of antigen presenting cells, has been proposed in
PBC; however, BEC do not express the co-stimulatory CD28 ligands B7-1 or B7-2
suggesting that BEC alone cannot activate T cells [225]. In spite of the absence of
B7in BEC, aberrant expression of MHC II has been reported, likely mediated by
the production of interferon gamma stimulated by the inammatory process, nding
that has led to the proposition that the incomplete ability to present antigens by BEC
renders the exposed T cell anergic. T cell anergy is dened as a state of long-lasting,
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partial, or total unresponsiveness induced by partial activation [226]; anergic T cells
operate like suppressor cells by interfering with the maturation and function of den-
dritic cells, interfering with the inammatory process [226]; thus, the ability of the
biliary epithelial cell to present antigen seems to contribute, at least in part, to the
prevention of further inammatory destruction in the complex CNSDC lesion of
PBC.Vulnerability to a T cell-mediated inammatory destruction of BEC, however,
is increased by the expression of functional adhesion molecules by BEC, which
attract cytotoxic T cells that can adhere to the biliary epithelium, susceptible to its
inammatory destruction [225]. Chemokines are cytokines that stimulate leuko-
cytes movement and regulate their migration from blood to tissues [224]. A reason
for T lymphocytes to be attracted to the biliary epithelium may also relate to the
chemokine environment of the intrahepatic bile ducts in PBC.In this regard, BEC
from patients with PBC and control subjects produce similar amounts of chemo-
kines in response to appropriate challenges invitro; however, chemokines expressed
by BEC from patients with PBC have been reported to trigger enhanced transmigra-
tion of liver lymphocytes from patients with PBC, as compared to controls, invitro
[227]. Furthermore, the addition of autologous liver mononuclear cells to the exper-
imental system has been associated with increased production of chemokines, sug-
gesting that the BEC’s inammatory destruction in the CNSDC lesion of PBC is
facilitated by local mononuclear cells [227]. Fractalkine (CX3C) is a chemokine
that participates in controlling leukocyte trafcking in the endothelium; it has a
soluble form and a membrane-bound form. Soluble fractalkine is a potent chemoat-
tractant for T cells and monocytes. The membrane anchored form, induced on acti-
vated primary endothelial cells, promotes adhesion of the cells it attracts [228]. The
receptor for fractalkine is CX3CR1, and it is expressed in mononuclear cells,
including NK cells [229]. The soluble form of fractalkine (CX3CL1) was increased
in the serum of patients with PBC and its receptor expressed in liver mononuclear
cells [230]. Isolated BEC can produce CX3CL1in response to Toll receptor ligands
and at contact with autologous liver mononuclear cells, and in the presence of tumor
necrosis factor (TNF) alpha in greater amounts than BEC from disease control liv-
ers [231]. In addition, the adherence of liver mononuclear cells from PBC livers to
endothelial cells and BEC is stronger than that of mononuclear cells from disease
control. Furthermore, activated T cells (CD 154+) and monocytes (CD 68+) have
been found in the periportal inammatory inltrate, and the latter, inltrating the
biliary epithelium of bile ducts affected by the CNSDC of PBC, in contrast to their
random presence in disease control liver samples [231]. Considering the limitations
of in vitro studies, as they may not reproduce the disease state in vivo, and the
anticipated differences in the hepatic inammatory milieu in different stages of the
disease (e.g., pre cirrhosis vs. cirrhosis), these reported ndings suggest that there is
a robust chemotactic milieu in the CNSDC of PBC that probably perpetuates the
inammatory destruction of BEC by attracting monocytes that have been stimulated
by Toll receptor ligands, and that are transported into the liver by the portal blood
ow, as has been proposed [231].
The presence of plasma cells expressing CD38 [232, 233] and intracellular IgM,
IgG, or both, has been reported around bile ducts in the lesion of CNSDC of PBC,
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and not in disease control liver tissue; the presence of CD+38 cells correlated with
high serum AMA titers [220]. The existence of B cells in the lesion of CNSDC has
suggested that immunological mechanisms related to this type of cell and humoral
immunity [31, 179], including AMA, may be involved in the pathogenesis of the
CNSDC of PBC [199, 201, 220]. Natural killer (NK) T cells express alpha beta
TCRs that are restricted to cells expressing CD1. NKT cells recognize lipid antigens
presented by CD1 molecules, including those associated with endocytosed microbes,
which may give NK T cells a role in defense against pathogens, especially those rich
in lipid components, including mycobacteria. The role of these cells in human dis-
ease is not clear; interestingly, however, is the report of an increase in the proportion
of NK T cells in the blood and the liver of patients with PBC [205].
Natural killer (NK) cells are important components of the innate immune
response. NK cells respond against intracellular viruses and bacteria. They are char-
acterized by their membrane expression of CD 56 and have also been reported as
increased in the blood and liver of patients with PBC and to have increased cyto-
toxic activity invitro [234]. Toll like receptors (TLRs) are members of a family of
pattern recognition receptors expressed on certain cell types and recognized microbe
products [224]. In vitro and under specic stimulation paradigms that involved TLR
3 and 4, NK cells’ cytotoxic activity from patients with PBC was reported to be
higher than that of control cells [235]. These ndings have been interpreted to sup-
port innate immunity mechanisms in the genesis of the CNSDC of PBC.
Processes inherent to cellular longevity have also been reported to contribute to
the lesion of CNSDC of PBC, including apoptosis and autophagy, and senescence.
Autophagy is a cellular process by which the cell balances energy and nutrients for
basic cell functions, including the removal of misfolded proteins resulting from
mutation or other pathological conditions, and the turnover of intracellular organ-
elles including mitochondria, endoplasmic reticulum, and peroxisomes, under
physiologic and pathological conditions [236, 237]. Autophagy is activated under
stress, leading to autophagosomes, where organelles are sequestered and delivered
to lysosomes by fusion, where they are digested to produce energy. Experiments
performed in cultured epithelial cells have suggested that autophagy mediates the
process of senescence of BEC [237]. Senescent BEC express senescent-associated
secretory phenotypes (SASP) (e.g., chemokines (CCL2 and CX3CL1), which,
invitro, were reported to attract macrophages (i.e., RAW264.7 cells), suggesting
that senescent cells may alter the microenvironment in which they exist [238]. Thus,
autophagy, by increasing senescence and senescent epithelial cells, by attracting
inammatory cells through chemokines, may contribute to the CNSDC of PBC.In
addition, endoplasmic reticulum stress may contribute to dysregulated biliary
autophagy and subsequent senescence, as suggested by the enhanced expression of
glucose-regulated protein 78 (GRP78) and protein disulde isomerases (PDI),
markers of ER stress, on BEC from patients with PBC versus control cells [239].
The anion exchanger 2 (AE2) protects the biliary epithelium from deleterious
effects of minuscule concentrations of toxic bile acids by secreting bicarbonate into
the bile duct lumen; it was reported that the expression of AE2in the biliary epithe-
lium of patients with PBC was decreased in association with dysregulated
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autophagy, abnormal expression of PDC-E2, and cellular senescence markers
p16INK4a and p21WAF1/Cip1, which has suggested that lack of protection due to
an impaired AE2 may result in dysregulated autophagy contributing to the patho-
genesis of PBC [240]. It was recently reported that senescent BECs were signi-
cantly increased in small bile ducts in PBC, as suggested by the expression of
senescent markers (p21
WAF1/Cip1
, p16
INK4a
) and B-cell lymphoma-extra large (Bcl-xL),
an important regulator of senescent cell anti-apoptotic pathway, as compared to
control hepatic tissue. Senescent BECs were notable in ductular reactions and stages
3 and 4 disease, versus stages 1 and 2 and control liver tissue. In addition, there was
a correlation between the number of senescent BEDs in bile ductules with the stage
of the disease and necroinammatory activity, with the expression of p16 being cor-
related with suboptimal response to UDCA.These results tend to support a patho-
genetic role of senescence of BECs in PBC, and that high degree of senescence
impairs the response to UDCA [241].
An increased number of apoptotic BEC has been recognized in the lesion of
CNSDC of PBC. Glutathionylation is a process through which the lysine-lipoic acid
moiety is changed with glutathione during apoptosis. Glutathionylation prevents the
accumulation of potentially autoreactive PDC-E2 and it is absent in BECs and in
salivary gland epithelial cells, which may also be affected in PBC [242]. Lack of
glutathionylation interferes with the process of apoptosis of BEC [173, 242], allow-
ing PDC-E2 to remain intact; it is hypothesized that intact PDC-E2 is recognized by
AMA, suggesting that apoptotic BECs can be a source of immunogenic PDC-E2in
PBC [173]. In a culture system where apoptosis was induced in BECs, intact PDC-E
2 within apoptotic blebs without permeabilization of the cell membrane was recog-
nized by AMA from various sources, including sera from patients with PBC, sug-
gesting that intracellular immunogenic PDC-E2 is accessible to immunological
recognition [177]. Furthermore, it has been reported that BECs can themselves
phagocytize apoptotic BEC [174] and present them to immunologically primed
cells that recognize immunogenic intracellular components (e.g., PDC-E2) [174].
In this regard, the presence of CD4 and CD8 T cells that specically react to the
major antigen of AMA in PBC, PDC E2 163–176 suggests that T cells have been
primed to react with this particular amino acid sequence, contributing importantly
to the CNSDC of PBC.Additional phenotypic studies of peripheral CD 8+ cells in
the blood of patients with PBC were reported to identify an increase in the number
of CD45ROhighCD57+ CD8high T cells that expressed alpha4beta7, a gut homing
integrin, supporting a role of adhesion in the inammatory process of the CNSDC
of PBC [243]. The expression of CD28 on the CD45ROhighCD57+CD8high was
decreased, suggesting a strong effector function [243, 244]. The CD45ROhigh sub-
set of CD57+CD8high group of cells was less susceptible to apoptosis [243]. The
cells produced more IL-5 than the control cells; the relevance of IL-5in PBC may
relate, in part, to eosinophils, which can be increased in the serum of patients with
PBC, and which are found in the lesion of CNSDC [202], a nding that provides
condence to the histological diagnosis of PBC.The presence of major basic pro-
tein in the lesion of CNSDC of PBC is consistent with eosinophils’ activation and
degranulation. Major basic protein also contributes to the differentiation of
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activated B cells into immunoglobulin producing cells [245], a relevant PBC nd-
ing. In this regard, serum concentrations of IL-5 have also been found to be increased
in patients with PBC [246]. Immunohistochemistry studies of CD8+ cells from a
small number of tissue samples from patients with PBC were reported to express
CD57+, compared to control tissue; the cells from the diseased livers responded to
stimulation with PDC-E2 with the secretion of interferon gamma, in contrast to the
control cells [243]. These studies were interpreted to support a role of
CD45ROhighCD57+ CD8high T cells, as terminally differentiated cytotoxic T
effector memory T cells, in the pathogenesis of the CNSDC of PBC [243].
The maintenance of tolerance to self antigens depends on a balance between
mechanisms that prevent the maturation of lymphocytes that have been sensitized to
self antigens and those that prevent the destruction of self-reactive lymphocytes that
have matured [216]. T cells play an important role in autoimmunity because they
are involved in the regulation of immune responses to proteins, which comprise the
majority of self antigens implicated in autoimmunity, and because of the integral
role of the major histocompatibility complex (MHC), human lymphocyte antigen
(HLA), which presents peptide antigens to T cells [216]. Breakdown of tolerance
against self-antigens in T lymphocytes may be central in autoimmune mediated
inammatory tissular processes. In addition, abnormalities in helper T cells may be
associated with autoantibody production, as helper T cells are required to produce
antibodies against protein antigens [216]. Autoimmunity is considered to play a role
in the pathogenesis of PBC [14].
In summary, PBC was described as a dry gland syndrome [247], as it can be
associated with a reduction of tear and saliva production, presumably from inam-
matory involvement of the epithelial structures of salivary and lacrimal glands, lim-
ited pancreatic secretions, and biliary cirrhosis from ductopenia due to specic
injury of intrahepatic bile ducts. The latter is the fundamental pathogenetic process
in PBC; thus, two central processes are the focus of research in PBC: the vulnerabil-
ity of intrahepatic bile ducts to destruction and the development and potential role
of AMA in the pathogenesis of the CNSDC of PBC.In this regard, the manner in
which PDC-E2 is accessible to T cells may be related to the peculiar defect in glu-
tathionylation of BEC, which, in the process of apoptosis, allows for PDC-E2 to
remain intact in apoptotic blebs, or apotopes, and presumably, exposed for recogni-
tion by T cells [14, 173, 177]. The combined effect of macrophages from patients
with PBC, biliary apotopes, and AMA can be associated with an important secretion
of inammatory cytokines [178], perpetuating inammation.
Treatment
The drugs approved for the treatment of PBC are ursodeoxycholic acid (URSO) and
obeticholic acid (Ocaliva®). Although there is no cure, several drugs are being
developed to treat PBC, including agonists at nuclear receptors and ileal bile acid
transporter inhibitors.
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The rst drug approved for the treatment of PBC was ursodeoxycholic acid
(URSO), the chemical name of which is 3α, 7ß-dihydroxy-5-cholan-24-oic acid.
UDCA is a hydrophilic bile acid that comprises approximately 2% of the endoge-
nous bile acid pool. The administration of UDCA changes the proportion of the bile
acid pool from the hydrophobic prole of cholestasis to a hydrophilic one, thus
decreasing the exposure of the hepatic cells to the toxic bile acid milieu. UDCA
stimulates the insertion of bile salt export pump (BSEP) and multidrug resistance
associated protein 2 (MRP2) in the canalicular side of the hepatocyte thus, stimulat-
ing the export of bile acids by the former and organic anions by the latter, giving it
choleretic properties; also, UDCA has been reported to prevent hepatocyte apopto-
sis induced by bile acids [248]. Perisinusoidal brosis and degree of apoptosis were
lower in liver tissues from patients with PBC in association with UDCA treatment
for 2years than in the liver tissue from the group of patients treated with placebo, in
which the number of apoptotic cells increased [249]. The dose recommended for the
treatment of PBC is 13–15 mg/kg of body weight, in divided doses, taken with
meals. It is generally well tolerated. In some patients, the use of UDCA is associated
with pruritus, which is a major inconvenience to those patients who already have
pruritus from the disease. Another matter is an average of 3.6kg weight gain over
the rst year of treatment that remained stable for the 4years reported in the study
[250]. UDCA may be injurious in patients with decompensated liver disease, i.e.,
Child’s B and C, in regard to liver injury, a likelihood score of D, i.e., a possible rare
cause of acute decompensation of preexisting liver disease. The mechanism of liver
injury is described as possibly related to choleresis and not intrinsic or idiosyncratic
reaction to the drug itself [251]. The guidelines from the American Association for
the Study of Liver Disease report that UDCA should be used in all stages of the
disease; however, its use in decompensation is not addressed [3]. Vigilance is
required if UDCA is used in patients with advanced disease by providing close
follow-up.
A combined analysis of three controlled clinical trials of UDCA for the treatment
of PBC revealed that the use of the drug had been associated with an increase in the
time free of liver transplantation in patients with stages III and IV disease, as com-
pared to the patients who had been randomized to placebo at the time of initiation of
the study; it was inferred that a survival advantage was not demonstrated in the
group of patients with stages I and II because the duration of the studies was limited
to 4years, which would not allow for the natural history of the disease to reveal
itself [20]. Combined analysis of available paired liver biopsies from participants,
200 randomized to UDCA and 167 to placebo, from four clinical trials, revealed a
lack of difference in the progression of the histological stage between the two
groups; however, in the group of patients with disease stages I and II, there was a
signicant decrease in the progression of the disease, as compared to the group of
patients that had taken the placebo. There was a substantial halt in the progression
of periportal inammation and bile ductular proliferation in the UDCA group rela-
tive to the placebo group. These results were interpreted to support the use of UDCA
for patients with stages I and II of PBC [252]. In contrast, the review of paired liver
biopsies from patients with PBC who participated in a placebo controlled study of
3 Primary Biliary Cholangitis
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