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

Progenitor

Progenitor
Hematopoietic Stem Cell (HSC) deficiency
HSC are multipotent (differentiate into all blood cell types)
Self renewing cells
Lineage negative (mature B/T cell, granulocyte, Mf 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

HSC Thymic
Stromal
Cells

TCR MHC-matched for atleast1-2 alleles

T cells T cell depleted
 Hematopoiesis

Progenitor

Progenitor
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, Mf 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-g 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 (XX carrier daughter; XY affected son)
Carrier x Carrier Normal x Affected Carrier x Normal
Mother Father Mother Father Mother Father
Aa Aa aa Aa Xx XY

Autosomal Recessive Autosomal Dominant X-linked

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

Progenitor

Progenitor
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
TCR Ig
T B
cells cells

IL-2R gene defect

T cells/ IL-2 receptor
NK IL-2
cells
Adenosine deaminase (ADA) deficiency
Adenosine ADA 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 cell defect
Accept xenografts
 X-linked Agammaglobulinemia (x-LA)
Absence of Igs and B cells
Arrest at Pre-B cell stage (H-chain rearranged not L chain)
Hyper IgM Syndrome Pre B
cells
Deficiency in IgG, IgA and IgE
x-LA
Increased IgM in serum
B cells express IgD and IgM on membrane Mature B
cells
X-linked
Proliferation IgM
Recurrent infections
Selective Ig class deficiency
e.g. IgA deficiency Isotype
Differentiation CVD switching
Due to defect in isotype switching Plasma
cells
Recurrent respiratory, gastrointestinal and/or
genitourinary infection 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 x-LA
Low Ab titers against DPT or MMR Vaccines
Mature B
Usually not detected in children because of cells
maternal Abs Proliferation IgM
Also called Late-onset hypogammaglobulinemia,
Adult-onset agammaglobulinemia or Acquired
Isotype
agammaglobulinemia Differentiation CVD switching
Plasma
Ig replacement therapy and antibiotics cells

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 Lymphoid
Progenitor Progenitor
Severe combined
Congenital Immunodeficiency
Agranulocytosis SCID
Monocyte Pre-B Pre-T
Neutrophil

x-linked
agglobulinemia
xLA Mature B Thymus
DiGeorge
Chronic
Syndrome d
Granulomatous
Disease (x or r) Mature
Plasma T
Cell Memory B
Common Variable Hypogglobulinemia
/ x-linked hyperIgM syndrome/Selective Ig Bare Lymphocyte
deficiency Syndrome
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 CHRONIC AIDS

PHASE PHASE AIDS (<200cells/mm3)
 Structure of HIV

env
(Envelope)

(p24)
(p17)

Protease
Integrase Matrix gag
pol 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
Viral Replication
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 virus strain)

CD4 CCR5:
Ligands are RANTES (Regulated on activation,
normal T cell expressed and secreted),
MIP1a, MIP1b (Macrophage 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 course
Transmission of HIV
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