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 ß 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 H & L chain IgM,IgD

Stem Cell Pro-B Pre-B Immature B Mature B Effector B

Bone Marrow Peripheral lymphoid
organ or tissue
No antigen dependence Self antigen Foreign antigen
RAG-1 and RAG-2 expression 2. DEFECT IN
1. DEFECT IN B CELL MATURATION B CELL
ACTIVATION
 IMMUNODEFICIENCY
α ß

TCR

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

BM Thymus Periphery
No respon to antigen Pos & Neg Negative activation by
selection selection Foreign ant

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.

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© 2005 Elsevier
Defect in B and T Cell Maturation

Severe Combined
Immunodeficiency (SCID)
- Common γ 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 Pre-B Immature B Mature B Effector B

ADA, PNPdeficiency RAG deficiency γ-Chain deficiency

(Autosomal SCID) (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 Purine Nucleoside Phosphorilase

(ADA) deficiency (PNP) deficiency

Accumulation of Accumulation of
S-adenosylhomocysteine deoxyguanosine &
& deoxyadenosine deoxyguanosine
tripohosphate(dATP) 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
γ-Chain deficiency (X-Linked SCID)
Resessive mutation of
common γ 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 Immature B Mature B Effector B

Bone Marrow Peripheral lymphoid
organ or tissue

Deficiency B cell progenitor Agammaglobulinemia

kinase enzym

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 Abnormal in Calcium

Maturation homeostatis and tetany.

Absent of peripheral blood T cells.

 IMMUNODEFICIENCY
α ß

TCR

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

BM Thymus Periphery
No respon to antigen Pos & Neg Negative activation by
selection selection Foreign ant

DEFECT IN T CELL MATURATION Congenetal malformation

(DiGeorge Syndrome)

Absent of peripheral blood T cells. Deletion in chromosome 22q11.2

 DiGEORGE’S 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 Abnormal in
B Cell Differentiation T Cell help
? ?
Block in Differentiation from mature B cell to
Plasma Cell

IgA or Subclass IgG deficiency

 Common Variable Immunodeficiency

IgM,IgD

Immnoglobulin

Plasma Cell
Mature B 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 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
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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
4

membrane cells activation

CD40L TCR cytokines

Ag cytokine
CD40 MHC receptors
1
membrane cells

3 helper effect
No heavy chain
isotype switching
2
B cells
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) THE BARE LYMPHOCYTE

B7
LFA3
CD72
APC SYNDROME

DEFECT IN
T CELL
ACTIVATION CLASS II MHC
ANTIGEN
Accessory Molecules
CD4
(Coreceptor)
TCR-CD3
INFγ α ß COMPLEX
IL-2
TCR CD3
…..

CD5
CD28 CD2 HELPER
CD45 LFA-1 Zap-70 ζ ζ 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 CTL(CD8)

ER TCR

MHC-I
Mutation of TAP Gene
Defect in
Class-I MHC
NUCLEOTED CELLS Expression
 PEPTIDE PROCESSING & PRESENTATION
The Endocytic (Class II) Pathway
MECHANISM OF THE BARE LYMPHOCYTE SYNDROME

Endocytosis Peptide-MHC Bound

Phagocytosis Mature
Presentation CD4
TCR
Antigen ER
MHC-II Defect in Class-II
Thymic APC/ MHC expression
Epithelial Cell

Mutation of Tanscription No positive Selection

factor RFX5 or CIITA in the thymus
T CELL SELECTION IN THE THYMUS
Lack of Positive Negative
positive selection selection selection
Thymic Thymic Thymic
epithelial cell epithelial cell APC

MHC-II MHC-II MHC-II

TCR TCR
TCR

CD4 CD8 CD4 CD8

CD4 CD8 (low affinity) (high affinity)

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,

Product of Tumor Hodgkin Disease
metastatic to marrow
Cells (TGF-ß)
and leucemia

Interfere the growth and Impairment in

development of lymphocytes T Cell function
 INFECTIOUS

HIV HTLV-1 M-TBC/FUNGI. MALARIA

CD-4 T CELL ANERGY DEPRESSED

T CELL
FUNCTION
KILLING LYMPHOTROPIC

AIDS ATL
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

OppurtunisticInfection
Kaposi’s 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