central tolerance is induced and maintained in the thymus clonal deletion of self agressive b and t...
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CENTRAL TOLERANCE IS INDUCED AND MAINTAINED IN THE THYMUS
Clonal deletion of self agressive B and T cell clones (not complete)
B AND T CELLS WITH SELF REACTIVITY ARE PRESENT IN THE AVAILABLE PERIPHERAL T CELL REPERTOIRE
PERIPHERAL TOLERANCEMaintenance of self tolerance of T-lymphocytes against tissue-specific self proteins which are not represented in the thymus
Active mechanisms at the level of CD4+ helper T-lymphocytes
AUTOIMMUNE DISEASESDisturbance of tolerance
Misdirected adaptive immunity to healthy cells and tissues
Normal tissue cells do not express MHC class II
NO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules and do not produce T cell differentiating cytokines
NO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limitedAntigen presenting cells are not activated in normal tissues
NO SIGNAL 3. for CD4+ Th activation
PERIPHERAL TISSUES TOLERIZE THEMSELVES
PERIPHERAL TOLERANCE
IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
ANERGY – Functional unresponsiveness, no IL-2 secretion
SIGNAL 1 Recognition of auto-antigen on tissue cellSIGNAL 2 No B7 and CD40 expression, no co-stimulation
Tissue resident professional APC are not activated SIGNAL 3 Innate immunity is not activated No inflammation
CLONAL DELETION – Activation induced cell deathRequires persistant high antigen dose Fas – FasL interaction
SUPPRESSION – Activity of other cells Cytokine-mediated balance Effector functions are inhibited by regulatory T cells
CLONAL IGNORANCENo contact with the immune system
Immunologically privileged sites Central nervous system, eye
No recognition in the periphery
MECHANISMS OF PERIPHERAL TOLERANCE
NEGATIVE REGULATION OF THE IMMUNE SYSTEM
NEGATIVE REGULATION IN THE IMMUNE SYSTEM1. Decrease of antigen concentration in the course of the immune response2. Inhibition of B lymphocyte activation - antibody feedback
• Cross linking of BCR with FcRIIB (CD32) by antigen-antibody complex• ITIM-induced negative signaling of B cell activation - phosphatases• B cells without T cell help are excluded from follicles
3. Death of activated T lymphocytes• Passive cell death mediated by the shortage in survival factors (cytokines)• Activation induced FasL expression sensitizes activated T cells for Fas-• mediated apoptosis (AICD)• Activation induced cell death (AICD) is induced by repeated antigenic
stimulation4. Inhibition T lymphocyte activation• Anergy of CD4+ T lymphocytes • Late in the immune response activated T cells express CTLA-4, the ligand of
B74. Suppression by regulatory T lymphocytes
• Counter regulation of Th1 and Th2 cytokines• Production of suppressive cytokines• IL-10 inhibits APC function such as IL-12 secretion and B7 expression• TGF inhibits T-cell proliferation• IL-4 inhibits IFN-mediated functions• IL-10 and TGF inhibit macrophage activation
NEGATIVE REGULATION OF IMMUNE RESPONSES
Days5 10 15 20 25 30
Naive lymphocytes
Number of antigen specific cells
Primary effectors
Secondary effectors
Memory
DIFFERENTIATION
AICD
EXPANSION
AICD
MEMORY
Ia
SS
SS
SS
SS
SS
Ib
SS
SS
IIb1 IIb2/IIb3
S S S SS S
SS
SS
IIIa IIIb
SS
SS
SS
SS
SS
SS
ITIMITAM
S S
IIc
SS
SS
IIa trimerCa2+
Ca2+Ca2+
SS
ITAM
SS
tetramer
-S-S--S-S-
SS
SS
ITAM
SS
SS
SS
SS
SS
SS
poli-Ig receptor
SECRETORY PIECE
ITAM
Iγ-γ
FcγRI (CD64) FcεRIIFcγRII (CD32)
IIIaζ-ζ IIIaζ-γ IIIaγ-γ IIIaβ
α β γ-γ α γ-γ
γ-γ α
FcεRI
FcγRIII (CD16)
IMMUNOGLOBULIN BINDING Fc RECEPTORS
IgG Fc receptors
FcRI
Ig supergene family, MIRR
ITAM
ITIM
NEGATIVE REGULATION OF B LYMPHOCYTES BY IMMUNE COMPLEXES
FcRIIb
Activating receptorITAM
Expression Inhibitory receptorITIM
Expression
Fc receptorok
Ig supergene family BCR* B cell
TCR,* CD3* T cell
FcRIa (CD64)FcRI*
Macrophage, DC (internalization)
FcRIIa (CD32) Macrophage, DC (internalization)
FcRIIb (CD32) B cell
FcRIIIa (CD16) FcRI* vagy *
NK cell (ADCC)
FcRI, FcRI* Mast cell (ADCC)
C-type lectin
FcRIIb (CD23b) FcRIIa (CD23a) B cell
MHC I receptorok
Ig supergene family Human KAR Human KIR NK and T cell
C-típusú lektin Egér KIR
Human NKG2C/D NK and regulatory T cell Human NKG2A/B NK and regulatory T cell
Other receptors
BCR CD22 B cell
CD28 CTLA-4 T cell
MIRR Multisubunit Immune Recognition Receptors The ligand binding and signal transducing subunits are separated, they co-localize in membrane microdomains.
CD28
Activated T cell
CD28 cross linked by B7
Costimulatory molecules also associatewith inhibitory receptors
CTLA-4 binds CD28 with a higher affinity than B7 molecules
/CTLA-4
B7
CD28
T cell
B7
2 2Signal 1 +
Co-stimulationinduces CTLA-4
The lack of signal 2 to the T cell shuts down the T cell response.
Cross-linking of CTLA-4by B7 inhibits co-stimulationand inhibits T cell activation
- - -- -
NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4
CTLA-4
CD28
B7
LATE EXPRESSION
HIGHER AFFINITY TO B7 THAN CD28
TAPC
C D 8 + Tc
F a s
C D 4 + T h 1
F a s L
C D 4 +
T h 1
A P C
B
THE ROLE OF CD4+ T CELLS IN APOPTOSIS
T CELL HOMEOSTASIS SHUT OFF IMMUNE RESPONSES
REGULATORY T CELLS
TregTregCD25IL-2Rα
CTLA4B7 ligand
GITR
MARKERS OF THYMUS DERIVED NATURAL Treg CELLS
CD127IL-7Rα ↓
Treg differentiation, maintenance, functionTranscription factor – many target genesItself is not sufficient to confer suppressive function A TGFβ does not induce regulatory function
FoxP3
CD4+CD25+FOXP3+
REGULATORY T CELLS
FUNCTIONS OF REGULATORY T CELLSFUNCTIONS OF REGULATORY T CELLS
•Maintenance of peripheral tolerance
•Prevention of autoimmunity
•Limiting inflammatory processes (asthma, inflammatory bowel diseases)
•Inhibit protection against infectious diseases
•Limit immune responses to tumors
MECHANISM
Intrinsic and extrinsic regulation
Various inhibitory mechanisms
Cell contacts – Cytokines
Interaction with the target effector T cells
REGULATORY FUNCTION OF REGULATORY T LYMPHOCYTESREGULATORY FUNCTION OF REGULATORY T LYMPHOCYTES
IL-35
Inhibitory cytokines
TGFβ
IL-10
Cytolysis
Metabolic dysregulation Inhibition of dendritic cell maturation
Descreased cytokine production (IL-2)Adenosin around the cell
cAMP transfer
Indolamin2,3-dioxigenaseLAG-3 – CD4 homologTreg : effektor T cell = 1 : 8Treg : DC = 1 : 0,8
THE ROLE OF IL-35 IN THE FUNCTION OF REGULATORY T CELLSTHE ROLE OF IL-35 IN THE FUNCTION OF REGULATORY T CELLS
Induced capability, the effector cell is involved
NOT ONLY A FUNCTION
•The molecular patterns of activated Treg cells are different in the presence and absence of effector cells
•The expression of EBI3 and IL-12α/p35 (IL-35) subunits is increased in the presence of effector T cells
•Treg cells in contact with effector cell act also on effector cells out of contact through IL-35
Initial T cell activation Sensed by Treg cells
Increased suppressive mechanisms
TOLERANCE AND AUTOIMMUNITY
STRONG IMMUNE RESPONSES TO FOREIGN ANTIGENS WHILE SUSTAINED TOLERANCE TOWARD HUMAN MACROMOLECULES
AUTOIMMUNE DISEASES
Complicated multifactorial diseases
No single entity can be identified as the necessary and sufficient cause of a particular disease
Unlucky combination of genetic and environmental factors
Side effect of successfully fighting against infections
Disease HLA serotype
Relatív risk Sex ratioWomen/male
Ankylosing spondylitis B27 87.4 0.3
Acute anterior uveitis B27 10.04 <0.5
Goodpasture’s syndrome DR2 15.9 ~1
Multiple sclerosis DR2 4.8 10
Graves’s disease DR3 3.7 4 - 5
Myasthenia gravis DR3 2.5 ~1
Systemic lupus erythematosus DR3 5.8 10 - 20
Insulin dependent diabetes mellitus
DR3 and DR4
3.2 ~1
Rheumatoid arthritis DR4 4.2 3
Pemphigus vulgaris DR4 14.4 ~1
Hashimoto thyroiditis DR5 3.2 4 - 5
ASSOCIATIONS OF HLA ALLOTYPE WITH SUSCEPTIBILITY TO AUTOIMMUNE DISEASE
Maximum 20% of predisposed people develop the disease environmental factors
• Chronic inflammatory conditions• Repair mechanisms cannot compete with tissue destruction caused by
the immune system• Variety of symptoms and of target tissues • 2 – 3% of the population, females are more commonly affected• Mechanisms of recognition and effector functions are the same as
those acting against pathogens and environmental antigens
• Both genetic and environmental factors are involved in the pre-disposition to autoimmune diseases – HLA class I and II and other genetic factors affect susceptibility
• Runs in families and varies between populations• C1, C2 or C4 deficiency predisposes to systemic lupus erythematosus (SLE)
– Environmental factors• Goodpasture’s syndrome – autoantibodies to type IV collagen,
glomerulonephritis, smokers develop pulmonary hemorrhage as well• Symphathetic ophtalmia – provoked by demage• Infection – Wegener’s syndrome – antibodies to proteinase-3 of neutrophil
granules results in destruction of small blood vessels primarily in the lungAny infection can induce granulocyte activation and exposure of the autoantigen
AUTOIMMUNE DISEASES
TISSUE-SPECIFIC AUTOIMMUNE DISEASESEndocrine glands
• Tissue-specific proteins are not expressed in other cells• Vascularized tissues, secrete hormone to the blood
– Easy access to the immune system• Impaired function of a single type of epithelial cells• Thyroid gland
– Hashimoto’s thyroiditis• no thyroid hormone production – hypothyroid • CD4+ T cells and antibodies against thyroglobulin and microsomal proteins
– Graves’ disease• Antibodies to TSH receptor – hyperthyroid• Negative feedback regulation is not functional• CD4+ Th2 cells and antibodies against the muscle of eye – bulding eyes
• Islets of Langerhans in pancreas– Insulin-dependent diabetes
• T cells against insulin, glutamic acid decarboxylase GAD– Insulin-resistant diabetes
• Antagonistic antibodies to insulin receptor• Adrenal gland
– Addison’s disease – chronic adrenal gland hypofunction• Lymphocyte infiltration
DISEASES MEDIATED BY ANTIBODIES AGAINST CELL SURFACE RECEPTORSType II hypersensitivity
Syndrome Antigen Antibody Consequense
Grave’s disease Thyroid stimulating
hormon receptor
Agonist Hyperthyroidism
Myasthenia gravis Acetylcholine receptor
Antagonist Progressive muscle weakness
Insulin resistant diabetes
Insulin receptor Antagonist Hyperglycemia, ketoacidosis
Hypoglycemia Insulin receptor Agonist Hypoglycemia
Grave’s disease – signaling through the TSH receptor
the disease is transferred to the fetus by antibodies
can be cured by plasmapheresis
Myasthenia gravis – internalization and degradation of the receptor
PITUIARY
Tyroid stimulating hormon
TSH
PITUIARY
Tyroid hormonsT3/T4
HYPERTYROSIS
STIMULATING ANTIBODIES IN GRAVES’ DISEASE
Tyroid hormonsT3 triiodine tyronin
T4 tyroxinTyroglobulin
Folliculus lumen
NEGATIVE FEED BACK
Nerve impulse
Nerve impulse
Internalization
NO Na+ influxNO muscle contraction
MIYSTENIA GRAVIS
BLOCKING AUTO – ANTIBODIES IN MYASTENIA GRAVIS
NEURO-MUSCULAR JUNCTION
Muscle
Acetilcholin receptor
Degradation
InsulinInsulin
cell cell cell cell cell cell
PPaancreatic islet cellsncreatic islet cells
MECHANISM OF AUTOREACTIVITY IN INSULIN-DEPENDENT DIABETESType IV hypersensitivity
AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING β-CELLS
glucagon Somatostatin108 insulin secreting cells
SYSTEMIC AUTOIMMUN DISEASESAutoreactivity against common components of human cells
• Systemic lupus erythematosus SLE– Type III hypersensitivity– Autoantibodies against cell surface, cytoplasmic, nuclear proteins,
nucleic acid, nucleoprotein particles induce tissue demage– Comon nucleoprotein particles
• Nucleosome• Splicosome• Small cytoplasmic ribonucleoprotein complex – Ro, La
– Soluble cellular antigens bind antibodies and form soluble immune complexes – released form dying, dead cells
– Immune complexes are deposited to blood vessels,kidneys, joints and other tissues
• Rheumatoid arthritis – Type IV hypersensitivity– Cellular response to synovial membrane
• CD4+ and CD8+ T cells, B cells, plasma cells, neutrophils, macrophages• Production of rheuma factors – antibodies to IgG-Fc
FACTORS INVOLVED IN THE PATHOMECHANISM OF AUTOIMMUNE DISEASES
• Lack of AICD – mediated clonal deletion– mutation in Fas or FasL
• Block of anergy– induced by tissue necrosis or local inflammation breaking T cell anergy by increased B7 expression
• Novel Th epitope self reactive B cell activation drug induced hemolytic anemia
• Inefficiency of regulatory T cell function
• Molecular mimicry– cross reactivity of pathogenic and self proteins
• Polyclonal lymphocyte activation– LPS, superantigens
• Immunologically previledged sites Damage of anatomical barriers– Post-traumic uveitis
• Exposure of cryptic antigens, determinants, sub-dominant epitopes Damage of molecular barriers – APC function, pathogenic enzymes
ANY CHANGE DISTURBING THE PHYSIOLOGICAL THRESHOLD
ASSOCIATION OF INFECTION WITH IMMUNE-MEIDATED TISSUE DEMAGE
Infection HLA association Consequence
Group A Streptococcus ? Rheumatic fevercarditis, polya-arthritis
Chlymydia thrachomatis HLA-B27 Reiter’s syndromearthritis
Shigella felxneri Salmonella typhimurium Salmonella enteritidisYersinia enterocoliticaCampylobacter jejuni
HLA-B27 Reactive arthritis
Borella burgdorfei HLA-DR2, DR4 Chronic arthritis in Lyme disease
Type II HYPERSENSITIVITYIgG antibodies bound to cell surface or tissue antigen
• Antigen expressing cells – become sensitive to complement-mediated lysis and/or opsonized phagocytosis
• Frustrated phagocytosis tissue damage
• Antibodies inhibit or stimulate cell functions
• no tissue damage
HYPESENSITIVITY REACTIONS caused by
IMMUNCOMPLEXES
Type II and III
Cell Peptide modified by drug
Th
B
IgG type antibodies
MECHANISMS OF DRUG SENSITIVITY
„Butterfly„ flush on the face - discoid lupus erythematosus (DLE) – skin manifestation systemic lupus erythematosus (SLE)
Chronic inflammation in SLE upper dermis. Vacuolized and disintegrated basal layer, flushing purpura containing erythrocytes.
TYPE III HYPERSENSITIVITY IN SLE
Immunofluorescent staining with anti-complement antibody. IC deposition takes place at the dermal – epidermal border.
Immunofluorescent staining with anti-IgG antibody.
IMMUNE COMPLEX DEPOSITION IN THE SLE SKIN
Glomerulus in lupus nephritis. Lupus nephritis
KIDNEY LESIONS IN RHEUMATIC DISEASES