Mitzi Nagarkatti

Professor and Chair,

Dept. Pathology, Microbiology and Immunology
Deputy Director, Basic and Translational Research
SC Cancer Center
USC School of Medicine
Tel. # (803)733-3275
E-mail: mnagark@uscmed.sc.edu

Objectives
Definition
Primary Immunodeficiencies
Characteristics
Types

of primary immunodeficiency
disorders
Mode of inheritance
Diagnosis and Treatment
Secondary Immunodeficiency
Human Immunodeficiency Virus
Transmission
Therapy and prevention of AIDS

Immunodeficiency

Defect in 1 or more components of immune system

Types:
Primary or Congenital:
Born with the immunodeficiency
Inherited (Mutation in gene controlling immune cells)
Susceptible to recurrent, severe infection; starting in
children
Cannot recover without treatment
>125 immunodeficiency disorders
Secondary or Acquired: As a consequence of other
diseases or environmental factors
(e.g. infection, malignancy, aging, starvation,
medication, drugs) Human Immunodeficiency Virus

Hematopoiesis
Progenito
r

Progenito
r

Hematopoietic Stem Cell (HSC)

deficiency

HSC are multipotent (differentiate into all blood cell

types)
Self renewing cells
Lineage negative (mature B/T cell, granulocyte, M
markers absent)
CD34+, c-Kit+, Stem cell Ag (Sca-1+) on cell surface
Defect in HSC results in Reticular Dysgenesis
Affects development of all leukocytes
Patients are susceptible to all infections (bacterial,
viral, parasitic and fungal)
Fatal without treatment
Treated with bone marrow or HSC transplantation

Allogeneic BM/HSC
Transplantation

TCR

MHC

T cell
Thymus
T cell
MHC
Thymic
Stromal
Cells

HSC

TCR
T
cells

MHC-matched for atleast1-2 a

T cell depleted

Hematopoiesis
Progenito
r

Progenito
r

Myeloid Progenitor Cell Differentiation

Defect
Myeloid Progenitor Cells develop into

neutrophils and monocytes

Defect in differentiation from myeloid
progenitor cells into neutrophils results in
Congenital Agranulocytosis
Recurrent bacterial infections seen in
patients
Treated with granulocyte-macrophage
colony stimulating factor (GM-CSF) or G-CSF

Defective Neutrophils
Patients have neutrophils that are defective in

production of reactive oxygen species that is responsible

for killing of phagocytosed microrganisms.
Nitroblue tetrazolium test: reduction by superoxide (-ve)
This results in accumulation of granulocytes, M and T
cells forming granulomas. These patients suffer from
Chronic Granulomatous Disease.
Have recurrent bacterial infections
Commensals become pathogenic
X-linked or autosomal recessive
Treated with IFN-against infections

Inheritance

22 pairs of autosomes and 1 pair of sex chromosomes (X

and Y)
Autosomal recessive (most AA normal; Aa carrier; aa
affected)
Autosomal dominant (Aa affected; aa is normal)
X-linked
carrier daughter;
XY affected Carrier
son) x Normal
Carrier x (XX
Carrier
Normal x Affected
Mother
Aa

Father
Aa

Autosomal Recessive

Mother
aa

Father
Aa

Mother
Xx

Autosomal Dominant

Father
XY

X-lin

Leukocyte Adhesion deficiency

Adhesion molecule (e.g.CD18) may be lacking

on T cells and monocytes.

Autosomal recessive
Results in defective extravasation
Recurrent infections
Impaired wound healing
Treated with BM (depleted of T cells and
HLA matched) transplantation
or with gene therapy

Hematopoiesis
Progenito
r

Progenito
r

Defect in Lymphoid Progenitor

Results in Severe Combined Immunodeficiency

(SCID)
Lack T, B and/or NK cells
Thymus does not develop
Myeloid and erythroid cells are normal.
Generally lethal
Susceptible to bacterial, viral and fungal
infections.
In infants, passively transferred maternal Abs are
present.
Live attenuated vaccines (e.g. Sabin polio) can
cause disease.

Types
of
SCID

RAG-1/2 (Recombinase activating gene) deficiency:

Required for TCR and Ig gene rearrangement

T TCR
cell
s

B
cell
s

Ig

IL-2R gene defect

T
IL-2 receptor
cells/
IL-2
NK
cells
Adenosine deaminase (ADA) deficiency
AdenosineADA
Inosine
Uric acid
T, B and NK cell deficiency due to toxicity of accumulated
metabolites
First successful gene therapy done in patient

DiGeorge syndrome

Precursor T cell differentiation

defect

Athymic - DiGeorge Syndrome

Lack of T helper (Th) cells , Cytotoxic T cells
(CTL) and T regulatory (Treg) cells
B cells are present but T-dependent B cell
responses are defective
Anti-viral and anti-fungal immunity impaired
Developmental defect in the 3rd and 4th
pharyngeal pouch
Results in facial defect and congenital heart
disease
Treated with thymic transplant
Autosomal dominant trait

Nude Athymic mouse

nu/nu gene (autosomal recessive)

Hairless
Should be maintained in pathogen-free
environment
T helper cell defect
Results in impaired cytotoxic T cell activity
and Th-dependent B cell responses due to Th

X-linked Agammaglobulinemia (xAbsence of Igs and B cells

LA)

Arrest at Pre-B cell stage (H-chain rearranged not L

chain)

Hyper IgM Syndrome

Deficiency in IgG, IgA and IgE

Increased IgM in serum
B cells express IgD and IgM on
X-linked

Pre B
cells

x-LA
Mature B
cells
membrane
Proliferation

IgM

Recurrent infections

Selective Ig class deficiency

DifferentiationCVD
e.g. IgA deficiency
Plasma
Due to defect in isotype switching cells
Recurrent respiratory, gastrointestinal and/or

genitourinary infection

Isotype
switching

IgA def.

Common Variable
Immunodeficiency
B cells are normal
Defect in maturation to plasma cells
Decreased IgM, IgG and IgA or only IgG and IgA Pre B
cells
Susceptible to bacterial (e.g. pneumococci) infections
Low Ab titers against DPT or MMR Vaccines
Mature B
Usually not detected in children because
cellsof

x-LA

maternal Abs
Proliferation
Also called Late-onset hypogammaglobulinemia,
Adult-onset agammaglobulinemia or Acquired
DifferentiationCVD
agammaglobulinemia
Plasma
Ig replacement therapy and antibiotics
cells

IgM

Isotype
switching

IgA def.

Other
Immunodeficiencies
Bare lymphocyte syndrome:

Lack MHC class II on B cells, macrophages

and dendritic cells
Complement Deficiency

Primary
Immunodeficiencies
Stem Cell

Reticular
Dysgenesis

Myeloid
Progenitor
Congenital
Agranulocytos
is
Neutrophil

Chronic
Granulomatous
Disease (x or r)

Monocyte

Pre-B

Lymphoid
Progenitor
Severe combined
Immunodeficienc
y
SCID
Pre-T

x-linked
aglobulinemia
Mature B
Thymus
xLA
DiGeorge
Syndrome d

Plasma
Cell
Common Variable Hypoglobulinemia
/ x-linked hyperIgM syndrome/Selective
Ig deficiency

Memory B
Bare Lymphocyte
Syndrome

Mature
T

Adaptive Immunity
Deficiency
T cell deficiency
Susceptible to intracellular bacterial

infection
e.g. Salmonella typhi, Mycobacteria
Susceptible to viral, parasitic and fungal
infection
B cell deficiency
Susceptible to extracellular bacterial

infection e.g. Staphylococcal infection

Secondary or Acquired
Immunodeficiencies

Agent-induced immunodeficiency: e.g.

infections, metaboic disturbance, trauma,
corticosteroids, cyclosporin A, radiation,
chemotherapy
HIV

Human Immunodeficiency
Virus
Discovered in 1983 by Luc Montagnier and Robert

Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual, promiscuous
heterosexual, i.v. drug users, transfusion, infants
born to infected mothers
Opportunistic infections with Pnuemocystis carinii,
Candida albicans, Mycobacterium avium, etc.
Patients with HIV have high incidence of cancers
such as Kaposi sarcoma

Kaposi Sarcoma

Incidence of HIV

CDC 2008

Course of AIDS
Dissemination of virus;
Seeding of lymphoid organs

Anti-HIV Ab/CTL

ACUTE
PHASE

CHRONIC
PHASE AIDS

AIDS
(<200cells/mm3)

env

(Envelop
(p24)

(p17)

Protease
pol

Integrase

Matrixgag
Capsid

Abs are ineffective to

control
HIV

Virus grows intracellularly

Abs develop after ~3 weeks.
Thus cannot be used as a diagnostic test
initially (Reverse transcriptase is a sensitive
test)
Abs are not neutralizing

Role of T cells in development of

AIDS
Initially Th cells control viral load
Cytopathic virus
Syncitium formation with infected/uninfected

cells
Surviving Th cells are anergic
Destruction of infected Th cells by CTL
CTL that develop are ineffective because of high
viral mutations
Lack of Th affects CTL activation
Resistance to CTL by downregulation of class I
MHC on target cells

Animal Models
Primate Model:
HIV grows in chimpanzees but do not develop AIDS
Simian immunodeficiency virus (SIVagm in African
green monkey no disease; SIVmac in Macaques
AIDS like);
Feline immunodeficiency virus (FIV)
Mouse Model:
Grows in Severe Combined Immunodeficiency
(SCID) mice reconstituted with human lymphocytes

Coreceptors of HIV
Chemokine receptors
T cell-tropic (Syncitium-inducing; X4 virus strain)

CD4

CXCR4:
Ligand is SDF1 (Stromal cell
derived factor)

Macrophage-tropic (Nonsyncitium-inducing; R5

CD4
virus strain)CCR5:

Ligands are RANTES (Regulated on

activation, normal T cell expressed
and secreted),
MIP1, MIP1Macrophage
Inflammatory Protein);

Therapy

Inhibit binding of gp120 with CD4 by

Use of soluble CD4
Use of anti-CD4 Abs
Use of anti-gp120
Inhibit binding of HIV to coreceptors by

chemokines such as RANTES

Host Factors influencing

Transmission of HIV
course
Sexual contact
Breast feeding
Transfusion
During birth
Sharing needles

Resistance to HIV in individuals

CCR5D32
Some HLA types (HLA-A2) are resistant

while others (HLA-B35) are susceptible)

Therapeutic targets

Inhibit
binding

Kuby, 2007

Treatment and Prevention

Highly active anti-retroviral therapy (HAART;

combination therapy) + IL-2 (to reconstitute

the immune system)
Vaccines: Proteins, DNA, subunit and
recombinant virus (SIV-HIV chimeric virus )

Problems with therapy

HIV-1 infection gives rise to AIDS despite the

presence of Abs
Low immunogenicity of virus
Vaccine alone leads to destruction of CD4+ T cells
Integration of virus in host genome
Virus undergoes mutations
High rate of virus replication (109 viruses/day)
Live attenuated may result in AIDS
Heat killed organism is not antigenic
Vaccine administered through oral or respiratory
route (Route of exposure to HIV is through genital
tract)
Lack of animal models and in vitro testing system
Drugs do not cross blood-brain barrier to reach
virus in brain

Summary
Primary immunodeficiencies are inherited
They can affect hematopoietic stem cells,

lymphoid or myeloid cells.

Secondary immunodeficiencies are due to
infections, aging, cancer or chemical exposure
HIV affects immune system by eliminating
CD4+ T cells
Vaccine development has been hindered by
lack of an experimental model, antigenic
variation, rapid proliferation of the virus

Reading
Immunology

By Male, Brostoff, Roth and Roitt

7th Edition
Pages299-324