KUSMARDILAB. OF IMMUNOPATHOLOGY

DEPT. OF ANATOMICAL PATHOLOGY

FACULTY OF MEDICINE

UNIVERSITY OF INDONESIA

KUSMARDILAB. OF IMMUNOPATHOLOGY

DEPT. OF ANATOMICAL PATHOLOGY

FACULTY OF MEDICINE

UNIVERSITY OF INDONESIA

THE SCOPE OF IMMUNOPATHOLOGY

I. ESSENTIAL IMMUNOLOGY

II. HYPERSENSITIVITY

III. IMMUNODEFICIENCY

IV. AUTOIMMUNE DISEASE

AntigenTISSUES

CELLS --------Tumour

--------Parasitic

--------Fungi

--------Bacteria

--------Virus

--------Molecules-----Protein

-----Carbohydrate

-----Lypoprotein

THE COMPONENT OF THE IMMUNE SYSTEMCELLULAR

LYMPHOCYTES MACROPHAGES

K (NK) CELLS

POLYMORPHS

SOLUBLE HUMORAL IMMUNOGLOBULIN

COMPLEMENT LYMPOKIN

THE ORIGIN OF THE CELLULAR COMPONENT OF THE IMMUNE SYSTEM

STEMCELLS

LYMPHOID

B CELLS

T CELLS

TH

TS

TDTH

TC

MYELOID

MACROPHAGESMONO

HISTI

GRANULOCYTES EO

NET

BA

MAST

THE CHARACTERISTIC OF IMMUNE RESPONSE

1. SELF RECOQNATION

2. SPECIFICITY

3. MEMORY

NATURAL IMMUNITY

IMMUNITY NONSPECIFIC PHYSICAL LYSOZYME

CHEMICAL COMPLEMENT

SPECIFIC INTERFERON

CELLULER POLYMORPS

MO

THE SPECIFIC IMMUNE RESPONSEPRIMARY RESPONSE ANTIGEN DISEASE

(FIRST ATTACK)

IMMUNE SPECIFIC

REACTION IMMUNE

RESPONSE

RECOVERY DESTRUCTION SPECIFIC

OF ANTIGEN IMMUNE STATE

SECONDARY RESPONSE

(SUBSEQUENT CONTACT) ANTIGEN

SPECIFIC MEMORY

AND RECOGNITION

OF ANTIGEN

ALMOST IMMEDIATE RAPID ACTIVATION OF

IMMUNE REACTION IMMUNE RESPONSE

NON DISEASE VERY RAPID

DESTRUCTION SPECIFIC IMMUNE

OF ANTIGEN STATE ENHANCED

APC

Ag

MHC II

APC Ag TH

TH TH

memory

IL-2R

B

Plasma cellIL-2

Tc

BCGF

BCDF

IMMUNE REACTION

1. PRECIPITATION of a soluble Ag

2. AGGLUTINATION of a particulate Ag (e.g. bacteria)

3. ANTITOXIC EFFECT:The Ag/Ab combination neutralised the

toxic activity Toxic

molecule Anti-toxin(Ig)

4. ENHANCEMENT of the nonspecific immune response

a. Phagocytic activity

b. Complement activitation

Phagocytic activity

AgAg Ag Ag

Ag/Ab macrophage Efficient phagocytosis

COMPLEMENT ACTIVATIONActivation-

classical pathway

Ag/Ab

1

2 3 4 5 6 7

8 9

Fc(IgM or Ig G)

Activation-alternate pathway,

endotoxin

Bactericidal effect

Bacterium

Punched out holes in

terget cell membrane RBC

Cytolytic effect

HYPERSENSITIVITY

TYPE I ANAPHYLACTIC/ALLERGY ASMA, RINITIS, URTIKARIA

IgE

TYPE II CYTOTOXIC

RX TRANFUSI, Rh, OBAT IgG, IgM

TIPE III RX KOMPLEKS IMUN

GLOMERULONEFRITIS IgG

TIPE IV TIPE LAMBAT, DELAYED TYPE, CELL

MEDIATED IMMUNITY DERMATITIS KONTAK, TUBERKULIN,

GRANULOMA LIMFOSIT T

Such cross-linking leads to rapid degranulation (60-300 secs) of the mast cells and the release of primary inflammatory mediators stored in the granules. These mediators cause all the normal consequences of an acute inflammatory reaction - increased vascular permeability, smooth muscle contraction, granulocyte chaemotaxis and extravasation etc. Mast cell activation via Fc epsilonRI also leads to the production of two other type of mediators. These secondary mediators, unlike the stored granule contents, must be synthesised de novo and comprise arachadonic acid metabolites (prostaglandins and leukotrienes) and proteins (cytokines and enzymes).

HIPERSENSITIVITAS TIPE I

• IgE = REAGIN, AFINITAS vs MAST & BASOFIL

• IgG4, AFINITAS RENDAH vs MAST & BASOFIL

First exposure Formation

to Ag of Ig E

Second exposure

to Ag

Fixation of IgE to mast cells and basophils by Fc fragment

Degranulation

of mast cell

Release of mediators and

vasoactive subtances

Ag/Ab reaction on surface of mast cell

Type 1 Anaphylaxis, atopy, allergy

Antigens and ‘allergens’

most potent antigen

very large molecules

molecular weights from 15 to 40,000

common allergens : ATS, Penc, Bee venom, etc.

Antibody

IgE

Plasma cells forming Ig E : tonsil, adenoid, bronchi, GI tract, Urinary Bladder.

Mast cells

In the same areas the IgE-producing plasma cells, plus skin, uterus and synovial membranes

Clinical example of type I reaction

Anaphylactic shock Hay Fever Asthma

1st injection of horse serum 1st contact with 1st contact

(ATS), penc bee sting grass pollen horse mite dust

General sensitivition local sensitivition animal dander

conjunctiva and local sensitivition

passage of bronchi

2nd injection 2nd contact 2nd contact

bronchial irritation of Bronchial constriction

constriction conjunctiva difficult breathing

perhaps a skin rash

may be fatal

Ag (cell surface) specific Ab combination produces

Complement Increased phagocytic Increased

activation activity (opsonic effect) “killer”cell

activity

DESTRUCTION OF CELL

Type III- Immune complex (Arthus) type Vasoactive amines Effect on

Ag/Ab Complement (anaphilatoxin) vessel wall

activation Polymorphs

(chemotaxis)

Platelet Thrombosis

aggregation

destruction of renal glomeruli

IgG or IgM

Type IV-Cell-mediated (delayed)

Usually local

Sensitised T cells

Skin reaction to chemical contact dermatitis

IMMUNE DEFICIENCY STATES(1) THE SPESIFIC SYSTEM humoral

cell-mediated

(2) THE NON-SPESIFIC SYSTEM phagosytes

complement

Primary (inhereted) deficiencies

B cell, T cell,

B and T cell deficits associated with recurring infections

Secondary deficiencies

T cell activity

B cell deficit

Malnutrition-

particularly with protein deficiency

Latrogenic effect -

e.g. immunosuppressorrs : cytotoxics

corticosteroids

Infections -

acute viral, chronic bacterial

chronic protozoal, e.g. malaria

Chronic debilitating disease -

e.g. renal failure : diabetes millitus

Malignant disease -

e.g. lymphoma, Hodkin’s disease

IMPAIRED IMMUNITY

INFECTION

often OPPORTUNISTIC

common predisposing conditions

AGAMAGLOBULINEMIA (PENY. BRUTON)X-LINKEDHAMPIR SLL PD PRIABELUM JELAS HINGGA 6 BLN (Ig ibu <<)DEF PRIMER TERBANYAK PRELIMFOSIT B TIDAK BISA MATURE infeksi bakteri sering kambuh faringitis, sinusitis, bronkitis, pneumonia, hepatitis

.limfosit B (-) dlm sirkulasi, prelimfosit B (N) pd sstl

.KGB, tonsil (-/rudimenter)

.Sel plasma (-) dlm sirkulasi

.Limfosit T dan CMI (N)I

The gene Bruton's tyrosine kinase (Btk) plays an essential role in the maturation B cells in the bone marrow, and when mutated, immature pre-B lymphocytes are unable to develop into mature B cells that leave the bone marrow into the blood stream.

SINDROME DiGEORGE, HIPOPLASIA TIMUS

KANTONG FARING III & IV (-) TIMUS & PARATIROID (-)

TIMUS (-/RUDIMENTER) LIMFOSIT T(-/ )

INFEKSI JAMUR, VIRUS,BAKTERI

PARATIROID (-) HIPOKALSEMIA TETANI

TANSPLANTASI TIMUS

IMMUNE DEFICIENCY STATES-AIDS

Infection Latent stages Stages of opportunistic

No initial (months-years) infection and tumours

symptoms (1-2 years)

Virus present in Infection opportunistic

limphoncytes others

- no signs malignant Kaposi’s

- persistent limph tumours sarcoma

node enlargement lymphomas

Simplified Life Cycle of the Human Immunodeficiency Virus

AIDS - ASSOCIATED DISEASE

1. Brain Tumours

Inflamation

2. Mouth, Trachea, Oesophagus Candidiasis

3. Lung Pneumocystis carinii infection

Fungal infections, Tuberculosis

4. Intestines Protozoal, Salmonella infection

5. Skin Kaposi’s sarcoma, Fungal infections,

Herpes Zoster

BLOOD CHANGES OF AIDS

Immunoglobulin may be elevated in the early stages

T4 (helper) lymphocytes are severely reduced

T4/T8 ratio reversed

Human Immunodeficiency Virus Infection. A 7-year-old girl with human immunodeficiency virus (HIV) infection and a Kaposi sarcoma lesion.

ETIOLOGY

1. Unknown

2. Multifactors

Figure 1. Requirements for the development of an autoimmune disease.The immune response of a genetically predisposed individual to an environmental

pathogen, in association with defects in immunoregulatory mechanisms, can lead to the development of an autoimmune disease. The importance of the single components

represented in this Venn diagram may vary between individuals and diseases. However, the appearance of an autoimmune disease requires the convergence of all

three components. T, T cell; B, B cell; DC, dendritic cell.Bob Crimi

I. Expose of sequested antigen

II. Homeostatic disturbance

I. Expose of sequested antigenI. Expose of sequested antigen

isolated antigenisolated antigen

(e.g. sperm, lens)(e.g. sperm, lens)

nonself antigennonself antigen

Ig antispermIg antisperm

Ig antilensIg antilens

virus

A. self antigen self antigen modification neo-Ag failure of Th recognation autoactivity autoimmune diseases

B. Nonself Ag (Streptococcus ~myocard cells )

anti myocard

MHC II

normal:

*on the cell surface of: mo, B cell, T cell, dendritic, langerhans

*in the cytoplasm of: other cells

Patologic:

MHC on the surface of tyroid cells vs anti HLA_DR

Grave’s tyrotoxicosis

1. TYROID CELL Hashimoto’s, Grave’s disease

2. PARIETAL CELLS of stomach Pernicioous anaemia

3. RBC Haemolitic anaemia

4. PANCREATIC CELL Type I DM

5.ADRENAL CORTICAL CELLS Addison’s disease

6. PARATHYROID CELLS Primary hypoparathyroidism

7. ACETYLCHOLINE RECEPTOR Myasthenia gravis

1. MITOCHONDRIA of liver => Prim. Biliary cirrhosis

2.SMOOTH MUSCLE of liver =>Chronic active hepatitis (CAH)

3.NUCLEAR CONSTITUENT of liver => CAH

of skin &muscle =>conn. Tissue dis.

4. Ig in the kidney, blood vessel, joint => RA, SLE

GANGGUAN HEMATOPOETIC

Hematopoesis:

proses pembentukan sel darah dan pematangannya.

Ganguan Hematopoesis :gangguan pada proses pembentukan sel darah maupun proses pematangannya, meliputi sel darah merah, sel darah putih, sistem koagulasi

gangguan hematopoetik:1. Pada sumsum tulang

Misal: reticulin fibrosis, myelofibrosis, dll

2. Pada sel darah Misal: anemia

SEL DARAH MERAHberbentuk bulat, bikonkaf shg dapat

menampung oksigen sebanyak banyaknya.

tidak berintidiameter 8 µmtebal 2 µmbanyak mengandung haemoglobin (02

berikatan dengan Hb lbh banyak di bagian tepi daripada bagian tengah. Hb memberikan warna merah pacla sel darah.

SEL DARAH MERAHFungsinya:1. Alat transport yang membawa zat

yang cliperlukan oleh sel/jaringan, mis: oksigen, makanan, dan vitamin.

2. Membawa zat-zat yang tidak diperlukan tubuh untuk dikeluarkan dari tubuh, misal COz, senyawa nitrogen, dan racun.

3. Perbaikan saluran-saluran

Sumsum Tulang (Non) Patologis

1. Hipersellular

peningkatan bentuk (membesar) salah satu atau lebih sel.

Contoh: Granolocytic hyperplasia non patologi

sediaan hapus darah tepi, bentuk sel granulosit menjadi lebih besar daripacla normal

sebagai respon karena memfagositosis mikroorganisme.

Sumsum Tulang (Non) Patologis

2. Aplasia atau hipoplasia

Kekurangan/ketiadaan bentuk (mengecil) salah satu atau lebih sel.

Penyebab: idiopatik (tdk diketahui pasti)

Latrogenik (salah penatalaksanaan)Obat-obatan

Sumsum Tulang (Non) Patologis

3. Folikel Limfoid

Pembentukan folikel di dalam limfoid, terjadi pada orang dewasa.

Penyebab: konsumsi obat yang berpengaruh pada sumsum

tulang spt antikanker (siklofosfamid), kloramfenikol

Sumsum Tulang (Non) Patologis

4. Fibrosis Retikulin Peningkatan jumlah retikulin (kolagen tipe III).

5.MyelofibrosisPeningkatan jumlah kolagen

6. OsteosklerosisProliferasi jaringan tulang

AnemiaKeadaan dimana jumlah RBC total berkurang

Patofisiologi:1. Kebanyakan karena hipoproliferasi RBC,

menyebabkan gangguan bentuk dan jumlah.

1. Sedikit karena destuksi RBC berlebihan, biasanya jumlah normal tapi cepat lisis (hemolitik), akibat infeksi Plasmodium (malaria), cacing pita.

AnemiaPengaruh anemia: Anoksia, hipoksia

1. Perubahan metabolisme aerob menjadi anaerob ATP sedikit letih/lesu.

1. Banyakdihasilkan radikal bebas.

2. Dihasilkan asam laktat pegal, letih.

Kompensasi tubuh melawan anemia:

1. Penurunan afinitas Hb-O2 DeoksiHb produksi 2,3 difosfogliserat.

1. Redistribusi aliran darah: vasokontriksi pembuluh darah pada organ yang tidak vital, untuk mensuplai darah pada organ yang vital.

1. Peningkatan curah jantung.

Tanda dan Gejala AnemiaKehilangan 20% darah dari vol. total.Sulit nafas krn oksigen kurang.Letih/lesu karena metabolisme anaerob.Sakit kepala krn darah ke otak kurang.Hypotensi.Syncope (sempoyongan).Takikardi (denyut jantung meningkat).Pucat pada kulit, kuku, wajah krn

sekresi bilirubin meningkat.

Klasifikasi Anemia1. Bentuk Sel/ sitometrik

A. normokrom pada normositik anemiaB. hipokrom pada mikrositik anemiaC. Normokromik pada makrositik anemia2. Eritrokinetik

A. hemolisis B. Hemoragi3. Biokimia

1. Bentuk Sel/ sitometrikA. normokrom normositik anemia

Warna, bentuk, jumlah RBC normal.Hb normal.Penderita menunjukkan gejala anemia spt

lelah, pucat, lemah, sakit kepala, hipotensi.Tjd pada: anemia penyakit kronik, anemia

hemolitik spt pad mens, anemia akut krn perdarahan, anemia aplastis.

1. Bentuk Sel/ sitometrikB. hipokrom pada mikrositik anemia

Warna sel pudar, bentuk sel mengecil, jumlah RBC berkurang.

Hb berkurang.Tjd pada: anemia defisiensi Fe, Thalasemia,

anemia krn penyakit kronis.

1. Bentuk Sel/ sitometrik C. Normokromik pada makrositik anemia

Warna sel normal, bentuk sel membesar, jumlah RBC normal.

Hb normal.Tjd pada: anemia defisiensi vit B12, anemia

defisiensi folat.

2. Eritrokinetik A. Hemolisis

Destruksi RBC berlebihan krn infeksi (co: cacing, malaria)

B. HemoragiKehilanagn RBC dari pembuluh darah krn perdarahan akibat faktor mekanik/ kecelakaan.

3. Biokimia A. Kekurangan enzim glukosa 6 fosfat

dehidrogenase.

Orang negro dg infeksi sal kemih + kloramfenikol/sulfonamid ggn sintesis DNA anemia hemolitik.

B. Kekurangan kofaktor spt Fe, Vit B12

Bleeding and thrombotic disordersBleeding may result from abnormalities:

Platelets Blood vessels walls Coagulation

Platelet Disorders1. Trombocytopenia normal : 150.000-350.000/µl abnormal:<100.00U/ µl causes:

1. production defects such as marrow injury (drugs, irradiation) 2. marrow failure (aplastis anemia) 3. splenomegaly 4. accelerated destruction: thiazide, ethanol, sulfa, etc

Platelet Disorders2. ThrombocytosisPlatelet count > 350.000 /ulcause : iron deficiency B 12 deficiency drugs (vincristine,efinefiin, etc)

3. Disorders of Platelet Function

defect is in platelet adhesion, aggregation,or granule release

cause : drugs (aspirin,NSAID) uremia,cirrhosis, etc.

4. Disorders of Blood Coagulation

Congenital DisordersHemophilia Aincidence 1:10,000‘sex linked recessive dificiency of factor VIII

5. Acquired DisordersVitamin K deficiency impairs production of factors II (prothrombin ) VII,IX,and X.