KUSMARDI

LAB. OF IMMUNOPATHOLOGY DEPT. OF ANATOMICAL PATHOLOGY FACULTY OF MEDICINE

KUSMARDI
LAB. OF IMMUNOPATHOLOGY DEPT. OF ANATOMICAL PATHOLOGY FACULTY OF MEDICINE

UNIVERSITY OF INDONESIA

THE SCOPE OF IMMUNOPATHOLOGY

I. ESSENTIAL IMMUNOLOGY

II.
III.

HYPERSENSITIVITY
IMMUNODEFICIENCY

IV.

AUTOIMMUNE DISEASE

Antigen
TISSUES CELLS --------Tumour --------Parasitic

--------Fungi
--------Bacteria --------Virus --------Molecules-----Protein -----Carbohydrate -----Lypoprotein

THE COMPONENT OF THE IMMUNE SYSTEM

CELLULAR SOLUBLE HUMORAL

LYMPHOCYTES MACROPHAGES K (NK) CELLS POLYMORPHS

IMMUNOGLOBULIN COMPLEMENT LYMPOKIN

THE ORIGIN OF THE CELLULAR COMPONENT OF THE IMMUNE SYSTEM

B CELLS LYMPHOID T CELLS STEMCELLS MACROPHAGES MYELOID GRANULOCYTES HISTI EO NET BA MAST TH TS TC TDTH MONO

THE CHARACTERISTIC OF IMMUNE RESPONSE

1. SELF RECOQNATION 2. SPECIFICITY 3. MEMORY

NATURAL IMMUNITY
IMMUNITY NONSPECIFIC PHYSICAL LYSOZYME COMPLEMENT INTERFERON

CHEMICAL SPECIFIC

CELLULER

POLYMORPS
MO

THE SPECIFIC IMMUNE RESPONSE

PRIMARY RESPONSE (FIRST ATTACK) IMMUNE REACTION SPECIFIC IMMUNE ANTIGEN DISEASE

RESPONSE

RECOVERY

DESTRUCTION OF ANTIGEN

SPECIFIC 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 OF ANTIGEN SPECIFIC IMMUNE STATE ENHANCED

Ag APC MHC II BCGF APC

Ag

TH BCDF

TH memory
Tc

TH IL-2 IL-2R Plasma cell

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 Ag

Ag

Ag

Ag

Ag/Ab

macrophage

Efficient phagocytosis

COMPLEMENT ACTIVATION
Activationclassical pathway Ag/Ab

1 Fc (IgM or Ig G) 2 3 4 5 6 7

Activation-alternate pathway, endotoxin

Bactericidal effect

8 9 Punched out holes in

terget cell membrane

Cytolytic effect
RBC

Bacterium

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 (60300 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,
BASOFIL

AFINITAS vs MAST

&

IgG4,

AFINITAS RENDAH vs MAST

& BASOFIL

Type 1 Anaphylaxis, atopy, allergy

First exposure to Ag Formation of Ig E Fixation of IgE to mast cells and basophils by Fc fragment

Second exposure to Ag

Degranulation of mast cell

Ag/Ab reaction on surface of mast cell

Release of mediators and vasoactive subtances

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 1st injection of horse serum (ATS), penc bee sting General sensitivition Hay Fever 1st contact with grass pollen local sensitivition Asthma 1st contact horse mite dust animal dander

conjunctiva and
passage 2nd injection bronchial constriction perhaps a skin rash may be fatal 2nd contact irritation of conjunctiva

local sensitivition
of bronchi 2nd contact Bronchial constriction difficult breathing

Ag (cell surface)

specific Ab combination produces

Complement

Increased phagocytic

Increased

activation

activity (opsonic effect)

killercell
activity

DESTRUCTION OF CELL

Type III- Immune complex (Arthus) type

Vasoactive amines
Ag/Ab Complement activation (anaphilatoxin)

Effect on

vessel wall

Polymorphs (chemotaxis) Platelet aggregation Thrombosis

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

Malnutritionparticularly with protein deficiency Latrogenic effect e.g. immunosuppressorrs : cytotoxics corticosteroids

common predisposing conditions

Infections acute viral, chronic bacterial chronic protozoal, e.g. malaria Chronic debilitating disease e.g. renal failure : diabetes millitus Malignant disease e.g. lymphoma, Hodkins disease INFECTION often OPPORTUNISTIC IMPAIRED IMMUNITY

AGAMAGLOBULINEMIA (PENY. BRUTON)

X-LINKED HAMPIR SLL PD PRIA BELUM 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 (-/RUDIMENTER) TIMUS & PARATIROID (-) LIMFOSIT T(-/ ) INFEKSI JAMUR, VIRUS,BAKTERI

PARATIROID (-) HIPOKALSEMIA TETANI

TANSPLANTASI TIMUS

IMMUNE DEFICIENCY STATES-AIDS Infection No initial symptoms Virus present in Latent stages (months-years) Stages of opportunistic infection and tumours (1-2 years) Infection opportunistic

limphoncytes
- no signs - persistent limph node enlargement malignant tumours

others
Kaposis sarcoma 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 5. Skin

Protozoal, Salmonella infection Kaposis 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 antigen

isolated antigen
(e.g. sperm, lens) nonself antigen

Ig antisperm
Ig 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

Graves tyrotoxicosis

1. TYROID CELL disease

Hashimotos, Graves Pernicioous

2. PARIETAL CELLS of stomach anaemia 3. RBC Haemolitic anaemia

4. PANCREATIC CELL

Type I DM
Addisons

5.ADRENAL CORTICAL CELLS disease 6. PARATHYROID CELLS hypoparathyroidism

Primary

7. ACETYLCHOLINE RECEPTOR Myasthenia

1. MITOCHONDRIA of liver => Prim. Biliary cirrhosis 2.SMOOTH MUSCLE of liver =>Chronic active hepatitis (CAH) 3.NUCLEAR CONSTITUENT of liver => CAH =>conn. Tissue dis. of skin &muscle

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 MERAH

berbentuk bulat, bikonkaf shg dapat

menampung oksigen sebanyakbanyaknya. tidak berinti diameter 8 m tebal 2 m banyak mengandung haemoglobin (02 berikatan dengan Hb lbh banyak di bagian tepi daripada bagian tengah. Hb memberikan warna merah pacla sel darah.

SEL DARAH MERAH

Fungsinya:

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.Myelofibrosis Peningkatan jumlah kolagen 6. Osteosklerosis Proliferasi jaringan tulang

Anemia
Keadaan 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.

Anemia
Pengaruh anemia: Anoksia, hipoksia
1.

Perubahan metabolisme aerob menjadi anaerob ATP sedikit letih/lesu. Banyakdihasilkan radikal bebas. Dihasilkan asam laktat pegal, letih.

1. 2.

Kompensasi tubuh melawan anemia:

1.

Penurunan afinitas Hb-O2 2,3 difosfogliserat.

DeoksiHb

produksi

1.

Redistribusi aliran darah: vasokontriksi pembuluh darah pada organ yang tidak vital, untuk mensuplai darah pada organ yang vital. Peningkatan curah jantung.

1.

Tanda dan Gejala Anemia

Kehilangan 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 Anemia
1. Bentuk Sel/ sitometrik
A. normokrom pada normositik anemia B. hipokrom pada mikrositik anemia C. Normokromik pada makrositik anemia

2. Eritrokinetik A. hemolisis B. Hemoragi 3. Biokimia

1. Bentuk Sel/ sitometrik

A. 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/ sitometrik

B. 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. Hemoragi
Kehilanagn 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 disorders

Bleeding may result from abnormalities:

Platelets Blood vessels walls Coagulation

Platelet Disorders
1. Trombocytopenia normal : 150.000-350.000/l abnormal:<100.00U/ l
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 Disorders
2. Thrombocytosis Platelet count > 350.000 /ul cause : 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 Disorders
Hemophilia A incidence 1:10,000

sex linked recessive dificiency of factor VIII

5. Acquired Disorders
Vitamin K deficiency

impairs production of factors II (prothrombin ) VII,IX,and X.