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 TOLERANCE Maintenance 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 DISEASES Disturbance 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

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

Graves’ disease

Graves' ophthalmopathy

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

Nerve impulse Internalization NO Na+ influx NO muscle contraction MYASTENIA GRAVIS BLOCKING AUTO – ANTIBODIES IN MYASTENIA GRAVIS NEURO-MUSCULAR JUNCTION Muscle Acetilcholin receptor

Insulin  cell  cell  cell  cell  cell Pancreatic islet cells MECHANISM OF AUTOREACTIVITY IN INSULIN- DEPENDENT DIABETES Type IV hypersensitivity AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING β-CELLS glucagon Somatostatin 10 8 insulin secreting cells

Type I diabetes

FACTORS INVOLVED IN THE PATHOMECHANISM OF AUTOIMMUNE DISEASES

DiseaseHLA allotypeRelatív riskSex ratio Women/male Ankylosing spondylitisB Acute anterior uveitisB <0.5 Goodpasture’s syndromeDR215.9~1 Multiple sclerosisDR Graves’s diseaseDR Myasthenia gravisDR32.5~1 Systemic lupus erythematosusDR Insulin dependent diabetes mellitus DR3 and DR4 3.2~1 Rheumatoid arthritisDR44.23 Pemphigus vulgarisDR414.4~1 Hashimoto thyroiditisDR 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 diseases Involve 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 APC Signal 2 Co-stimulation Signal 1 pMHC - TCR Signal 3 Cytokines PRIMARY ACTIVATION OF T LYMPHOCYTES IS UNDER TIGHT CONTROL DENDRITIC CELLS ARE IMPORTANT REGULATORS OF T CELL RESPONSES

REGULATORY T CELLS Homeostatic regulation THYMUS Natural– nTreg PERIPHERY Induced – iTreg Induced regulation Treg Autoimmune diseases Transplantation tolerance Malignant diseases DC AKTIVATION INDUCTION COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND DENDRITIC CELLS

FUNCTIONS OF REGULATORY T CELLS Maintenance of peripheral tolerance Maintenance of peripheral tolerance Prevention of autoimmunity Prevention of autoimmunity Limitation of inflammatory processes asthma, inflammatory diseases Limitation of inflammatory processes asthma, inflammatory diseases Inhibition of protection against infectious diseases Inhibition of protection against infectious diseases Limitation of anti-tumor immunity and protections Limitation of anti-tumor immunity and protections MECHANISMS OF ACTION Internal and external regulation Various inhibitory mechanisms Cell contacts – Cytokines Interaction with the effector T cells as targets

nTreg THYMUS PERIPHERY FoxP3+ FoxP3- IL-2/TGFβ MaintenancenTreg Effector T IL-10/IL-35/TGFβSupression Effector T DC FoxP3- Tr1 IL-10/ TGFβ IL-10 Suppression Suppression FoxP3+ Th3 TGFβ IL-10/ TGFβ mTEC CD4+T FoxP3- iTreg FoxP3+ PERIPHERY ORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLS

Treg CD25 IL-2Rα CTLA4 B7 ligand GITR MARKERS OF THYMUS DERIVED NATURAL Treg CELLS CD127 IL-7Rα ↓ Treg differentiation, maintenance, function Transcription factor – many target genes FoxP3 by itself is not sufficient to confer suppressive functions FoxP3 CD4 + CD25 + FOXP3 + REGULATORY T CELLS

B71/2 T APC CD28 activation CTLA-4 ITIM NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4 LATE EXPRESSION HIGHER AFFINITY TO B7 THAN TO CD28

TOLEROGENITÁS IMMUNOGENITÁS DIFFERENCIÁCIÓ TOLEROGENIC DC STIMULATED DC THE TOLEROGENIC NATURE OF DENDRITIC CELLS DEPENDS ON THEIR STIMULATORY STATE

MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONS IL-35 Inhibitory cytokines TGFβIL-10 Cytolysis Metabolic disturbanceInhibition of dendritic cell differentiation Reduced cytokine production (IL-2) Peri-cellular adenosine cAMP transfer Indolamine-2,3 dioxigenase LAG-3 – CD4 homologue

Inhibition of dendritic cell functions by Treg cells Sakaguchi, Nat Immunol, 2010 In the absence of T reg 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 Teff DC Treg Teff soluble factors DC Treg Treg : effector T cell = 1 : 8 Treg : DC = 1 : 0,8 HOGYAN HATNAK A REGULÁLÓ T SEJTEK EFFICIENT WAY OF INHIBITION THROUGH DENDRITIC CELLS

Defective central tolerance: A utoimmune PolyEndocrinopathy Candidiasis-Ectodermal Dystrophy (APECED), AIRE deficiency Finnish population, Sardinians, Iranian Jews

APECED’ clinical signs

Regulatory T cells inhibit the activation of autoreactive T-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 smoke Goodpasture 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