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IMMUNODEFICIENCY
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

IMMUNODEFICIENCY H & L chain IgM,IgD Stem Cell Pro-B Pre-B Effector B Bone Marrow Immature B

H chain

H & L chain

IMMUNODEFICIENCY H & L chain IgM,IgD Stem Cell Pro-B Pre-B Effector B Bone Marrow Immature B
IMMUNODEFICIENCY H & L chain IgM,IgD Stem Cell Pro-B Pre-B Effector B Bone Marrow Immature B
IgM,IgD
IgM,IgD
IMMUNODEFICIENCY H & L chain IgM,IgD Stem Cell Pro-B Pre-B Effector B Bone Marrow Immature B

Stem Cell

Pro-B

Pre-B

Effector B

   

Bone Marrow

Immature B Mature B Peripheral lymphoid organ or tissue

No antigen dependence

Self antigen

Foreign antigen

IMMUNODEFICIENCY H & L chain IgM,IgD Stem Cell Pro-B Pre-B Effector B Bone Marrow Immature B

RAG-1 and RAG-2 expression

2. DEFECT IN

1. DEFECT IN B CELL MATURATION

B CELL

 

ACTIVATION

IMMUNODEFICIENCY

IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T BM Thymus Immature T Naive mature T Periphery
IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T BM Thymus Immature T Naive mature T Periphery

TCR

IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T BM Thymus Immature T Naive mature T Periphery
α ß
α
ß

Stem Cell

Pro-T

Pre-T

Immature T

BM

 

Thymus

Immature T Naive mature T 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

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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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

IgM,IgD
IgM,IgD
IgM,IgD Pre-B Effector B Immature B Mature B RAG deficiency (Autosomal SCID) Stem Cell Pro-B γ

Pre-B

IgM,IgD Pre-B Effector B Immature B Mature B RAG deficiency (Autosomal SCID) Stem Cell Pro-B γ

Effector B

Immature B Mature B

RAG deficiency (Autosomal SCID)

IgM,IgD Pre-B Effector B Immature B Mature B RAG deficiency (Autosomal SCID) Stem Cell Pro-B γ

Stem Cell

Pro-B
Pro-B

γ-Chain deficiency (X-Linked SCID)

ADA, PNPdeficiency (Autosomal SCID)

TCR
TCR
IgM,IgD Pre-B Effector B Immature B Mature B RAG deficiency (Autosomal SCID) Stem Cell Pro-B γ
IgM,IgD Pre-B Effector B Immature B Mature B RAG deficiency (Autosomal SCID) Stem Cell Pro-B γ
IgM,IgD Pre-B Effector B Immature B Mature B RAG deficiency (Autosomal SCID) Stem Cell Pro-B γ

Stem Cell

Pro-T

Pre-T

Immature T

Immature T Naive mature T

ADA, PNP deficiency (Autosomal SCID)

DNA synthesis

DNA synthesis

ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)

Autosomal resessive of inheritance

ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)
ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)

Adenosine Deaminase

(ADA) deficiency

ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)

Accumulation of S-adenosylhomocysteine & deoxyadenosine tripohosphate(dATP)

ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)

Purine Nucleoside Phosphorilase (PNP) deficiency

ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)

Accumulation of deoxyguanosine &

deoxyguanosine

Triphosphate (dGTP)

ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)
ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)

Cell injury by accumulation of purine toxic metabolites

ADA, PNP deficiency (Autosomal SCID) DNA synthesis DNA synthesis Autosomal resessive of inheritance Adenosine Deaminase (ADA)

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

Mutation RAG-1 or RAG-2 genes

 
Mutation RAG-1 or RAG-2 genes Defect antigen receptor

Defect antigen receptor

 
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
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
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
HISTORY  1953 BRUTON OBSERVED 8 YEARS BOY WHO HAD SEPSIS AND ARTHRITIS SINCE AGE 4

BRUTON DISEASE:

BRUTON DISEASE: • NO B CELLS IN THE BLOOD AND LYMPHOID TISSUE • X LINKED AGAMMAGLOBULINAEMIA
• NO B CELLS IN THE BLOOD AND LYMPHOID TISSUE • X LINKED AGAMMAGLOBULINAEMIA AFFECTING MALES
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
BRUTON DISEASE: • NO B CELLS IN THE BLOOD AND LYMPHOID TISSUE • X LINKED AGAMMAGLOBULINAEMIA

Defect in B Cell Maturation

X-linked agammaglobulinemia

Chromosome Xq22 (mutation or deletion of gene)

Defect in B Cell Maturation X-linked agammaglobulinemia Chromosome Xq22 (mutation or deletion of gene) Deficiency B

Deficiency B cell progenitor

kinase enzym

Stop in Pre B Cell

Stop in Pre B Cell

Stop in Pre B Cell

Agammaglobulinemia

X-LINKED AGAMMAGLOBULINEMIA

IgM,IgD

X-LINKED AGAMMAGLOBULINEMIA IgM,IgD Pre-B Bone Marrow Pro-B Effector B Immature B Mature B Peripheral lymphoid organ
X-LINKED AGAMMAGLOBULINEMIA IgM,IgD Pre-B Bone Marrow Pro-B Effector B Immature B Mature B Peripheral lymphoid organ
Pre-B Bone Marrow
Pre-B
Bone Marrow

Pro-B

X-LINKED AGAMMAGLOBULINEMIA IgM,IgD Pre-B Bone Marrow Pro-B Effector B Immature B Mature B Peripheral lymphoid organ

Effector B

Immature B Mature B Peripheral lymphoid

organ or tissue

X-LINKED AGAMMAGLOBULINEMIA IgM,IgD Pre-B Bone Marrow Pro-B Effector B Immature B Mature B Peripheral lymphoid organ

Deficiency B cell progenitor kinase enzym

Agammaglobulinemia

X-LINKED AGAMMAGLOBULINEMIA IgM,IgD Pre-B Bone Marrow Pro-B Effector B Immature B Mature B Peripheral lymphoid organ

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

Defect in T Cell Maturation The Digeorge Syndrome Congenetal malformation of the tymus and parathyroid glands

Deficient T Cell Maturation

Defect in T Cell Maturation The Digeorge Syndrome Congenetal malformation of the tymus and parathyroid glands

Abnormal in Calcium homeostatis and tetany.

Absent of peripheral blood T cells.

IMMUNODEFICIENCY

IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T Immature T Naive mature T Thymus Pos &
IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T Immature T Naive mature T Thymus Pos &
IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T Immature T Naive mature T Thymus Pos &

TCR

IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T Immature T Naive mature T Thymus Pos &
α ß
α
ß

Stem Cell

Pro-T

Pre-T

Immature T

Immature T Naive mature T

Thymus Pos & Neg Negative selection selection
Thymus
Pos & Neg
Negative
selection
selection

BM

No respon to antigen

Periphery

activation by

Foreign ant

DEFECT IN T CELL MATURATION (DiGeorge Syndrome)

IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T Immature T Naive mature T Thymus Pos &

Congenetal malformation

IMMUNODEFICIENCY TCR α ß Stem Cell Pro-T Pre-T Immature T Naive mature T Thymus Pos &

Absent of peripheral blood T cells.

Deletion in chromosome 22q11.2

DiGEORGE’S SYNDROME

DiGEORGE’S SYNDROME • T CELL DEFICIENCY • THYMUS AND PARATHYROID NOT DEVELOP • LOST CELLULAR IMMUNITY
DiGEORGE’S SYNDROME • T CELL DEFICIENCY • THYMUS AND PARATHYROID NOT DEVELOP • LOST CELLULAR IMMUNITY

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

Defect in B Cell Activation Selective immunoglobulin Isotypes deficiency (IgA or Subclass of IgG) Abnormal in

?

Abnormal in T Cell help

Defect in B Cell Activation Selective immunoglobulin Isotypes deficiency (IgA or Subclass of IgG) Abnormal in

?

Block in Differentiation from mature B cell to Plasma Cell

Defect in B Cell Activation Selective immunoglobulin Isotypes deficiency (IgA or Subclass of IgG) Abnormal in

IgA or Subclass IgG deficiency

Common Variable Immunodeficiency

IgM,IgD

Common Variable Immunodeficiency IgM,IgD Mature B Cell Immnoglobulin Defect in differentiation from Mature B Cell to

Mature B Cell

Common Variable Immunodeficiency IgM,IgD Mature B Cell Immnoglobulin Defect in differentiation from Mature B Cell to
Common Variable Immunodeficiency IgM,IgD Mature B Cell Immnoglobulin Defect in differentiation from Mature B Cell to

Plasma Cell

Common Variable Immunodeficiency IgM,IgD Mature B Cell Immnoglobulin Defect in differentiation from Mature B Cell to

Immnoglobulin

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

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).

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THE X LINKAGE HYPER IgM SYNDROME

Nucleous

T cells

4 membrane cells activation CD40L TCR Ag MHC CD40 1 3 helper effect 2 No heavy
4
membrane cells
activation
CD40L
TCR
Ag
MHC
CD40
1
3
helper effect
2
No heavy chain
isotype switching
Nucleous

cytokines

cytokine

receptors

membrane cells

B cells

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.

ICAM-1(CD54) CD22 THE BARE LYMPHOCYTE LFA3 APC SYNDROME B7 CD72 DEFECT IN T CELL ACTIVATION CLASS
ICAM-1(CD54)
CD22
THE BARE LYMPHOCYTE
LFA3
APC
SYNDROME
B7
CD72
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
CD3
CD45
ζ
ζ
Zap-70
HELPER
T CELL
LFA-1

PEPTIDE PROCESSING & PRESENTATION

The Cytosolic (Class I) Pathway

MECHANISM OF DEFECTIVE CLASS I MHC EXPRESSION

Endoplasmic Reticulum self & foreign peptide Peptide-MHC Bound CTL(CD8) TAP Presentation ER TCR MHC-I Mutation of
Endoplasmic Reticulum
self & foreign
peptide
Peptide-MHC Bound
CTL(CD8)
TAP
Presentation
ER
TCR
MHC-I
Mutation of TAP Gene
Defect in
Class-I MHC
NUCLEOTED CELLS
Expression
PEPTIDE PROCESSING & PRESENTATION The Cytosolic (Class I) Pathway MECHANISM OF DEFECTIVE CLASS I MHC EXPRESSION

The Endocytic (Class II) Pathway

MECHANISM OF THE BARE LYMPHOCYTE SYNDROME

Endocytosis Peptide-MHC Bound Mature Phagocytosis Presentation CD4 TCR Antigen ER MHC-II Thymic APC/ Epithelial Cell Defect
Endocytosis
Peptide-MHC Bound
Mature
Phagocytosis
Presentation
CD4
TCR
Antigen
ER
MHC-II
Thymic APC/
Epithelial Cell
Defect in Class-II
MHC expression
Mutation of Tanscription
factor RFX5 or CIITA
No positive Selection
in the thymus
The Endocytic (Class II) Pathway MECHANISM OF THE BARE LYMPHOCYTE SYNDROME Endocytosis Peptide-MHC Bound Mature Phagocytosis

T CELL SELECTION IN THE THYMUS

 

Lack of

positive selection

 
 
 

Thymic

epithelial cell

 
MHC-II

MHC-II

   
TCR

TCR

CD4

CD8

Lack of positive selection Thymic epithelial cell MHC-II TCR CD4 CD8 Apoptosis

Apoptosis

 
T CELL SELECTION IN THE THYMUS Lack of positive selection Thymic epithelial cell MHC-II TCR CD4
Positive selection Thymic epithelial cell MHC-II TCR CD4 CD8 (low affinity) Survive
Positive
selection
Thymic
epithelial cell
MHC-II
TCR
CD4
CD8
(low affinity)
Survive

Negative

selection

Thymic

APC

MHC-II TCR CD4 CD8
MHC-II
TCR
CD4
CD8

(high affinity)

T CELL SELECTION IN THE THYMUS Lack of positive selection Thymic epithelial cell MHC-II TCR CD4

Apoptosis

WISKOTT-ALDRICH SYNDOME (WAS) • THE CAUSE  mutasi pada gen yang mengkode pembentukan protein ( WAS
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) • THE CAUSE  mutasi pada gen yang mengkode pembentukan protein ( WAS
WISKOTT-ALDRICH SYNDOME (WAS) • LOW THROMBOCYT THROMBOCYTOPENIA • AFFECTED MALES (X-linked disease) • DEVELOP SEVERE ECZEMA
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.
WISKOTT-ALDRICH SYNDOME (WAS) • LOW THROMBOCYT THROMBOCYTOPENIA • AFFECTED MALES (X-linked disease) • DEVELOP SEVERE ECZEMA

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

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

Product of Tumor

Cells (TGF-ß)

Bone marrow tumors, metastatic to marrow

and leucemia

Hodgkin Disease

Impairment in

T Cell function

Interfere the growth and

development of lymphocytes

INFECTIOUS

INFECTIOUS HTLV-1 HIV M-TBC/FUNGI . MALARIA CD-4 T CELL ANERGY KILLING LYMPHOTROPIC DEPRESSED T CELL FUNCTION

HTLV-1

INFECTIOUS HTLV-1 HIV M-TBC/FUNGI . MALARIA CD-4 T CELL ANERGY KILLING LYMPHOTROPIC DEPRESSED T CELL FUNCTION
HIV
HIV

M-TBC/FUNGI.

MALARIA

INFECTIOUS HTLV-1 HIV M-TBC/FUNGI . MALARIA CD-4 T CELL ANERGY KILLING LYMPHOTROPIC DEPRESSED T CELL FUNCTION
INFECTIOUS HTLV-1 HIV M-TBC/FUNGI . MALARIA CD-4 T CELL ANERGY KILLING LYMPHOTROPIC DEPRESSED T CELL FUNCTION

CD-4 T CELL

INFECTIOUS HTLV-1 HIV M-TBC/FUNGI . MALARIA CD-4 T CELL ANERGY KILLING LYMPHOTROPIC DEPRESSED T CELL FUNCTION
INFECTIOUS HTLV-1 HIV M-TBC/FUNGI . MALARIA CD-4 T CELL ANERGY KILLING LYMPHOTROPIC DEPRESSED T CELL FUNCTION

ANERGY

KILLING

LYMPHOTROPIC

DEPRESSED

T CELL FUNCTION

AIDS
AIDS
ATL
ATL

HIV INFECTION

CLINICAL LATENCY

Figure 20-3 Structure of HIV-1. An HIV-1 virion is shown next to a T cell surface.

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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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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Figure 20-5 HIV life cycle. The sequential steps in the life cycle of HIV are shown,

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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Figure 20-7 Progression of HIV infection. The progression of HIV infection correlates with spread of the

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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Figure 20-8 Clinical course of HIV disease . A. Plasma viremia , blood CD4+ T cell

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
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 IMMUNOLOGIC FEATURES  REDUCED HELPER/SUPRESSOR T RATIOS  REDUCED PHERIPHERAL BLOOD LYMPHOCYTE RESPONSE TO MITOGENS
Major Clinical Form Oppurtunistic Infection Kaposi’s Sarcoma Other Cancer Lymphadenopathy Syndrome
Major Clinical Form
Oppurtunistic Infection
Kaposi’s Sarcoma
Other Cancer
Lymphadenopathy
Syndrome
Figure 20-6 Mechanism of HIV entry into a cell. In the model depicted, sequential conformational changes

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

CLINICAL SYMPTOMS EXTENSIVE VIRUS REPLICATION OPPURTINISTIC INFECTIONAND NEOPLASM IMMUNOPATHOGENESIS OF HIV INFECTION • CD4+T CELLS AND

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