lecture 10 autoimmunity

8/13/2019 Lecture 10 Autoimmunity

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AUTOIMMUNE DISEASES


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Autoimmune Disease

Autoimmunity: acquired immunereaction, against self antigens

Autoimmune diseases: the autoimmunereaction induces lesions in tissues

Auto-antibodies (Auto-Ab): Abs againstself Ags (usually IgG or IgM)


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Autoimmune Reaction

Natural up to a point Needed to eliminate unwanted auto-Ags

(old, non -efficient, alternated), or toreduce the immune response activated inexcess (anti -idiotyp)

T ly, by linking to MHC stimulate B ly tosecrete Auto-Abs (there are auto-Ab anti-albumin etc)


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Immune Tolerance

This Immune tolerance induce eitherdeletion or inactivation of autoreactive T

ly1. Central Tolerance : immature T and B lybecame tolerant to self Ags clonallydeletion (takes place during the thymusmaturation, usually an irreversibleprocess. Its is followed by positive ornegative selection)


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Immune Tolerance

Induce deletion or inactivation ofautoreactive T ly

2. Peripheral Tolerance: takes place insecondary lymphoid organs (C lonal

Anergy) proliferative functions andsecretion one are inhibited by leak ofcostimulitory mediators/signals


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Immune Tolerance

Induce deletion or inactivation ofautoreactive ly T

3. Activation of some suppressormechanisms : Ts ly act by inhibatingcytotoxic cells; idiotype anti-idiotypenetwork or death of autoreactive cells)


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Autoimmunity Hypothesis

Theory of the hidden Ags (in NervousSystem, crystalline, thyroid, sperm cells,

bile) Theory of forbidden clone (some error

in deletion of autoreactive ly during fetal

life). Forbidden clones might appear alsoafter somatic mutation (normally they areeliminated)


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Theory of clonal anergy : another form

of forbidden clones. Clones whichencounter the self Ag are not eliminated,they are just temporally suppressed (theyrecover at high quantities of Ags, or longpersistent of them)


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Theory of immune deficiency : there isfunctional inhibition of suppressor cells(CD8+ T ly) which do not block anymore

auto-aggressive phenomenon


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Bach, J.-F. N Engl J Med 2002;347:911-920

Inverse Relation between the Incidence of PrototypicalInfectious Diseases (Panel A) and the Incidence of

Immune Disorders (Panel B) from 1950 to 2000


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IL-4 GATA-3

IL-12 T-BET

Th2

Th1

IL-4IL-5CRTH2

IFN- g

TIM-3

IgE

EosinophilImmediate-typeresponses

IgG1

Antigen-presenting cellsInflammatoryresponses

Naive

TGF-b FOXP3

Treg

CD25CTLA-4IL-10TGF-b

IgG4, IgAFibroblasts, epithelial cellsRegulatory and repairresponses

Schmidt-Weber, Blaser; Curr Opinion Immunol 2004; 16:709 716


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IL-4 IL-10 IL-12

Th2 Th1

Treg

IgEIgG4, IgA

IgG1


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Immune Recognition

High organ Specificity

Without organ Specificity (systemicreactions)


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Auto-Abs

Anti-molecule Immune Complexes (CI)deposition in vessel, glomeruls

(colagenosis; SLE) Anti-cells (Ag in membranes)

cytotoxicity (C activation) or cell-mediated

cytotoxicity (CCAD) or phagocytosis Anti-receptor (cell receptor)

stimulation of function or neutralization of

receptor (myasthenia, hypertiroiditis)


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Pathogenic Effects of Auto-Abs

Cytotoxic (dependent of C, mediated bycells)

Blocking, agglutination or masking (ofsome cell function)

Activation of phagocytosis (oposonizationand activation of macrophages)


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Autoreactive T Lymphocytes

Present in experimental encephalitis inmice

NK Cells usually suppressed (they losetheir regulatory role of down-regulation ofimmune responses)


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Predisposing Factors

Genetic Factors :

HLA-B27 with Ankylosis spondylitis

- in other diseases, the importance ofgenetic factors is lesser


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Association of the Autoimmune diseases and HLA

Autoimmune diseases Gena HLA Risc

Ankylosis spondylitis B27 87.4%Reiters Syndrome B27 37%

Goodpastures Sd. DR2 15.9%

SLE DR3 15%Diabetes mellitus DR3/DR4 25%Systemic Sclerosis DR2 5%Graves Disease DR3 3.7%Hashimotos Thyroiditis DR3 3.2%Myastenia gravis DR3 2.5%Rheumatoid Artritis DR4 4%

Psoriasis DR4 14%


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Age : frequent in old age, but colagenosisare seen in young people (SLE, RA)

Sex : female (SLE ratio F/M = 10/1;Graves disease: 7/1; spondylitis mostly

in male)


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Infection (antigenic mimetism) :virus (vi: Epstein-Barr, Cocksakie);

bacteria (mycoplasma, Klebsiella, Borreliaburgdorferi etc)

Drugs : procainamide, hidralazine(phenomenon lupus-like)


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Autoimmune DiseasesHashimotos Thyroiditis

Autoimmune atrophic Gastritis

Pernicious Anemia

Addisons disease

Myasthenia gravis

Goodpastures Sd.

Diabetes

Autoimmunehemolytic Anemia

Thrombocytopeniaidiopathic Purpura

Sjgrens Sd.Ulcerative Colitis

Primitive Biliary Cirrhosis

Systemic Lupuserythematous

Dermatomiositis

Sclerodermia

Rheumatoid Arthritis

With organ specificity

Systemic


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Hashimotos autoimmuneThyroiditis Mechanism: humoral and cellular thyroid Cell Auto-Ab anti-tireoglobuline; - anti-

peroxidaza from thyroid La female (F/M = 5/1) 30-60 years Diffuse infiltration with ly, eosinophils,atresia of parenchimatous cells Hypothyroidism


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Graves disease Auto-Ab anti-receptor TSH (stimulatory hormone

of thyroid) - mechanism HS type II

Hyperthyroidism

Gointre (hyperplasic, diffuse)

Extrathyroid signs (exophthalmia, peritibialmixedema)


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Myasthenia gravis Auto-Ab anti-receptor for acetylcholine Neuromuscular: post-synaptic block of

nervous influx transmition to motor plate Rare: incidence 2-6 cases in 1 million of

persons

Muscular fatigue very severe: ocular,extension up to respiratory insufficiency) Treatment: extirpation of hypertrofiated

thymus (sometimes might work)


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Myasthenia gravis:- neuron-muscular junction -

Receptorsfor Ach

Auto-Ab antireceptor for Ach

Acetylcholine (Ach)


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Other autoimmune disease - organ-spf

Pancytopenia (H, L, Tr) autoimmune

Anemia pernicious (Biermer) intrinsec factor Diabetes (insulin-dependent) (B cells from

pancreas)

Addisons Disease (receptors for ACTH andmicrosoms) Systemic Sclerosis (basic myelin protein from

brain, bown marrow)

Guillain-Barr Sd (peripheral nerves ganglioside)

Pemfigus keratinocytes


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SYSTEMIC LUPUS

ERITHEMATOUSDiana Dumitrascu


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Definition Affection with unknown etiology,

where the tissues are damaged by Auto-antibodies and ImmuneComplexes


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Ethiology


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Epidemiology

90% are Female, aged 20-30 years

More frequent in blacks, followed byHispanic populations, and Asiaticpopulations

Prevalence 15-50/100,000 (SUA)


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Pathology

Lesions induced by AutoAb, IC

1. Hyperreactivity of T, B lymphocytes2. Genetic Induce

3. Environment factors: viruses,bacteria, drugs


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PathologyGenetic Induce :

- more frequent in monozigots (25 - 58%) vs dizigots(0-6%)

- more frequent in families with one patients- more frequent in pts with defects or deletion of allele of classes

III C4AQO (40-50% pts)- more frequent in homozygote with defects of C (C1q,C2, C4) (< 5% pts)

- haplotype B8.DR3.DQw2.C4AQO predispose to SLEin population from north of Europe

Genetic Predisposition for SLE induce by drugs: dependence ofthe acetilation of the drug


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Pathology- Associated with HLA-DR2 or DR3 (gene for

autoimmunity) - Cz 1 (1q23) has gene for Fc RIIA; and 1q41-

42 has poli gena (DNA-ribosil) polymerase(PARP) and them may produce defects of theway DNA is repaired and defects of apoptosis

- AutoAb are associated with some symptoms inSLE:

AutoAb to Ro/La (SS-A/SS-B) in sub acute SLEnormal Allele of Fc RIIA or Fc RIIIA whichbound to IgG2/IgG3 are more frequent innephritis (CI are not eliminated from

circulation)


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Pathology

Immunological Factors :- IFN type I (cz 9p21): -there are 13

isoforms of IFN-1 - they activate the program of T ly for IFN -2 secretion (former)

- Toll Receptors (role in innate immune sistand allows the formation of acquiredimmunity; stimulatory and inhibitory functions)

- Dendritic plasmocitoide Cells (they secreteIFN- 1 ) receptors to identified BDCA-2 si

BDCA-4


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Discoid Lupus


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Histopathology Lesions of basal membrane (epidermis) Discontinuing of dermal-epidermal junctions Infiltration with monocytes around the vessels

Hyperkeratosis IgG and C deposits (80 -100%) may bepresents in normal tissues (50%)

Leucocytoclastic vasculitis Glomerulonephritis - IC deposits or the might be

generated in situ in mesangium or in glomerularbasal membrane (if Ig and C deposits are out ofmesangium severe prognostic)

Discoid Lupus


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Clinical forms

Systemic lupus erithematous

Discoid lupus erithematous skinlesions (skin atrophy) 20%

Subacute lupus erithematous skinlesions - vasculitis type


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Symptoms

Onset One organ (after that systemic)

Systemic (most frequent: fatigue, malaise,fever, anorexia, loss in weight)

Severity : mild severe


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Symptoms

Muscular, joint, bone:- mialgia, arthralgia (most of the pts):

intermittent arthritis, usually symmetric:small

joints: hand, foot, sometimes knee etc tenosinovitis inflammatory myopathy (or after treat: K ,

GCS, hidroxiclorochin) ischemic necrosis in the bone: pelvic joint,

knee, shoulder (post-GCS)


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Symptoms Skin and mucosa:- Rash - butterfly on the face - without scarf lesion (only in discoid lupus) - Rare: urticaria, vesicles, erithema multiform,

lichen plan, paniculitis (= profound lupus)- Vasculitis lesions (SLE systemic, discoid,

subacute): purpura, subcutaneous nodules,infarctation at nails, ulcers, vasculitic urticaria,

paniculitis, necrosis of fingers - Mucosa: Ulcer on oral, nasal mucosa


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Symptoms

Renal:-

pts - glomerulonephritis (most of thepts have Ig deposits in glomeruls)

- Focal glomerulonefritis renalsclerosis

- Without symptoms or nephrotic edema- haematuria, proteinuria, renal failure


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Symptoms

Neurological symptoms:- meningitis, spine cord, central and peripheral

nerves- Unique or multiples- Associated with another organ lesions- Mild cognitive dysfunction (most frequent),

headache (migraine or unspecific headache),muscular contraction

- Rare: psychosis, acute confusion, cerebro-vascular disease, aseptic meningitis, mielopathy,mono or polineuropathy, Guillan-Barr polineuropathy, depression, anxiety


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Symptoms

Vascular symptoms:- thrombosis in the vessel (anti fosfolipidic

antibodies: anticoagulant (LA),

anticardiolipid induce coagulation withoutvasculitis)- Vasculitis- Cerebral embolus (Libman-Sacks

endocarditis)- Vascular and cerebral lesions - IC and

hyperlipidemia (induced by GCSs) inchronic disease


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Symptoms

Hematological:

- Anemia chronic disease in most of the pts- hemolytic anemia rare, withCoombs Test +

- Low Leucocytes (and lymphocytes)- Low platelets (sometimes with purpura)- Seldom Abs anti - factors for coagulation

(VIII, IX) hemorrhage


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Symptoms

Heart and lungs:

- Pericarditis- Myocarditis dysrhithmias- Endocarditis (Libman-Sacks)

- Pleuritis - Lung involvement: most frequent

infections, lupic Pneumonitis, lung fibrosis,PHT (rare)


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Symptoms

Gastrointestinal:- Nausea, diarrhea, abdominal pain- Peritonitis- Vasculitis- Pseudo-obstruction of the bowel- Lesion like scleroderma (motility

disorder)- Acute pancreatitis (disease, therapy withcorticosteroid, azathioprine)

- High level of enzymes (ASAT, ALAT)(without significant hepatic lesions)


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Symptoms

Eyes:- Retinian vasculitis blindness

- Conjunctivitis

- Episcleritis

- Optic nerve lesion

- Sicca sd.


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Acut Lupus

Discoid lupusLupus Paniculitis


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Investigations

C low (= activity of disease) CH50 total hemolytic function of C C3, C4 low CH50 very low + C3 normal = innate deficiency ofC (associated frequent with SLE - ANA neg) Anemia (normochrom, sometimes hemolytic),

low leucocytes, low lymphocytes, low plattelets

ESR is correlated with activity of disease(sometimes) Proteinuria, hematuria, creatinin may be

(periodic renal control to all pts)


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Auto-AbsIncidence Ag Clinical significance

Antinuclear 98% nucleus diagnostic Anti-ADN 70% ADN

(ds)Spf, renal les.,activity index

Anti-Sm 30% Prot.Cuplatedto nucl.

ARN

spf

Anti-RNP 30% Prot.Bond toU1ARN

In Overlap sd. with SLE,polimyositis,scleroderma, mixt conj.tis. diseaseMay protect for Renal

les.

Auto Abs


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Auto-AbsIncidence Ag Clinical

significance

Anti-Ro(SS-A)

30% Prot. Bondto y 1-y 5

ARN

Sj gren Sd., subacutlupus, deficiency ofC, lupus with ANA -neg, renal Les.

Anti-La(SS-B)

10% Fosfopro-tein

Always Associatedwith Anti-Ro,Sj gren Sd.

Rarely in nephritis

Anti-histon

70% Histon SLE induce by drugs


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Auto-AbsIncidence Ag Clinical

Significance Anti-Phospholipids

50% Phospholipids

3 type: lupus- Anticoagulant (LA) Anticardiolipin (aCL)False + syphilis(BFP)

Anti-

erythrocyte

60% Erythrocyt

e

Hemolisis (nu to all)

Anti-platelets

30% Pl Surfaceandcytoplasm

Low Pl (15%)

Anti- 70% Ly. Surface Low Leukocyte, T ly


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Auto-Abs

Incidence Ag Clinicalsignificance

Anti-neuronali 60%Suprafataneurons si aly

Lez. diffuse of CNSat high values

Anti-

ribosomal P

20% RibosomalProt. P

CNS les., psychosis,depression


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Diagnostic

Diagnostic Criteria ARA (1997):4 criteria (dg. + 98% spf and 97% sensib.)1. Rash one face2. Discoid Rash3. Photo sensibility4. Oral Ulcers5. Arthritis6. Serositis7. Renal lesion8. Neurological involvement9. Hematological Abnormalities10. Immunologic Abnormalities11. Antinuclear Antibodies


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Differential Diagnostic

Rheumatoid Arthritis Other autoimmune diseases Dermatitis Neurological Diseases: systemic sclerosis Psychiatric Diseases Hematological Diseases: idiopathic

purpura with low platelets


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Progression of the disease

Remission rarely

25% have a mild form of SLE - no lethal risk

With activity and remission periods


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Treatment No curative treatment Mild Form : better without glucocorticosteroids (GCS)

NSAD - COX-2 inhibitors Antimalarics : hidroxiclorochin (400 mg/day) UV protection oigments Topic or intralesional : GCS, quinacrin,

retinoids, dapson for drug induce withdraw the drug (rarely

short term GCS)


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Treatment Severe Form (renal, nervous system

etc) : Gluco-Corticosteroids :

- 1-2 mg/kg/day (in 2-3 dose, at8-12 hours; pulse therapy withmetilprednisolon 1000 mg/day iv, 2-5 days)

- after that in the morning, in alternativedays with GCS with short action:prednisone, prednisolon, metilprednisolonwith maintenance doses: lowest dosewithout symptoms


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Treatment

Severe Form (renal, cardiac etc) :To Reduce side effects of GCS:

vaccine supplement: Vit D , Calcium ,

Calcitonin ,

Biphosphonats association with other therapy

Treatment


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Treatment

Severe Form (renal, etc) : Cytotoxic Agent (immunosuppressive) : Azathioprin 2-3 mg/kg/day p.o., Clorambucil , Ciclofosfamid 10 -15mg/kg/day iv for 4 weeks and 1,5-2,5 mg/kg/day p.o.,Methotrexat 5-20 mg/day, once/week, p.o. or s.c.,Mofetil Micofenolate [CellCept R , cp 500mg] - 1-2,5g/day, p.o.) reduce the GCS dose: two even 3 drugs (ciclofosfamid +

azathioprina) in renal lesions (GCS + ciclofosfamida iv most efficient, but

very toxic) try to reduce doses when the disease is controlled, (even

withdraw them)


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Treatment

Severe Form (renal etc) : Anticoagulants (warfarina)

Ig iv renal transplant - allograph (high riskof

rejection) plasmaferesis (associated with

cytotoxicity)

cyclosporine


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New Treatments

Mild Forms: dihidroepiandrosteron Rituxan (Mo Ab anti B Ly - anti CD20)

Blocking the activity of B ly with anti-Blys (member of TNF superfamilymolecules)

induce tolerance to ADN MoAb anti - TNF - disappointment


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Prognostic Prognostic is good in drug induced lupus (those drugsmay be administered in pts with SLE) Remission (frequent, but short period) la 20% Survival at 2 years: 90-95%

at 5 years: 71-80%at 10 years: 63-75%

Prognostic is sever for renal involve. (mortality 50% at10 years), CNS les.

Prognostic is severe when C is very low, or platelets arelow Death: either from active disease, either infections in

first prima 10 years, or thrombembolism in next 10-20years


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Sjgren Sd.

Female (F/M = 9/1)

Young age

HLA-B8, HLA-DR3 modified Ags (viral retrovirusuri?)

lymphoid infiltration


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Sjgren Sd.

oral involvement (xerostomia)

ocular involvement (kerato-conjunctivitis) exocrine glandular involvement extra glandular symptoms

Many Auto-Abs: RF, anti-nuclear Abs, etc


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Therapy

NSAID GCS

Immunomodulation (cytostatic:methotrexat, ciclofosfamid, azathioprin)

Immunomodulation (cyclosporine,tacrolimus)

Mo Ab (anti-CD3, -CD2, -CD4, CD7, -CD8,CD25, -CD20; anti-TNF, anti-IL-6, anti-IL-8)


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RHEUMATOID ARTHRITIS


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1859 Sir Alfred Garrod - Rheumatoid Arthritis 1893 W.A. Lane surgical therapy 1897 - acetil salicic Acid 1929 Gold Salts 1939 - Sir McFarlane Burnet - Autoimmune Theory 1948 - Philip Hench & E. C. Kendall - antiinflamatory

effect of steroid hormons 1955 prednison was use for the first time 90 immunomodulatory effects of Mo Ab anti TNF

(Infliximab - Remicade R )



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4500 b.h. indian scheleton in Tenesseee 123 a.h. - Carata Samhita: tumefaction,pain of joints, initial at hand and legs, andafter, extension in hole body, losingappetite, occasionaly fever

1591 - Guillaume de Baillou first bookabou arthritis : - RA + fibromialgy

1763 first treatments with willowextracts

J b J d (1593 1678) Th A ti t


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Jacob Jordaens (1593-1678) The ArtistFamily

Prado, Madrid


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David Teniers, young (1610-1690)

The Temptation of Saint Anthony

Antwerpen


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Test

Which are arguments for SLE:1. 25 years old Man

2. Polyserositis3. High circulate immune complexes4. High IgE5. Radiology signs at sacroiliac joints


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Test

Which are arguments for SLE:1. 25 years old Man

2. Polyserositis3. High circulate immune complexes4. High IgE5. Radiology signs at sacroiliac joints

lecture 10 autoimmunity

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