Poruchy imunity
Imunodeficity
Hypersensitivita
Alergie
Autoimunita
Orgány imunitního systému
imunitní systém
(nespecifická a
specifická
imunita)
bakterie
viry
paraziti
plísně
toxiny
nádorové buňky
cizorodé buňky a
tkáně (vč.
transplantace)
invaze a
rekognice
cizorodého
účelná
imunitní
reakce
obnovení původního stavu
genetika (MHC aj. lokusy)
stimulace zevními faktory
během vývoje imunitního
systému (tj. prodělané
infekce, (ne)hygiena, ATB,
vakcinace aj.)
Fyziologické použití imunitního systému
hypersenzitivní
reakce
typ I - V
genetika
patologická reaktivita vůči
ZEVNÍM antigenům, které by
normálně měly být
tolerovány
patologická reaktivita vůči
VLASTNÍM antigenům,
které by normálně měly
být tolerovány
alergie
autoimunitní
nemoci
patologická stimulace
zevními faktory
(senzibilizace alergeny,
virová infekce, aj.)
Patologická aktivita imunitního systému
Hypersenzitivní reakce (Coombs & Gell)
Klasifikace poruch imunity
• imunodeficity
– problém nespecifické (fagocytóza, komplement) nebo
specifické imunity (T či B lymfocyty, protilátky)
• primární, vrozené (detailněji viz Imunologie)
– genetika
• sekundární, získané
– nemoci GIT (malabsorpce), ledvin (nefrotický sy), kostní dřeně
(aplasie, leukemie), výživy (kachexie), nádory, infekce (AIDS), ….
• hypersenzitivní reakce - výhradně záležitost
specifické (adaptivní) imunity!!!
– alergie (mechanizmus viz Resp. systém - astma bronchiale)
– autoimunitní nemoci
PRINCIPY IMUNITNÍ TOLERANCE
(AUTOTOLERANCE)
Imunitní tolerance vs. autoimunita a
autoimunitní nemoci
• autoimunita = imunitní
reaktivita proti vlastním
antigenům („self“ antigeny)
– původní představa
• autoimunita = nežádoucí fenomén
(„horror autotoxicus“, Paul Ehrlich)
– ale ve skutečnosti běžný (nicméně
klinicky němý) fenomén
• prokazatelná existence
autoreaktivních klonů T-lymfocytů
– musí být tudíž zaručena tolerance
vlastních nepoškozených buněk
(self tolerance) na více úrovních
• centrální
• periferní
• autoimunitní choroby
– detekovatelné morfologické a
funkční poškození
Autoimunita je záležitostí adaptivní
(specifické) imunity!!!
Molekulární mechanizmy centrální imunotolerance
• B &T lymfocyty mají původ v kostní dřeni
• pozitivní a negativní selekce upravuje jejich repertoár
– B lymf. maturují a jsou selektovány v „bone marrow“
– T lymf. maturují a jsou selektovány v thymu
• tudíž většina autoreaktevních lymfocytů je centrálně
odstraněna (apoptóza) nebo je anergická
Jak se dosahuje diverzity receptorů lymfocytů (B a T)
Somatická rekombinace
- B lym – v kostní dřeni
- T-lymf v thymu
vede k produkci
obrovského množství
náhodných variant vč.
těch autoreaktivních
T lymfocyt
Centrální a periferní tolerance B lymfocytů
• možnosti v případě autoreaktivity
– apoptóza
– receptor editing
• protože stimulace B lymfocytů periferně vyžaduje spolupráci
T lymf., jejich tolerance musí být kontrolována důsledněji
Thymus
Centrální tolerance T lymfocytů – thymus
diferenciace a zároveň selekce
Princip of centrální tolerance – maturace thymocytů
• immature thymocytes from
the bone marrow undergo Tcell
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 MHC-presented
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
Role MHC v selekci T lymfocytů
Peptide generation  loading on MHC
z cytoplazmy (např. virové)
proteazom (+IFN)
kratší délky
z ednozomu (např.
extracelulární fagocytované)
lyzozomální proteázy
delší délky
Selekce T lymfocytů v thymu je podmíněna afinitou
jejich TCR k antigenům/ peptidům MHC II
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 selfpeptide–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 self-reactive 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).
Thymus opouštějí kompetentní ale „naivní“ T
lymfocyty, které ale musí být aktivovány v periferii
Normální aktivace T lymfocytů
• 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.
Normální aktivace Th lymfocytů
• 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 T-lymphocyte become
activated and aggressive
– an aggressive response results in the
multiplication of that clone of Tlymphocytes,
which also develop the
ability to kill all further infected cells, using
a similar recognition process to that shown
above
Aktivace Th lymfocytů tedy zásadně závisí
na „lokálním prostředí“
• 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
Aktivace T lymfocytů vede k jejich proliferaci ve
funkčně různorodé efektorové buňky
Funkce T lymf. (CD4/CD8) se liší primárně
podle jejich cytokinového profilu
Funkce T lymf. (CD4/CD8) se liší primárně
podle jejich cytokinového profilu
Molekulární mechanizmy
periferní autotolerance
• NEZBYTNÁ, CENTRÁLNÍ BY SAMA O SOBĚ NESTAČILA!!!
– 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 natural 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)
Existují ještě další (CD25-) subpopulace supresorových Treg
lymfocytů které jsou inducibilní
Shrnutí mechanizmů autotolerance
AKTIVAČNÍ A EFEKTOROVÉ
MECHANIZMY AUTOIMUNITY
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
– production of proinflammatory/costimulatory signals
– cross-reactivity (molecular and viral mimicry)
– polyclonal B cell activation by viruses and bacteria
• (3) release of sequestered antigen (several sites of
„immune privilege“)
• (4) haptens becoming immunogenic
• (5) inappropriately high, abnormal MHC expression
Molecular mechanisms of abnormal B or
T cell activation, i.e. autoimmunity
• (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 (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
Příklad (1): APS 1 – geneticky podmíněné
selhání negativní selekce v thymu
• autoimunní polyglandulární syndrom typu 1 (APS1)
• autozomálně recesivní
• defective autoimmune regulator – AIRE (AutoImmune Regulator) gene
(chromosom 21q22.3)
– AIRE protein - transcription factor exprimován v lymfoidních orgánech
• role v indukci imunitní tolerance
– kontroluje expresi důležitých „self-antigenů“, zejm. těch, které jsou jinak
exprimovány jen v endokrinních žlázách, na úrovni epiteliálních buněk thymu
Endokrinopatie u APS 1
Genetické predispozice k autoimunitním nemocem
• silná (často monogenní)
– skupina autoimunitních
polyglandulárních syndromů
• defekt AIRE = APS 1 (syn. APECED
(autoimunní polyendokrinopatie –
candidiasis - ektodermální
dystrofie), Whitakerův syndrom)
– M. Addison, +
hypoparathyreoidismus, další
• heterogenní genetický defekt =
APS 2 (Schmidtův syndrom)
– M. Addison, hypothyreoidismus,
T1DM
• defekt FoxP3 = IPEX (immune
dysfunction, polyendocrinopathy,
and enteropathy, X-linked)
• polygenní
• MHC alely
• jiné geny
Příklady non-MHC genetických variant
asociovaných s rizikem autoimunitních nemocí
Molecular mechanisms of abnormal B or
T cell activation, i.e. autoimmunity
• (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
• (2) mechanisms related to infection
– production of proinflammatory/costimulatory signals
– 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, …
• (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
Příklad (2): Role infekcí v rozvoji
autoimunity
Taken together - the most common
postulated mechanism of autoimmunity
1
2
3
produkce
prozánětových cytokinů
a exprese
kostimulačních molekul
Molekulární mimikry
• 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
Revmatická horečka jako příklad mol. mimikry
• 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, i.e. autoimmunity
• (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
• (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
Příklad (3): Ztráta „imunitní privilegovanosti“
• the original idea of „requested antigens“
– auto-antigens separated from auto-reactive
T-lymphocytes 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 antiinflammatory
cytokines
– high expression of FasL  high
activity of apoptosis of T lymph
– etc.
• 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, i.e. autoimmunity
• (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
Příklad (5): abnormální exprese antigenů
MHC II. třídy v neimunitních bb.
• MHC II antigens are
normally expressed only
on certain cells!!!
• due to pathologic
activation by proinflammatory
cytokines
(IFN) this can change
(MHC II are expressed
together with tissuespecific
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)
AUTOIMUNITA A PRINCIPY
ETIOPATOGENEZE AUTOIMUNITNÍCH
NEMOCÍ
Autoimunitní nemoci (AN)
• postihují cca 3 - 5 populace
• results from a failure or breakdown of the mechanisms normally
responsible for maintaining self-tolerance in B cells, T cells, or both
– nicméně patologická autoimunitní odpověď je obvykle cílena na omezené
množství autoantigenů, která vede k poškození tkání, je velmi specifická,
většina imunitní tolerance zůstává zachována
• major factors that contribute to the development of
autoimmunity are
– genetic susceptibility
– environmental triggers
• such as infections , vitamin levels (vit. D), nutrition?, …
• AN 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 ):
– autoimmune reactions 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
Systémové vs. orgánově specifické AN
(A) Příklady buněčných (T-lymfocyty
zprostředkovaných) AN
(B) Příklady AN zprostředkovaných
tkáňově specifickými protilátkami
AN podle typu převažující hypersensitivní
reakce – typ II, III a IV
Prevalence a pohlavně specifické rozdíly
• 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 titer 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 antiinflammatory
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)
PŘÍKLADY NĚKTERÝCH SYSTÉMOVÝCH
AN (SLE A REVMATOIDNÍ ARTRITIDA)
Systémový lupus erythematoides (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
Revmatoidní artritida (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 pro-inflammatory 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 lose 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 proinflammatory
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.
PŘÍKLADY AN V GIT (CELIAKIE A
NESPECIFICKÉ STŘEVNÍ ZÁNĚTY)
GIT je lokalizací mnoha běžných AN
• autoimmune
– salivary glands
• Sjögren syndrome
– stomach
• atrophic gastritis
– intestine
• celiac disease
• inflammatory bowel disease
– Crohn’s disease
– 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 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
Atrofická gastritida
• 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
Celiakie
• synonyms: celiac sprue, glutensensitive
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
Patofyziologie celiakie
• 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 resisitant to digestion by
GIT enzymes, and allow
immunogenic peptides to
reach mucosal surfaces
• infection by adenoviruses
molecular mimicry
damage of intestinal barrier
Co je 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
Patoyziologie celiakie
• 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 proinflammatory
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
Manifestace celiakie
– 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
Imunitní systém střeva
• 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.
Etiologie nespecifických střevních zánětů
• 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.
Crohnova choroba
• = 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
Etiopatogeneze 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
Ulcerativní kolitida
• 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
Imunologie v kostce