DEVELOPMENT OF

AUTOIMMUNITY

ARPAD LANYI PhD

CENTRAL AND PERIPHERAL TOLERANCE

TO SELF ANTIGENS

Central tolerance:

Elimination of self-reactive clones.

BUT!!! Some clones escape.

Peripheral tolerance:

Elimination of „fugitive” or altered clones is an important

role for regulatory T-cells.

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

UNDER NORMAL CIRCUMSTANCES PERIPHERAL TISSUES ARE PROTECTED

FROM IMMUNE RESPONSE

IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY

GENERAL FEATURES OF AUTOIMMUNE DISORDERS

Autoimmune diseases may be either systemic or organ specific, depending on the distribution of the autoantigens that are recognized.

• Circulating immune complexes – SLE • Autoantibodies or T-cell responses against self antigens

with restricted tissue distribution - Type 1 diabetes

Various effector mechanisms are responsible for tissue injury in different autoimmune diseases.

• Autoantibodies• Immune complexes• Autoreactive T lymphocytes

All autoimmune diseases involve breaking T-cell tolerance.

AUTOANTIBODY PRODUCTION IS DEPENDENT ON THE

AVAILABILITY OF AUTOREACTIVE T-CELLS

Practically all autoimmune diseases

involve some T-cell defects

In the absence of T-cell help autoreactive

B-cells are retained in the T-cell zone and

die by apoptosis

SINGLE GENE MUTATIONS CAUSE AUTOIMMUNITY

• AIRE - Failure of central tolerance - APECED

AUTOIMMUN REGULATOR (AIRE)A transcription factor expressed by thymic medullary

epithelial cells and induces expression of many tissue-specific genes

Deficiency in establishing central T-cell tolerance

allows too many

self reactive T-cell clones to leave the thymus

AUTOIMMUNE POLYENDOCRINOPATHY-

CANDIDIASIS-ECTODERMAL DYSTROPHY

(APECED)

Rare disease, but more frequently seen in inbred

populations

Finnish, Iranian Jews and in the island of Sardine

SYMPTOMS OF APECED

• Anti-Th17 specific antibodies!!!!!

• Role of Th17 discovered by studying a rare immunodeficiency

• https:///jimneydandme.wordpress.com/james-story

SINGLE GENE MUTATIONS CAUSE AUTOIMMUNITY

• AIRE - Failure of central tolerance - APECED•FOXP3 – Deficiency of functional regulatory T cells - IPEX•CTLA4 - Failure of anergy in CD4+ T cells; defective function of regulatory T cells - several autoimmune disorders•CD25 - Defective development, survival, or function of regulatory T-cells – IPEX-like•C4 - Defective clearance of immune complexes; failure of B cell tolerance – SLE•FAS/FASL - Defective deletion of anergic self-reactive B cells; reduced deletion of mature CD4+T cells - Autoimmune lymphoproliferative syndrome (ALPS)

These genes are associated with rare autoimmune diseases, their identification

has provided valuable information about the importance of various molecular

pathways in the maintenance of self-tolerance.

MOST AUTOIMMUNE DISEASES ARECOMPLEX

POLYGENIC TRAITS

MULTIPLE INHERITED GENETIC POLYMORPHISMSCONTRIBUTE TO

DISEASE SUSCEPTIBILITY

HLA IS THE DOMINANT GENETIC FACTOR AFFECTING

SUSCEPTIBILITYTO AUTOIMMUNE DISEASE

Family studies reveal that HLA type

correlateswith susceptibility to type 1

diabetes

Similar results are seen for manyautoimmune diseases

Haplotype is a group of genes within an

organism that was inherited together from a single parent

ASSOCIATIONS OF HLA ALLOTYPES WITH AUTOIMMUNE DISEASE

HLA associations reflect the

importance of T-cell

tolerance in preventing

autoimmunity

Many more autoimmune

diseases are associated with

HLA II than with HLA I

indicating that CD4+T-cells are

inherently more likely

to lose tolerance to a self antigen

than are CD8+T-cells

PREFERENTIAL ALLELE ASSOCIATIONS:

LINKAGE DISEQUILIBRIUMParticular alleles of the different polymorphic genes

arecombined in HLA haplotypes at frequencies higher

than expected by chanceA1–B8–DR3–DQ2 haplotype, which includes alleles for HLA-A, -B, -C, -DR, and -DQ is characteristic of Caucasian populations (up to 11%).

Association with several common autoimmune diseases: type 1 diabetes, SLE, myasthenia gravis, autoimmune hepatitis, primary biliary cirrhosis.

COMBINATIONS OF HLA CLASS IIALLOTYPES CONFER

SUSCEPTIBILITY TO TYPE 1 DIABETES

Common Caucasian HLA haplotypes that encode either the DQ2 or the DQ8 allotype confer susceptibility to type 1 diabetes.

Heterozygous individuals are more susceptible to diabetes.

This augmented susceptibility is due to a novel HLA-DQ heterodimer consisting of the DQ8 α-chain and the DQ2 β-chain.

POLYMORPHISMS IN NON-HLA GENES ASSOCIATED WITH AUTOIMMUNITY

GENETIC PREDISPOSITION IS NOT EQUAL TO AUTOIMMUNE DISEASE

INDIVIDUALS WITH GENETIC PREDISPOSITION

DEVELOP AUTOIMMUNE DISEASE

WITH A MAXIMUM FREQUENCY OF 20%

ENVIRONMENTAL FACTORS PLAY AROLE

IN DEVELOPING OF AUTOIMMUNITY

DRUG INDUCED HEMOLYTIC ANEMIA

• Alpha methyldopa therapy results in the formation of red blood cell autoantibodies in 10-20% of patients taking the drug for longer than 4 months. True autoantibodies: directed against an autoantigen on the red

blood cell membrane, not against the drug  The target membrane antigen is usually within the Rhesus system

• Drug-dependent Abs Penicillin, cefotetan: covalently bind to rbc membrane proteins.

o Anti-drug Ab (usually IgG) - attaches to the drug-coated RBCs - clearance by macrophages

Ceftriaxone: binds non-specifically to RBC membrane proteinso Abs are formed to the combined membrane-drug (hapten)

complex, can be IgM or IgG, and often activate complement - acute rapid intravascular hemolysis

SMOKING

Smoking damages the mucosa of the airways and exacerbates many diseases.

All patients with Goodpasture’s syndrome develop glomerulonephritis, but only those who habitually smoke cigarettes develop pulmonary hemorrhage.

In nonsmokers, the basement membranes of lung alveoli are inaccessible to antibodies.

In smokers the lack of integrity gives circulating antibodies access to the basement membranes.

PHYSICAL TRAUMA

INFECTIONS:

ENVIRONMENTAL FACTORS THAT CAN TRIGGER

AUTOIMMUNE DISEASE

ROLE OF INFECTIONS IN THE DEVELOPMENT OF AUTOIMMUNITY

MOLECULAR MIMICRY MAY LEAD TO SEVERE AUTOIMMUNE

REACTIONS

INFECTIONS ASSOCIATED WITH THE START OF AUTOIMMUNITY

ANTIBODIES AGAINST STREPTOCOCCAL CELL-WALL ANTIGENSCROSS-REACT WITH ANTIGENS ON HEART TISSUE

• In response to IFN-γ MHCII expression is induced on thyroid cells (on the β cells of the pancreas as well as on microglia).

• Insufficient for the activation of naive T-cells (not normally present in the periphery anyway), BUT effector T-cells cross-reacting with autoantigens may be activated.

INDUCTION OF HLA CLASS II EXPRESSION ON TISSUE CELLS

FACILITATES AUTOIMMUNITY

GENETIC AND ENVIRONMENTAL FACTORSACT TOGETHER

TO CAUSE AUTOIMMUNITY

smokers

nonsmokers

Smoking, HLA-DR4 and an

immune response to citrullinated proteins are all tied together in

the same disease-causing

mechanism

Basic residues in the peptide-binding groove of the DRβ*04 chain are

necessary to confer susceptibility to

rheumatoid arthritis

Smoking is the major environmental factor

associated with rheumatoid arthritis

ACPA+: strong association with

HLA-DR4 and smoking

APCA-: no association

RHEUMATOID ARTHRITIS IS INFLUENCEDBY GENETIC AND ENVIRONMENTAL FACTORS

INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS:

CELIAC DISEASEStrong genetic predisposition: DQ2, DQ8 allotypes – celiac disease - 80% DQ2 (the same DQ allotypes that predispose to type 1 diabetes)

Caucasian populations • bread: staple• DQ2:30%• Celiac disease: 0.5-1%• The concordance rate in monozygotic twins: 75-

80%

Environmental factors:• Antibodies, memory T-cells – cross-reaction• Repeated infections with rotavirus• IFN-γ therapy (hepatitis)• Gluten introduction – maternal IgA

ROLE OF THE GUT MICROBIOTA IN AUTOIMMUNITY

doi:10.1038/nri3430

doi:10.1038/nri3430

doi:10.1038/nri3430

doi:10.1038/nm0911-1055

ROLE OF THE GUT MICROBIOTA IN AUTOIMMUNITY

ROLE OF OTHER INTRINSIC FACTORS IN AUTOIMMUNITY

Most autoimmune diseases are more prevalent in women than men.

Conservative estimates indicate that nearly 80% of

individuals with autoimmune diseases are women.

Ankylosing spondylitis occurs more frequently in men.

HORMONES

SENESCENCE OF THE THYMUS

AND THE T-CELL POPULATIONCONTRIBUTES TOAUTOIMMUNITYT-cell populations are dynamic:

• T-cells must divide periodically to survive.

• 1% of the body’s T-cells being replaced each day.

Once the thymus can no longer fulfill the demand for naive T-cells, the immune system compensates:

• expanding the size of existing T-cell clones

• altering the properties of T-cells - make them more resistant to apoptosis; CD28 - KIRRA: large clones of expanded autoreactive CD4 T-

cells

• lack of CD28

• express NK-cell receptors - KIR2DS2

• produce large amounts of IFN-γ

• not anergic

Self antigens are persistent, and once an immune response starts,

many amplification mechanisms are activated that perpetuate the

response Tissue injures result in the release and alterations of other tissue

antigens, activation of lymphocytes specific for these other antigens,

and exacerbation of the disease

AUTOIMMUNE DISEASES TEND TO BE CHRONIC, PROGRESSIVE AND SELF-

PERPETUATING

MECHANISMS OF CHRONICITY OF AUTOIMMUNE DISEASES

PEMPHIGUS FOLIACEUS

INTRAMOLECULAR EPITOPE SPREADING

INTERMOLECULAR EPITOPE SPREADING IN SLE

DYSFUNCTION OF REGULATORY T-CELLS

FOXP3 deficiency: IPEX

)

IL-6 mediated resistance in psoriasis

Autoimmunity in Dry Eye:

qualitative Treg defect – resistance Th17 cells

CTLA-4 haploinsufficiency: autoimmunity

IL-10: severe colitis

doi:10.1038/nri2889

LOSS OF REGULATION OF AUTOREACTIVE T-CELLS RESULTS IN AUTOIMMUNITY

Average Pixel Density within Indicated Cellsa

Average Pixel Density within Keratinocytesa pb

Fold Increase over

Keratinocytesc

CD11c+ 966.5 ± 30.3 587.1 ± 30.6 0.039 1.98 ± 0.37

CD3+ 914.1 ± 35.7 676.2 ± 21.3 0.0044 1.38 ± 0.09

Mac387+ 1014.0 ± 38.4 958.9 ± 28.7 0.4056 1.08 ± 0.06

CD31+ 1495.2 ± 81.2 832.3 ± 36.3 0.0015 1.87 ± 0.23

IL-6 MEDIATED RESISTANCE IN PSORIASIS

IL-6 is overexpressed in

lesional psoriatic skin

Immune cell subsets including DCs, as well as CD31+ endothelial cells, represent major sources of IL-6 in lesional psoriatic skin

IL-6 is necessary and

sufficient for reversal

of Treg suppressive

function

 10.4049/jimmunol.0803721

AUTOIMMUNITY IN DRY EYE: DEFECT IN TREGS IS QUALITATIVE NOT QUANTITATIVE

doi: 10.4049/jimmunol.182.3.1247

THANK YOU

ROLE OF INFECTIONS IN THE DEVELOPMENT OF AUTOIMMUNITY

MOLECULAR MIMICRY MAY LEAD TO SEVERE AUTOIMMUNE

REACTIONS

smokers

nonsmokers

Smoking, HLA-DR4 and an

immune response to citrullinated proteins are all tied together in

the same disease-causing

mechanism

Basic residues in the peptide-binding groove of the DRβ*04 chain are

necessary to confer susceptibility to

rheumatoid arthritis

Smoking is the major environmental factor

associated with rheumatoid arthritis

ACPA+: strong association with

HLA-DR4 and smoking

APCA-: no association

RHEUMATOID ARTHRITIS IS INFLUENCEDBY GENETIC AND ENVIRONMENTAL FACTORS