Autoimmunity, immunotolerance

László Tornóci

Semmelweis University

Institute of Pathophysiology

http://xenia.sote.hu/depts/pathophysiologyhttp://xenia.sote.hu/depts/pathophysiology

Definition of autoimmunity

The immune system mounts an attack against the tissues of its own host without a clear reason.

Implicit statements:

• If we know the reason of the immune reaction, it is not called autoimmunity (e.g. viral infection)

• The immune system can distinguish between The immune system can distinguish between selfself and and non-self (dogma)non-self (dogma)

• The immune system will not attack tissues recognized as The immune system will not attack tissues recognized as self (the concept of self (the concept of tolerancetolerance))

The frequency of autoimmune diseases

• 4-5% of the population affected

• Highest prevalence (cca. 1-1%):– Autoimmune diseases of the thyroid

(Graves disease, Hashimoto thyreoiditis)– Rheumatoid arthritis (RA)

• A few dozens of rare diseases also belong to this group

Clinical classification of autoimmune diseases

• Graves (Basedow) dis.• Hashimoto thyreoiditis• Pernicious anemia • Addison’s disease• DM type 1• Myasthenia gravis• Guillain-Barré sy.

• SLE• RA• Scleroderma• Dermatomyositis• Vasculitis

organ specific systemic

Significance of autoimmune diseases

• Potentially fatal disease

(e.g. DM type 1, pernicious anemia)

• Lifelong treatement is necessary • They cause severe, progressive inflammatory

reactions (the systemic ones)

Frequently affected organs

organ specificorgan specificdiseasesdiseases

systemicsystemicdiseasesdiseases

Combined occurrance of autoantibodies

organ specificorgan specificdiseasesdiseases

systemicsystemicdiseasesdiseases

Occurrence of autoantibodies in a family

Presence of an autoantibody by itself Presence of an autoantibody by itself doesn’tdoesn’t n necessarilyecessarily cause cause clinical symptomsclinical symptoms!!

Hashimoto thyreoiditis 1Clinical pictureClinical picture

enlargement of the thyroidenlargement of the thyroid gland gland

Hashimoto thyreoiditis 2Histological picture of the thyroidHistological picture of the thyroid

healthyhealthy Hashimoto thyreoiditisHashimoto thyreoiditis

SLE: systemic lupus erythematodes

A A frequent and most typical symptomfrequent and most typical symptom of of the disease is a butterfly-shaped erythema the disease is a butterfly-shaped erythema on the cheekson the cheeks. . It is caused by It is caused by photosensitivityphotosensitivity..

The tissue damage occurs by the type 3 The tissue damage occurs by the type 3 hypersensitivity reaction. The symptoms hypersensitivity reaction. The symptoms are very variable, depending where the are very variable, depending where the circulating immune complexes get circulating immune complexes get deposited, causing an inflammatory deposited, causing an inflammatory reactionreaction..

Causes/risk factors

• MHC I, II• complement• apoptosis• CTLA-4• TNF-

• infection(molecular mimicry)

• fetal/neonatal infection• haptens (drugs)

inheritedinherited/geneti/geneticc acquiredacquired

Inherited/genetic factors

Susceptibility to autoimmune disease was linked to Susceptibility to autoimmune disease was linked to more than two dozens of genes in mice experimentsmore than two dozens of genes in mice experiments. . Only a few examples are presented hereOnly a few examples are presented here..

The role of MHC I, II alleles

• In most autoimmune diseases, certain MHC alleles were found to be risk factors

• Some alleles can be protective (e.g. in DM type 1)• Some alleles are risk factors in certain races only

AAntigntigeennss get presented associated with get presented associated with MHCMHC, so the efficiency, so the efficiencyof the presentation of a particular antigen (and the possibilityof the presentation of a particular antigen (and the possibilityof an autoimmune reaction) may be determined by MCH alleles.of an autoimmune reaction) may be determined by MCH alleles.

The role of complement

The first few members of the coThe first few members of the complementmplement system system (C1, C4,(C1, C4, C2, C3) C2, C3) play an important role in the elimination of immune play an important role in the elimination of immune complexes. Immune complexes carrying complexes. Immune complexes carrying C3b C3b are bound toare bound toRBCs, get taken up by the RES, where they are degraded.RBCs, get taken up by the RES, where they are degraded.

Congenital deficiency of Congenital deficiency of C1,C2,C3,C4 C1,C2,C3,C4 frequently leads tofrequently leads toautoimmunautoimmunee diseasesdiseases ( (the pathomechanism of the tissue the pathomechanism of the tissue damage is type damage is type 33 hypersensitivity reaction hypersensitivity reaction).).

The role of apoptosis

A mutation in the genes regulating apoptosis can cause autoimmunity

ALPS: Autoimmune lymphoproliferative syndrome

A: lymphadenopathA: lymphadenopathyy

B: HE B: HE stainingstaining• hyperplasia, hyperplasia, • plasmocytosisplasmocytosis

C: CD3C: CD3++ stainingstaining

DD: CD: CD44++ sstainingtaining

EE: CD: CD88++ sstainingtaining

B-EB-E:: lymph node lymph node

A rare congenitalA rare congenital diseasedisease: : chchrroniconic, n, nononmalignmalignantant proliferation of lymph nodes,proliferation of lymph nodes,splenomegalysplenomegaly, , large number of double negativelarge number of double negative (CD3 (CD3++, CD4, CD4, CD8, CD8) ly, ) ly, autoimmunautoimmunee phenomena.phenomena.

Ann Intern Med (1999) Ann Intern Med (1999) 130130: 591: 591

ALPS

• Mutation in the Fas/CD95 gene

• Overexpression of IL-10

• Autoantibodies– positive Coombs test– anticardiolipin,

antinuclear antibodies

• Cytopenias of autoimmune origin– RBC (AIHA)– platelet (ITP)– neutrophil

PathogenetiPathogeneticc factorsfactors AutoimmunAutoimmunee phenomenaphenomena

The signaling system of apoptosis

The role of CTLA-4

CTLA-4 CTLA-4 = cytotoxic-T-lymphocyte-associated protein 4 (CD 52)= cytotoxic-T-lymphocyte-associated protein 4 (CD 52)..A receptor protein on the surface of T cells, through whichA receptor protein on the surface of T cells, through whichactivated T cells can get deactivating signals.activated T cells can get deactivating signals.

AAn inheritedn inherited mutation of the gene, which causesmutation of the gene, which causesslight changes in the function of the receptorslight changes in the function of the receptoris associated with the following diseases:is associated with the following diseases:

• AutoimmunAutoimmunee diseases of the thyroiddiseases of the thyroid• DM type DM type 11• PrimPrimaryary bili biliaryary cirrhosis cirrhosis

Acquired/environmental factors

• infection(superantigens, molecular mimicry)

• fetal/neonatal infections

• haptens (e.g. drugs)

Molecular mimicry 1

• The outbreak autoimmune diseases is frequently preceded by a viral infection

• sounds possible

• Infections are very common, autoimmunity is not

If an antigen of a microbe is identical or very similar to anIf an antigen of a microbe is identical or very similar to anantigen of the bodyantigen of the body (mole(moleccululaar mimr mimicicrryy),), then infection by thethen infection by themicrobe can activate clones which are originally autoreactive microbe can activate clones which are originally autoreactive or capable of cross-reacting with the self antigen.or capable of cross-reacting with the self antigen.

ForFor:: AgainstAgainst::

Molecular mimicry 2Molecular mimicry is implicated in the Molecular mimicry is implicated in the pathogenesis of the following diseases pathogenesis of the following diseases

(no direct proof is available yet in any of them):(no direct proof is available yet in any of them):

Disease Pathogen, Ag Autoantigen

Rheumatic fever Streptococcus cardiac myosin

Guillain-Barré sy. Campylobacter jejuni

lipopolysaccharide

myelin ganglioside (GM1)

DM type 1 Coxsackie virus

P2-C protein

GAD (glutaminic acid decarboxilase)

Multiplex sclerosis EBV, influenza virus A,

human papilloma virus

myelin basic protein

(MBP)

Guillain-Barré syndrome

An acute demyelinating An acute demyelinating polyneuropathpolyneuropathy causing paralysis. They causing paralysis. The paralysis paralysis is typically is typically “ascending“ascending” (” (starts at the feet, and spreads starts at the feet, and spreads upwardsupwards).).

Many cases are preceded by Many cases are preceded by Campylobacter jejuni Campylobacter jejuni infectioninfection((especially of serotype especially of serotype O:19). O:19). Antibodies against Antibodies against gangliogangliossididee (GM1) (GM1) appear in the blood as a result of the infection.appear in the blood as a result of the infection.

The role of fetal/neonatal infections

NEJM (NEJM (20012001) ) 345345: : 13311331

If the titer of maternal Ig-s If the titer of maternal Ig-s is low, the cytopathogenicis low, the cytopathogenicand immune mediated and immune mediated damaging effects of the damaging effects of the infection can lead later to infection can lead later to autoimmune diseaseautoimmune disease(e.g. DM type 1).(e.g. DM type 1).

ZinkernagelZinkernagel

This theory can explain why This theory can explain why there is a parallel increasethere is a parallel increaseof DM with better hygienicof DM with better hygienicstandards.standards.

The role of haptens

Many drugs cause hemolytic anemia, thrombocytopenia, neutropenia, or SLE-like disease with an autoimmune mechanism.

Many Many autoimmunautoimmunee disease shows geographical variation.disease shows geographical variation.

The role of The role of gliadin gliadin in the development of celiac diseasein the development of celiac diseaseis also proven.is also proven.

Therapeutical possibilities

CClassilassic approachc approach::generalgeneral inhibition of inflammation, inhibition of inflammation, immunimmunoosuppressisuppressionon

NewNew m methodsethods::

Inhibition of Inhibition of TNF-TNF-: : RA, Crohn RA, Crohn diseasediseaseInhibition of Inhibition of IL-10:IL-10: SLESLEDestroy the immune system, then transplant Destroy the immune system, then transplant

allogallogeennic stem cellsic stem cells: s: severeevere SLE SLE

The mechanism of tolerance 1

The first theory (not accepted any more)The first theory (not accepted any more): : toleranctolerancee = deletion of forbidden clones= deletion of forbidden clones, , i.e.i.e.autoimmune diseaseautoimmune disease = presence of = presence of autoreaautoreaccttiivvee clonesclones

Examples ofExamples of having having autoreaautoreaccttiivvee autoanti autoantibodiesbodies::

• antibodies against myocardial cells after antibodies against myocardial cells after AMIAMI• antiantiphphososphpholipid olipid antibodiesantibodies in a number of infectionsin a number of infections

The transient presence of autoantibodies occurring after majorThe transient presence of autoantibodies occurring after majortissue damage is accepted nowadays a normal part of the tissue damage is accepted nowadays a normal part of the inflammatory reaction.inflammatory reaction.

The mechanism of tolerance 2

There are a number of proofs that the deletion of forbidden There are a number of proofs that the deletion of forbidden clones is not complete. clones is not complete. AutoreaAutoreaccttiivvee T T andand B B clonesclones are are always present in healthy individualsalways present in healthy individuals.. So an additional, So an additional, so so called called periperipheralpheral toleranc tolerancee mechani mechanism must exist.sm must exist.

The majority of forbidden clones get destroyed by apoptosisThe majority of forbidden clones get destroyed by apoptosis (T (T cells in the cells in the thymus, B thymus, B cells in the bone marrowcells in the bone marrow). ).

CentrCentralal toleranc tolerancee

One experimental proof of peripheral tolerance

Mouse TCR-GP TCR-GP GP

Virus LCMV Vaccinia, mutant LCMV

LCMV

DM

(days)

+

(3-4)

0 +

(9-10)

All 3 mouse strains were apparently All 3 mouse strains were apparently healthy.healthy. But But LCMV vLCMV viirral infection al infection caused the development of caused the development of DM: DM:

TheThe GP GP mice expressedmice expressed LCMV-GP LCMV-GP on on the surface of the surface of pancre pancretic tic cellscells. . TheThe TCR TCR mice had T cells with TCRs mice had T cells with TCRs recognizing recognizing GP. GP. The The TCR-GP TCR-GP doubledouble transgtransgeennicic mice had both.mice had both.

The mechanism of tolerance 3

Central Peripheral Suppression (peripheral 2)

deletion deletion

anergy

ignorance

suppressor cells?

anti-idiotypes

TTolerancolerance is achieved by at least two levels of protectione is achieved by at least two levels of protection

Heretic ideas

Maybe the job of the immune system is not to Maybe the job of the immune system is not to distinguish self from non-self.distinguish self from non-self.

„„DangerDanger” ” modelmodel

HomeostatiHomeostatic theoryc theory

Two new models of the immune system:Two new models of the immune system: