Pathophysiological consequences of immune
hypersensitive reactions
Immune deficiency
Hypersensitivity
Allergy
Autoimmunity
Organs of immune system
immune system
(innate and
specific
immunity)
bacteria
viruses
parasites
fungi
toxins
tumor cells
foreign cells and
tissues (incl.
transplantation)
invasion
and
recognition
of foreign
agent
purposeful
immune
reaction
restoration of initial state
genetics (MHC and other loci)
stimulation by external
(environmental) factors (e.g.
infections, hygiene, ATB,
vaccination etc.)
Physiologic use of immune system
hypersensitive
reactions
type I - V
genetics (MHC and
other loci) pathologic reactivity
against EXTERNAL
antigens that should
normally be tolerated
pathologic reactivity
against SELF-ANTIGENS
that should normally be
tolerated
allergy
and other
hypersensitive
reactions against
external antigens
autoimmune
diseases
hypersensitive
reactions against
internal antigens
pathologic
stimulation by
external factors
(sensibilisation,
viral infection etc.)
Pathologic activity of immune system
Hypersensitive reactions (Coombs & Gell)
Classification of immune disorders
• immune deficiencies
– problem of innate (e.g. phagocytosis, complement) or specific immunity (T or B
lymphocytes, antibodies)
• primary, inborn (rare)
– genetics (for more detail see immunology)
• secondary, acquired (much more common)
– e.g. diseases of GIT (malabsorption), kidneys (nephrotic sy), bone marrow (aplasia, leukemias),
nutrition (cachexia), tumors, infections (HIV/AIDS), ….
• hypersensitive reactions – solely the case of adaptive immunity!!!
– reactions directed against environmental antigens
• allergies
• other non-IgE hypersensitivities
– reactions directed against body self-antigens
• autoimmune diseases
PRINCIPLES OF IMMUNE TOLERANCE (SELF-
TOLERANCE)
Immune tolerance vs. autoimmunity and
autoimmune diseases
• autoimmunity = immune reactivity against self-
antigens
– original view
• autoimmunity = unwanted phenomenon („horror autotoxicus“,
Paul Ehrlich)
– but it is common in reality (though clinically silent)
phenomena
• existence of auto-reactive clones of T-lymphocytes
– tolerance of self, undamaged cells and tissues must be
ensured continually !!! (self-tolerance)
• autoimmune disease
– detectable morphologic and functional damage
Autoimmunity is a case of adaptive (specific) immunity
Molecular mechanisms of central immune tolerance
• B &T lymphocytes originate in the bone
marrow
– B &T-cell receptor specificities are
generated randomly
• Positive and negative selection
mechanisms shape the lymphocyte
repertoire
– B cells mature in the bone marrow
– T cells mature in the thymus
• therefore, majority of anti-self
lymphocytes are centrally deleted
(apoptosis) or anergic
Central and peripheral tolerance of B lymphocytes
In the thymus and after …
Thymus
Selection of T cells in the thymus based on the affinity of their
TCR for MHC II peptides
Principles of central tolerance - thymocyte maturation
• Immature thymocytes from the bone
marrow undergo T-cell receptor (TCR)
rearrangement.
• Stage 1: once immature CD4+8+ thymocytes
enter the thymus they undergo MHC
restriction, whereby only CD4+8+
thymocytes that interact with MHCpresented
antigen on epithelial cells receive
a positive survival signal
– those that do not interact are deleted by
apoptosis.
• Stage 2: this stage involves the negative
selection of thymocytes that survive stage 1.
Thymocytes with too strong an association
for self-MHC and self-antigens are deleted
by apoptosis, allowing the remaining
thymocytes to mature into CD4+ T-helper
(Th) cells or CD8+ cytotoxic (Tc) cells
Quantitative perspective
• The affinity of the T-cell receptor (TCR) for self-peptide–
MHC ligands is the crucial parameter that drives
developmental outcome in the thymus.
– Progenitors that have no affinity or very low affinity die by
neglect. This is thought to be the fate of most thymocytes.
– If the TCR has a low affinity for self-peptide–MHC, then the
progenitor survives and differentiates, a process that is known as
positive selection.
– If the progenitor has a high affinity for self-peptide–MHC, then
several outcomes are possible.
• First, the progenitor can be selected against, a process that is known as
negative selection. The main mechanism of negative selection is clonal
deletion, but receptor editing and anergy have also been described.
• Second, there seem to be mechanisms that select for high-affinity selfreactive
cells and result in differentiation into a 'regulatory'-cell
phenotype. It is not known what determines whether a T cell is
tolerized by negative selection or is selected to become a regulatory T
cell.
– (IEL, intestinal epithelial lymphocyte; NKT cell, natural killer T cell; TReg cell,
CD4+CD25+ regulatory T cell).
Molecular mechanisms of peripheral
immune tolerance
• INDISPENSABLE, CENTRAL ONLY INSUFFICIENT ON ITS OWN!!!
– it is not possible to express all self-antigens in thymus and ensure the
elimination of entire pool of auto-aggressive T lymphocytes
• (1) very low number of self-reactive lymphocytes (surviving the clonal
deletion) escape the central mechanisms and leave the thymus
– autoreactive B & T lymphocytes are normally present in healthy
individuals
• but in order to be activated they need many other signals, mainly from the innate
immune cells
– usually in the presence of infection or tissue damage
• (2) intentional survival of autoreactive T cell differentiated into
peripheral Treg to boost immune tolerance
– CD4+CD25+ (about 5-10% of CD4 cells)
– their development and maintenance is highly dependent on costimulation
and IL-2
– Treg express CD25, TNFa receptor, CTLA-4, and Foxp3
– act in tissues to control inflammation via direct effects on effector
T cells or DCs
– suppression is contact and also cytokine dependent (TGF-b/ IL-10)
But there are other (CD25-) sub-population of
suppressor lymphocytes that are inducible
Summary of mechanisms of self-tolerance
ACTIVATING AND EFFECTOR
MECHANISMS OF AUTOIMMUNITY
Normal activation of T lymphocytes
• T-lymphocytes express a CD4, a receptor for the
MHC-class II molecule
• antigens from the infectious organism or foreign
tissue are processed into peptides by APCs (B
cells, Mac, and DCs) and these peptides that
bind to the MHC-II molecules that are
recognised by the T-lymphocyte using its antigen
receptor
– MHC restriction
• A number of other adhesion molecules and
growth factors are also used to send signals
between the T- lymphocyte and the APCs, and
only if all the signals are correct does the Tlymphocyte
become activated and aggressive
– an aggressive response results in the multiplication
of that clone of T- lymphocytes, which also develop
the ability to kill all further infected cells, using a
similar recognition process to that shown above
Normal activation of T lymphocytes
• An important part of determining
which signalling molecules are present
is the local environment within the
architecture of the immune system =
i.e. the inflammatory environment
shapes the activation of both T cells
and APCs
• Infections tend to cause inflammation
and the release of inflammatory
cytokine molecules like interferongamma,
and find their way into the
immune system via the lymph system
to the lymph-nodes. Therefore the
lymph-node is specialized for
presenting foreign antigens to
generate immune responses.
MHC
Activation of T lymphocytes therefore crucially
depends on „local environment“
• outside the immune system many of the
important molecules for signaling
aggression are not expressed
• In this situation, although antigen can still
be recognized by the T-lymphocyte, the
response is not one of aggression, but
rather of tolerance
• This non-inflammatory environment can be
reinforced by the presence of antiinflammatory
cytokines like IL-4 and IL-10,
that can either be produced by healthy
tissues, or by a population of T-lymphocytes
that are protective and tend to yet further
suppress any tendency to (self) aggression
Activation of T lymphocytes then results in the proliferation of
functionally different effector cells
The function of T cells (CD4/CD8) differs primarily according
to their cytokine profile
Molecular mechanisms of abnormal B or T cell
activation, i.e. autoimmunity
• (1) genetically determined failure of central or peripheral self-
tolerance
• (2) mechanisms related to infection
– cross-reactivity (molecular and viral mimicry)
– polyclonal B cell activation by viruses and bacteria
• (3) release of sequestered antigen(s)
– several sites of „immune privilege“ in the body
• (4) haptens becoming immunogenic
• (5) inappropriately high, abnormal MHC expression
Molecular mechanisms of abnormal B or T cell activation
• (1) genetically determined failure of central or peripheral self-tolerance
– strong or nearly monogenic determination
• mutated AIRE (APS 1) = insufficient expression of tissue-specific antigens in v thymus
• mutated FoxP3 (IPEX) = impaired differentiation of Treg
• mutated Fas = defects of apoptosis (a thus negative selection)
– moderate to weak genetic predisposition (see further)
• (2) mechanisms related to infection
– cross-reactivity (molecular and viral mimicry)
• viral and non-viral peptides can mimic self-peptides and induce autoimmunity
– polyclonal B cell activation by viruses and bacteria
• typical for some bacteria and viruses (e.g. G- bacteria, CMV, EBV) inducing nonspecific polyclonal activation of Blymphocytes
(expressing IgM) in absence of Th-ly („by-pass oeffect“)
• if B cells reactive to self-peptides are activated, autoimmunity can occur
• (3) release of sequestered antigen (several sites of „immune privilege“)
– eye, testes , brain, uterus, …
• (4) haptens becoming immunogenic
• (5) inappropriately high, abnormal MHC expression
– e.g. type I diabetes: pancreatic β cells might express abnormally high levels of MHC I and MHC II upon the
pathologic stimulation
• MHC II – APC only! this may hypersensitize TH cells to β cell peptides
Example (1): APS 1 – genetically predisposed failure of
negative selection in thymus
• autoimmune polyglandular syndrome type 1 (APS1)
– autosomal recessive
• defective autoimmune regulator – AIRE (AutoImmune REgulator) gene (chromosome 21q22.3)
– AIRE protein - transcription factor expressed in lymphoid organs
• role in the induction of immune tolerance
– controls expression of important self-antigens by epithelial cells of thymus, esp. those otherwise
expressed only in endocrine glands
Endocrinopathies associated with APS 1
Strength of genetic predisposition to autoimmune diseases
• strong (often monogenic)
– family of autoimmune polyglandular
syndromes
• defective AIRE = APS 1 (syn. APECED
(autoimmune polyendocrinopathy –
candidiasis - ectodermal dystrophy),
Whitaker syndrome)
– M. Addison, + hypoparathyreoidism,
others
• heterogenic genetic defects = APS 2
(Schmidt syndrome)
– M. Addison, hypothyreoidism, T1DM
• defective FoxP3 = IPEX (immune
dysfunction, polyendocrinopathy, and
enteropathy, X-linked)
• weaker (polygenic)
• MHC alleles
• other non-MHC genes
Examples of non-MHC gene variants enhancing the risk
of autoimmune diseases
Molecular mechanisms of abnormal B or T cell activation
• (1) genetically determined failure of central or peripheral self-tolerance
– strong or nearly monogenic determination
• mutated AIRE (APS 1) = insufficient expression of tissue-specific antigens in v thymus
• mutated FoxP3 (IPEX) = impaired differentiation of Treg
• mutated Fas = defects of apoptosis (a thus negative selection)
– moderate to weak genetic predisposition (see further)
• (2) mechanisms related to infection
– cross-reactivity (molecular and viral mimicry)
• viral and non-viral peptides can mimic self-peptides and induce autoimmunity
– polyclonal B cell activation by viruses and bacteria
• typical for some bacteria and viruses (e.g. G- bacteria, CMV, EBV) inducing nonspecific polyclonal activation of Blymphocytes
(expressing IgM) in absence of Th-ly („by-pass oeffect“)
• if B cells reactive to self-peptides are activated, autoimmunity can occur
• (3) release of sequestered antigen (several sites of „immune privilege“)
– eye, testes , brain, uterus, …
• (4) haptens becoming immunogenic
• (5) abnormal or inappropriately high MHC expression
– e.g. type I diabetes: pancreatic β cells might express abnormally high levels of MHC I and MHC II
upon the pathologic stimulation
• MHC II – APC only! this may hypersensitize TH cells to β cell peptides
Example (2): Role of infection in autoimmunity
induction of „pro-
inflammatory“
environment,
production of
stimulators for preexisting
autoreactive T
lymphocytes
cross-reactivity,
random principle
Molecular mimicry
• sequential or structural
identity or similarity of
microbe with host tissue
– auto-aggressive reaction is
mediated by the same
effector mechanisms used for
host defense against
pathogen
– however, often in the terrain
of genetic predisposition
• mainly MHC II alleles
• but also MHC I – e.g. HLA B27
Rheumatic fever (RF) - an example
• Etiology: Streptococci group A (angina, pharyngitis)
• Pathogenesis: Ab X-react w/ connective tissue in susceptible individuals autoimmune reaction (2- 3 wks) 
inflammation (T cells, macrophages)  heart, skin, brain & joints
• Acute RF – acute inflammation
– heart – pancarditis
– skin – erythema marginatum
– CNS – chorea minor (Sydenham)
– migrating polyarthritis
• Chronic RF
– deformities of heart valves
• most commonly mitral stenosis
Molecular mechanisms of abnormal B or T cell activation
• (1) genetically determined failure of central or peripheral self-tolerance
– strong or nearly monogenic determination
• mutated AIRE (APS 1) = insufficient expression of tissue-specific antigens in v thymus
• mutated FoxP3 (IPEX) = impaired differentiation of Treg
• mutated Fas = defects of apoptosis (a thus negative selection)
– moderate to weak genetic predisposition (see further)
• (2) mechanisms related to infection
– cross-reactivity (molecular and viral mimicry)
• viral and non-viral peptides can mimic self-peptides and induce autoimmunity
– polyclonal B cell activation by viruses and bacteria
• typical for some bacteria and viruses (e.g. G- bacteria, CMV, EBV) inducing nonspecific polyclonal
activation of B-lymphocytes (expressing IgM) in absence of Th-ly („by-pass oeffect“)
• if B cells reactive to self-peptides are activated, autoimmunity can occur
• (3) release of sequestered antigen (several sites of „immune privilege“)
– eye, testes , brain, uterus, …
• (4) haptens becoming immunogenic
• (5) inappropriately high, abnormal MHC expression
– e.g. type I diabetes: pancreatic β cells might express abnormally high levels of MHC I
and MHC II upon the pathologic stimulation
• MHC II – APC only! this may hypersensitize TH cells to β cell peptides
Example (3): Loss of immune privilege
• the original idea of „requested antigens“
– auto-antigens separated from auto-reactive Tlymphocytes
by anatomical barriers
• nowadays more of a functional concept of
„immune priviledge“
– anatomic factors
– absence of lymphatics
– absence of APCs
– low expression of MHC I antigens
– high concentration of anti-inflammatory cytokines
– high expression of FasL  high activity of apoptosis
of T lymph
– other mechanisms
• examples
– eye  sympathetic ophthalmia
• against lens proteins (crystallin)
– testes  anti-sperm & orchitis
– brain (BBB)  antibodies in blood can attack myelin
basic Protein if blood-brain barrier is breached
– uterus (placenta)  abortion
– hair follicles  alopecia
FasL expression may play a role in "immune privilege"
• FasL expression in brain, eye,
placenta, and reproductive
organs is believed to contribute
to immunological privilege
• Aberrant FasL expression may
also be an adaptation of
tumors to evade immune
surveillance
Molecular mechanisms of abnormal B or T cell activation
• (1) genetically determined failure of central or peripheral self-tolerance
– strong or nearly monogenic determination
• mutated AIRE (APS 1) = insufficient expression of tissue-specific antigens in v thymus
• mutated FoxP3 (IPEX) = impaired differentiation of Treg
• mutated Fas = defects of apoptosis (a thus negative selection)
– moderate to weak genetic predisposition (see further)
• (2) mechanisms related to infection
– cross-reactivity (molecular and viral mimicry)
• viral and non-viral peptides can mimic self-peptides and induce autoimmunity
– polyclonal B cell activation by viruses and bacteria
• typical for some bacteria and viruses (e.g. G- bacteria, CMV, EBV) inducing nonspecific polyclonal
activation of B-lymphocytes (expressing IgM) in absence of Th-ly („by-pass oeffect“)
• if B cells reactive to self-peptides are activated, autoimmunity can occur
• (3) release of sequestered antigen (several sites of „immune privilege“)
– eye, testes , brain, uterus, …
• (4) haptens becoming immunogenic
• (5) inappropriately high, abnormal MHC expression
– e.g. type I diabetes: pancreatic β cells might express abnormally high levels of MHC I
and MHC II upon the pathologic stimulation
• MHC II – APC only! this may hypersensitize TH cells to β cell peptides
Example (5): abnormally high expression of MHC II. class
antigens
• MHC II antigens are normally
expressed only on APCs!!!
• due to pathologic activation by proinflammatory
cytokines this can
change (MHC II are expressed
together with tissue-specific Ag)
• auto-reactive T lymphocytes
become activated
• examples
– pancreas
•  cells normally low MHC I expression, no
MHC II
•  cells in T1DM – high expression of MHC
I and II
– upon stimulation by infection?
– similarly thyroid gland in autoimmune
thyroiditis (Hashimoto)
Taken together - the most common postulated
mechanism of autoimmunity
AUTOIMMUNE DISEASES
Autoimmune diseases (AD)
• AD affect  3 - 5 of population
• Autoimmunity results from a failure or breakdown of the mechanisms
normally responsible for maintaining self-tolerance in B cells, T cells, or both
– however, pathologic autoimmune reactivity is very specific and limited to small number
of auto-antigens (responsible for tissue and organ damage)
– majority of overall immune tolerance is preserved
• The major factors that contribute to the development of autoimmunity are
– genetic susceptibility
– environmental triggers
• such as infections , vitamin levels (vit. D), nutrition?, …
• Autoimmune diseases may be either
– systemic
– organ-specific
• Various effector mechanisms are responsible for tissue injury in different
autoimmune diseases
– (A) cell-mediated (hypersensitive reaction type IV)
– (B) antibody-mediated (hypersensitivity type II, III, V)
• Epitope spreading (progression and exacerbation of the disease ):
– AD initiated against one self-antigen that injure tissues may result in the release and
alterations of other tissue antigens, activation of lymphocytes specific for these other
antigens
Autoimmunity is one of the causes of chron. inflammation
• chronic inflammation appears as a
consequence of
– persistent infection
• pathogens escape the immune system
– intracellular pathogens
– granulomas
– absceses
• immune system is incapable to clear infection
due to its defect
– immune deficiency
– persistent irritation/damage
• mechanical
• chemical
• physical
• foreign body
– autoimmunity
Systemic vs. organ-specific AD
(A) Examples of T cell-mediated AD
(B) Examples of AD caused by cell- and tissue- specific
antibodies
AD according to the type of hypersensitive reaction
Prevalence and gender-specific differences
• Sex-based differences in AD can be traced to sex
hormones
– sex hormones circulate throughout the body and alter immune
response by influencing gene expression
– (in general) estrogen can trigger autoimmunity and
testosterone can protect against it
• Gender-difference in immune response
– ♀ produce a higher titre of antibodies and mount more vigorous
immune responses than ♂
– ♀ have a slightly higher cortisol secretion than ♂
– ♀ have higher levels or CD4+ T-cells and serum IgM
• Pregnancy
– during this, ♀ mount more of a TH2-like response
– the change in hormones creates an anti-inflammatory
environment (high cortisol levels)
– diseases enhanced by TH2-like responses are exaggerated
– diseases that involve TH1 inflammatory responses are
suppressed
• Fetal cells can persist in the mother’s blood or the
mother’s cells may appear in the fetus (microchimerism)
– this can result in autoimmunity if the fetal cells mount an
immune response in the mother’s body (or vice versa)
Systemic lupus erythematodes (SLE)
• affected organs
– skin (butterfly rash)
– vessels (vasculitis)
– kidneys (lupus nephritis)
– joints (arthritis)
– CNS (encephalopathy)
• Immune mechanism
– abnormal activation of DNA specific B cells by
engagement of their TLR9 (binding of CpG motifs) and
DNA receptors by antigens released from apoptotic cells
– production of Ab against nuclear components
• dsDNA (double stranded)
• RNA-protein complexes
• histones
– complexes are formed (e.g. anti-dsDNS-DNA) and
deposited in predilection sites (e.g. glomerulus, synovia,
vessel wall) or in sites of death cells releasing DNA and
DAMPs
• this explains rash after sun exposure (UV-induced apoptosis of
keratinocytes)
• very variable clinical course
– 80 patients survive 10 yrs after diagnosis
Rheumatoid Arthritis (RA)
• Demographics
– affects 1-2% of worldwide population
– patients are 75% women between 40-60 years of age
• RA mostly damages joints, but it can also affect the
heart, kidneys and eyes
• Molecular Mechanism
– T-cell mediated AD, however Ab are Also produced
• Rheumatoid Factor (Rf): IgM antibodies to Fc fragment of IgG
– HLA-DR4 association (MHC II)
• Mechanism of Tissue Damage
– Invasion of T lymphocytes in the synovia and proinflammatory
cytokine production
– immune cells accumulate in the joints (bones, cartilage,
surrounding tissue) and cause chronic inflammation.
The inflammation causes destruction and scarring of
the joints. Later the joints deform and loose their
structure
Molecular mechanism operating in RA
T cells (primarily CD4+ memory cells) invading the synovial membrane
produce IL-2 and IFN-gamma. Through cell–cell contact and through
cytokines (produced also by APCs, such as IFN-gamma, TNFa IL-17) these
T cells activate monocytes, macrophages and synovial fibroblasts. They
then overproduce pro-inflammatory cytokines, mainly TNF-, IL-1 and IL-
6 causing chronic inflammation. These cytokines also activate a variety
of genes characteristic of inflammatory responses, including genes
coding for various cytokines and matrix metalloproteinases (MMPs)
involved in tissue degradation. TNF- and IL-1 also induce RANK
expression on macrophages which, when interfering with RANKL on
stromal cells or T cells, differentiate into osteoclasts that resorb and
destroy bone. in addition, chondrocytes also become activated, leading
to the release of MMPs
Inflammatory response of the
synovial membrane ('synovitis')
• Transendothelial influx and/or local activation of a
variety of mononuclear cells, such as T cells, B
cells, plasma cells, dendritic cells, macrophages,
mast cells, as well as by new vessel formation. The
lymphoid infiltrate can be diffuse or, commonly,
form lymphoid-follicle-like structures. The lining
layer becomes hyperplastic (it can have a thickness
of >20 cells) and the synovial membrane expands
and forms villi. However, in addition, the hallmark
of RA is bone destruction . The destructive portion
of the synovial membrane is termed 'pannus', and
the destructive cellular element is the osteoclast;
destruction mostly starts at the cartilage–bone–
synovial membrane junction. Polymorphonuclear
leukocytes are found in high numbers in the joint
fluid, enzymes, together with enzymes secreted by
synoviocytes and chondrocytes, lead to cartilage
degradation.
EXAMPLES OF AUTOIMMUNE DISEASES IN GIT
(CELIAC AND INFLAMMATORY BOWEL DISEASES)
GIT is a common site of immune disorders
• autoimmune
– salivary glands (Sjögren syndrome)
– stomach (atrophic gastritis)
– intestine (celiac disease, IBD such as Crohn’s disease and ulcerative colitis)
– liver (primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune hepatitis)
– pancreas (autoimmune pancreatitis)
• allergy - food allergy
– e.g. milk or dairy products (more precisely to particular proteins)
– difference from lactose intolerance due to enzyme disorder (lactase deficiency)
• extremely frequent – mainly due to the fact that lifetime ability to digest milk (i.e. lactose) is considered a normal state
• however, most mammals and part of human population loses the activity of lactase after weaning
• the lifetime activity could be considered exceptional – persistence of lactase
– genetic polymorphism (geographical distribution is evidently a consequence of genetic selection) in promoter of gene for lactase
» highest prevalence of lactase persistence in Europe in Swedes a Danes (90 %)
» Czech population  70 %
» lowest in Turks ( 20 %)
» outside Europe high fervency of persistence e.g. in desert nomadic populations in North Africa
• the reason for selection of persistence haplotype in northwest Europe could be the richer source of calcium in low vit. D generation
climate
• manifestation
– intestinal discomfort after fresh milk intake (not after diary fermented products such as cheese or yogurt)
– diarrhea, flatulence, abdominal pain
Atrophic gastritis
• destruction of mainly parietal cells by
cytotoxic T-lymphocytes
• compensatory  gastrin
• antibodies against
• intrinsic factor (IF) and complexes IF/B12
• Na/K-ATPase
• carbonic anhydrase
• gastrin receptor
• consequences
– achlorhydria leading to sideropenic
anaemia
– later megaloblastic (pernicious)
anaemia
– precancerosis
normally
absence of parietal
cells
Celiac disease
• synonyms: celiac sprue, gluten-sensitive
enteropathy, gluten intolerance
• T-cell mediated autoimmune reaction against
intestinal mucosa (mainly duodenum and
jejunum) initiated by gluten and its products
(gliadins)
• prevalence 1% of populations
– but commonly underdiagnosed
• manifestation:
– often starts in child after the stop of breast feeding
when flour is introduced (though latency of many
years)
– but anytime in life
• symptoms are very variable!!!
– typical
– untypical
Pathophysiology of celiac disease
• etiology
– gen. predisposition –
• variants of MHC II genes
– DQ2 and DQ8 haplotypes
– celiac d. often associated with other autoimmunities, e.g.
T1DM
• other non-HLA alleles
– external factors
• gluten in diet
– gluten consist of two component (= peptides) gliadin and
glutenin polypeptides
» i.e. a heterogeneous mixture of gliadins (prolamines)
and glutenins
– relatively resistant to digestion by GIT enzymes, and allow
immunogenic peptides to reach mucosal surfaces
• infection by adenoviruses
– molecular mimicry
– damage of intestinal barrier
What is gluten
• gluten (= proteins) is a part of endosperm of cereals (especially
wheat)
– “gluten” is a term applied specifically to the combination of the
prolamin proteins (called gliadins) and the glutelin proteins (called
glutenins) that are found in wheat
• gluten is found in the following grains:
– wheat, barley, bulgur, rye, spelt, oats (possibly, the proportion of
individuals with gluten sensitivity that are also sensitive to the storage
proteins in oats is likely less than 1%), kamut, triticale, semolina,
pumpernickel, farro
• gluten is not found in the following grains:
– rice (all varieties), buckwheat, teff, amaranth, quinoa, corn, hominy,
millet
• gluten adds elasticity to dough (makes bakery products chewy,
pizza dough stretchy, and pasta noodles elastic so that they can be
pulled through the pasta press without breaking when they are
made
– thus, getting a desirable texture in gluten free baked goods can be
difficult
Pathophysiology of celiac disease
• pathogenesis
• HLA-DQ2 and HLA-DQ8 prefer to bind peptides with negative charges, but gluten peptides are
usually devoid of these
– enzyme transglutaminase 2 (TG2) can modify gluten peptides, either by introducing negative charges
through deamination or through crosslinking gliadin peptides with each other or the TG2 enzyme itself
– TG2 is usually expressed intracellularly in an inactive form and is released when inflammation or other
stressors damage the cell
• thus under normal circumstances gluten proteins are unaltered and cannot bind to HLA-DQ
• if TG2 is present and native gluten peptides are presented to CD4+ cells, IFNy is released and an inflammatory response
occurs
• this in turn leads to more damage and release of TG2, and this loop leads to the damage caused by celiac disease
– HLA-DQ8 usually binds to peptides that are not proline rich, and thus several deamination steps are
required before the gluten peptide becomes immunogenic
• this limits the risk of developing celiac disease in individuals that are only HLA-DQ8+
• activated gluten-specific CD4+ T helper 1 (Th1) cells secrete high levels of pro-inflammatory
cytokines (e.g. IFN)gamma and IL-21 that promote the activation of intraepithelial cytotoxic CD8+ T
lymphocytes
• Th2 response – via B cells – leads to production of antibodies against gliadin, reticulin and
transglutaminase
Manifestation of celiac disease
• consequences of auto-aggressive inflammation villous
atrophy, crypt hyperplasia and intraepithelial
lymphocytosis (typical markers for celiac disease)
• clinical course & symptoms
– diarrhea
– abdominal pain
– bloating
– malabsorption of main nutrients, vitamins, trace
elements
• hypo-/malnutrition or weight loss
– non-gastrointestinal manifestation
• children: short stature, anemia, neurological symptoms
• adults: dermatitis herpetiformis, anaemia, reduced bone
density, infertility, irritable bowel syndrome, dyspepsia,
esophageal reflux, neurological symptoms
– in 20-40 years risk of intest. lymphoma (50%) or
carcinoma (10%)
Inflammatory bowel diseases (IBD)
• both Crohn’s disease (CD) and ulcerative colitis (UV)
exhibit certain similar features
– manifestation in young adults
– clinical course
• intermittent flares (exacerbations) followed by remissions
– genetic predisposition
• though different genes in CD and UC
– abnormal reactivity of innate immune system to
intestinal microbiota (bacteria)
– abnormal lymphocyte activity and subsequent
cytokine spectrum
• predominance of Th1/Th17 in CD
• atypical Th2 in UC
• localization
– m. Crohn – any segment of GIT, transmural,
granulomatous inflammation
– ulcerative colitis – only rectum and colon,
inflammation confined to mucosa
The intestinal immune system
• Unique with respect to its close apposition to intraluminal bacteria,
which are separated from the underlying lamina propria by only a single
layer of epithelial cells
• The epithelial-cell layer is comprised of absorptive and secretory cells,
goblet cells (formation of the protective mucus layer) and Paneth cells.
• Immune Microfold cells (M cells) and dendritic cells (DCs) sample
intestinal luminal contents
– under normal conditions, the innate immune cells in the intestinal mucosa are
largely tolerogenic, in order to prevent inflammatory responses to beneficial
commensal bacteria in the gut
– macrophages and dendritic cells have a key role in this regard. Intestinal
macrophages are involved in phagocytosis of pathogens and removal of cell
debris. Unlike most macrophages, intestinal macrophages do not produce proinflammatory
cytokines in response to phagocytic activities
• due to downregulation in the expression of certain cell surface receptors, like
CD14 (which reduces ability to response to lipopolysaccharide) and several of
the TLRs
– CD103+ DCs in the gut are able to induce the formation of regulatory T cells,
which are one of the cell types involved in the adaptive component of
tolerance
– the anti-inflammatory environment of the intestinal mucosa is promoted by
the presence of cytokines such as IL-10 and TGFb which are associated with
many anti-inflammatory functions
• The presence of either pathogenic bacteria or disruption of the
epithelial-cell barrier results in activation and migration of DCs to the
mesenteric lymph nodes, where they activate naive T cells, which then
undergo differentiation under the influence of factors released by DCs
and other stromal elements.
IBD etiology
• genetic factors cases abnormal immune reactivity of innate immune system
– CD
• mutation causing altered expression of pattern-recognition receptors (PRRs), e.g. Toll-like receptors (UC)
or NOD2 and abnormal activity of autophagy  bacterial invasion and defective bacterial clearance 
low production of pro-inflammatory cytokines  granulomatous lesions
– UC
• primary defects in intestinal barrier (tight junctions)  excessive production of pro-inflammatory
cytokines (TNFa)  inflammatory infiltration of mucosa by leucocytes
– abnormal adaptive immune response is likely secondary
• therefore some propose CD and UC are in fact immune deficiencies
• environmental factors
– incidence rises in Europe and N. America
– the same is now evident on southern hemisphere and in Asia
• microbial factors
– gut microflora is very complex
• Bacteroidestes
• Firmicutes
• Actionobacteria
• Preoteobacteria
– modified by plethora of factors
• way delivery (vaginal vs. CS), use of ATB (esp. in sensitive periods such as infancy), quality and quantity of
food, food additives, xenobiotics, drugs etc.
Crohn’s disease
• = ileitis terminalis, enteritis regionalis
• chronic, relapsing, systemic inflammatory disease of
– commonly small intestine
• but can affect any part of GIT beginning with oral cavity to anus
• manifestation typically between 3. to 6. decade, more often women
– extraintestinal manifestations
• arthritis
• uveitis
• pyoderma gangrenosum and erythema nodosum
• manifestation & clinical course
– periods of exacerbations (stomach pain, diarrhea, fever, seizures,
blood in stools (enterororhagia)/remissions
• histopathology
– granulomatous type of inflammation affects all layers of intest.
wall
– ulcerations and bleeding
– penetrated ulcers create fistulas (often perirectal)
– affected areas interspersed by unaffected
Etiopathogenesis of CD
• multifactorial
– genetic factors (= predisposition) lead to
abnormal immune response of intest. mucosa
to natural commensal bacterial antigens (>500
bact. strains, aerobes and anaerobes)
• normally opposed by production of defensins
• GWAS
– mutation in gene for CARD15
– autophagy protein ATG16L1
– many other loci
– triggering environmental factors nor known
(infection?) = sterile animals protected
• lipopolysaccharide, peptidoglycan, flagellin, …
• suspects Mycobacteria, Listeria and Yersinia (the
latter two unconfirmed)
• reaction to intraluminal bacteria – normally
“controlled inflammation”
• intracellular recognition of components of bacterial
wall (pathogen-associated molecular patterns,
PAMPs), e.g. muramyl-dipeptide (MDP) by NOD2
(product of CARD15 gene) lead to oligomerization
and activation of NFk-B
• secretion of chemokines and defensins by Paneth cells
• variants of NOD2 associated with Crohn’s d. lead to
deficient epithelial response, loss of barrier function
and increased exposition to intest. microflora
• impaired secretion of chemokines and defensins
• altered expression of pattern-recognition receptors
(PRRs), e.g. Toll-like receptors
• production of inflammatory cytokines
• activation of dendritic cells and production of Ig and
activation of Th1 lymph.
Defective bacterial clearance in CD
• Defective post-translational modifications
in macrophages direct cytokines and
chemokines to the lysosome, thus
reducing secretion and leading to
decreased neutrophil recruitment and
persistence of bacteria in the intestinal
mucosa. Vesicle transport defects also lead
to reduced bacterial clearance in the
autophagolysosome. Impaired epithelial
barrier integrity contributes to increased
bacterial load, thereby exacerbating the
adaptive immune response. Mutations in
the NOD2 receptor reduce the acute
inflammatory response to bacteria and
amplify the chronic inflammatory response
by inhibiting the transcription of IL-10
Ulcerative colitis
• two peak incidence between 20 – 40. na after 50 years of age
• typically Caucasian race, north-south gradient
• inflammation limited to mucosa
– starts at the bottom of Lieberkuhn’s crypts (infiltration by
immune cells)
• mainly rectum and sigmoideum
– hyperemia, abscesses and ulcerations, bleeding, pseudopolyps,
event. strictures
– high activity of TNFa ( treatment with anti-TNFa antibodies)
• clinical course
– periodical = exacerbations x remissions (diarrhea, bleeding,
abdominal pain, fever)
– extraintestinal manifestations (5 – 15%):
• polyarthritis, osteoporosis, uveitis, cholangitis
– chronic anemia, strictures, hemorrhoids
– carcinoma
• in severe form indication for colectomy
Immunology in a nutshell