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

IMMUNODEFICIENCY
H chain

Stem Cell

Pro-B

Pre-B

Bone Marrow
No antigen dependence

H & L chain

IgM,IgD

Immature B Mature B Effector B

Peripheral lymphoid
organ or tissue
Self antigen Foreign antigen

RAG-1 and RAG-2 expression

1. DEFECT IN B CELL MATURATION

2. DEFECT IN
B CELL
ACTIVATION

IMMUNODEFICIENCY

TCR

Stem Cell Pro-T Pre-T Immature T Immature TNaive mature T

BM

No respon to antigen

Periphery

Thymus

Pos & Neg

selection

Negative
selection

1. DEFECT IN T CELL MATURATION

activation by
Foreign ant
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. IL7R 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.
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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

SEVERE COMBINED IMMUNODEFICIENCY (SCID)

IgM,IgD

Stem Cell

Pro-B

ADA, PNPdeficiency
(Autosomal SCID)

Pre-B

Immature B Mature B Effector B

RAG deficiency -Chain deficiency

(Autosomal SCID) (X-Linked SCID)

TCR

Stem Cell Pro-T Pre-T Immature T Immature TNaive mature T

DiGEORGE SYNDROME (LACK OF THYMUS)

ADA, PNP deficiency (Autosomal SCID)

DNA synthesis

DNA synthesis
Autosomal resessive
of inheritance

Adenosine Deaminase
(ADA) deficiency
Accumulation of
S-adenosylhomocysteine
& deoxyadenosine
tripohosphate(dATP)

Purine Nucleoside Phosphorilase

(PNP) deficiency

Accumulation of
deoxyguanosine &
deoxyguanosine
Triphosphate (dGTP)

Cell injury by accumulation of purine toxic metabolites

No maturation from Stem Cells to Pro and

from Pro to Pre Lymphocytes.

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 help factors
No differentiation of B cell to
antibody-producing plasma cells

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
Chromosome Xq22
(mutation or deletion of gene)
Deficiency B cell progenitor
kinase enzym
Stop in Pre B Cell
Agammaglobulinemia

X-LINKED AGAMMAGLOBULINEMIA
IgM,IgD

Pro-B

Pre-B

Bone Marrow

Immature B Mature B Effector B

Peripheral lymphoid
organ or tissue

Deficiency B cell progenitor

kinase enzym

Agammaglobulinemia

Chromosome Xq22 (Gene mutation)

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.

IMMUNODEFICIENCY

TCR

Stem Cell Pro-T Pre-T Immature T Immature TNaive mature T

BM

No respon to antigen

Periphery

Thymus

Pos & Neg

selection

DEFECT IN T CELL MATURATION

(DiGeorge Syndrome)

Absent of peripheral blood T cells.

Negative
selection

activation by
Foreign ant

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

Common Variable Immunodeficiency

IgM,IgD

Immnoglobulin
Mature B Cell

Plasma Cell

Defect in differentiation from Mature B Cell to Plasma Cell

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 hyperIgM 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
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protein MUNC13-4, are all causes of hemophagocytic lymphohistiocytosis (HLH). 2005 Elsevier

Nucleous

THE X LINKAGE HYPER

IgM SYNDROME

T cells

activation

membrane cells
CD40L

TCR

cytokines

MHC

cytokine
receptors

Ag
1

CD40

membrane cells
3

No heavy chain
isotype switching

helper effect

B cells

2
Nucleous

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.

CD22 ICAM-1(CD54)
LFA3
B7
CD72
DEFECT IN
T CELL
ACTIVATION

APC

THE BARE LYMPHOCYTE

SYNDROME

CLASS II MHC

Accessory Molecules

ANTIGEN
CD4

(Coreceptor)

INF
IL-2
..
CD5
CD28 CD2
CD45 LFA-1 Zap-70

TCR

TCR-CD3
COMPLEX

CD3

HELPER
CD3
T CELL

PEPTIDE PROCESSING & PRESENTATION

The Cytosolic (Class I) Pathway
MECHANISM OF DEFECTIVE CLASS I MHC EXPRESSION

Endoplasmic Reticulum

self & foreign

peptide

Peptide-MHC Bound

TAP

Presentation
ER

MHC-I

CTL(CD8)

TCR

Mutation of TAP Gene

NUCLEOTED CELLS

Defect in
Class-I MHC
Expression

PEPTIDE PROCESSING & PRESENTATION

The Endocytic (Class II) Pathway
MECHANISM OF THE BARE LYMPHOCYTE SYNDROME
Endocytosis

Peptide-MHC Bound

Phagocytosis
Presentation

Mature
CD4

TCR
Antigen

ER
MHC-II

Thymic APC/
Epithelial Cell
Mutation of Tanscription
factor RFX5 or CIITA

Defect in Class-II
MHC expression

No positive Selection
in the thymus

T CELL SELECTION IN THE THYMUS

Lack of
positive selection

Positive
selection

Thymic
epithelial cell

Thymic
epithelial cell

MHC-II

Negative
selection
Thymic
APC
MHC-II

MHC-II
TCR

TCR

CD4 CD8
(low affinity)

CD4 CD8
(high affinity)

TCR

CD4

CD8

Apoptosis

Survive

Apoptosis

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

Product of Tumor
Cells (TGF-)

Interfere the growth and

development of lymphocytes

Hodgkin Disease

Impairment in
T Cell function

INFECTIOUS

HIV

HTLV-1

CD-4 T CELL

KILLING

AIDS

M-TBC/FUNGI.

ANERGY

LYMPHOTROPIC

ATL

MALARIA

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.)

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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.)

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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.

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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.

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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.

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2005 Elsevier

HIV VIRION

CLINICAL SYMPTOMS
EXTENSIVE VIRUS REPLICATION

OPPURTINISTIC INFECTIONAND NEOPLASM

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

TYPICAL COURSE OF HIV INFECTION