Immunity

Immunological Tolerance and Autoimmune Diseases

Immunological Tolerance

a state of specific immunological unresponsiveness to a particular antigen in a fully immunocompetent person - Immunogen - tolerogen

Immunological Tolerance

Types of tolerance: Naturally acquired (Neonatal, self ,auto tolerance) Tolerance to self is initially induced during embryonic life, and is maintained by antigen , continues to occur at some level throughout life (as new lymphocytes are produced from bone marrow stem cells) Specifically Induced

Induced Tolerance Therapeutic Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases -T cells becomes tolerance quicker & last longer than B cells -The simpler the Ag gets Better Tolerance because has less epitopes Can be achieved by Low Zone Tolerance High Zone Tolerance

Mechanisms of Immunological Tolerance - Overview

Central Tolerance through Clonal Deletion Clones of cells that have receptors for self-antigens are deleted during development Peripheral tolerance

Peripheral Tolerance

1- Immunological ignorance to some self antigens (anatomical barrier) 2- T-cell anergy a- signal block: failure of APC to deliver a second signal during antigen presentation (example: B7-CD28 interaction) b- engagement of inhibitory receptors (CTLA-4)

Peripheral Tolerance

3- Suppression of responses by regulatory T- cells (CD4+ CD25+) : secretion of immunosuppressive cytokines (IL-10 & TGF-B) 4- Deletion (activation-induced cell death): T- cell apoptosis by engagement of death receptors (Fas-Fas L)


Central Tolerance

Central Tolerance

Anti-self Lymphocyte
Self Ag
ClonalDeletion
Anti-non-self Lymphocyte
Activation
Foreign Ag + second signal
DEVELOPMENT MATURITY
Differentiation


APC
TCR
T cell
CD28
Activated T cells
APC
TCR
Functional unresponsiveness
Normal T cell response
Anergy
Apoptosis (activation-induced cell death)
APC
Deletion
APC

Block in activation
Suppression
Regulatory T cell
Peripheral tolerance
Off signals
Activated T cell

Pathways to Peripheral Tolerance

Fas
FasL
cytokines
Apoptosis
Inhibition of proliferation & effector action
Activated T cells
NormalResponse
CD28
B7
Proliferation & differentiation
Antigen Recognitionwithout co-stimulation
Anergy
CTLA4
B7
FunctionallyUnresponsive
CTL4-B7 interaction
Fas-FasL interaction
Cytokine-mediated suppression
Activation induced cell death
Cytokine regulation
Pathways to Peripheral Tolerance

Properties of regulatory T cells Th 3 (T reg)

Phenotype: CD4, high IL-2 receptor (CD25), low IL-7 receptor, other markersMechanisms of action: multiplesecretion of immune-suppressive cytokines (TGF, IL-10, ), inactivation of dendritic cells or responding lymphocytes

Regulatory T cells

FunctionallyUnresponsive T cell
Production of IL-10 or TGF-b
RegulatoryT cell

The Two Signal Hypothesis for T-cell Activation

Mature Dendritic cell APC
TH cell
CD28
B7
MHC II
TCR
Signal 2
Signal 1
Activated TH cell

Hypothetical mechanism of tolerance in mature T cells

CD28
Resting B-cell APC
TH0 cell
Tolerance (anergy or apoptosis) from lack of signal 2
Signal 1
Tolerant T cell

Regulation by CTLA-4

CTLA4
B7
FunctionallyUnresponsive (Anergic) T cell
CTLA4-B7 interaction
Activated T cell

Activated T cells

NormalResponse
CD28
B7
Proliferation & differentiation
Summary: Lack of co-stimulation can lead to tolerance (anergy)
Antigen Recognitionwithout co-stimulation
Anergy

Generation of immune repertoires

Central Tolerance
Peripheral Tolerance
Autoimmune Diseases
Tolerance fails
Wrong environment (viral infection?)
Wrong genes or mutations
Bone Marrow
Thymus
Self-reactive lymphocytes Deleted by negative selection
    Leakage of self-reactive lymphocytes controlled
Tolerance: Establishment and Failure

Autoimmune Diseases

Immune reaction against self-antigen which present in own tissues, they are characterized by tissue damage, disturbed physiological function, chronicity & usually non reversible Affect female > male Usually started at 20-40 years of age

Autoimmune Diseases

Predisposing Factors: 1- Advancing age 2- Hormonal factors (more common in females) 3- Genetic predisposition 4- Environmental factors (infection, drugs, U.V light, psychological stress, dietary factors)


Mechanisms of Autoimmune Disease (Loss of self-tolerance)
1- Emergence of sequestered antigens (e.g., eye, brain ,thyroid , sperm ) 2- Molecular mimicry Microbes share epitopes with self-antigens Ex. Streptococci and rheumatic heart disease 3- Polyclonal lymphocyte activation (Endotoxin, EBV , AIDS , CMV)

4- Alteration of normal proteinsProcainamide induces SLE5- Inappropriate expression of class II MHC moleculesNormally only on APC sAfter viral infection or trauma the released gamma IFN leads to expressing class II MHC molecules on some cells like Pancreatic beta cells ---IDDM or thyroid cells6- Genetic predisposing (association with MHC gene)Ankylosing spondylitis (HLA- B27)SLE DR- 2,3IDDM DR- 3,4

7-Cytokine dysregulation &Break down (FAILURE) of suppressor mechanisms 8-Thymus defect (Increasing with age) 9-Hormonal factor ( more in females)

Pathogenesis of autoimmunity

Susceptibility genes
Environmental trigger (e.g. infections, chemicals tissue injury)
Failure of self-tolerance
Activation of self-reactive lymphocytes
Immune responses against self tissues
Persistence of functional self-reactive lymphocytes


-Clinical types of auto immune diseases Organ specific Graves’ disease Myasthenia gravis Systemic SLE-Ab non specific but organ specific as primary biliary cirrhosis-Multiple autoimmune diseases can be occurred in the same patient

Type II — Antibodies react with cell-surface antigens in specific organs Ex. auto-immune Hemolytic anemiaType III (Immune Complex) — IgM and/or IgG react with soluble cell material, complexes are deposited, initiate complement activation, inflammation Ex. SLEType IV — Mediated by cytotoxic & CD4 + T cells Ex. MS *

Stimulating auto-antibodies against growth receptors on thyroid gland Cross reactive autoantigens in the eyes Patients develop goiter, bulging staring eyes
*


Systemic Lupus Erythematosus
Incidence 1:2500 Female: male 10:1 2nd/3rd decade of life Skin, kidney, serosal membranes, joints, heart Many autoantibodies Failure to maintain self-tolerance

Anti-Nuclear Antibodies (ANA)

Abs to DNA Abs to histone Abs to non-histone proteins bound to RNA Abs to nucleolar antigens

Systemic Lupus Erythematosus

Genetic factors 30% concordance in monozygotic twins Increased risk in family members HLA-DQ & DR locus and SLE association Non-Genetic factors Drugs: procainamide, hydralazine Sex hormones (estrogens>androgens)\ UV light


Auto-antibodies against nuclear components RBC, Platelets, clotting factors Immune complexes activate complement Excess complexes are deposited in small blood vessels Local inflammation in skin, joints and kidneys, multi-organ damage
*