IMMUNODEFICIENCY

Syarifuddin Wahid
IMMUNODEFICIENCY
CONGENEAL (PRIMRY)
IMMUNODEFICENCY

ACQUIRED (SECONDARY)
IMMUNODEFICIENCY
CONGENETAL (PRIMARY)
IMMUNODEFICIENCY
Phagocytic Disfunction
Complement Deficiencies.
Leucocyte Adhesion Deficiency
Defect In Lymphocyte Maturation
Defect in Lymphocyte Activation
Immunodeficiency Associated with
other Inherited Diseases.
(Wiskot-Aldrich Syndrome dan
Ataxia-telangiectasia)
Defect in Innate Immunity
1. Chronic Granulomatous Disease (GSD)
Mutation of the phagocyte oxidase
enzyme (X-linked/autosomal resessive)
sehingga neutropil dan makrofag tak dapat
membunuh bakteri yang difagositosisnya
2. Leucocyte Adhesion Deficiency (LAD)
Mutation of Integrin, LFA-1, MAC-1
(autosomal resessive) sehingga
leukosit tak dapat berhenti dalam
sirkulasi.
Defect in Innate Immunity
3. Complement Deficiency
C3 deficiency
Classical Pathway Deficiency
Alternative Pathway Deficiency
Mannan-Binding Lectin Deficiency
Terminal Component Deficiency
Control Protein Deficincy
Complement Receptor Deficiency
Management of Complement Deficiency
Stem Cell Pro-B Pre-B Immature B Mature B
Bone Marrow

Peripheral lymphoid
organ or tissue
IgM,IgD
No antigen dependence Self antigen Foreign antigen
Effector B
1. DEFECT IN B CELL MATURATION
2. DEFECT IN
B CELL
ACTIVATION
IMMUNODEFICIENCY
RAG-1 and RAG-2 expression
H chain
H & L chain
Stem Cell Pro-T Pre-T Immature T Immature T
BM Periphery
TCR
No respon to antigen

Pos & Neg
selection
activation by
Foreign ant
Naive mature T

Thymus
Negative
selection
IMMUNODEFICIENCY
1. DEFECT IN T CELL MATURATION 2. DEFECT IN
T CELL
ACTIVATION
Immunodeficiency caused by
defects in B and T cell maturation.
Primary immunodeficiencies caused by
genetic defects in lymphocyte
maturation are shown. These defects
may affect T cell maturation alone, B
cell maturation alone, or both. The
survival of all lymphocyte progenitor
populations requires the purine salvage
pathway enzymes, ADA, and PNP. IL-
7R signaling (γC, IL-7Rα,
and JAK3) is required for human pro-T
cell generation. The V(D)J
recombination machinery (RAG-1,
RAG-2, and ARTEMIS) is required for
generating pre-B and pre-T cells, as is
signaling through the pre-TCR (CD45,
CD3) specifically for pre-T cells and the
pre-BCR (Igμ chain, λ5,
Igα, and BLNK) for pre-B cells.
DP, double-positive; FoB, follicular B
cells; HSC, hematopoietic stem cell;
MZB, marginal zone B cells.
Downloaded from: StudentConsult (on 20 November 2007 07:29 AM)
2005 Elsevier
Defect in B and T Cell Maturation
Severe Combined
Immunodeficiency (SCID)
- Common Chain Receptor deficiency.
(X-Linked SCID)
- Adenosine Deaminase (ADA) deficiency
- RAG-1 or RAG-2 deficiency
Stem Cell Pro-T Pre-T Immature T Immature T
TCR
Naive mature T
Stem Cell Pro-B Pre-B Immature B Mature B
IgM,IgD
Effector B
ADA, PNPdeficiency
(Autosomal SCID)
RAG deficiency
(Autosomal SCID)
SEVERE COMBINED IMMUNODEFICIENCY (SCID)
-Chain deficiency
(X-Linked SCID)
DiGEORGE SYNDROME (LACK OF THYMUS)
ADA, PNP deficiency (Autosomal SCID)
Adenosine Deaminase
(ADA) deficiency
Autosomal resessive
of inheritance
Accumulation of
S-adenosylhomocysteine
& deoxyadenosine
tripohosphate(dATP)
DNA synthesis
Purine Nucleoside Phosphorilase
(PNP) deficiency
Accumulation of
deoxyguanosine &
deoxyguanosine
Triphosphate (dGTP)
No maturation from Stem Cells to Pro and
from Pro to Pre Lymphocytes.
DNA synthesis
Cell injury by accumulation of purine toxic metabolites
RAG deficiency (Autosomal SCID)
Autosomal Resessive
of Inherittance
Mutation RAG-1 or RAG-2 genes
Defect antigen receptor
No mature Lymphocytes
-Chain deficiency (X-Linked SCID)
Resessive mutation of
common Chain in X-Chr.
No Receptor of IL-12, IL-7.IL-5 & IL-19
No Signal of Thymocyte Maturation
No maturation of T Cell
No differentiation of B cell to
antibody-producing plasma cells
No help factors
DEFECT IN B CELL MATURATION
1. X-Linked Agammaglobulinemia
(BRUTON DISEASE)
2. Transient
Hypogammaglobulinemia of
Infancy
HISTORY
1953 BRUTON OBSERVED 8 YEARS
BOY WHO HAD SEPSIS AND ARTHRITIS
SINCE AGE 4 YEARS
NO RESPONSE TO THYPOID AND
DIFTERI IMUNIZATION
SERUM PROTEIN NO GAMMA
GLOBULIN
BRUTON DISEASE:
NO B CELLS IN THE BLOOD AND LYMPHOID
TISSUE
X LINKED AGAMMAGLOBULINAEMIA AFFECTING
MALES
LYMPH NODES VERY SMALL.
THEIR SERUM CONTAINS NO IgA, IgM, IgD OR
IgE. IgG ONLY SMALL AMOUNT
IN THE 6-12 MONTHS PROTECTED FROM
INFECTION BY MATERNAL IgG
AFTER MATERNAL IgG EXHAUSTED
RECURRENT PYOGENIC INFECTION.
INFUSED I.V. LARGE DOSES OF GAMMA
GLOBULIN REMAIN HEALTHY
Defect in B Cell Maturation
X-linked agammaglobulinemia

Deficiency B cell progenitor
kinase enzym
Agammaglobulinemia
Chromosome Xq22
(mutation or deletion of gene)
Stop in Pre B Cell
Pro-B Pre-B Immature B Mature B
Bone Marrow

Peripheral lymphoid
organ or tissue
IgM,IgD
Effector B
Deficiency B cell progenitor
kinase enzym
Agammaglobulinemia
Chromosome Xq22 (Gene mutation)
X-LINKED AGAMMAGLOBULINEMIA
DEFECT IN T CELL MATURATION
1. Digeorge Syndrome.
2. Chronic Mucocutaneous Candidiasis
3. Natural Killer Cell Deficiency.
4. Idiophatic CD4 Lymphocytopenia
5. Biotin-Dependent Carboxilase Deficiency.
Defect in T Cell Maturation
The Digeorge Syndrome
Congenetal malformation of
the tymus and parathyroid glands
Deficient T Cell
Maturation
Abnormal in Calcium
homeostatis and tetany.
Absent of peripheral blood T cells.
Stem Cell Pro-T Pre-T Immature T Immature T
BM Periphery
TCR
No respon to antigen

Pos & Neg
selection
activation by
Foreign ant
Naive mature T

Thymus
Negative
selection
IMMUNODEFICIENCY
DEFECT IN T CELL MATURATION
(DiGeorge Syndrome)
Absent of peripheral blood T cells.
Congenetal malformation
Deletion in chromosome 22q11.2
DiGEORGES SYNDROME
T CELL DEFICIENCY
THYMUS AND PARATHYROID NOT DEVELOP
LOST CELLULAR IMMUNITY
EASY INFECTION BY FUNGUS AND VIRUS
TETANY
T CELL DEFICIENCY VARIABLE HOW
BADLY THE THYMUS GLAND IS AFFECTED
2. DEFECT IN B CELL ACTIVATION
1. Selective immunoglobulin isotypes
deficiency (IgA, IgG Subclass).
2. Defect in T cell dependent B cell
activation (The X-linked Hyper-IgM
Syndrome)
3. Defect in B Cell differentiation
(Common Variable Immunodeficiency)
Defect in B Cell Activation
Selective immunoglobulin
Isotypes deficiency
(IgA or Subclass of IgG)
Abnormal in
B Cell Differentiation
Abnormal in
T Cell help
Block in Differentiation from mature B cell to
Plasma Cell
IgA or Subclass IgG deficiency
?
?
IgM,IgD
Mature B Cell
Plasma Cell
Common Variable Immunodeficiency
Defect in differentiation from Mature B Cell to Plasma Cell
Immnoglobulin
Cause : ?
Symptoms :
- Absent of plasma cells in lymphoid tissue
- Hypogammaglobulinemia
(immunoglobulin deficiency)
X LINKAGE HYPER IgM
SYNDROME
1. Mutasi pada gen yang mengkode
protein CD40, tidak dapat menghantar
signal dari sel T ke sel B.(Ch.X)
2. Tidak ada aktipasi (help factor) dari sel
T ke sel B.
3. Tidak ada switch IgM ke IgG dan IgA
4. Terjadi peninggian kadar IgM.
Immunodeficiency caused by defects in B and T cell activation. Primary immunodeficiencies may be
caused by genetic defects in molecules required for T or B lymphocyte antigen receptor signaling, for
helper T cell-mediated activation of B cells and antigen presenting cells (APCs), or for the activation of
cytotoxic T lymphocytes and NK cells. Common variable immunodeficiency (CVID) has a number of
causes, including mutations in ICOS (inducible costimulator) and TACI (transmembrane activator and
calcium modulator and cyclophilin ligand interactor). TACI mutations are also a frequent cause of selective
IgA deficiency. Patients with hyper-IgM syndrome who harbor mutations in the CD40 signaling pathway
(CD40 ligand [CD40L], CD40, or NEMO) have defects in both T helper cell-mediated B cell activation and
the activation of APCs and cell-mediated immunity. The most frequently mutated gene causing the hyper-
IgM syndrome is the CD40L gene, which is X-linked. Mutations in the enzymes AID and in UNG cause
hyper-IgM syndromes that only affect B cells. Mutations in a signaling molecule (SAP), in perforin, and in
genes encoding proteins involved in granule exocytosis, such as Rab27A, and the Rab27A binding
protein MUNC13-4, are all causes of hemophagocytic lymphohistiocytosis (HLH).
Downloaded from: StudentConsult (on 20 November 2007 07:29 AM)
2005 Elsevier
MHC
TCR
helper effect
activation
T cells
B cells
cytokine
receptors
cytokines
CD40
CD40L
Ag
membrane cells
membrane cells
Nucleous
Nucleous
THE X LINKAGE HYPER
IgM SYNDROME
1
3
2
No heavy chain
isotype switching
4
Defect in T Cell Activation
Defect in expression of molecule(s) for
T cell Activation
Defective Class-II MHC Expression (The
Bare Lymphocyte Syndrome)
Defective Class-I MHC Expression.

CD3
CD3


TCR
HELPER
T CELL
APC
CLASS II MHC
CD4
(Coreceptor)
ANTIGEN
TCR-CD3
COMPLEX
CD2
LFA3
CD28
B7
LFA-1
ICAM-1(CD54)
CD45
CD22
..
CD72
CD5
Accessory Molecules
Zap-70
INF
IL-2
DEFECT IN
T CELL
ACTIVATION
THE BARE LYMPHOCYTE
SYNDROME
TCR
self & foreign
peptide
Peptide-MHC Bound
Presentation
ER
CTL(CD8)
MHC-I
PEPTIDE PROCESSING & PRESENTATION
The Cytosolic (Class I) Pathway
Endoplasmic Reticulum
NUCLEOTED CELLS
TAP
Mutation of TAP Gene
Defect in
Class-I MHC
Expression
MECHANISM OF DEFECTIVE CLASS I MHC EXPRESSION
TCR
Phagocytosis
Antigen
Endocytosis
Peptide-MHC Bound
Presentation
Thymic APC/
Epithelial Cell
ER
Mature
CD4
MHC-II
PEPTIDE PROCESSING & PRESENTATION
The Endocytic (Class II) Pathway
No positive Selection
in the thymus
Defect in Class-II
MHC expression
MECHANISM OF THE BARE LYMPHOCYTE SYNDROME
Mutation of Tanscription
factor RFX5 or CIITA
CD4 CD8
TCR
MHC-II
Thymic
epithelial cell
CD4 CD8
TCR
MHC-II
Thymic
APC
CD4 CD8
TCR
MHC-II
Thymic
epithelial cell
Apoptosis Apoptosis Survive
Lack of
positive selection
Positive
selection
Negative
selection
(low affinity)
(high affinity)
T CELL SELECTION IN THE THYMUS
WISKOTT-ALDRICH SYNDOME
(WAS)
THE CAUSE mutasi pada gen yang
mengkode pembentukan protein ( WAS
Protein) yang akan mengikat berbagai
molekul adaptor dan komponen
sitoskeletal dalam sel hematopoietik
sehingga trombosit dan neutropil kecil,
tidak berkembang normal dan gagal
bermigarsi

WISKOTT-ALDRICH SYNDOME
(WAS)
LOW THROMBOCYT THROMBOCYTOPENIA
AFFECTED MALES (X-linked disease)
DEVELOP SEVERE ECZEMA AS WELL AS
PYOGENIC AND OPPORTUNISTIC
INFECTIONS.
IN THE SERUM IgA AND Ig E INCREASED, IgG
NORMAL, IgM DECREASED
T CELLS DEFECTED IN FUNCTION.
ACQUIRED IMMUNODEFICIENCY
MALNUTRITION
NEOPLASMA
INFECTIONS
SPLEENECTOMY
CHEMOTHERAPOITIC DRUGS.
ANTI-INFLAMATORY &
IMMUNOSUPRESSIVE DRUGS.
MALNUTRITION
global metabolic disturbance
Adversly affect on maturation and function
of immuno competent cells
IMMUNODEFICIENCY
NEOPLASMS
Bone marrow tumors,
metastatic to marrow
and leucemia
Interfere the growth and
development of lymphocytes
Product of Tumor
Cells (TGF-)
Hodgkin Disease
Impairment in
T Cell function
INFECTIOUS
HIV HTLV-1 M-TBC/FUNGI.
CD-4 T CELL
KILLING LYMPHOTROPIC
AIDS ATL
MALARIA
ANERGY
DEPRESSED
T CELL
FUNCTION
HIV INFECTION
CLINICAL LATENCY
Figure 20-3 Structure of HIV-1. An HIV-1 virion is shown next to a T cell surface. HIV-1 consists of two identical strands of RNA (the viral genome) and associated
enzymes, including reverse transcriptase, integrase, and protease, packaged in a cone-shaped core composed of p24 capsid protein with a surrounding p17 protein
matrix, all surrounded by a phospholipid membrane envelope derived from the host cell. Virally encoded membrane proteins (gp41 and gp120) are bound to the
envelope. CD4 and chemokine receptors on the host cell surface function as HIV-1 receptors. (© 2000 Terese Winslow.)
Downloaded from: StudentConsult (on 20 November 2007 07:29 AM)
2005 Elsevier
Figure 20-4 HIV-1 genome. The
genes along the linear genome are
indicated as differently colored
blocks. Some genes use some of
the same sequences as other
genes, as shown by overlapping
blocks, but are read differently by
host cell RNA polymerase.
Similarly shaded blocks separated
by lines indicate genes whose
coding sequences are separated in
the genome and require RNA
splicing to produce functional
mRNA. (Adapted from Greene W.
AIDS and the immune system.
Copyright 1993 by Scientific
American, Inc. All rights reserved.)
Downloaded from: StudentConsult (on 20 November 2007 07:29 AM)
2005 Elsevier
Figure 20-5 HIV life cycle. The sequential steps in the life cycle of HIV are shown, from initial infection of a host cell to viral replication and release of a new virion. For the
sake of clarity, the production and release of only one new virion are shown. An infected cell actually produces many virions, each capable of infecting cells, thereby
amplifying the infectious cycle.
Downloaded from: StudentConsult (on 20 November 2007 07:29 AM)
2005 Elsevier
Figure 20-7 Progression of HIV
infection. The progression of
HIV infection correlates with
spread of the virus from the
initial site of infection to lymphoid
tissues throughout the body. The
immune response of the host
temporarily controls acute
infection but does not prevent
the establishment of chronic
infection of cells in lymphoid
tissues. Cytokine stimuli induced
by other microbes serve to
enhance HIV production and
progression to AIDS.
Downloaded from: StudentConsult (on 20 November 2007 07:29 AM)
2005 Elsevier
Figure 20-8 Clinical course of HIV disease. A. Plasma viremia, blood CD4+ T cell counts, and clinical
stages of disease. About 12 weeks after infection, blood-borne virus (plasma viremia) is reduced to very
low levels (detectable only by sensitive reverse-transcriptase polymerase chain reaction assays) and
stays this way for many years. Nonetheless, CD4+ T cell counts steadily decline during this clinical
latency period because of active viral replication and T cell infection in lymph nodes. When CD4+ T cell
counts drop below a critical level (about 200/mm3), the risk for infection and other clinical components of
AIDS is high. B. Immune response to HIV infection. A CTL response to HIV is detectable by 2 to 3
weeks after the initial infection and peaks by 9 to 12 weeks. Marked expansion of virus-specific CD82+ T
cells occurs during this time, and up to 10% of a patient's CTLs may be HIV specific at 12 weeks. The
humoral immune response to HIV peaks at about 12 weeks.
MAJOR IMMUNOLOGIC FEATURES
REDUCED HELPER/SUPRESSOR T RATIOS
REDUCED PHERIPHERAL BLOOD
LYMPHOCYTE RESPONSE TO MITOGENS
AND ANTIGENS
ELEVATED IMMUNOGLOBULINS LEVEL
REDUCED TO ABSENT ANTIBODY
RESPONSE FOLLOWING IMMUNIZATION
INCREASED CIRCULATING IMMUNE
COMPLEXES
REDUCED NK CELL ACTIVITY
REDUCED INTERLEUKIN 2 PRODUCTION
Major Clinical Form
Oppurtunistic Infection
Kaposis Sarcoma
Other Cancer
Lymphadenopathy
Syndrome
Figure 20-6 Mechanism of HIV entry into a cell. In the model depicted, sequential conformational changes in gp120 and gp41 are induced by binding to CD4. These
changes promote binding of the virus to the coreceptor (a chemokine receptor) and fusion of the HIV-1 and host cell membranes. The fusion peptide of activated gp41
contains hydrophobic amino acid residues that mediate insertion into the host cell plasma membrane.
Downloaded from: StudentConsult (on 20 November 2007 07:29 AM)
2005 Elsevier
HIV VIRION
CLINICAL SYMPTOMS
IMMUNOPATHOGENESIS OF HIV INFECTION

CD4+T CELLS AND MACROPHAGES ARE THE MAYOR TARGET OF HIV
INFECTION OF THESE TWO CELLS LEAD A MARKED LOSS OF CD4+TCELL
DISSEMINATION OF HIV TO VARIOUS TISSUE ESPECIALLY THE CNS
EXTENSIVE VIRUS REPLICATION
OPPURTINISTIC INFECTIONAND NEOPLASM
TYPICAL COURSE OF HIV INFECTION