PATHOPHYSIOLOGY OF
HYPERSENSITIVITY AND AUTOIMMUNE
DISEASES
VLA- 10. 4. 2018
Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics
Gastroenterology. 2013 August;145(2):293-308.
Contemporary view of diseases pathogenesis
•Diseases have been traditionally
studied under a paradigm of “one
microbe, one disease.” However, a
new understanding is emerging on
how disease phenotypes are actually
a result of complex interactions
between bacteria, viruses, and
eukaryotes, as well as their
interactions with the host or with
certain drugs. Virulence of some
eukaryotes is, for instance, linked to
the presence of certain bacteria,
such as in the case of E. histolytica
and E. coli or S. dysenteriae. The
susceptibility of the host to viral
infections is conditioned by the
particular configuration of the
microbiota, whereas herpesvirus
infection can confer resistance to
certain bacterial infections.
Antibiotics can significantly reshape
the composition of the microbiota. As
a clear correlation has been
observed between many diseases
and dysbiosis, the widespread use of
antibiotics may be linked to the
dramatic increase observed in
autoimmune diseases over the last
years. Conversely, helminthes confer
resistance to autoimmune diseases.
EFFECT OF INTERACTIONS OF BACTERIA, VIRUSES, AND
EUKARYOTES IN HEALTH AND DISEASE
17.4.2018
3
Cell 2012; 148: 1258–1270
DEVELOPMENT OF THE MICROBIOTA
17.4.2018
4
The gastrointestinal tract of the fetus is sterile until birth, after which the newborn is initially colonized.
Depending on delivery mode, the initial communities tend toward a skin-like (caesarean section) or a vaginallike
(vaginal delivery) configuration. During the first weeks of life, there is a reduced activity of TLRs, potentially
allowing the necessary formation of a stable bacterial community in the gut. As the infant grows, and with the
introduction of solid foods, the microbiota diversity increases, and the community converges toward an adultlike
state. At the same time, the immune system “learns” to differentiate between commensal and pathogenic
bacteria. By adulthood, a relatively stable community composition (but varying between different individuals)
is achieved, dominated mostly by Bacteroidetes and Firmicutes. Different diseases are characterized by
significant changes in the microbiota and associated changes in the production of cytokines.
Cell 2012; 148: 1258–12
Probiotics demonstrating a beneficial effect in clinical studies of eczema.
Type of clinical study Probiotic
Treatment Lactobacillus rhamnosus GG
Lactobacillus rhamnosus HN001
Lactobacillus sakei KCTC
Lactobacillus acidophilus La-5
Lactobacillus acidophilus*
Lactobacillus salivarius LS01
Lactobacillus fermentum VR1
Bifidobacterium lactis Bb12
Bifidobacterium lactis UABLA-12**
Bifidobacterium bifidum
Prevention Lactobacillus rhamnosus GG
Lactobacillus rhamnosus LC705
Lactobacillus paracasei F19
Bifidobacterium breve Bb99
Propionibacterium freudenreichii***
The loss of universal helminth infection as occurred in earlier human evolution may alter the numbers or types of
bacterial and fungal commensals and thus affect normal mucosal tissue homeostasis. In susceptible or highly
exposed individuals, such alterations might alter the balance between immunotolerance, immunosurveillance and
nutrient extraction. This imbalance may contribute to the appearance of inflammatory systemic dysregulation at
mucosal surfaces, resulting in increases in asthma and allergic diseases, particularly in the setting of
environmental changes that have increased exposure to indoor allergens and pollutants, and even to increases in
obesity, which can be a risk factor for severe asthma.
2015 Mar 25;7(1):33. doi: 10.1186/s13148-015-
0068-2. eCollection 2015.
From inflammaging to healthy aging by
dietary lifestyle choices: is epigenetics the key
to personalized nutrition?
Vel Szic KS1, Declerck K1, Vidaković M2,
Vanden Berghe W1.
Overview of the mechanisms and consequences of epigenetic regulation by nutritional compounds.
Modulation of different classes of chromatin writers-erasers by phytochemicals (left panel). Genes encoding
absorption, distribution, metabolism, and excretion (ADME) proteins can be epigenetically regulated and
thereby determine individual nutritional responses. Epigenetic modification of disease-related genes can
contribute to diagnosis (biomarker) as well as disease prevention or progression (right panel).
2015 Mar 25;7(1):33.
doi: 10.1186/s13148-
015-0068-2.
eCollection 2015.
From inflammaging
to healthy aging by
dietary lifestyle
choices: is
epigenetics the key
to personalized
nutrition?
Vel Szic KS1,
Declerck K1,
Vidaković M2,
Vanden Berghe W1.
Pivotal roles of vitamins in the maintenance of immunologic homeostasis in the gut. Vitamin
A-derived retinoic acid promotes the differentiation of naive T cells to Treg cells and
simultaneously inhibits the induction of Th17 cells in the steady state. Like retinoic acid,
Vitamin D (as an active form1α,25-dihydroxyvitamin D3) inhibits the production of proinflammatory
cytokines such as IFN-γ, IL-17 and IL-21 from T cells together with the promoted
differentiation of Treg cells. It also prevents differentiation and maturation of DCs and
increases the expression of tight junction protein such as claudins in the epithelial cells. Upon
the differentiation of Treg cells, they express high levels of vitamin B9 receptor (folate
receptor 4, FR4), which essential for their survival. α-tocopherol, an isoform of vitamin E, can
inhibit T cell infiltration into intestine through the negative regulation of signal transduction
from VCAM-1 and ICAM-1 by antagonizing protein kinase C.
Immune Netw. 2017 Feb;17(1):13-19.
Vitamin A is converted to retinoic acid by retinal dehydrogenases (RALDH) expressing dendritic cells in the Peyer's
patches, which induces the expression of gut homing molecules (α4β7 integrin and CCR9) on antigenprimed cells (e.g.,
IgA+ B cells) and allows them to traffic into the intestinal lamina propria. In the lamina propria, IgA+ B cells differentiate
into IgA-producing plasma cells. IgA is then transported into the intestinal lumen, where it binds to pathogens to inhibit
their invasion and function. Vitamin B1 is essential for energy metabolism, especially maintenance of TCA cycle, and
therefore associates with maintenance of naive B cells which utilize predominantly TCA cycle for energy generation.
Vitamin B2 also involves in the energy metabolism of immune cells. In addition, bacterial metabolite of vitamin B2
activates mucosal associated invariant T (MAIT) cells via the presentation by major histocompatibility complex (MHC)
related protein MR1. Vitamin D enhances production of antimicrobial peptides from Paneth cells and macrophages via
vitamin D receptor, which provides an additional immunosurveillance system.
Various roles of vitamins in the regulation of
gut immunity
Immune Netw. 2017 Feb;17(1):13-19.
IMMUNE SYSTEM AND ITS FUNCTION
Decresed resistance to
infection
Pathological reaction to
extrinsic antigens
antigeny
Pathological reaction to
intrinsic antigens
Decrease of
immunosurveillance
immunodeficiency
allergy
autoimmunity
oncologic diseases
distinguishes „good and bad“
guarantees protection of the organism
guarantees immunosurveillance
guarantees immunotolerance
ANTIBODY RESPONSE - TIMING
HLA – MHC-6p21.3
 Responsibility for histocompatibility
 Immunotolerance
 HLA molecule combination is unique for every human
being
 The only total HLA compatibility – monozygotic twins
 Graft rejection
MHC
 MHC class I and II classical molecules are cell surface
glycoproteins which mediate presentation of peptides
to T-cell receptors, and play a key role in triggering
adaptive immune responses when the bound peptide
is recognized as foreign.
 In humans, they are coded by HLA class I (HLA-A, -B,
and -C), and II (HLA-DR, -DQ, and -DP) classical genes.
The class I and class II HLA classical genes are the most
polymorphic in the human genome, and knowledge
about their function in the immune response supports a
role for balancing selection in driving the diversity
patterns at these loci.
MHC
 A number of findings suggest MHC genes have experienced
balancing selection: unusually high level of heterozygosity with
respect to neutral expectations; existence of trans-species
polymorphisms ; high levels of linkage disequilibrium ; site
frequency spectra with excess of common variants; high levels of
identity-by-descent compared to genomic averages ; positive
correlation between HLA polymorphism and pathogen diversity,
and significant associations of HLA alleles with the course of
infectious diseases.
 Information on the crystal structure of MHC molecules allowed
the identification of a specific set of amino acids that make up
the antigen recognition site (ARS), which determines the peptides
that the molecule is able to bind. The codons of the ARS were
shown to have increased nonsynonymous substitution rates
consistent with the hypothesis that adaptive evolution at HLA loci
is driven by peptide binding properties.
HLA GENES
 HLA III.class: complement compounds, TNF, HSP…
HLA region
D HLA III. class B C E A G F
DP DQ DR
chromosome 6
HLA AND ANTIGENS
 Antigenes originate either from extracellular
compartment (extrinsic antigens), or from
intracellular compartment (intrinsic antigenes).
 There are great differences betwwen these two
antigen types. They induce different type of
immune reaction.
 Intrinsic antigenes are presented using HLA class I;
 extrinsic antigenes use HLA class II.
ANTIGENE PRESENTATION
 Antigens are able to stimulate immune
response
 They are proteins, glycoproteins and/or
polysaccharides.
 Outer antigens get to body by GIT tract,
respiratory tract, skin and or artificially
(injection…)
 Inner antigens found in cells (proteins coded
by viral genes, proteins coded by mutated
genes in tumor cells)

ANTIGEN PROCESSING
exogenic antigens, HLA class IIendogenic antigens, HLA class I
CD NOMENCLATURE
CD3 = T cells
CD4 = T (helpers)*
CD8 = cytotoxic T*
CD19 = B cells
CD10 = inmature lymphoid cells *
CD34 = progenitors*
*and other cells
CD40/CD40L
ALLERGY AND ATOPY
Atopy:
 Family history
 Characteristic reaction on extrinsic allergens
 Circulating antibodies
 IgE antibodies (30-40% of population)
 Correlation between IgE blood levels and
hyperreactivity of airways.
 Genetic and epigenetic factors which modify IgE
levels.
 Candidate genes for IL-3, IL-4, IL-5, IL-9, IL-13 and
GM-CSF –cluster on 5q31-33.
 Hygienic theory of asthma development
The heterogeneity of asthma. Asthma is a complex disease caused by multiple factors.
There are several different forms of asthma (allergic, non-allergic and intrinsic), and in
some patients these forms can coexist. Allergic asthma can be induced by allergens and
is mediated by TH2 immune responses. Non-allergic asthma can also be caused by
several factors, such as air pollution and infection. Non-TH2 cells and various cells of the
immune system other than TH2 cells contribute to non-allergic asthma. Some of the
many genes involved in development of spontaneous asthma are presented here.
ASTHMA TYPES
 Extrinsic – clear external cause.
 Intrinsic – there is no clear cause.
 Extrinsic asthma in atopic patients with
positive prick tests for inhalation antigens
(90% of children with persistent asthma, only
50% adult patients). Child asthma often
combined with atopic dermatitis
 Intrinsic asthma - delayed onset
Clinical asthma
phenotype
Requirement
for TH2 cell Mechanisms or effector cells
Allergen Yes IL-4, IL-5, IL-9, IL-13, TSLP, IL-25, IL-33, IL-17?
CD4+ cells, DCs, eosinophils, mast cells,
basophils, NKT cells
Viral infection No IL-13? (TH2 cytokines?) alveolar
macrophages, NKT cells (innate immune
cells)
Air pollution, cigarette
smoke, diesel particles,
smoke
No IL-17, oxidative stress, small particles,
neutrophils, NKT cells
Aspirin No Leukotrienes, loss of prostaglandin E2
Obesity No Oxidative stress?
Severe, steroid resistant No IL-17, neutrophils, NKT cells?
Exercise, cold air No Heat transfer, change in mucosal
osmolality, cytokines?
Intrinsic ? Smooth muscle irritability?
Induction and effector mechanisms in type I hypersensitivity
APCs in the lung.
(a) DCs are key APCs in
the lung. After antigen
challenge, lung DCs
process antigen and
induce antigen-specific
TH2 cell responses.
TCr, T cell antigen
receptor.
(b) (b) Other cells can also
function as APCs to
initiate TH2 responses.
Basophils, eosinophils,
mast cells and natural
helper cells express
MHC class II and
costimulatory
molecules. Therefore,
these cells of the innate
immune system can be
the initial sources of
TH2 cytokines as well
as potential APCs in
the lung. SCF, stem
cell factor; LTC4,
leukotriene C4; Lin,
lineage.
ACQUIRED IMMUNITY IN PATHOGENESIS OF ASTHMA
 The induction of adaptive immunity requires antigen-presenting cells (APCs), and
dendritic cells (DCs) are the main type of APC involved in the induction of TH2
responses to allergens in asthma. In the lung,
 DCs can be found throughout the conducting airways, interstitium, vasculature
and pleura and in bronchial lymph nodes. Lung DCs express many receptors,
including Toll-like receptors, Nod-like receptors and C-type lectin receptors and
upregulate the expression of several costimulatory molecules (such as CD80 and
CD86) and chemokines (such as CCL17 and CCL22) that attract T cells, eosinophils
and basophils into the lungs19. In the OVA-induced asthma model, depletion of
DCs from the airways through the use of mice transgenic for CD11c–diphtheria
toxin receptor20 or thymidine kinase–transgenic mice treated with the antiviral drug
ganciclovir21 abolishes the characteristic features of asthma, including eosinophilic
inflammation and TH2 cytokine production. Furthermore, TH2 cells do not produce
IL-4, IL-5 or IL-13 in the absence of CD11c+ DCs, and endogenous lung DCs or
adoptively transferred bone marrow–derived DCs loaded with antigen are
sufficient to induce TH2 immune responses.
 In humans, monocyte-derived conventional DCs promote TH2 responses by
secreting proinflammatory cytokines and upregulating the expression of
costimulatory molecules after antigen stimulation. Together these findings indicate
that lung DCs are the main APCs and are necessary for TH2 cell stimulation during
airway inflammation.
The IgE-primed mast
cell releases granules
and powerful
chemical mediators,
such as histamine,
cytokines, granulocyte
macrophage colonystimulating
factor (GMCSF),
leukotrienes,
heparin, and many
proteases into the
environment. These
chemical mediators
cause the
characteristic
symptoms of allergy.
Mutat Res. 2010 August 7; 690(1-2): 24–39.
doi: 10.1016/j.mrfmmm.2009.09.005
Atopic bronchial asthma
Immune cells and the inflammatory
cascade in asthma. Initial
exposure(s) to allergen leads to the
activation of allergen-specific Th2
cells and IgE synthesis (sensitization).
Subsequent allergen exposures
cause inflammatory-cell recruitment,
activation and mediator release. IgEsensitised
mast cells expressing the
high affinity IgE receptor (FcɛRI)
degranulate, releasing both preformed
and newly synthesized
mediators including histamine,
leukotrienes and cytokines, which
promote vascular permeability,
smooth muscle contraction and
mucus production. Chemokines
released by inflammatory and
resident cells direct recruitment of
inflammatory cells characterized
eosinophils and Th2 cells. Eosinophils
release an array of pro-inflammatory
mediators, including leukotrienes and
basic proteins and mediators such
as, IL-5.
APC, antigen-presenting cell; EpC, epithelial cell; GM-CSF, granulocyte
monocyte colony stimulating factor; MHC, major histocompatibility; TCR, T cell
receptor; TSLP, thymic stromal lymphopoietin
Schematic representation of asthma pathophysiology. A range of environmental factors interact
with the epithelium and dendritic cells to direct a Th2 inflammatory response, comprising mast cell
activation, and eosinophil, basophil and neutrophil recruitment. Growth factors and cytokines from
these cells also activate fibroblasts for new matrix deposition to remodel the airways and contribute
to increased airway narrowing and asthma symptoms. Damage to the epithelium and the release
of a range of cytokines and growth factors sustains the inflammation and drives remodelling of the
airways in an aberrant ‘wound response’ to injury. Together, these two processes generate the
hyper-responsive airway characteristic of asthma
Trends Immunol. 2007 Jun;28(6):248-51. Epub 2007 Apr 27
CLINICAL SIGNS OF BRONCHIAL ASTHMA
 Bronchioles are narrowing ( as a result of
remodeling – higher content of smooth muscle
cells).
 Atelectasis develops (microscopic, segmental
or lobar) as a result of complete obstruction by
mucus or by edema of airways.
 Decrease ventilation/ perfusion proportion with
decreased hemoglobin saturation by oxygen.
 Hyperinflation and hyperexpansion of thorax
decrease function and ability of breathing
muscles.
TSLP provides a link between epithelial injury and the generation of an
allergic-type inflammatory response. TSLP interacts with dendritic cells to
upregulate the co-stimulatory molecules OX40, CD40 and CD80 that
facilitate polarization of helper T lymphocytes to a Th2 phenotype. Th2
cells generate the allergic inflammatory response through induction of
IgE, activation of mast cells and recruitment of eosinophils.
Trends Immunol. 2007 Jun;28(6):248-51. Epub 2007 Apr 27
TSLP (= THYMIC STROMAL LYMPHOPOIETIN)
 TSLP is expressed by structural and immune cells
at the site of allergen entry in the airways.
 Stimuli for release of TSLP include common
triggers of asthma symptoms.
 TSLP levels correlate with disease severity.
 TSLP regulates helper T cell 2 (Th2) humoral
immunity through upregulating OX40L on
dendritic cells (DCs), which drives Th2
lymphocytes; however, activation of several
other cells by TSLP also supports the
development of Th2 inflammation.
Gene environment interactions in asthma. Asthma is an inflammatory
disorder of profound heterogeneity with strong genetic and environmental
components. Local airway susceptibility factors together with allergenspecific
immune polarisation interact both in the induction and subsequent
expression of the disease phenotype. Key: EpC, epithelial cell.
Mutat Res. 2010 August 7; 690(1-2): 24–39.
doi: 10.1016/j.mrfmmm.2009.09.005
Remodelling of airways in asthma
Key: ASM, airway smooth muscle; ECM, extracellular matrix; EMTU,
epithelial to mesenchymal trophic unit; Epc, EpC, epithelial cell;
TGF-β, transforming growth factor-β.
Mutat Res. 2010 August 7; 690(1-2): 24–39.
doi: 10.1016/j.mrfmmm.2009.09.005
Antigens causing allergic rhinitis and bronchial asthma
Effects of allergic sensitization on antiviral responses—a complex interplay. viruses and allergens first
encounter barrier epidermis or respiratory epithelium. 1 genetic predisposition (polymorphisms
shown in bold italics) as well as allergen-induced impaired barrier function likely increases
susceptibility to infection. 2 virus infection of either the skin keratinocytes or respiratory epithelial
cells results in secretion of pro-inflammatory cytokines and chemokines which recruit antigen
presenting cells (dcs and monocytes) and have 3 impaired antiviral type i ifn responses. allergen
stimulation of antigen presenting cells impairs anti-viral responses by 4 blocking type i ifn release
from plasmacytoid dcs and 5 inhibiting virus-induced antigen presentation and th1 differentiation
by monocytes. 6 ige receptor engagement also leads to additional pro-inflammatory cytokine
release and impairs monocyte phagocytosis. 7 th2 cytokines promote b cell class switching to
produce more ige, ehancing allergic effects. 8 this environment recruits additional allergic effector
cells (ilc2, eosinophils, and basophils) further increasing th2 mediated responses and inflammation.
9 culminating in a increase in the Th2/Th1 balance
ATOPIC DERMATITIS (AD)
 is a chronic or chronically relapsing, eczematous, severely pruritic
skin disorder mostly associated with IgE elevation and skin barrier
dysfunction due to decreased filaggrin expression. The lesional
skin of AD exhibits Th2- and Th22-deviated immune reactions that
are progressive during disease chronicity. Th2 and Th22 cytokines
further deteriorate the skin barrier by inhibiting filaggrin expression.
Some IgEs are reactive to self-antigens. The IgE autoreactivity may
precipitate the chronicity of AD. Upon activation of the ORAI1
calcium channel, atopic epidermis releases large amounts of
thymic stromal lymphopoietin (TSLP), which initiates the Th2 and
Th22 immune response. Th2-derived interleukin-31 and TSLP induce
an itch sensation. Taken together, TSLP/Th2/Th22 pathway is a
promising target for developing new therapeutics for AD.
Enhancing filaggrin expression using ligands for the aryl
hydrocarbon receptor may also be an adjunctive measure to
restore the disrupted barrier function specifically for AD.
Skin barrier dysfunction and Th2/Th22-deviated immune reactions are the fundamental abnormality
in AD. Genetic mutations in filaggrin (FLG) cause barrier disruption and dehydration, which make
the external allergens permeable. The barrier-disrupted epidermis abundantly releases thymic
stromal lymphopoietin (TSLP), which triggers the Th2/Th22 immune response. The Th2/Th22 deviation
is further accelerated during disease progression, for example, from acute to chronic or childhood
to adult AD. In addition, Th1 but not Th17 cells tend to participate in the chronic phase of AD. Th2
cytokines (IL-4 and IL-13) stimulate B cells to produce IgE antibodies to allergens. Some IgEs react to
self-antigens. IgE autoreactivity also contributes to disease activity. In addition, IL-4, IL-13 and IL-22
are strong suppressors of FLG expression. Pruritus is evoked by TSLP and Th2-derived IL-31, and the
subsequent scratching further worsens skin barrier dysfunction. The release of TSLP from
keratinocytes is dependent on calcium influx regulated by the ORAI1 channel. Targeting
TSLP/Th2/Th22 as well as ORAI1 pathways is a promising strategy to overcome atopic inflammation.
Pathogenesis
of atopic dermatitis (AD)
Allergol Int. 2017 Jan 2.
The schematic illustration of AD etiology. Genetic and epigenetic reasons lead to
the alteration of gene expression and function of AD associated genes. AD
associated genes majorly belong to two pathways: skin barrier and
innate/adaptive immunity. Dysregulation of innate/adaptive immune responses
and impaired skin barrier reciprocally affect each other to drive AD development.
Allergy Asthma Clin
Immunol. 2016; 12: 52.
AUTOIMMUNE DISEASES
 Autoimmune disorders (AIDs), which as a group affect
approximately 8.5% of individuals worldwide, are
responsible for a substantial amount of disability and
morbidity.
 Some AIDs are organ specific (for example, type 1
diabetes (T1D) targets the pancreas, autoimmune
thyroid disease (AITD) attacks the thyroid gland),
whereas others can affect multiple organs and/or be
associated with systemic manifestations.
 Systemic lupus erythematosus (SLE) is the prototypic
systemic AID that can affect multiple organs and can
also be associated with significant systemic
manifestations, morbidity and early mortality.
AUTOIMMUNE DISEASES
 Most AIDs, including rheumatoid arthritis (RA),
ankylosing spondylitis (AS), inflammatory bowel disease
(IBD) and multiple sclerosis (MS) have a predilection for
specific organs (for example, the synovial joints in RA
and the gastrointestinal tract in IBD) but are also
associated with manifestations outside the primary
target organ. Reasons for the diverse manifestations
exhibited by different AIDs remain unclear, but recent
progress in elucidating genetic susceptibility loci for this
group of disorders promises to shed light on this
important issue.
AUTOIMMUNE DISEASES
 several features suggest that they share common
etiologic factors.
 Most AIDs are characterized by female predominance,
and
 Many are associated with the production of
autoantibodies (for example, anti-citrullinated-peptide
antibodies are observed among 70 to 80% of RA
patients).
 These shared disease features, in conjunction with
epidemiologic evidence that demonstrates the
clustering of multiple AIDs within individuals and
families, strongly implicate shared etiologic factors,
including shared genetic loci.
Degree of epigenetic sharing across systemic autoimmune diseases.
Venn diagram showing the number of differentially methylated CpG sites in whole blood
comparing those obtained from EWAS results for SLE (blue), SjS (yellow) and RA (red).
Data was obtained from supplementary materials of Yeung et al., Imgerberg-Kreuz et al.
and Liu et al. Reactome pathway enrichment analyses were performed in the set of genes
showing overlapped DMCs using the ToppGene Suite database https://toppgene.cchmc.org.
q-value refers to adjusted P-values corrected for Benjamini & Hochberg False Discovery
Rate. DMCs: Differentially methylated CpG sites. SAD: Systemic autoimmune diseases
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