Autoimmune diseases

CENTRAL TOLERANCE IS INDUCED AND MAINTAINED IN THE BONE MARROW AND 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 limited

Antigen presenting cells are not activated in normal tissues

NO SIGNAL 3.

PERIPHERAL TISSUES TOLERIZE THEMSELVES

PERIPHERAL TOLERANCE

IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY

(autoimmune regulator- AIRE)

• Chronic inflammatory conditions• Repair mechanisms cannot compete with tissue

destruction caused by the immune system• Variety of symptoms and of target tissues

• Mechanisms of recognition and effector functions are the same as those acting against pathogens and environmental antigens

AUTOIMMUNE DISEASES

MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS

Killing of target cell by effector-macrophage orNK-cell

Killing of targetcell by complement-mediated lysis

complement activation

IgG

IgG

Receptor-specific autoantibodyinterferes withsignal transduction

NKMf

C '

ADCC

Autoimmune hemolytic anemia

Goodpasture's syndrome

Glomerulus stained for IgG deposition by immunofluorescence

Pemphigus is a rare skin disorder characterized by blistering of the skin and mucous membranes. The most common type is pemphigus vulgaris, which involves painful sores and blisters on the skin and in mouth. Autoantibodies attack desmosomes.

Pemphigus vulgaris

Acute rheumatic fever

MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS

Killing of target cell by effector-macrophage orNK-cell

Killing of targetcell by complement-mediated lysis

complement activation

IgG

IgG

Receptor-specific autoantibodyinterferes withsignal transduction

NKMf

C '

ADCC

Graves’ disease

Graves' ophthalmopathy

Hashimoto’s disease – hypothyreosis(antibodies and effector T cells)

Nerve impulse

Nerve impulse

InternalizationNO Na+ influx

NO muscle contraction

MYASTENIA GRAVIS

BLOCKING AUTO – ANTIBODIES IN MYASTENIA GRAVIS

NEURO-MUSCULAR JUNCTION

Muscle

Acetilcholin receptor

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

Type I diabetes

FACTORS INVOLVED IN THE PATHOMECHANISM

OF AUTOIMMUNE DISEASES

Disease HLA allotype 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

Frequency of autoimmune diseases is elevated in vomen

Tolerance : Role of genetic and environmental factors

Practically all autoimmune diseasesInvolve some T-cell defects

In the absence of T cell help autoreactive B cells ate trapped in the T-cell zone and die

NEGATIVE REGULATION OF IMMUNE RESPONSES BY REGULATORY T CELLS

Professional APCProfessional APC

Signal 2Co-stimulation

Signal 1pMHC - TCR

Signal 3Cytokines

PRIMARY ACTIVATION OF T LYMPHOCYTES IS UNDER TIGHT CONTROL

DENDRITIC CELLS ARE IMPORTANT REGULATORS OF T CELL RESPONSES DENDRITIC CELLS ARE IMPORTANT REGULATORS OF T CELL RESPONSES

REGULATORY T CELLSREGULATORY T CELLS

Homeostatic regulationHomeostatic regulation

THYMUSTHYMUS

Natural– nTregNatural– nTreg

PERIPHERYPERIPHERY

Induced – iTregInduced – iTreg

Induced regulationInduced regulationTregTreg

Autoimmune diseasesAutoimmune diseases Transplantation toleranceTransplantation tolerance

Malignant diseasesMalignant diseases

DCDC

AKTIVATIONAKTIVATION INDUCTIONINDUCTION

COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND DENDRITIC CELLS DENDRITIC CELLS

FUNCTIONS OF REGULATORY T CELLS FUNCTIONS OF REGULATORY T CELLS

• Maintenance of peripheral toleranceMaintenance of peripheral tolerance

• Prevention of autoimmunityPrevention of autoimmunity

• Limitation of inflammatory processes asthma, inflammatory diseasesLimitation of inflammatory processes asthma, inflammatory diseases

• Inhibition of protection against infectious diseasesInhibition of protection against infectious diseases

• Limitation of anti-tumor immunity and protectionsLimitation of anti-tumor immunity and protections

MECHANISMS OF ACTIONMECHANISMS OF ACTION

Internal and external regulationInternal and external regulation

Various inhibitory mechanismsVarious inhibitory mechanisms

Cell contacts – Cytokines Cell contacts – Cytokines

Interaction with the effector T cells as targetsInteraction with the effector T cells as targets

nTregnTreg

THYMUSTHYMUS

PERIPHERYPERIPHERYFoxP3+

FoxP3-

IL-2/TGFβ MaintenanceMaintenance

nTregnTreg

Effector T

IL-10/IL-35/TGFβSupressionSupression

Effector T

DC

FoxP3-Tr1Tr1

IL-10/ TGFβ

IL-10

SuppressionSuppression SuppressionSuppression

FoxP3+Th3Th3

TGFβ

IL-10/ TGFβ

mTEC

CD4+TCD4+TFoxP3-

iTregiTreg

FoxP3+

PERIPHERYPERIPHERY

ORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLSORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLS

TregTregCD25IL-2Rα

CTLA4B7 ligand

GITR

MARKERS OF THYMUS DERIVED NATURAL Treg CELLS

CD127IL-7Rα ↓

Treg differentiation, maintenance, functionTranscription factor – many target genesFoxP3 by itself is not sufficient to confer suppressive functions

FoxP3

CD4+CD25+FOXP3+

REGULATORY T CELLS

B71/2

TAPC

CD28 activation

CTLA-4

ITIM

NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4

LATE EXPRESSION

HIGHER AFFINITY TO B7 THAN TO CD28

TO

LER

OG

EN

ITÁ

SIM

MU

NO

GE

NIT

ÁS

DIFFERENCIÁCIÓDIFFERENCIÁCIÓ

TOLEROGENIC DC

STIMULATED DC

THE TOLEROGENIC NATURE OF DENDRITIC CELLS THE TOLEROGENIC NATURE OF DENDRITIC CELLS DEPENDS ON THEIR STIMULATORY STATEDEPENDS ON THEIR STIMULATORY STATE

MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONSFUNCTIONS

IL-35

Inhibitory cytokines

TGFβ

IL-10

Cytolysis

Metabolic disturbance Inhibition of dendritic cell differentiation

Reduced cytokine production (IL-2)Reduced cytokine production (IL-2)Peri-cellular adenosinePeri-cellular adenosine

cAMP transfercAMP transfer

Indolamine-2,3 dioxigenaseIndolamine-2,3 dioxigenaseLAG-3 – CD4 homologueLAG-3 – CD4 homologue

Inhibition of dendritic cell functions by Treg cells

Sakaguchi, Nat Immunol, 2010

In the absence of Treg cells the effector T-cells act as adjuvants as they promote DC activation through increasing the expression of MHC and co-stimulatory molecules and the production of inflammatory cytokines.

cell-cell contact

TeffTeff

DC

Treg

TeffTeff

soluble factors

DC

Treg

Treg : effector T cell = 1 : 8Treg : DC = 1 : 0,8

HOGYAN HATNAK A REGULÁLÓ T SEJTEK

EFFICIENT WAY OF INHIBITION THROUGH DENDRITIC CELLS

Defective central tolerance: Autoimmune PolyEndocrinopathy Candidiasis-Ectodermal Dystrophy (APECED), AIRE deficiencyFinnish population, Sardinians, Iranian Jews

APECED’ clinical signs

Regulatory T cells inhibit the activation of autoreactiveT-cells

IPEX: Immune dysregulation, Polyendocrinopathy, enteropathy, and X-linked syndrome

FoxP3 deficiency

Antibodies against streptococcal cell-wall antigens cross-react with antigens on heart tissue

Self peptides that mimic pathogen-derived peptides can stimulate T-cell responses

Sympathetic ophtalmia

Environmental factors – cigarette smokeGoodpasture syndrome

Glomerulus stained for IgG deposition by immunofluorescence

Induction of MHC-II expression on tissue cells facilitates autoimmunity

In SLE the immune response is broadened in an antigen-specific manner

Age

CD28 KAR