Basesoftransplantationimmunity. Immunologyofreproduction. Immunologyoftumors. Immunology of tumors Clinicalandimmunologicalaspectsof autoimmundiseases.

Lecturer:professor,DM V. Babadzhan.

History
1933: Yu Yu Voronoy of the Soviet Union performed the first human to human kidney transplant human-to-human 1954: Joseph E. Murray performed the first successful kidney transplant Donor and recipient identical t i id ti l twins Early attempts at immunosuppression -Whole-body X-irradiation -Nitrogen mustard -6-mercaptopurine The main hystocompartable complex was opened y p p p in 1952 1957: George Hitchings and Gertrude Elion modify 6 MP 6-MP to produce azathioprine 1963: Thomas Starzl observed that large doses of corticosteroids can reverse rejection episodes and stabilize allograft function function. Chistian Barnard (REPUBLIC OF SOUTH AFRICA) in 1967 made 2 transplantations of heart. The first patient li d 17 days, died of pneumonia and ti t lived d di d f i d reaction of tearing. Another patient lived after the operation two years.

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BloodTypeCompatibility Blood Type Compatibility

Recipient Blood Type O B A AB Compatible Donors O B or O A or O A, B, AB or O

ESTIMATION OF COMPATIBILITY OF THE DONOR AND RECIPIENT BY HLA ANTIGENS

1. Typing of HLA antigens (lymphocytotoxic test): 1) Probed lymphocytes add to serum against HLA ) y p y g antigens; 2) after incubation add complement; 3) lymphocytes, bearings an antigen which serum is directed against, under the action of complement collapse; ll 4) Dye adds to lymphocytes which paints living cells only. only Result is estimated by the number of lost lymphocytes. Positive result testifies that lymphocytes carry the probed HLA antigen.
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2. The genetic typing is decoding of nucleotide sequence of HLA genes and exposure of distinctions between different alleles of these genes; utilize for typing of genes of MHC class II. 3. Reaction of mixed culture of lymphocytes - if the donor and recipient carry the different antigens of MHC class II in the mixed culture of lymphocytes, consisting of donors and recipients lymphocytes, donor s recipient s proliferation of T-lymphocytes begins after recognition of foreign antigen. g g 4. Reaction of cellular cytotoxity - in cultivation of recipient l i i t lymphocytes and diff h t d different f t from th them b th by the antigens of MHC class II cells of donor cytotoxic Tlymphocytes appear among the cells of recipient recipient.
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OpenNephrectomy Open Nephrectomy

LaproscopicNephrectomy Laproscopic Nephrectomy

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Hyperacute rejection occurs within hours of transplantation. Pre-existing antibodies bind the vasculature of the graft, inducing clotting g g g and occlusion of the vessels Is mediated by preformed f d antibodies tib di that recognize HLA antigens in donor organ. Usually th U ll these are f formed d as a consequence of blood transfusion, pregnancy, prior organ transplantation, autoimmune diseases. Fibrinoid necrosis lead to immediate graft loss. Delayed form may occur several days following transplantation. Plasmapheresis and pulse steroid may be used.
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Acute graft rejection occurs 1-2 weeks following transplantation as a result of an adaptive immune response

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Chronic rejection occurs months or years following transplantation, and is typified by graft vascular disease associated with inflammatory injury

Manifest clinically by a slow and gradual decline in renal function, usually more than 6 mon after transplant and typically accompanied b i d by moderate t d t to h heavy proteinuria. Histologically, characterized by glomerulosclerosis, interstitial fibrosis, and obliteration of arteriolar lumina. Treatment is unsatisfactory.

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Pretransplant evaluation Physical exam Chest x-ray Complete medical and surgical history y Electrocardiogram Ultrasound with Doppler examination Blood tests Pulmonary function test Viral testing - hepatitis CMV hepatitis, CMV, EBV, HIV Pretransplant evaluation Histocompatibility Laboratory Tests Blood Typing Tissue Typing Crossmatch Testing Panel Reactive Antibody (PRA)

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Diagnosis of rejection
Clinical signs:
Malaise Fever Oliguria Hypertension Graft tenderness Diagnosis hinges on serial creatinine measurements ti i t Elevation of 20% over baseline triggers further evaluation gg Rule out non-immunologic causes

Banff criteria
Interpretation of renal biopsy specimens for diagnosing rejection j ti have been greatly facilitated and Standardized Based on scores for glomerular, vascular, interstitial, and tubular Lesions Has been shown to have clinical relevance when predicting p g rejection reversal and may prove useful for choosing first-line therapy of rejection episodes

Ultrasonography Ult h Renal scanning Percutaneous biopsy

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Rejection
SonographicManifestations
Increasedallograftsize g Increasedcorticalechogenicity Increased prominence of renal pyramids Increasedprominenceofrenalpyramids Focalcorticalhypoechoicregions Decreasedechogenicityofrenalsinus Increasedflowresistanceinparenchymalarteries p y

Rejection
Acute Chronic

Grade 1: Moderate interstitial mononuclear inflammation affecting g 25-50% of the sampled parenchyma

Grade 2: Moderate interstitial mononuclear infiltrate l i filt t involving 26-50% of the renal parenchyma Grade 3: severe transmural arteritis t l t iti and/or transmural fibrinoid change and necrosis of smooth muscle cells 29

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Elimination of Preformed Antibody

Plasma exchange is the most commonly used modality for rapid elimination of preformed antibody Length and frequency of plasma exchange depend on:
Antibody titers Antibody specificity

IVIg: Inhibition of Circulating Antibody g g y and Complement Activation

Polyclonal immune globulins derived from p pooled human p plasma of 50,000-100,000 , , or more screened donors. >90% intact IgG F (ab)2 fragments and IgG, (ab ) traces of IgM and IgA.

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Suppression of the T-cell TResponse

Induction Therapy:
Depleting Vs Non-depleting antibodies

Maintenance immunosuppression

Rituximab: B-cell Depletion B Genetically engineered chimeric murine/human monoclonal antibody

Variable light- and heavychain regions from murine anti-CD20 antibody IDEC2B8 H Human I Gk constant IgGk t t regions

First monoclonal antibody to be approved by the FDA for treatment of cancer f

 T i l R f 3 12 TripleRxfor312monthsaftertransplantation h f l i followedbywithdrawalof1ofthe3drugsto minimiselongtermsideeffects(mostcommonly minimise long term side effects (most commonly withdrawndrugiscorticosteroid). Antilymphocyte Abs are also widely used in the pts AntilymphocyteAbsarealsowidelyusedinthepts (polyclonal&monoclonalAbsareavailable).

 TheinitialRxofrejectioninvolvesthe administrationofIVIcorticosteroids (methylpred2501000mgdailyfor3/7or dexamethasone100mgdailyfor3/7). dexamethasone 100mg daily for 3/7)

UW Highly Sensitized Protocol (Deceased Donor)

Pre-Transplant Protocol: Pre In vitro IVIg induced inhibition of PRA IVIg (2g/Kg/month x 6) IVI (2 /K / h Rituximab 375 mg/m2 BSA x 2 g Monitoring of PRA Class I and Class II by Luminex while on treatment

UW Positive Crossmatch Protocol (Living Donor)

Protocol:
Pre- and Post-transplant plasmapheresis PrePost Pre- and Post-transplant IVIg ( PrePostp g (100 mg/Kg) g g) Tacrolimus (Prograf) and MPA (Cellcept /Myfortic) 2 weeks before transplantation y p IV ATG 1.5 mg/kg and IV steroids prepreoperatively p y Maintenance immunosuppression:
Tacrolimus+MPA+steroids

IMMUNOLOGY OF REPRODUCTION Forming of reproductive immunity of men comes in the period of pubescence, pubescence when masculine gametes begin to be produced produced. Mechanisms of spermatozoa deviation from an immunological supervision in a masculine organism: 1. Passive immunological tolerance, conditioned the low threshold of seepage of sperm antigens over the gemato-testicular hurdle. Gematotesticular a barrier consists of three layers: endothelium of capillaries, boundary shell (basal membrane) and muscle cells. 2. Active immunological tolerance is provided by immunoregulatory mechanisms into testicles steroidy macrophages suppressor cells prevent steroidy, macrophages, activating of immunological recognition.. Carried out by the Sertoli cells, which is characteristic by: fagocitarnaya activity; products of suppressor factors which repress proliferation of lymphocytes; induction of apoptosis of activated lymphocytes. 3. The peripheral immunomodulation of testicles prevents the products of antisperm antibodies i th reproductive system of man b th f ll i ti tib di in the d ti t f by the followings mechanisms:- activating of the T-suppressor-cell in an epididymis (appendage of testicle)- immunosuppressive activity of seminal liquid (a component i selected i sperm, adopted immunoprotein relating f t t is l t d in d t d i t i l ti factor of f Immunoglobulin binding factor - IBF, which reduces activating of V42 lymphocytes and represses activity of T-helpers.

ANTIGENS OF SPERMATOZOA WHICH REACTS ON WOMEN'S IMMUNE SYSTEM - superficial antigens - RN-20, RN-30, CLQR, Cr3, FCR-R, Cd46 (provide co-operating with an ovule); - acrosomal antigens proacrosine, acrosine, G-B 24, TLX (have an anti-complementory action, penitrates transparent shell); - nuclear - histon, protamin (stabilize the structure of nucleosomas, nucleosomas the generations of antibodies promote); - tailed - akson, protene fibres, rings (provide motive activity to spermatozoon).

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There are two transplants in the organism of pregnant woman: fetus and trofoblast trofoblast. The immune answer of mother can be directed against each of them. As far as antigen is concern, foetus is 50% stranger for a mother, and that is why in her organism there are certain changes which provide formation of temporary tolerance. FUNCTIONS OF TROPHOBLAST 1. Barrier function between the immune system of mother and foetus. Hl f t Hla-antigeni absent i ti i b t in it which would h it, hi h ld have b been recognized by the immune system of mother or foetus. 2. Connection and i 2 C ti d inactivation of antigens of f t ti ti f ti f foetus b th by the blocking antibodies of mother. 3. 3 Decreasing lymphocytes activity , which get in trophoblast trophoblast, due to influence of local immunosupressive factors.

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MECHANISMS OF TEMPORARY TOLERANCE IN PREGNANCY

1. A placenta produces an alpha-fetoprotein which represses work of the immune system of mother. 2. Progesteron possesses immunosupressivnymi properties. 3. Decidual border of uterus,in which a blastocyst is implanted , warns the immunological tearing away of foetus. p ace ta abso bs a d ta es a t body o t e ot e s 4. A placenta absorbs and takes in antibody from the mother's organism to the HLA-antigens of the foetus. y yp p p , , 5. A decline synthesis of a 1 type T-helpers is FNO-alpha, Il-2, gamma-INF. (INF is a strong destructive factor for trofoblasta.) 6. Activating of T-helpers 2 types and synthesis by them Il-4 -5, 10 strengthening an immunosuppression in mother's organism . In an uterus these cells not only protect foetus but also stimulate a cell growth trofoblast and proliferation of cells of placenta.
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FACTORS, FACTORS ABLE TO ACTIVATE MOTHERS IMMUNE SYSTEM - endometrial infections on the early period of pregnancy are instrumental in activating of T-helpers of a 1 type and "start" i t t li ti ti fTh l f t d " t t" the cellular factors of aggression to the fetus; - medical abortions i di l b ti in anamnesis k i keeps after it lf ft itself inflammatory immunological and hormonal changes. During next pregnancy the mechanisms of immunological memory are provided by including of those factors and tearing away of fetus. - fetal infection, even on condition of its subclinical flow, is q g frequent reason of sudden abortions on a background clinically normal" flow of pregnancy.

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MECHANISMS OF INFERTILITY AT THE CLOSELYRELATED MARRIAGES Antibodies to the foreign HLA-antigens of foetus are fixed on a placenta, that stimulates in it blood circulation and forms its valuable growth. These immune complexes on a placenta are blackout and protect f t d t t foetus f from penetration of i t ti f immune f t factors of f mother in the foetus. If the married couples are identical on HLA antigens HLA-antigens (homozygotes), the immune system of mother does not recognize the antigens of foetus and does not form the blackout factors of immune answer. Absence of sensitivity of organism of mother to the y g foetus results in week growth of placenta, its tearing away and abortion.
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TREATMENT OF SPONTANEOUS IMMUNOLOGICAL ABORTIONS Immunization of woman the lymphatic cells of husband (enter 100 l h lyphocytes). t ) Treatment is conducted before an impregnation, in the process of pregnancy f d f for development of sufficient i l f ffi i immunesupressive potential and at appearance of the first appearence of threat of breaking pregnancy pregnancy. Immunization of woman with allogenic lymphocytes provides moderate sensitivity of its organism and trofoblast On the trofoblast. background of moderate previous sensitivity, immunological tolerance is easier to form.

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TREATMENT OF LATENT FORM OF GENITAL HERPES FOR WOMEN WITH SPONTANEOUS ABORTIONS I stage - prescribe dalargin appoint for 2 mgs of I/m daily, course 10 days II stage - after one month appoint a poly vitamines immunoprotein for 25 ml of I/v infusoin 3 times in every alternative days. III stage - after one month prescribe timalin 1 ml of I/v daily daily, course 10 days. IV stage - after one month conduct plasmapheresis after one day 3 times. A method provides immune correction which is correction, instrumental in the leadingout of herpesvirus from an organism with the subsequent maturing foetus.
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IMMUNOLOGY OF INFERTILITY Marriage which remains childless after 2 years of sexual life without using contraceptives is considered as Infertile marriage. A main place among reasons of infertility is occupied by inflammatory processes in genitalia and their consequences (more than 75 %) caused specific processes - b t i ( th %), d ifi bacteria (gonorrhoea, khlamidioz, micoplasmose, gardnereliose), viruses (herpes, cytomegaly), the simplest (trichomanase), rarer - by a non specific flora (collibacillus, streptococcus or staphylococcus). Immunological infertility: matrimonial pair at which even antispermal antibodies come to light at one of partners. 10 20% violations of reprocuctive function can be explained i l ti f ti f ti b l i d immune mechanisms.
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STATES, FORMING In ORGANISM of MAN ANTISPERM ANTIBODIES 1. Traumas of testicle, scrotum, varikocele (expansion of veins, circumferential a seminal rope). 2. Cryptorchidism; 3. Infections (chlamedi, micoplasms, herpesviruss and papillomavirusa), papillomavirusa) 4. Oncological pathologies. 5. blocage of sperm conductive ways. 6. Operations on an abdominal region. 7. Heavy infections of abdominal region, which the trauma of seminal veins can happen at. 8. Vibration (bicycle, motor cycle).

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LEVELS" OF IMMUNE SYSTEM, WHICH ANTISPERM ANTIBODY ARE TAKEN PLACE 1. Antibodies from a whey can get to sperm and cover the surface of spermatozoa, that complicates their contact with spermatozoa an ovule. 2. 2 Local humoral immunity through the antibodies of IgA, IgA which can be on-the-spot collecting ductus, in an urethra, in sperm, not getting to circulation of blood. The exposure of p , g g p antispermatozoydal antibodies must include: 1). antibodies, coverings the surface of spermatozoids, 2). free antibodies in a whey and in a spermal liquid.

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DetectiontestforAntisperm Ab DetectiontestforAntisperm
SpermMAR test Indirect Immunobead Test, , IBT( IBT(400)

(WHO

2208 ; Normal<10%) (WHO 2008 ; Normal<20%)

Ig G, Ig I G I A >> I M Ig

Antisperm Antibody
Infertility ith ti I f tilit with antisperm antibody tib d
Corticosteroid or immunosuppression After 3month

Antisperm antibody and semen analysis p y y Improvement* WHO: prednisolone 6~50% cyclosporine c closporine 33% Sperm washing, IUI or ICSI No improvement*

*; Combined empirical medical therapy

Antisperm Antibody
Corticosteroid prednisolone 60~90mg/day in 5~7day 5 7day prednisolone 20mg p.o. week 1~3 or 10mg p o week 4 p.o. prednisolone 5mg/day in 6 months

Immunosuppression

cyclosporine 5~10mg/day in 6 months

IMMUNOLOGICAL REASONS OF WOMEN'S INFERTILITY 1) second immunodeficit; ) 2) antigamate (antiovarian) immune conflict; 3) antigamate (antispermal) immune conflict; ) g ( p ) ; 4) high level of histocompatability between the married couples. The last 2 states are reasons of the so-called infertility of the married couples. It means that both man and woman potentially fertile and can have children with other partners, but they are childless exactly in combination in a such family pair. tl i bi ti i h f il i The second immunodeficit results in impossibility of conception and to the repeated abortions on the first months of pregnancy. It is accompanied the inflammatory processes of genitalia (salpingooforites in women and prostatitis for men) and endocrine disorders. 56

Immune Infertility
The developing embryo may be miscarried due to the mothers immune system recognizing it as a foreign body and attacking it. Also, the woman may p y produce anti-sperm antibodies p (ASA) to her partners sperm. ASA neutralize sperm by clumping them together p y p g g and destroying their membranes. They also coat over receptors involved in sperm egg sperm-egg binding and fertilization. An estimated 12 to 15 percent of unexplained infertility in women is linked to ASA.

CORRECTION OF SECOND IMMUNODEFICITE IN TREATMENT OF INFERTILITY 1) t treatment of i fl t t f inflammatory and endocrine disorders; t d d i di d 2) enterosorbentS and enzymes (vobenzim, flogenzim, ekstranaze optimize the action of antibacterial and antiviral facilities, warn p , formation of joints). Sorbents apply 7-10 days, enzymes 4-6 weeks; 3) biogenic stimulyators(plazmol, aloe) and herbal immunomodulyatory (ekhinaceya, ginseng); (ekhinaceya 4) Methyluracilum, nuclenate sodium, polyoxidal increases the synthesis of immunoproteins; 5) immunization of gono-, trikho- or autovaccines; 6) immunotropic drugs in accordance with the type of immunodeficit; 7) immunorehabilitation - physical therapy procedures (laser or magnet-therapy); 8) for the improvement of regulator connections between the immune and endocrine systems, prescribes epitalamin vitamin E; 9) the repeated immulogical investigation is conducted in 6 8 6-8 weeks after completion of immunocorrection.
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RHESUS-CONFLICT A rhesus-conflict - It is reason of gemolitic disease of newborn. Characterized a presence of foetus of Rh (D) of antigen (foetus Rh +) and absence of it in mother (mother of Rh -). A ) Appearing h i here i th organism of mother of I G in the i f th f IgG antibodies to Rh can penetrate through a placenta and cause destruction of red blood cells of foetus. Pregnancy of rhesus-negative mother Rh (-) to the rhesus p positive foetus of Rh (+) is the most frequent reason of ( ) q forming atierythrocyte antibodies . A method of investigation of antirhesus IgG is an indirect test of Kumbsa. I stage. The whey of blood of patient, containing IgG are antibodies to Rh, co-operates with an antigen-diagnosticum without visible di l ith t i ibl displays. II stage. An antiglobuline whey, which co-operates with antibodies to Rh adsorbed on an antigen diagnosticum is Rh, antigen-diagnosticum, brought in, with appearance of visible sediment. 59

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Tumor Immunology Processing and presentation of antigens 1. MHC class I: peptides to CD8+ T cells 2. MHC class II: peptides to CD4+ T cells 3. CD1d: glycolipids to NK T cells Recognition of tumors 1. Humoral Immunity: B cells 2. Cellular Immunity: T cells and NK T cells 3. Tumor antigens Tumor killing 1. Non-specific: NK cells, T cells (NKG2D), macrophages, NK T cells 2. Antigen-specific: 2 Antigen specific: Antibody (ADCC opsinization); T cells (ADCC, (cytokines, Fas-L, perforin/granzyme) 66

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Autoimmune diseases classified by mechanism of tissue damage

Systemic autoimmune diseases

SLE Dermatomyositis y Sklerodermia Sjgrens syndrome j g y Vasculitis Rheumatoid arthritis MCTD mixed connective tissue disease Antiphospholipide syndrom p p p y Sarcoidosis

SLE
Amultisystemdiseasecharacterisedby autoantibodiesdirectedagainstnuclearcomponents Incidence1:4000 Complexmultifactorialetiology Relapsingandremitting Clinicalandserologicaldiversity

SLE
AmericanCollegeofRheumatologycriteria(4/11) i ll f h l i i ( / ) Arthralgia Oralulcers Oral ulcers Serositis Malarrash M l h Discoidrash Photosensitivity Neurologicalabn Haematologicalabn Haematological abn Renaldisease Antinuclearfactor A i l f Immunologicalabn

Clinical features of SLE

Autoantibodies in SLE ANA(prevalence~100%) anti dsDNA (prevalence 40 90% levels fluctuate anti dsDNA(prevalence4090%,levelsfluctuate
withdiseaseactivity)

ENA(anti Sm) antoantibodies against blood cells antoantibodiesagainstbloodcells

Sjgren Sjgrens syndrom

Siccasyndrom drynessofeyes,nose,mouth,
airways,vagina,skin

polyarthralgia p y g

autoantibodies: ENA - SS-A SS A - SS-B risk of AV block in newborns

Dermatomyositis
proximal muscle weakness i l l k arthralgia, arthritis, dyspnea, dysphagia,arrhythmia, and dysphonia paraneoplastic manifestation: breast ca, ca GIT, lung ca

autoantibodies: ENA Jo1, , PM/Slc

Systemic sclerosis
Systemic connective tissue disease Essential vasomotor disturbances; fibrosis; subsequent atrophy of the skin, subcutaneous tissue, muscles, and internal organs Raynauds phenomenon Major features include centrally located skin sclerosis that affects the arms, face, and/or neck. Minor features include sclerodactyly, erosions, y y, , atrophia of the fingertips, and bilateral lung fibrosis. g p j SSc is diagnosed when a patient has 1 major and 2 minor criteria.

Systemic sclerosis
autoantibodies: ANA ENA (anti-topoisomerase I - Scl-70) anti-centromerase (ACA) i

Antiphospholipid syndrome
excessive clotting of blood and/or certain i l tti f bl d d/ t i complications of pregnancy trombosis abortus presence of antiphospholipid antibodies (cardiolipin - ACLA or lupus anticoagulant antibodies) prolonged APTT in over half of patients with SLE

Vasculitis
Largevessel Medium and smallvessel Smallvessel Takayasu Giant cell (temporal) arteriitis Polyarteritis nodosa Churg-Strauss arteritis Kawasaki disease H Henoch-Schnlein purpura h S h l i Wegeners granulomatosis

IKdeposits autoantibodies:ANCA

Autoimmune systemic diseases - characteristic autoantibodies

SLE Rheumatoid arthritis Dermato/polymyositis Sjgrens syndrome Sklerodermia MCTD Antiphospholip. Antiphospholip syndrome Vasculitides ANA, ANA dsDNA RF ENA Jo-1 ENA SS-A, SS-B ENA Scl 70 ENA RNP anti-phospholipides anti phospholipides ANCA

Organ-specific autoimmune diseases

Endocrine system Autoimmune (Hasimotos) thyroiditis Hyperthyroidism (Graves disease; thyrotoxicosis) Type I diabetes mellitus (insulindependent or juvenile diabetes) Insulin-resistant diabetes Autoimmune adrenal insufficiency (Addisons disease) Autoimmune oophritis

Neuromuscular system y Myasthenia gravis Autoimmune polyneuritis Multiple sclerosis Experimental allergic encephalomyelitis

Skin Pemphigus and other bullous diseases Cardiopulmonary System Rheumatic carditis Goodpastures syndrome p y Postcardiotomy syndrome (Dresslers syndrome)

Hematopoietic system Autoimmune haemolytic anemia Paroxysmal cold hemoglobinuria Autoimmune thrombocytopenia Autoimmune neutropenia Pernicious anemia Pure red cell anemia

Autoimmunediseasesofthyreoid Autoimmune diseases of thyreoid

1. Hashimotos thyreoiditis Hashimoto sthyreoiditis hypofunctionofthyreoid autoantibodies against thyreoglobulin autoantibodiesagainstthyreoglobulin andmicrosomesofthyreocytes

2. GravesBasedowsdisease hyperfunction of thyreoid, hyperfunctionofthyreoid, thyreotoxicosis autoantibodiesagainstTSHreceptor g p

Type 1 diabetes (T1D)

Also known as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes Organ-specific autoimmune disorder (pancreatic islets) Hyperglycaemia results from: H l i lt f - specific auto-destruction of insulin-secreting b-cells in the islets of Langerhans in the pancreas - autoantibodies agaist GAD65 Etiology and pathogenesis of autoimmune diabetes largely unknown

Summary: natural history of T1D y y

Putative environmental trigger Cellular (T-cell) autoimmunity Humoral antibodies Loss of first phase insulin response -cell mas ss Glucose intolerance

Genetic predisposition

-insulitis cell injury Prediabetes

Clinical onset

Diabetes Time

Localized autoimmune diseases with systemic autoantibodies

IBD:Crohndisease ulcerativecolitis ulcerative colitis celiacdisease autoimmunehepatitis primarybiliarycirrhosis primary biliary cirrhosis

Localized autoimmune diseases with systemic autoantibodies

C li di Celiacdisease
recurringabdominalbloatingandpain chronicdiarrhea/constipation failuretothriveininfants/lossofweight fatigue unexplainedanemia dermatitisherpetiformisDuhring p g

autoantibodies:antiendomysial(EMA)IgA antitissuetransglutaminase(aTG)

IBD inflammatory bowel diseases

Ulcerativecolitis
abdominalpain diarrhea rectalbleeding rectal bleeding affectionofcolon
discontinualaffectionofGIT autoantibodies:ASCA autoantibodies: ASCA Saccharomycescerevisiae

Crohndisease C h di
abdominalpain,ofteninthelower p , rightarea, chronicdiarrhea weightloss,arthritis,skinproblems, g , , p , andfever rectalbleeding

autoantibodies:ANCA

Therapy of autoimmune diseases

corticosteroids complex.action, cytokin inhibition inhib .DNA synthesis Prednison metylprednisolon cyclofosfamid azathioprin methotrexate th t t mykofenolate CyA, tacrolimus, rapamycin

antiproliferative

inhibitors inhib. of cytokines of immunophilins iv.Ig immunoglobulins complex, antiidiotypes

IVIG

Ab against T ly. inhib. depletion

ATG, anti CD3

Therapy
Antigen-specific
systemic aplication of Ag Copaxone Ag po. g/d T lymfocytes

insuline
experimental aproaches modified Ag gene therapy

Antigen non specific treatment

Cytokine mediated treatment TNFalpha infliximab, etanercept antiinflammatory cytokines Il-10 IL-1 IFN beta others blocade of adhesion molecules blocade of costimulatory signals

Bone marrow transplantation

Stem cell transplantation ALPS rheumatoid artiritis, systemic scleroderma, multiple sclerosis allogenic (mortality risk) or autologous (risk of relaps)