Clin Immunology Lecture 3

Bases of transplantation immunity.Immunology of reproduction.

Immunology of tumorsImmunology of tumors.Clinical and immunological aspects of 

autoimmun diseases.

Lecturer: professor, DM V. Babadzhan. 

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1933: Yu Yu Voronoy of the Soviet Union performed the first human to human kidney transplant

History

the first human-to-human kidney transplant1954: Joseph E. Murray performed the first successful kidney transplant Donor and recipient id ti l t iidentical twinsEarly attempts at immunosuppression -Whole-body X-irradiation-Nitrogen mustard-6-mercaptopurineThe main hystocompartable complex was opened y p p pin 1952 1957: George Hitchings and Gertrude Elion modify 6-MP to produce azathioprine6 MP to produce azathioprine1963: Thomas Starzl observed that large doses of corticosteroids can reverse rejection episodes andstabilize allograft functionstabilize allograft function.Chistian Barnard (REPUBLIC OF SOUTH AFRICA) in 1967 made 2 transplantations of heart. The first

ti t li d 17 d di d f i d

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patient lived 17 days, died of pneumonia and reaction of tearing. Another patient lived after the operation two years.

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Blood Type CompatibilityBlood Type Compatibility

Recipient Blood Type Compatible DonorsRecipient Blood Type Compatible Donors

O O

B B or O

A A or O

AB A, B, AB or O

ESTIMATION OF COMPATIBILITY OF THE DONOR AND RECIPIENT BY HLA ANTIGENSRECIPIENT BY HLA ANTIGENS

1. Typing of HLA antigens (lymphocytotoxic test): 1) Probed lymphocytes add to serum against HLA ) y p y gantigens; 2) after incubation add complement; 3) lymphocytes, bearings an antigen which serum is directed against, under the action of complement

llcollapse; 4) Dye adds to lymphocytes which paints living cells onlyonly. Result is estimated by the number of lost lymphocytes. Positive result testifies that lymphocytes carry thePositive result testifies that lymphocytes carry the probed HLA antigen.

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2. The genetic typing is decoding of nucleotidesequence of HLA genes and exposure of distinctionsbetween different alleles of these genes; utilize fortyping of genes of MHC class II.

3. Reaction of mixed culture of lymphocytes - if thedonor and recipient carry the different antigens ofdonor and recipient carry the different antigens ofMHC class II in the mixed culture of lymphocytes,consisting of donor’s and recipient’s lymphocytes,consisting of donor s and recipient s lymphocytes,proliferation of T-lymphocytes begins after recognitionof foreign antigen.g g

4. Reaction of cellular cytotoxity - in cultivation ofi i t l h t d diff t f th b threcipient lymphocytes and different from them by the

antigens of MHC class II cells of donor cytotoxic T-lymphocytes appear among the cells of recipientlymphocytes appear among the cells of recipient.

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Open NephrectomyOpen Nephrectomy

Laproscopic NephrectomyLaproscopic Nephrectomy

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Hyperacute rejection occurs within hours oftransplantation. Pre-existing antibodies bindthe vasculature of the graft, inducing clottingg g gand occlusion of the vessels

Is mediated byf d tib dipreformed antibodies

that recognize HLAantigens in donor organ.U ll th f dUsually these are formedas a consequence ofblood transfusion,pregnancy, prior organtransplantation,autoimmune diseases.Fibrinoid necrosis leadto immediate graft loss.Delayed form may occurseveral days followingtransplantation.Plasmapheresis and

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pulse steroid may beused.

Acute graft rejection occurs 1-2 weeks following transplantationas 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 injuryassociated with inflammatory injury

Manifest clinically by a slow and gradualManifest clinically by a slow and gradualdecline in renal function, usually more than 6mon after transplant and typically

i d b d t t haccompanied by moderate to heavyproteinuria.Histologically, characterized by glomerulo-

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sclerosis, interstitial fibrosis, andobliteration of arteriolar lumina.Treatment is unsatisfactory.

Pretransplant evaluationPhysical examChest x-rayComplete medical and surgical historyyElectrocardiogramUltrasound with Doppler examinationexaminationBlood testsPulmonary function testViral testing - hepatitis CMVViral testing - hepatitis, CMV, EBV, HIV

Pretransplant evaluationPretransplant evaluationHistocompatibilityLaboratory TestsBlood TypingTissue TypingCrossmatch Testing

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Panel ReactiveAntibody (PRA)

Clinical signs: Banff criteriaDiagnosis of rejection

Clinical signs:MalaiseFever

Banff criteriaInterpretation of renal biopsyspecimens for diagnosing

j tiOliguriaHypertensionGraft tenderness

rejectionhave been greatly facilitated andStandardizedGraft tenderness

Diagnosis hinges on serialti i t

Based on scores for glomerular,vascular, interstitial, and tubularLesionscreatinine measurements

Elevation of 20% over baselinetriggers further evaluation

LesionsHas been shown to have clinicalrelevance when predictinggg

Rule out non-immunologic causesUlt h

p grejection reversal and may proveuseful for choosing first-linetherapy of rejection episodesUltrasonography

Renal scanningPercutaneous biopsy

therapy of rejection episodes

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Percutaneous biopsy

RejectionRejection

• Sonographic Manifestations– Increased allograft sizeg

– Increased cortical echogenicity

Increased prominence of renal pyramids– Increased prominence of renal pyramids

– Focal cortical hypoechoic regions

– Decreased echogenicity of renal sinus

– Increased flow resistance in parenchymal arteriesp y

RejectionRejection

Acute Chronic

Grade 1: Moderate interstitial mononuclear inflammation affecting g25-50% of the sampled parenchyma

Grade 2: Moderate interstitial l i filt tmononuclear infiltrate

involving 26-50% of the renal parenchyma

Grade 3: severe t l t ititransmural arteritis and/or transmural fibrinoid change and

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necrosis of smooth muscle cells

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Elimination of Preformed AntibodyElimination of Preformed AntibodyElimination of Preformed AntibodyElimination of Preformed Antibody• Plasma exchange is the mostPlasma exchange is the most

commonly used modality for rapid elimination of preformed antibodyelimination of preformed antibody

• Length and frequency of plasma exchange depend on:exchange depend on:– Antibody titers– Antibody specificity

IVIg: Inhibition of Circulating Antibody IVIg: Inhibition of Circulating Antibody g g yg g yand Complement Activationand Complement Activation

• Polyclonal immune globulins derived from pooled human plasma of 50,000-100,000 p p , ,or more screened donors.

• >90% intact IgG F (ab’) fragments and• >90% intact IgG, F (ab )2 fragments and traces of IgM and IgA.

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Suppression of the TSuppression of the T--cellcellSuppression of the TSuppression of the T cell cell ResponseResponse

• Induction Therapy:Induction Therapy: – Depleting Vs Non-depleting antibodies

Maintenance immunosuppression• Maintenance immunosuppression

Rituximab: BRituximab: B cell Depletioncell DepletionRituximab: BRituximab: B--cell Depletioncell Depletion

• Genetically engineered chimeric murine/human monoclonal antibody– Variable light- and heavy-

chain regions from murinechain regions from murine anti-CD20 antibody IDEC-2B8H I Gk t t– Human IgGk constant regions

• First monoclonalFirst monoclonal antibody to be approved by the FDA for treatment

fof cancer

T i l R f 3 12 h f l i• Triple Rx for 3‐12 months after transplantation followed by withdrawal of 1 of the 3 drugs to minimise long term side effects (most commonlyminimise long term side effects (most commonly withdrawn drug is corticosteroid).

• Antilymphocyte Abs are also widely used in the pts• Antilymphocyte Abs are also widely used in the pts (polyclonal & monoclonal Abs are available).

• The initial Rx of rejection involves the administration of IVI corticosteroids (methylpred 250‐1000mg daily for 3/7 or dexamethasone 100mg daily for 3/7)dexamethasone 100mg daily for 3/7).

UW Highly Sensitized ProtocolUW Highly Sensitized ProtocolUW Highly Sensitized Protocol UW Highly Sensitized Protocol (Deceased Donor(Deceased Donor))

•• PrePre--Transplant Protocol:Transplant Protocol:PrePre Transplant Protocol:Transplant Protocol:–– In vitro IVIg induced inhibition of PRAIn vitro IVIg induced inhibition of PRA

IVI (2 /K / h 6)IVI (2 /K / h 6)–– IVIg (2g/Kg/month x 6)IVIg (2g/Kg/month x 6)–– Rituximab 375 mg/mRituximab 375 mg/m2 2 BSA x 2BSA x 2gg–– Monitoring of PRA Class I and Class II Monitoring of PRA Class I and Class II

by Luminexby Luminex® ® while on treatmentwhile on treatmentby Luminexby Luminex while on treatmentwhile on treatment

UW Positive CrossmatchUW Positive CrossmatchUW Positive Crossmatch UW Positive Crossmatch Protocol (Living Donor)Protocol (Living Donor)

•• Protocol:Protocol:–– PrePre-- and Postand Post--transplant plasmapheresistransplant plasmapheresis–– PrePre-- and Postand Post--transplant IVIg (100 mg/Kg)transplant IVIg (100 mg/Kg)p g ( g g)p g ( g g)–– Tacrolimus (PrografTacrolimus (Prograf®®) and MPA (Cellcept) and MPA (Cellcept® ®

/Myfortic/Myfortic®®) 2 weeks before transplantation) 2 weeks before transplantationyy ) p) p–– IV ATG 1.5 mg/kg and IV steroids preIV ATG 1.5 mg/kg and IV steroids pre--

operativelyoperativelyp yp y–– Maintenance immunosuppression:Maintenance immunosuppression:

•• Tacrolimus+MPA+steroidsTacrolimus+MPA+steroids

IMMUNOLOGY OF REPRODUCTIONForming of reproductive immunity of men comes in the period of

pubescence when masculine gametes begin to be producedpubescence, when masculine gametes begin to be 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. Gemato-testicular a barrier consists of three layers: endothelium of capillaries,boundary shell (basal membrane) and muscle cells.

2. Active immunological tolerance is provided by immunoregulatorymechanisms into testicles steroidy macrophages suppressor cells preventmechanisms into testicles steroidy, macrophages, suppressor cells preventactivating of immunological recognition.. Carried out by the Sertoli cells,which is characteristic by: fagocitarnaya activity; products of suppressorfactors which repress proliferation of lymphocytes; induction of apoptosis offactors which repress proliferation of lymphocytes; induction of apoptosis ofactivated lymphocytes.

3. The peripheral immunomodulation of testicles prevents the products ofti tib di i th d ti t f b th f ll iantisperm antibodies in the reproductive system of man by the followings

mechanisms:- activating of the T-suppressor-cell in an epididymis(appendage of testicle)- immunosuppressive activity of seminal liquid (a

t i l t d i d t d i t i l ti f t fcomponent is selected in sperm, adopted «immunoprotein relating factor» ofImmunoglobulin binding factor - IBF, which reduces activating of V-lymphocytes and represses activity of T-helpers. 42

ANTIGENS OF SPERMATOZOA WHICH REACTSANTIGENS 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);shell);- nuclear - histon, protamin (stabilize the structure of nucleosomas the generations of antibodies promote); tailednucleosomas, the generations of antibodies promote); - tailed - akson, protene fibres, rings (provide motive activity to spermatozoon).spermatozoon).

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There are two transplants in the organism of pregnant woman:fetus and trofoblast The immune answer of mother can befetus and trofoblast. The immune answer of mother can bedirected against each of them. As far as antigen is concern, foetusis 50% stranger for a mother, and that is why in her organism thereare certain changes which provide formation of temporarytolerance.

FUNCTIONS OF TROPHOBLAST

1. Barrier function between the immune system of mother andf t Hl ti i b t i it hi h ld h bfoetus. Hla-antigeni absent in it, which would have beenrecognized by the immune system of mother or foetus.

2 C ti d i ti ti f ti f f t b th2. Connection and inactivation of antigens of foetus by theblocking antibodies of mother.

3 Decreasing lymphocyte’s activity which get in trophoblast3. Decreasing lymphocyte’s activity , which get in 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 represseswork of the immune system of mother.

2. Progesteron possesses immunosupressivnymi properties.

3. Decidual border of uterus,in which a blastocyst is implanted ,3. Decidual border of uterus,in which a blastocyst is implanted ,warns the immunological tearing away of foetus.

4. A placenta absorbs and takes in antibody from the mother'sp ace ta abso bs a d ta es a t body o t e ot e sorganism to the HLA-antigens of the foetus.

5. A decline synthesis of a 1 type T-helpers is FNO-alpha, Il-2,y yp p p , ,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 alsostimulate a cell growth trofoblast and proliferation of cells ofstimulate a cell growth trofoblast and proliferation of cells ofplacenta.

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FACTORS ABLE TO ACTIVATE MOTHER’S IMMUNE SYSTEMFACTORS, ABLE TO ACTIVATE MOTHER’S IMMUNE SYSTEM- endometrial infections on the early period of pregnancy are i t t l i ti ti f T h l f 1 t d " t t"instrumental in activating of T-helpers of a 1 type and "start" the cellular factors of aggression to the fetus;

di l b ti i i k ft it lf- medical abortions in anamnesis keeps after itselfinflammatory immunological and hormonal changes. Duringnext pregnancy the mechanisms of immunological memorynext pregnancy the mechanisms of immunological memoryare provided by including of those factors and tearing awayof fetus.- fetal infection, even on condition of its subclinical flow, isfrequent reason of sudden abortions on a backgroundq gclinically “normal" flow of pregnancy.

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MECHANISMS OF INFERTILITY AT THE CLOSELY-RELATED MARRIAGES

Antibodies to the foreign HLA-antigens of foetus arefixed on a placenta, that stimulates in it blood circulationand forms its valuable growth.

These immune complexes on a placenta are blackoutd t t f t f t ti f i f t fand protect foetus from penetration of immune factors of

mother in the foetus.If the married couples are identical on HLA antigensIf the married couples are identical on HLA-antigens

(homozygotes), the immune system of mother does notrecognize the antigens of foetus and does not form therecognize the antigens of foetus and does not form theblackout factors of immune answer.

Absence of sensitivity of organism of mother to they gfoetus results in week growth of placenta, its tearing awayand abortion.

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TREATMENT OF SPONTANEOUS IMMUNOLOGICAL ABORTIONSABORTIONS

Immunization of woman the lymphatic cells of husband (enter100 l h t )100 lyphocytes).Treatment is conducted before an impregnation, in the

f f d l f ffi i iprocess of pregnancy for development of sufficient immune-supressive potential and at appearance of the firstappearence of threat of breaking pregnancyappearence of threat of breaking pregnancy.Immunization of woman with allogenic lymphocytes providesmoderate sensitivity of its organism and trofoblast On themoderate sensitivity of its organism and trofoblast. On thebackground of moderate previous sensitivity, immunologicaltolerance 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 dayscourse 10 daysII stage - after one month appoint a poly vitamines immunoprotein for 25 ml of I/v infusoin 3 times in everyimmunoprotein 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 dailyIII stage - after one month prescribe timalin 1 ml of I/v daily, course 10 days.IV stage after one month conduct plasmapheresis afterIV stage - after one month conduct plasmapheresis after one day 3 times.A method provides immune correction which isA method provides immune correction, which isinstrumental in the leadingout of herpesvirus from anorganism with the subsequent maturing foetus.organism with the subsequent maturing foetus.

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IMMUNOLOGY OF INFERTILITYMarriage which remains childless after 2 years of sexualMarriage 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 ( th 75 %) d ifi b t i(more than 75 %), caused specific processes - bacteria (gonorrhoea, khlamidioz, micoplasmose, gardnereliose), viruses (herpes, cytomegaly), the simplest (trichomanase),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% i l ti f ti f ti b l i d20% violations of reprocuctive function can be explained immune mechanisms.

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STATES, FORMING In ORGANISM of MAN ANTISPERM ANTIBODIESANTIBODIES

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.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 PLACEANTIBODY ARE TAKEN PLACE

1. Antibodies from a whey can get to sperm and cover the surface of spermatozoa that complicates their contact withsurface of spermatozoa, that complicates their contact with an ovule. 2 Local humoral immunity through the antibodies of IgA2. Local humoral immunity — through the antibodies of 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 pantispermatozoydal antibodies must include: 1). antibodies, coverings the surface of spermatozoids,1). antibodies, coverings the surface of spermatozoids, 2). free antibodies in a whey and in a spermal liquid.

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Detection test for Detection test for AntispermAntisperm AbAb

SpermMAR testIndirect Indirect ImmunobeadImmunobead Test, Test, ,,IBT(IBT(××400)400)

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

II GG II A >>A >> II MM

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

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

IgIg G, G, IgIg A >> A >> IgIg MM

AntispermAntisperm AntibodyAntibodyAntispermAntisperm AntibodyAntibody

I f tilit ithI f tilit ith titi tib dtib dInfertility with Infertility with antispermantisperm antibodyantibody

Corticosteroid orCorticosteroid or immunosuppressionimmunosuppressionCorticosteroid or Corticosteroid or immunosuppressionimmunosuppressionAfter 3monthAfter 3month

AntispermAntisperm antibody and semen analysisantibody and semen analysispp y yy y

ImprovementImprovement** No improvementNo improvement**

Sperm washing, IUI or ICSISperm washing, IUI or ICSI

WHO:

prednisolone 6~50% c closporine 33%cyclosporine 33%

**;; Combined empirical medical therapy

AntispermAntisperm AntibodyAntibodyCorticosteroid prednisolone 60~90mg/day in

5~7day5 7dayprednisolone 20mg p.o. week 1~3 or

10mg p o week 410mg p.o. week 4prednisolone 5mg/day in 6 months

Immunosuppression cyclosporine 5~10mg/day in 6 months

IMMUNOLOGICAL REASONS OF WOMEN'S INFERTILITY1) 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

tl i bi ti i h f il iexactly in combination in a such family pair.

The second immunodeficit results in impossibility ofconception and to the repeated abortions on the firstmonths of pregnancy. It is accompanied the inflammatoryprocesses of genitalia (salpingooforites in women andprocesses of genitalia (salpingooforites in women andprostatitis for men) and endocrine disorders. 56

Immune Infertility• The developing embryo may be miscarried due to

the mother’s immune system recognizing it as a “foreign body” and attacking it.

• Also, the woman may produce anti-sperm antibodies y p p(ASA) to her partner’s sperm.

• ASA neutralize sperm by clumping them together p y p g gand destroying their membranes.

• They also coat over receptors involved in sperm-eggThey also coat over receptors involved in sperm egg binding and fertilization.

• An estimated 12 to 15 percent of unexplainedAn estimated 12 to 15 percent of unexplained infertility in women is linked to ASA.

CORRECTION OF SECOND IMMUNODEFICITE IN TREATMENT OF INFERTILITY

1) t t t f i fl t d d i di d1) treatment of inflammatory and endocrine disorders; 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);immunomodulyatory (ekhinaceya, ginseng);

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;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 6-89) the repeated immulogical investigation is conducted in 6 8

weeks after completion of immunocorrection.58

RHESUS-CONFLICTA rhesus-conflict - It is reason of gemolitic disease of new-born. Characterized a presence of foetus of Rh (D) ofantigen (foetus Rh +) and absence of it in mother (mother ofRh ) A i h i th i f th f I GRh -). Appearing here in the organism of mother of IgG –antibodies to Rh can penetrate through a placenta andcause destruction of red blood cells of foetus.cause destruction of red blood cells of foetus.Pregnancy of rhesus-negative mother Rh (-) to the rhesuspositive foetus of Rh (+) is the most frequent reason ofp ( ) qforming atierythrocyte antibodies . A method of investigationof antirhesus IgG is an indirect test of Kumbsa.I stage. The whey of blood of patient, containing IgG areantibodies to Rh, co-operates with an antigen-diagnosticum

ith t i ibl di lwithout visible displays.II stage. An antiglobuline whey, which co-operates withantibodies to Rh adsorbed on an antigen diagnosticum isantibodies to Rh, adsorbed on an antigen-diagnosticum, isbrought in, with appearance of visible sediment.

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Tumor Immunology• Processing and presentation of Processing and presentation ofantigens1. MHC class I: peptides to CD8+ T cells2. MHC class II: peptides to CD4+ T cells3. CD1d: glycolipids to NK T cells• Recognition of tumors• Recognition of tumors1. Humoral Immunity: B cells2. Cellular Immunity: T cells and NK T cells2. Cellular Immunity: T cells and NK T cells3. Tumor antigens• Tumor killing1. Non-specific: NK cells, γδ T cells (NKG2D), macrophages,NK T cells2 Antigen specific: Antibody (ADCC opsinization); T cells

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2. Antigen-specific: Antibody (ADCC, opsinization); T cells(cytokines, Fas-L, perforin/granzyme)

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Autoimmune diseases classified by mechanism of tissue damagedamage

Systemic autoimmune diseases• SLE• Dermatomyositisy• Sklerodermia• Sjögren´s syndromej g y• Vasculitis• Rheumatoid arthritis• MCTD – mixed connective tissue disease• Antiphospholipide syndromp p p y• Sarcoidosis

SLESLE• “ A multisystem disease characterised by 

autoantibodies directed against nuclear components”

• Incidence 1:4000

• Complex multifactorial etiology

• Relapsing and remitting

• Clinical and serological diversity

SLESLEi ll f h l i i ( / )American College of Rheumatology criteria (4/11)

Arthralgia Neurological abn

Oral ulcers Haematological abnOral ulcers Haematological abn

Serositis Renal disease

M l h A i l fMalar rash Anti‐nuclear factor

Discoid rash Immunological abn

Photosensitivity

Clinical features of SLE

Autoantibodies in SLE• ANA (prevalence ~ 100%)

• anti dsDNA (prevalence 40 90% levels fluctuate• anti – dsDNA (prevalence 40‐90%, levels fluctuate with disease activity)

• ENA (anti – Sm)

• antoantibodies against blood cellsantoantibodies against  blood cells 

SjögrenSjögren´́s syndroms syndromSjögrenSjögren s syndroms syndrom• Sicca syndrom – dryness of eyes, nose, mouth,   

airways, vagina, skin

• polyarthralgiap y g

• autoantibodies: ENA - SS-Aautoantibodies: ENA SS A- SS-B

risk of AV block in newborns

Dermatomyositisi l l k• proximal muscle weakness

• arthralgia, arthritis, dyspnea, dysphagia,arrhythmia, and dysphoniadysphonia• paraneoplastic manifestation: breast ca, ca GIT, lung ca

• autoantibodies: ENA – Jo1,,PM/Slc

Systemic sclerosisSystemic sclerosis• Systemic connective tissue disease• Essential vasomotor disturbances; fibrosis;• Essential vasomotor disturbances; fibrosis;

subsequent atrophy of the skin, subcutaneous tissue, muscles, and internal organsmuscles, and internal organs

• Raynaud´s phenomenon• Major features include centrally located skin sclerosisMajor 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.• SSc is diagnosed when a patient has 1 major and 2 g p j

minor criteria.

Systemic sclerosis• autoantibodies: ANA

ENA (anti-topoisomerase I - Scl-70)i (ACA)anti-centromerase (ACA)

Antiphospholipid syndrome

i l tti f bl d d/ t i• excessive clotting of blood and/or certain complications of pregnancy

trombosis

abortus

• presence of antiphospholipid antibodies (cardiolipin- ACLA or lupus anticoagulant antibodies)

abortus

- ACLA or lupus anticoagulant antibodies)• prolonged APTT• in over half of patients with SLE• in over half of patients with SLE

Vasculitis• Large vessel • Takayasu

• Giant cell (temporal) arteriitis• Medium and 

small vessel• Polyarteritis nodosa

• Small vessel

• Polyarteritis nodosa • Churg-Strauss arteritis

• Kawasaki diseaseH h S hö l i• IK deposits

• autoantibodies: ANCA

• Henoch-Schönlein purpura • Wegener´s granulomatosis

Autoimmune systemic diseases - characteristic autoantibodies

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

Endocrine system

Organ-specific autoimmune diseasesNeuromuscular systemEndocrine system

Autoimmune (Hasimoto’s) thyroiditisHyperthyroidism (Graves’ disease; thyrotoxicosis)

yMyasthenia gravisAutoimmune polyneuritisMultiple sclerosisthyrotoxicosis)

Type I diabetes mellitus (insulin-dependent or juvenile diabetes)Insulin-resistant diabetes

Multiple sclerosisExperimental allergic

encephalomyelitis

Autoimmune adrenal insufficiency (Addison’s disease)Autoimmune oophritis

SkinPemphigus and other

Hematopoietic system

Pemphigus and other bullous diseases

Cardiopulmonary SystemAutoimmune haemolytic anemia Paroxysmal cold hemoglobinuriaAutoimmune thrombocytopenia

Cardiopulmonary SystemRheumatic carditisGoodpasture’s syndrome

Autoimmune neutropeniaPernicious anemiaPure red cell anemia

p yPostcardiotomy syndrome

(Dressler’s syndrome)

Autoimmune diseases of thyreoidAutoimmune diseases of thyreoid

1. Hashimoto´s thyreoiditis1. Hashimoto s thyreoiditis

‐ hypofunction of thyreoid

‐ autoantibodies against thyreoglobulinautoantibodies against thyreoglobulin and microsomes of thyreocytes

2. Graves‐Basedow´s disease

‐ hyperfunction of thyreoid,hyperfunction of thyreoid, thyreotoxicosis

‐ autoantibodies against TSH receptorg p

Type 1 diabetes (T1D)Also known as

insulin-dependent diabetes mellitus (IDDM) orinsulin-dependent diabetes mellitus (IDDM) orjuvenile-onset diabetes

Organ-specific autoimmune disorder (pancreatic islets)

H l i lt fHyperglycaemia results from:- 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 largelyEtiology and pathogenesis of autoimmune diabetes largely unknown

Summary: natural history of T1DSummary: natural history of T1Dy yy y

Putative environmental triggerPutative environmental triggerCellular (T-cell) autoimmunity

Humoral antibodies

ss

Loss of first phase insulin response

Genetic predisposition β-insulitis

cell injuryβ-ce

ll m

as

Glucose intolerance

‘Prediabetes’

β Clinical onset

Diabetes

Time

Localized autoimmune diseases with systemic autoantibodies

• IBD: Crohn disease

ulcerative colitisulcerative colitis

• celiac disease

• autoimmune hepatitis

• primary biliary cirrhosisprimary biliary cirrhosis

Localized autoimmune diseases with systemic

C li di

autoantibodies

• Celiac disease 

• recurring abdominal bloating and pain • chronic diarrhea/constipation • failure to thrive in infants/loss of weight• fatigue • unexplained anemia• dermatitis herpetiformis Duhringp g

• autoantibodies: anti‐endomysial (EMA) IgAanti‐tissue transglutaminase (aTG)

IBD – inflammatory bowel diseases

C h di• Ulcerative colitis • Crohn disease

• abdominal pain, often in the lower • abdominal pain

• diarrhea

• rectal bleeding

p ,right area, 

• chronic diarrhea• weight loss, arthritis, skin problems, rectal bleeding 

• affection of colon

g , , p ,and fever

• rectal bleeding

• autoantibodies: ANCA

• discontinual affection of GIT

• autoantibodies: ASCA –autoantibodies: ASCA Saccharomyces cerevisiae

Therapy of autoimmune diseasescorticosteroids complex.action, Prednison

cytokin inhibition metylprednisolon

antiproliferative inhib .DNA synthesis cyclofosfamid azathioprin

th t tmethotrexatemykofenolate

inhibitors inhib. of cytokines CyA, tacrolimus, rapamycinof immunophilins

iv.Ig immunoglobulins complex, IVIGantiidiotypes

Ab against T ly. inhib. depletion ATG, anti CD3

TherapyAntigen-specific

– systemic aplication of Ag• Copaxone

– Ag po.g/d T lymfocytes• insulineinsuline

– experimental aproaches• modified Agmodified 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

ALPSrheumatoid artiritis, systemic scleroderma,multiple sclerosismultiple sclerosisallogenic (mortality risk) or autologous (risk of relaps)