PATOFISIOLOGI

IMUNOLOGI
OUTLINE

• Pengantar sistem imun

• Gangguan yang berkaitan dengan sistem imun
 PENDAHULUAN

• Imunologi
ilmu yang mempelajari reaksi terhadap
komponen mikroba maupun makromolekul
(seperti protein dan polisakarida), dan zat
kimia yang dikenal sebagai asing
 mempelajari peristiwa seluler dan molekuler yang
terjadi setelah tubuh terpapar mikroba dan
makromolekul asing
 PENDAHULUAN...

• Imunitas
 kemampuan tubuh untuk menahan atau menghilangkan benda asing atau
sel abnormal yang berpotensi merugikan

• Sistem imun
 sistem pertahanan internal yang berperan dalam mengenal dan menghancurkan
atau menetralkan benda-benda di dalam tubuh yang asing bagi ‘diri normal’
 gabungan sel, molekul dan jaringan yang berperan dalam resistensi terhadap
infeksi

• Respon imun
 reaksi yang dikoordinasi sel-sel, molekul-molekul, dan bahan lainnya terhadap
benda asing
 PENDAHULUAN...

Imunogenesitas: kemampuan suatu substansi untuk

merangsang respon imun (respon seluler maupun respon
imun humoral atau keduanya), apabila substansi tersebut
masuk ke dalam tubuh

Imunogen: substansi yang memiliki imunogenesitas

Antigen: substansi yang dapat bereaksi dengan antibodi

(yang diproduksi sel B) atas rangsangan imunogen
 molekul asing besar unik yang memicu respon imun
spesifik terhadap dirinya jika masuk ke dalam tubuh
 FUNGSI SISTEM IMUN

Mempertahankan tubuh dari patogen invasif

(mikroorganisme penyebab penyakit: bakteri/virus)
Menyingkirkan sel yang ‘aus’ dan jaringan yang
rusak oleh trauma atau penyakit
 memudahkan jalan untuk penyembuhan luka
dan perbaikan jaringan
Mengenali dan menghancurkan sel abnormal
atau mutan yang berasal dari tubuh
SEL-SEL SISTEM IMUN (IMUNOSIT)
 RESPON IMUN

• Rangsangan terhadap imunosit terjadi jika ke dalam tubuh masuk suatu zat
yang oleh sel atau jaringan dianggap ‘asing’

• Respon imun:
1. Respon imun bawaan (innate)
 respon non spesifik yang secara non selektif
mempertahankan tubuh dari benda asing bahkan pada pajanan
pertama
2. Respon imun didapat (adaptive)
 respon imun spesifik yang secara selektif menyerang benda
asing tertentu yang telah tersensitisasi oleh pajanan
sebelumnya
 RESPON IMUN BAWAAN DAN RESPON IMUN
DIDAPAT
Respon imun Respon imun
bawaan: didapat:
• Pertahanan lini • Pertahanan lini
pertama kedua
• Ada sejak lahir • Setelah infeksi /
• Non spesifik vaksinasi/
• Tidak ada memori dipelajari
• Spesifik
• Sel memori
RESPON IMUN BAWAAN
 RESPON IMUN BAWAAN (NON SPESIFIK)

Respon imun bawaan, membentuk lini pertama

pertahanan terhadap sel atipikal (sel asing,
mutan, atau cedera) di dalam tubuh
 respon langsung terhadap antigen
 tidak ditujukan terhadap mikroorganisme tertentu
 RESPON IMUN BAWAAN

Meliputi :
• Peradangan
• Interferon
• Sel natural killer
• Sistem komplemen
RESPON IMUN BAWAAN: PERADANGAN
(INFLAMASI)

• Peradangan adalah suatu respon non spesifik terhadap invasi

benda asing atau kerusakan jaringan yang terutama
diperantarai oleh fagosit profesional (neutrofil dan monosit
yang berubah menjadi makrofag) serta berbagai sekresinya
 infeksi mikroba, perlukaan akibat suhu dingin, panas, atau
trauma
PROSES INFLAMASI
RESPON IMUN BAWAAN: PERADANGAN
(INFLAMASI)

• Sel fagositik menghancurkan sel asing dan sel rusak

dengan :
 fagositosis
 pengeluaran bahan-bahan kimia mematikan
• Vasodilatasi dan peningkatan permiabilitas kapiler lokal
 dipicu oleh histamin (di tempat invasi atau cedera)
 memungkinkan peningkatan penyaluran lekosit fagositik
dan prekursor plasma inaktif yang penting bagi proses
peradangan (misalnya faktor pembekuan dan komponen-
komponen sistem komplemen)
RESPON IMUN BAWAAN: PERADANGAN
(INFLAMASI)

• Perubahan vaskuler menghasilkan manifestasi peradangan

lokal :
 pembengkakan (tumor), kemerahan (rubor), panas (calor)
dan nyeri (dolor)

• Bahan-bahan kimia yang dibebaskan oleh fagosit:

 meningkatkan peradangan
 memicu manifestasi sistemik misalnya demam
 meningkatkan respon imun didapat
RESPON IMUN BAWAAN : INTERFERON

• Interferon → protein
• Interferon dibebaskan secara non spesifik oleh sel yang
terinfeksi virus  secara transien menghambat multiplikasi
virus di sel lain
• Interferon juga memiliki efek:
o antikanker dengan memperlambat
pembelahan dan pertumbuhan sel tumor
o meningkatkan kekuatan sel pemusnah
RESPON IMUN BAWAAN: SEL NATURAL
KILLER
• Sel natural killer (NK)
 Sub set limfosit
 secara non spesifik melisiskan dan menghancurkan sel
yang terinfeksi virus dan sel kanker pada pajanan
pertama
• Kerjanya = sel T sitotoksik
tetapi lebih cepat
non-spesifik
bekerja sebelum sel T sitotoksik menjadi lebih banyak dan
berfungsi
RESPON IMUN BAWAAN: KOMPLEMEN

• Komplemen:
• Protein yang berperan dalam sistem imun
nonspesifik dan spesifik
• Berfungsi dalam inflamasi, opsonisasi, dan
kerusakan (lisis)
• Komplemen diaktifkan oleh :
 mikroba ditempat invasi
 antibodi yang dihasilkan terhadap mikroba
RESPON IMUN BAWAAN : KOMPLEMEN

Komplemen yang teraktivasi akan:

1. Berikatan dengan basofil dan sel mast  menginduksi
penglepasan histamin  reaksi inflamasi
2. Berperan sebagai faktor kemotaksis yang meningkatkan
fagositosis
3. Berikatan dengan permukaan bakteri dan bekerja sebagai
opsonin (opsonisasi)  fagositosis
4. Menempel pada membran dan membentuk struktur berbentuk
tabung yang melubangi membran sel dan menyebabkan
lisis sel.
RESPON IMUN DIDAPAT
 RESPON IMUN DIDAPAT

• Menghancurkan patogen yang lolos dari sistem kekebalan non-

spesifik.
• Respon imun didapat sistem imun adaptif
• mampu mengenal molekul asing yang berbeda dari molekul
diri-sehingga reaksi imun destruktif tidak menghancurkan
tubuh sendiri
• dapat membedakan antara jutaan molekul asing yang
berbeda
• Sel efektor imunitas didapat  limfosit
 dilengkapi oleh reseptor membran permukaan yang berikatan
(seperti kunci dan anak kunci) dengan hanya satu molekul asing
kompleks spesifik, yang dikenal sebagai antigen
RESEPTOR SEL B DAN SEL T
 RESPON IMUN DIDAPAT

• Respon imun didapat :

a. Imunitas yang diperantarai oleh antibodi (imunitas
humoral)
b. Imunitas yang diperantarai sel (imunitas seluler)
• Pada keduanya :
 hasil akhir dari pengikatan limfosit dengan antigen
spesifiknya : destruksi antigen
 tetapi : sel efektor, rangsangan dan taktik yang digunakan
berbeda
 SEL EFEKTOR IMUNITAS DIDAPAT:
LIMFOSIT
Limfosit B (sel B): Limfosit T (sel T):
• Sel B berkembang dari • Turunan sel T berasal dari
turunan limfosit yang limfosit yang bermigrasi
matang di sumsum tulang. dari sumsum tulang ke
• Sel plasma yang berasal timus untuk menyelesaikan
dari limfosit B (sel B) proses pematangannya
berperan dalam imunitas • Limfosit T (sel T)
yang diperantarai oleh melaksanakan imunitas
antibodi yang diperantarai oleh sel
LIMFOSIT B :
IMUNITAS YANG DIPERANTARAI ANTIBODI

• Setiap sel B mengenali mikroba atau benda asing yang

berada dalam keadaan bebas misalnya bakteri dan
toksinnya serta beberapa virus.
• Setelah diaktifkan oleh pengikatan dengan antigen spesifiknya
:
• sel B berproliferasi dengan cepat, menghasilkan satu
klon dari jenisnya sendiri yang dapat secara spesifik
melancarkan serangan terhadap antigen tersebut
• Sebagian besar limfosit dalam klon sel B adalah sel
plasma yang berperan dalam respon primer terhadap
penyerang
 LIMFOSIT B : IMUNITAS YANG
DIPERANTARAI ANTIBODI
• Sel plasma
 mengeluarkan antibodi  beredar secara bebas untuk
mengepung bakteri (atau benda asing lain) dalam bentuk
bebas yang memicu pembentukannya
• Antibodi  molekul berbentuk Y.
• Bagian pengikat antigen diujung masing-masing lengan
antibodi menentukan antigen spesifik apa yang dapat diikat
olehnya
• Bagian ekor antibodi menentukan apa yang dilakukan
antibodi setelah berikatan dengan antigen
 LIMFOSIT B : IMUNITAS YANG
DIPERANTARAI ANTIBODI

Eliminasi mikroba penginvasi oleh antibodi :

1. Secara fisik menghambat antigen melalui:
a. Netralisasi
b. Aglutinasi dan presipitasi
2. Memperkuat respon imun bawaan dengan :
c. Mengaktifkan sistem komplemen
d. Meningkatkan fagositosis melalui opsonin
e. Merangsang sel pemusnah
FUNGSI ANTIBODI
REAKSI AG-AB
 LIMFOSIT B : IMUNITAS YANG
DIPERANTARAI ANTIBODI
• Sebagian dari limfosit yang baru terbentuk dalam klon sel B
aktif tidak ikut serta dalam pertempuran
 menjadi sel memori yang diam menunggu, siap
melancarkan respon sekunder yang lebih cepat dan lebih
kuat seandainya benda asing tersebut kembali masuk ke
tubuh
 LIMFOSIT T : IMUNITAS YANG
DIPERANTARAI OLEH SEL
• Sel T melaksanakan imunitas seluler dengan cara
berkontak langsung dengan sasarannya
• Terdapat 2 jenis sel T :
a. sel T penolong: CD4 (Th1 dan Th2)
b. sel T sitotoksik: CD8
• Sel T sitotoksik :
 sasaran sel T sitotoksik adalah sel yang dimasuki oleh virus
dan sel kanker  dihancurkan dengan mengeluarkan :
molekul perforin yang membentuk kompleks
pembuat lubang di membran sel korban
 granzim yang memicu sel korban bunuh diri
(melakukan apoptosis)
 MEKANISME
SEL T SITOTOKSIK
MELISISKAN
SEL YANG DIMASUKI
VIRUS
 SEL T PENOLONG

• Sel T penolong meningkatkan pola respon imun yang berbeda dengan

mengeluarkan jenis-jenis sitokin yang berbeda
• Sel Th1 mengobarkan respons yang diperantarai oleh sel (sel T
sitotoksik), yang sesuai untuk infeksi oleh mikroba intrasel,
misalnya virus
 IL-12 mendorong sel T naif spesifik untuk antigen
menjadi sel Th1
• Sel Th2 mendorong imunitas yang diperantarai antibodi oleh sel B
dan meningkatkan aktivitas eosinofil untuk pertahanan terhadap
cacing parasitik
 IL-4 mendorong sel T naif spesifik untuk antigen menjadi
sel Th2
• Sel T :
• mengandung reseptor yang spesifik antigen
• mengalami seleksi klon
• melaksanakan respon primer dan sekunder
• membentuk sel-sel memori untuk imunitas jangka panjang
terhadap sasaran yang pernah ditemuinya
• Sel B dan sel T dapat mengenal dan mengikat antigen
hanya jika antigen telah diproses dan disajikan oleh sel
penyaji antigen, misalnya makrofag dan sel dendritik
• Sel B dan sel T memiliki sasaran yang berbeda karena
persyaratan keduanya untuk mengenal antigen berbeda
• Sel B mengenal antigen yang beredar bebas,
misalnya bakteri, yang dapat menyebabkan destruksi
antigen dalam jarak jauh
• Sel T memiliki persyaratan ganda untuk dapat
mengikat antigen asing, yaitu keterkaitan antigen
dengan molekul MHC (antigen diri) di permukaan
salah satu sel tubuh sendiri
 MHC (MAJOR HISTOCOMPATIBILITY
COMPLEX)

• Berbagai antigen diri utama di permukaan sel tubuh dikenal

sebagai molekul MHC, yang disandi oleh kompleks
histokompatibilitas mayor (major histocompatibility complex,
MHC), sekelompok gen dengan sekuens DNA yang unik
untuk setiap orang
• Adanya antigen diri MHC kelas I atau kelas II di permukaan
sel pejamu yang mengandung antigen asing ini menyebabkan
2 jenis sel T berinteraksi secara berbeda dengannya :
1. Sel T sitotoksik mampu berikatan hanya dengan sel
pejamu yang terinfeksi virus atau sel kanker, yang selalu
mengandung antigen diri MHC kelas I yang berikatan
dengan antigen asing atau abnormal, sel T ini mengeluarkan
bahan-bahan toksik yang mematikan sel tubuh yang berbahaya
tersebut
2. Sel T penolong hanya dapat berikatan dengan sel T lain,
sel B, makrofag yang telah bertemu dengan antigen asing.
• Sel-sel imun ini mengandung penanda diri MHC kelas II yang
berikatan dengan antigen asing
• Kemudian sel T penolong meningkatkan kekuatan imun sel-sel
efektor lain tersebut dengan mengeluarkan mediator-mediator
kimiawi tertentu
 IMMUNE TOLERANCE

• Limfosit yang terbentuk secara kebetulan dan dapat

menyerang sel-sel yang mengandung antigen tubuh
sendiri, dieliminasi atau ditekan sehingga limfosit ini
tidak berfungsi
• Dengan cara ini tubuh mampu ‘menoleransi ‘ (tidak
menyerang) antigen-antigennya sendiri
• Toleransi dicapai dengan seleksi klonal, anergi klonal,
penyuntingan reseptor, sel T regulatorik (penekan),
pengabaian imunologis dan keistimewaan imun
• Pengaktifan berbagai jenis limfosit tersebut menjamin bahwa
terbentuk respon imun spesifik yang sesuai untuk
menyingkirkan musuh tertentu secara efisien
• Selain itu, sel B, berbagai sel T, dan makrofag saling
memperkuat strategi pertahanan masing-masing terutama
dengan mengeluarkan sejumlah produk sekretorik penting
• Dalam proses surveilans imun, natural killer cell, sel T
sitotoksik, makrofag dan interferon secara kolektif
dikeluarkan, normalnya untuk memusnahkan sel-sel
kanker yang baru terbentuk sebelum sel-sel ini memiliki
kesempatan untuk menyebar
PEMBENTUKAN KEKEBALAN JANGKA PANJANG
(LONG-TERM IMMUNITY)

• Pada kontak pertama dg

antigen mikroba, respons
antibodi terjadi lambat dlm
bbrp hari sampai terbentuk
sel plasma & akan mencapai
puncak dlm bbrp minggu
(Respons primer); & akan
membentuk sel memori
• Jika terjadi kontak dg
antigen yg sama, krn adanya
sel memori, respons yg
terjadi mjd lebih cepat
(Respons sekunder)
 DISORDERS OF IMMUNE RESPONSE

 The immune system :

 protect against invading microorganisms
 prevent the proliferation of cancer cells
 mediate the healing of damaged tissue.
under normal conditions, the immune response deters or prevents
disease.
 Inadequate, inappropriate, or misdirected activation of the immune
system:
 allergic or hypersensitivity reactions
 transplantation rejection
 autoimmune disorders
 immunodeficiency states
DISORDERS OF OF IMMUNE RESPONSE

• Hypersensitivity Disorders
• Transplantation Immunopathology
• Autoimmune Disease
• Immunodeficiency Disorders
HYPERSENSITIVITY DISORDERS

• Although activation of the immune system normally leads to

production of antibodies and T-cell responses that protect the
body against attack by microorganisms, it is also capable of
causing tissue injury and disease.
• Gangguan yang disebabkan oleh respons imun secara kolektif
disebut sebagai reaksi hipersensitivitas
seseorang yang terlalu reaktif terhadap bahan yang ditoleransi oleh
kebanyakan orang
 HYPERSENSITIVITY DISORDERS
Hypersensitivity disorders are commonly classied into four groups according to the type of immune
response causing the injury and the nature and location of the antigen that is the target of the response:

• Type I, Immediate Hypersensitivity Disorders

• Systemic (Anaphylactic) Reactions
• Local (Atopic) Reactions
• Type II, Antibody-Mediated Disorders
• Complement- and Antibody-Mediated Cell Destruction
• Complement- and Antibody-Mediated Inflammation
• Antibody-Mediated Cellular Dysfunction
• Type III, Immune Complex–Mediated Disorders
• Systemic Immune Complex Disorders
• Local Immune Complex Reactions
• Type IV, Cell-Mediated Hypersensitivity Disorders
• Direct Cell-Mediated Cytotoxicity
• Delayed-Type Hypersensitivity Disorders
 CLASSIFICATION OF
HYPERSENSITIVITY RESPONSES
 TYPE I, IMMEDIATE HYPERSENSITIVITY DISORDERS

• Type I hypersensitivity reactions are IgE-mediated reactions that

begin rapidly, often within minutes of an antigen challenge. Often,
they are referred to as allergic reactions and the antigens are called
allergens.
• Typical allergens include the proteins in plant pollens, house dust
mites, animal dander, foods, and chemicals like the antibiotic
penicillin.
• Exposure to the allergen can be through inhalation, ingestion,
injection, or skin contact.
• Depending on the portal of entry, type I reactions may be limited to
merely annoying (e.g., seasonal rhinitis), severely debilitating
(asthma), or systemic and potentially life-threatening (anaphylaxis).
Type I, IgE-mediated hypersensitivity reaction.
• The stimulation of B-cell differentiation by
an antigen-stimulated type 2 helper T (TH2)
cell leads to plasma cell production of IgE
and mast cell or basophil sensitization.
• Subsequent binding of the antigen produces
degranulation of the sensitized mast cell or
basophil with release of preformed mediators
that leads to a primary, or early-phase,
response.
• TH2 T-cell recruitment of eosinophils, along
with the release of cytokines and membrane
phospholipids from the mast cell, leads to a
secondary, or late-phase, response.

• IgE, immunoglobulin E; IL, interleukin.

 SYSTEMIC (ANAPHYLACTIC) REACTIONS

• Anaphylaxis is a systemic life-threatening hypersensitivity reaction

characterized by widespread edema, difficulty breathing, and vascular
shock secondary to vasodilation.
• It results from the presence of antigen introduced by injection, insect sting,
or absorption across the epithelial surface of the skin or gastrointestinal
mucosa.
• Within minutes after exposure, itching, hives, and skin erythema develop,
followed shortly by bronchospasm and respiratory distress. Vomiting,
abdominal cramps, diarrhea, and laryngeal edema and obstruction follow, and
the person may go into shock and die unless effective treatment is instituted.
• The initial management of anaphylaxis focuses on the establishment of a
stable airway and intravenous access, and the administration of
epinephrine
 LOCAL (ATOPIC) REACTIONS
• Local or atopic reactions usually occur when the antigen is confined to a particular site by
virtue of exposure.
• The term atopic refers to a genetically determined hypersensitivity to common environmental
allergens mediated by an IgE–mast cell reaction.
• Persons with atopic disorders commonly are allergic to more than one (often many)
environmental allergens.
• The most common atopic disorders are urticaria (hives), allergic rhinitis (hay fever), atopic
dermatitis, food allergies, and some forms of asthma.
• The susceptibility to immediate hypersensitivity disorders tends to be inherited.
• The genetic basis of atopy is unclear; however, linkage studies suggest an association with
cytokine genes on chromosome 5q that regulate the expression of circulating IgE.
• 1 persons with atopic allergic conditions tend to have high serum levels of IgE and
increased numbers of basophils and mast cells.
• Although the IgE-triggered response is likely a key factor in the pathophysiology of atopic
allergic disorders, it is not the only factor and may not be solely responsible for conditions
such as atopic dermatitis and certain forms of asthma.
 TYPE II (ANTIBODY-MEDIATED)
HYPERSENSITIVITY
• Type II (antibody-mediated) hypersensitivity reactions are
mediated by IgG or IgM antibodies directed against target
antigens on cell surfaces or in connective tissues.
• The antigens may be endogenous antigens that are present on the
membranes of body cells, or they may be exogenous antigens, such
as drug metabolites, that are adsorbed on the membrane surface.
• Three different antibody-mediated mechanisms are involved in type
II reactions:
(1) complement- and antibody–mediated cell destruction
(2) complement- and antibody-mediated inflammation
(3) antibody-mediated cellular dysfunction
• Type II, hypersensitivity reactions result from
binding of antibodies to normal or altered
surface antigens .
(A) Opsonization and complement- or
antibody receptor–mediated phagocytosis or
cell lysis through membrane attack complex
(MAC).
(B) Complement- and antibody receptor–
mediated inflammation resulting from
recruitment and activation of inflammation-
producing leukocytes (neutrophils and
monocytes).
Antibody-mediated cellular dysfunction, in
which (C) antibody against the thyroid-
stimulating hormone (TSH) receptor increases
thyroid hormone production. (D) Antibody to
acetylcholine receptor inhibits receptor binding
of the neurotransmitter in myasthenia gravis.
TYPE III, IMMUNE COMPLEX–MEDIATED DISORDERS

• Immune complex allergic disorders are mediated by the formation of insoluble

antigen–antibody complexes, complement fixation, and localized inflammation.
• Immune complexes formed in the circulation produce damage when they come in
contact with the vessel lining or are deposited in tissues, such as the renal
glomerulus, skin venules, lung tissue, and joint synovium.
 once deposited, the immune complexes elicit an inflammatory response by
activating complement, thereby leading to chemotactic recruitment of neutrophils
and other inflammatory cells activation of these inflammatory cells by immune
complexes and complement, accompanied by the release of potent inflammatory
mediators, is directly responsible for the injury.
• Type III reactions are responsible for the vasculitis seen in certain autoimmune
diseases such as systemic lupus erythematosus (SLE) or the kidney damage seen with
acute glomerulonephritis.
• As with type I hypersensitivity reactions, type III immune complex disorders may
present with systemic manifestations or as a local reaction.
• Type III, immune complex
reactions involving complement-
activating IgG or IgM
immunoglobulins with
(1) formation of blood-borne
immune complexes that are
(2) deposited in tissues .
Complement activation at the
site of immune complex
deposition (3) leads to attraction
of leukocytes that are
responsible for vessel and tissue
injury
TYPE IV, CELL-MEDIATED HYPERSENSITIVITY DISORDERS

• Type IV hypersensitivity reactions involve cell-mediated rather than

antibody-mediated immune responses.
• Cell-mediated immunity is the principal mechanism of response to a
variety of microorganisms, including intracellular pathogens such
as Mycobacterium tuberculosis and viruses, as well as extracellular
agents such as fungi, protozoa, and parasites.
• It can also lead to cell death and tissue injury in response to
chemical antigens (contact dermatitis) or self-antigens (autoimmunity).
• Type IV hypersensitivity reactions, which are mediated by specifically
sensitized T lymphocytes, can be divided into two basic types: direct
cell-mediated cytotoxicity and delayed-type hypersensitivity
• Type IV, cell-mediated
hypersensitivity reactions ,
which include
(A)direct cell-mediated
cytotoxicity in which CD8+
T cells kill the antigen-be a
ring target cells , and
(B) delayed-type
hypersensitivity reactions
in which presensitized
CD4+ cells release cell-
damaging cytokines .
 TRANSPLANTATION
IMMUNOPATHOLOGY
• Transplantation is the process of taking cells, tissues, or organs, called a graft,
from one individual and placing them into another individual.
 sometimes grafts are transplanted from another site in the same individual.
• The individual who provided the tissue is called the donor, and the individual who
receives the graft is called either the recipient or the host.
• Transplantation rejection is discussed here because it involves several of the
previously discussed immunologic reactions.
• A major barrier to transplantation is the process of rejection, in which the
recipient’s immune system recognizes the graft as foreign and attacks it.
• The cell surface antigens that determine whether the tissue of transplanted organs is
recognized as foreign are the MHC or human leukocyte antigens (HLA)
TRANSPLANTATION IMMUNOPATHOLOGY…

• Transplanted tissue can be categorized as an autologous graft if the donor

and recipient are the same person, syngeneic graft if the donor and
recipient are identical twins, and allogeneic (genetic variations of the same
gene within a given species) if the donor and recipient—whether related or
not—share similar HLA types.
• The molecules that are recognized as foreign on allografts are called
alloantigens.
• Donors of solid organ transplants can be living or dead (cadaver) and
related or nonrelated (heterologous).
• Rejection of allografts is a response to MHC molecules, which are so
polymorphic that no two individuals are likely to express the same MHC
molecules, unless they are identical twins. The likelihood of rejection
varies indirectly with the degree of MHC or HLA relatedness between the
donor and recipient.
 TRANSPLANTATION
IMMUNOPATHOLOGY
• Immune Recognition of Allografts
• Solid Organ Rejection
• Patterns of Rejection
• Transplantation of Hematopoietic Cells
• Graft-Versus-Host Disease
• Destruction of the cells or tissues of the graft can result from direct
action of the recipient’s cytotoxic T cells , from T-cell–generated
cytokines and a delayed hypersensitivity reaction, or from antibodies
generated against antigens in the graft.
• Hyperacute rejection occurs almost immediately after transplantation and
is caused by existing recipient antibodies to graft antigens that initiate a type
III, Arthus -type hypersensitivity reaction in the blood vessels of the graft.
• Acute rejection occurs within the first few weeks or months after
transplantation and occurs when graft tissue or blood vessels are damaged
by aloreactive T cells or antibodies .
• Chronic rejection occurs over a prolonged period and is caused by T-cell–
generated cytokines that damage blood vessels , causing ischemic damage
to graft tissue.
• Graft-versus -host disease (GVHD), which occurs most
often following bone marrow transplantation, develops
when immunologically competent cells or precursors are
transplanted into recipients who are immunologically
compromised.
• Three basic requirements are necessary for GVHD to develop:
(1) the transplant must have a functional cellular immune
component, (2) the recipient tissue must bear antigens foreign
to the donor tissue, and (3) recipient immunity must be
compromised to the point that it cannot destroy the
transplanted cells .
 AUTOIMMUNE DISEASE

• Immunologic Tolerance
• B-Cell Tolerance
• T-Cell Tolerance
• Mechanisms of Autoimmune Disease
• Genetic Susceptibility
• Environmental Factors
• Diagnosis and Treatment of Autoimmune Disease
• Autoimmune diseases represent a group of disorders that are
caused by a breakdown in the ability of the immune system
to differentiate between self- and nonself-antigens.
• They can affect almost any cell or tissue in the body.
• Some autoimmune disorders, such as Hashimoto thyroiditis,
are tissue specific, whereas others, such as SLE, affect
multiple organs and systems.
• To function properly, the immune system must be able to
differentiate foreign antigens from self-antigens in a process
called self-tolerance.
• Self-tolerance is maintained through central and
peripheral mechanisms that delete autoreactive B or T
cells or otherwise suppress or inactivate immune responses
that would be destructive to host tissues .
• Defects in any of these mechanisms could impair self-
tolerance and predispose to the development of autoimmune
disease.
 MECHANISMS OF AUTOIMMUNE
DISEASE
• It is not known what triggers autoimmunity, but both genetic
susceptibility and environmental factors such as infectious
agents, appear to play a role
• Genetic Susceptibility
• Role o f Infections
There are three proposed mechanisms through which
infections can trigger autoimmunity: breakdown of T-cell
anergy, molecular mimicry, and superantigens.
• Release of Sequestered Antigens
 • Suggested criteria for determining whether a disorder is an
autoimmune disease include the following:
• evidence of an autoimmune reaction
• determination that the immunologic findings are not
secondary to another condition
• no other identiable causes for the disorder.
• Currently, the diagnosis of autoimmune disease is based
primarily on clinical findings and serologic testing.
• Treatment of autoimmune disease is based on the tissue or
organ that is involved, the effector mechanism involved, and
the magnitude and chronicity of the effector processes.
• Ideally, treatment should focus on the mechanism underlying
the autoimmune disorder.
• Corticosteroids and immunosuppressive drugs may be used
to arrest or reverse the downhill course of some autoimmune
disorders.
• Purging autoreactive cells from the immune repertoire through
the use of plasmapheresis is also an option in some severe
cases of autoimmunity.
IMMUNODEFICIENCY DISORDERS

• Primary Immunodeficiency Disorders

• Humoral (B-Cell) Immunodeficiency Disorders
• Cellular (T-Cell) Immunodeficiency Disorders
• Combined T-Cell and B-Cell Immunodeficiency Disorders
• Acquired Immunodeficiency Syndrome
• HIV Infection
• Immunodeficiency can be defined as an abnormality in one or more components
of the immune system that renders a person susceptible to diseases normally
prevented by an intact immune system.
• These disorders can be broadly classified into two groups: primary and secondary.
• The primary or congenital immunodeficiencies are genetic defects that result in
increased susceptibility to infection that is frequently manifested early in life
• Secondary or acquired immunodeficiency is not inherited but develops as a
consequence of malnutrition, selective loss of immunoglobulins through the
gastrointestinal or genitourinary tracts, treatment with immunosuppressant drugs,
or human immunodeficiency virus (HIV), the etiologic agent of acquired
immunode ciency syndrome (AIDS).
• Regardless of the cause, primary and secondary deficiencies can produce the same
spectrum of disease.
• The severity and symptomatology of the various disorders depend on the type
and extent of the deficiency.
• Until recently, little was known about the causes of primary immunodeficiency
diseases.
• Ten Warning Signs of Primary Immunodeficiency
■ Four or more new ear infections within 1 year
■ Two or more serious sinus infections within 1 year
■ Two or more months on antibiotics with little effect
■ Two or more pneumonias within 1 year
■ Failure of an infant to gain weight or grow normally
■ Recurrent, deep skin or organ abscesses
■ Persistent thrush in mouth or fungal infections of the skin
■ Need for intravenous antibiotics to clear infections
■ Two or more deep-seated infections including septicemia
■ A family history of primary immunodeficiency
• Immunodeficiency is an absolute or partial loss of the normal immune response,
which places a person at increased risk for development of infections or malignant
complications.
• It can be classified as primary (i.e., congenital or inherited) or secondary (i.e., due to
another disease or condition).
• Primary Immunodeficiency Disorders
• Humoral (B-Cell) Immunodeficiency Disorders
• Cellular (T-Cell) Immunodeficiency Disorders
• Combined T-Cell and B-Cell Immunodeficiency Disorders
• Defects in humoral immunity increase the risk of recurrent pyogenic infections but
have less effect on the defense against intracellular bacteria (mycobacteria), fungi,
protozoa, and viruses (except for the enteroviruses that cause gastrointestinal infections).
• Defects in cellular immunity increase the risk of developing fungal, protozoan, viral,
and intracellular bacterial infections , and malignant cell proliferation.
ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

• Acquired immunodeficiency syndrome (AIDS), the most common type

of secondary immunodeficiency, is caused by infection with the human
immunodeficiency virus (HIV), a retrovirus that infects the body’s
CD4+ T cells and macrophages.
• Destruction of CD4+ cells constitutes an attack on the entire immune
system because this subset of lymphocytes exerts critical regulatory and
effector functions that involve both humoral and cellular immunity.
■ The clinical course of HIV infection can be divided in to three phases
: a primary phase th t occurs shortly after infection and is usually
manifested by mononucleosis-like symptoms , a latency phase that may
last for years , and an overt AIDS phase that is characterized by a marked
decrease in CD4+ T cells and the development of opportunistic
infections, malignancies , wasting syndrome, and metabolic disorders .
• There is no cure for AIDS.
• Treatment largely involves the use of drugs that interrupt the
replication of HIV and prevention or treatment of
complications such as opportunistic infections.
• Women who are infected with HIV may transmit the virus to
their offspring in utero, during labor and delivery, or through
breast milk.
• Diagnosis of HIV infection in children born to HIV-infected
mothers is complicated by the presence of maternal HIV
antibody, which crosses the placenta to the fetus . This antibody
usually disappears within 18 months in uninfected children .
TERIMA KASIH