IMUNOGENETIK

Yoes Prijatna Dachlan

Fakultas Kedokteran
Universitas Wijaya Kusuma
Surabaya
 Faktor genetik mempengaruhi sistem
imun
• Kerentanan (susceptibility) terhadap agen infeksi berbasis pola
hubungan keluarga: daya tahan yang tinggi ataupun rentan →
suatu karakteristik yang diturunkan oleh keluarga (familial
inheritance characteristic)
• Penyakit adalah dibawah kendali poligenik : banyak gen
terlibat dalam mengatur kerentanan atau daya tahan individu
terhadap penyakit
• Dengan kemajuan teknologi imunologi dan molekuler → peta
dan identifikasi gen-gen yang terlibat dalam mengatur respons
terhadap beberapa penyakit
• Upaya mengidentifikasi calon gen yang berpotensi dalam
mengatasi suatu penyakit

(Yoes Prijatna Dachlan, 2014)

 Mempengaruhi
kemampuan merespons
suatu Ag
Mengendalikan respons
Gen terhadap infeksi

High antibody responder Mempengaruhi

suseptibilitas terhadap
infeksi

Memberi proteksi dari

infeksi
o
Polimorfisme gen dan
Intermediate antibody Antigen hubungannya dengan
responder kerentanan terhadap
infeksi

(Roitt, 2006)
Low antibody responder
 Berbagai faktor genetik mempengaruhi
sistem imun
• Banyak faktor mempengaruhi hasil akhir dari suatu respons
imun.
• Variasi genetik dari antigen permukaan.
Antigen termasuk salah satu faktor yang juga menentukan
hasil akhir suatu respons imun, dan ini bergantung dari : dosis
antigen, cara pemberian (route of administration) antigen, dan
latar belakang genetik dari patogen dalam mengendalikan
antigenisitas
• Mekanisme tersebut digunakan untuk menghindar dari respons
imun (escape mechanisms)

(Yoes Prijatna Dachlan, 2014)

 IMMUNE DEFECTS
Multiple immune genetic defects → mempengaruhi suseptibilitas terhadap patogen
•Penyakit : defisiensi IFN-γ receptor 1 dan IFN-γ receptor 2 karena defek gen
(complete defects) IFNGR1 dan IFNGR2 → sangat rentan terhadap Mycobacteria
•Polimorfisme TLR9 (Toll-like receptor; SNP T1237C dan G1174A)) menunjukkan adanya
hubungan yang bermakna dengan peningkatan pro-inflammatory cytokine IFN-γ
pada anak dengan malaria otak (cerebral malaria)
•HIV (human immunodeficiency virus): mutasi ko-receptor CCR5 → individu resistant
terhadap virus HIV
•Bacterial sepsis neonatorum in Dr Soetomo General Hospital Surabaya (Yulia Iriani,2011)
- mostly Gram-negative bacteria (75%)
- genotype polymorphism/SNP of T-16934A of the TLR2 were: AA 50%; TA 33.3%; TT
16.7%

Sumber: ~Blackwell JM, 2011; Wiltshire S,2011;

~Sam Agudu NA, 2010
~Unair

(Yoes Prijatna Dachlan, 2014)

 Mechanisms of immune evasion by bacteria
Extracellular bacteria
Antigenic variation
Menghambat aktivasi komplemen
Tahan terhadap fagositosis
Scavenging of ROS
(Yoes Prijatna Dachlan, 2014)
Neisseria gonorrhea,
Escherrichia coli
Antigen permukaan berada
pada pili, suatu struktur
yang digunakan oleh bakteri
untuk adhesi pada sel host
Antigen pada pili gonococci
adalah protein, disebut pilin
Gen pilin mampu
memproduksi 10⁶ molekul
antigenik pili yang berbeda
Berbagai bakteria
Pneumococcus
Catalase-positive
staphylococci
(Abbas AK etal.,2012)
 DNA degradation

adenosine deoxyadenosine deoxyadenosine

Adenosine deaminase (ADA)

deficiency T and B cell
lymphotoxicity

inosine deoxyiguanosine

•ADA mengubah adenosine menjadi inosine

dan deoxyadenosine menjadi SCID
severe
deoxyguanosine
combined immunodeficiency
•Pada defisiensi ADA, deoxyadenosine akumulasi
dalam sel limfosit dan berefek limfotoksik,
membunuh sel dengan menghalangi replikasi dan
pembelahan sel T dan B → SCID
(Yoes Prijatna Dachlan, 2014)
UNIT DASAR ANTIBODI
(monomer) H = rantai H (heavy), rantain panjang →
N 1 pasang
L H terminus H L L = rantai L (light), rantai pendek →
1 pasang
V V V V
Rantai H dan rantai L terdiri dari :
(a) bagian (region) CONSTANT (C) →
C C urutan asam amino dengan jenis
S S S S bersifat konstan pada setiap molekul
antibodi
(b) bagian (region) VARIABLE (V) →
S S urutan asam amino dengan jenis
bervariasi
C C

S S Interchain disulfide bond

(Yoes Prijatna Dachlan,

2014)
C
terminus
 Mechanisms of Ab synthesis
Ehrlich‘s side chain hypothesis :
is close to to the present view of clonal
selection
↓
Dreyer & Bennett : ″one gene, one
polypeptide″ dogma untenable
↓
Proved D & B hypothesis; somatic
recombination
(Yoes Prijatna Dachlan, 2014)
 Germline DNA

Recombined VDJ gene

mRNA

Heavy chain
(Janeway’s.ImmBiol., 2008)

(Yoes Prijatna Dachlan, 2014)

 Antibody diversity – A vast antigen
receptor repertoir in human

H-chain gene recombination: λL-chain genes,

the germline, on chrom 14, on chrom 22
V gene segments 38 to 46 V gene segments 29 to 33,
23 D gene segments 7 – 11 J gene segments
6 J gene segments
κL-chain genes,
on chrom 2,
V gene segments 31 to 35,
5 Jκgenes

(Yoes Prijatna Dachlan, 2014)

 Chromosomal locations of
Ig genes
in human and mouse

GENE Chromosome
H M
λ Light chain 22 16
Κ Light chain 2 6
Heavy chain 14 12

H = human
M = mouse

(Yoes Prijatna Dachlan, 2014)

 Empat tipe Reaksi Hipersensitivitas (Kuby,2013) (Yoes Prijatna Dachlan, 2014)

Type I Type II Type III Type IV

Allergy dan Atopy Antibody- Immune complex- Delayed type
mediated mediated hypersensitivity
hypersensitivity hypersensitivity

Immune IgE IgG atau IgM Immune T cell

mediator complexes
Mekanisme Ag – IgE – Ab – Ag Ag-Ab Sensitized T cell
mast cell/basophil permukaan sel complexes (Th1, Th2, dll)
dan pelepasan ↓ deposit ↓
vasoactive amin destruksi sel diberbagai sitokin
melalui aktivasi jaringan ↓
komplemen ↓ Mengaktivasi
atau ADCC Aktivasi MØ atau Tc
komplemen dan ↓
respons Kerusakan sel
inflamatori
karena infiltrasi
neutrophil
Manifestasi Systemic anaphylaxis Reaksi transfusi Localized Arthus Contact dermatitis
khas dan localized darah reaction Graft rejection
anaphylaxis Erythroblastosis Reaksi umum:
 The Genetics of Asthma and Allergy
• Hipotesa penderita asthma:
polimorfisme pada region structural dan regulatori dari gen
IL-4 yang mengakibatkan tingginya produksi kadar IL-4
• Kerangka teori:
Human chromosome 5: 5q31-33→terdiri dari cluster gen IL-3,
IL-4,IL-5, IL-9,IL-13 dan gen penyandi GM CSF
Polimorfisme terkait dengan predisposisi asthma terpetakan
pada promoter region IL-4

(Kuby,2013)
(Yoes Prijatna Dachlan, 2014)
 MHC and HLA

•The genetic system that determines the out come of transplant is

complex and highly polymorphic.
• MHC comprises a stretch of tightly linked genes that encode
proteins associated with intercellular recognition and antigen
presentation to T lymphocytes.
• The diseases associated with particular MHC alleles include
autoimmune disorders, certain viral diseases, some neurologic
disorders, and several different allergies.
• The absence of an MHC molecule that can bind and present a given
peptide could result in the abscence of immune responsiveness.

Yoes Prijatna Dachlan 2014

 MHC

Grafting of tissues organs If tissue or organ are

between genetically unrelated transplanted genetically
individuals identical individuals

REJECTION of grafted Rejection DOES NOT

tissue or organ TAKE PLACE

Yoes Prijatna Dachlan 2014

Medical Immunol, 6th ed, 2007
 Grafted among
animals with the same No rejection
inbred strains

Grafting involved mice Recipients rejected the

of different strains graft

To accep or reject to a graft is under a genetic control

(specificity and memory). Speed and intensity of the
rejection are dependent on the degree genetic relatedness

HISTOCOMPATIBILITY DETERMINANTS
Yoes Prijatna Dachlan 2014
Medical Immunol, 6th ed, 2007
 THE GENETICS of THE
MHC

The mouse MHC

Genetic locus MHC genes control

that responsible for immune responsiveness
tissue graft rejection to protein antigens

20 yrs 1960s – 1970s

(Yoes Prijatna Dachlan 2014) (Abbas, 2010)
 (Marino SG, Jaramillo A, Fernandez-Vina MA, 2008)
Handbook of human immunol, 2nd ed.
ed. by O’Gorman & Donnenberg,CH18,p541, CD
Yoes Prijatna Dachlan 2014
Yoes Prijatna Dachlan 2014 KUBY, ch.7
Yoes Prijatna Dachlan 2015 KUBY, ch.7
 Peptide binding cleft

Yoes Prijatna Dachlan 2015 KUBY, ch.7

 (Marino SG, Jaramillo A, Fernandez-Vina MA, 2008)

Yoes Prijatna Dachlan 2014

Yoes Prijatna Dachlan 2014 KUBY, ch.7
 Imunodefisiensi
• Primary immunodeficiency resulting from an
inherited genetic or developmental defect in some
components of the immune system
• Secondary immunodeficiency (acquired immunodefi
ciency), is the loss of immune function that results
from exposure to an external agent, often an
infection, e.g. AIDS/HIV, acquired
hypogammaglobulinemia

Yoes Prijatna Dachlan 2014

 Sebuah Contoh Primary human immunodeficiency diseases and underlying
genetic defects
Immunodeficiency Specific defect Fungsi yang terganggu
disease
Severe combined RAG1/RAG2 deficiency Tidak terbentuk TCR
immunodeficiency (T cell receptor) atau tidak
(SCID) terjadi Ig gene rearrangement

ADA deficiency Metabolit toksik terhadap sel T

PNP deficiency dan B

JAK-3 deficiency Signal dari IL-2,-4,-7,-9,-15,-

IL-2 Rγ deficiency .21 terganggu

ZAP-70 deficiency Signal dari TCR terganggu

RAG-1 dan RAG-2= Recombination activating genes diperlukan untuk rekombinasi segmen gen V,D,dan J
PNP= Purine nucleoside phosphorylase gene
JAK-3= Janus kinases, grup enzim untuk mengaktifkan fosforilasi silang, khususnya terlibat dalam
pengiriman sinyal dari reseptor sitokin
ZAP70, suatu tyrosine kinase kedua, bergabung dengan gugusan tirosin dari CD3 chain

Yoes Prijatna Dachlan 2014 (Kuby,2013)

 Recognition of MHC-associated peptides

(Yoes Prijatna Dachlan,2010)

Events in T cell activation
 Contoh-contoh lain: Primary human immunodeficiency diseases and
underlying genetic defects

• Bare-lymphocyte syndrome Defect in class II MHC gene promoter

• Waskot-Aldrich syndrome
• Mendelian susceptibility to
mycobacterial diseases
• DiGeorge syndrome
• Gammagobulinemias
• Chronic granulomatous disease
• Chediak-Higashi syndrome
• Leukocyte adhesion defect
• Autoimmune polyendocrinopathy
and ectodermal dystrophy
• Immune dysregulation
Cytoskletal protein (WASP)
IFNγR,IL-12/IL-12R
Thymic aplasia
X-linked agammaglobulinemia
No oxidative burst
Defective intracellular protein transport
Defective integrin β2 (CD18)
T cell tidak tolerance terhadap self antigen
FoxP3defect

Yoes Prijatna Dachlan 2014 (Kuby,2013)

 AIDS (Acquired Immunedeficiency
Syndrome). Fusi envelope virus dengan
membran sel host

CD4+ T cell

(Peterlin BM, Trono D, 2003)

Yoes Prijatna Dachlan 2014
Ag-Ab complexes Microorganisms
C3
(adaptive)

Lectin
Classical pathway pathway

Alternative pathway

C3a
C3b

C5b – 9
(Roitt, 2008)
membrane attack
pathway (Yoes Prijatna Dachlan, 2014)
 The complement system

Classical
pathway MBLectin
pathway
C1 Alternative
C4 pathway
C2 Lysis

C3 → C3b+C3a C5-6-7-8-9

Yoes Prijatna Dachlan 2014

Steps of the three complement activation
pathways

Yoes Prijatna Dachlan 2014

 ~ Activation of complement pathway is essential in the
host immune response to S. Pneumoniae
~ The key components C1q and C3b play a major role in
innate and adaptive immunity

c1qrs
C1q
•can bind either directly to bacteria or indirectly to
bacterial immune complexes
•consist of 18 polypeptide chains arranged into six
triplets
C1r and C1s monomer
•a catalytic domain with enzymatic activity and an
interaction domain that facilitates binding with C1q or
with each other

Binding of C5 and binding to C3b receptor on phagocytic

cells

(Ramos-Sevillano et al. 2012;

Yoes Prijatna Dachlan 2014 Janeway’s, 2012; Kubi, 2008)
 Genetic deficiencies of human complement
Group Type Deficiency Hereditary
AR AD XL
I Immune C1q •
complex disease C1s, atau C1r + •
C1s •
C2 •
C4
II Angiedema C1 inhibitor •
III Recurrent C3 •
pyogenic Factor H •
infections Factor I •
IV Recurrent C5 •
Neisseriia C6 •
infections C7 •
C8 •
Properdin •
Factor D •
V Asymptomatic C9 •

Yoes Prijatna Dachlan 2014 (Roitt, 2006)