KUSMARDI

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





KUSMARDI
LAB. 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


Antigen
TISSUES
CELLS --------Tumour
--------Parasitic
--------Fungi
--------Bacteria
--------Virus
--------Molecules-----Protein
-----Carbohydrate
-----Lypoprotein
THE COMPONENT OF THE IMMUNE SYSTEM
CELLULAR

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
MACROPHAGES
MONO
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 RESPONSE
PRIMARY 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 cell
IL-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
Ag




Ag
Ag
Ag
Ag/Ab macrophage
Efficient
phagocytosis
COMPLEMENT ACTIVATION
Activation-
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) killercell
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, Hodkins disease

IMPAIRED
IMMUNITY
INFECTION
often OPPORTUNISTIC
common
predisposing
conditions


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 & 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 Kaposis
- 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 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 Hashimotos, Graves
disease
2. PARIETAL CELLS of stomach Pernicioous
anaemia
3. RBC Haemolitic anaemia
4. PANCREATIC CELL Type I DM
5.ADRENAL CORTICAL CELLS Addisons
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 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.

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 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.