This document defines and describes various primary immunodeficiencies. It notes that primary immunodeficiencies are inherited defects in the immune system that cause susceptibility to recurrent infections from an early age if not treated. It then describes several specific types of primary immunodeficiencies that result from defects in hematopoietic stem cells, myeloid progenitor cells, neutrophils, lymphoid progenitors, T cell development, B cell development, and complement deficiency. It also discusses the inheritance, characteristic infections, and potential treatments for some of these immunodeficiency disorders.

2. Objectives
Definition
Primary Immunodeficiencies
Characteristics
Types of primary immunodeficiency disorders
Mode of inheritance
Diagnosis and Treatment

3. 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
>150 immunodeficiency disorders

4. Hematopoiesis
Progenit
or
Progenit
or

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

6. TCR
Allogeneic BM/HSC
Transplantation
HSC
Thymus
Thymic
Stromal
Cells
MHC
T cell
MHC
T cell
MHC-matched for atleast1-2 alleles
T cell depleted
TCR
T cells

7. Hematopoiesis
Progenit
or
Progenit
or

8. 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

9. 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, Mφ and T
cells forming granulomas. These patients suffer from
Chronic Granulomatous Disease.
Have recurrent bacterial infections
Commensals become pathogenic
X-linked or autosomal recessive

10. 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
Mother Father
Aa Aa
Normal x Affected
Mother Father
aa Aa
Carrier x Normal
Mother Father
Xx XY
Autosomal Recessive Autosomal Dominant X-linked

11. 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

12. Hematopoiesis
Progenit
or
Progenit
or

13. 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.

14. Types of SCID
RAG-1/2 (Recombinase activating gene) deficiency: Required for
TCR and Ig gene rearrangement
IL-2R gene defect
Adenosine deaminase (ADA) deficiency
Adenosine Inosine Uric acid
T, B and NK cell deficiency due to toxicity of accumulated metabolites
First successful gene therapy done in patient
T cells/
NK
cells
IL-2 receptor
IL-2
TCR
T
cells
B
cells
Ig
ADA

15. DiGeorge syndrome

16. 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

17. 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

18. Hyper IgM Syndrome
Absence of Igs and B cells
Arrest at Pre-B cell stage (H-chain rearranged not L chain)
Deficiency in IgG, IgA and IgE
Increased IgM in serum
B cells express IgD and IgM on membrane
X-linked
Recurrent infections
e.g. IgA deficiency
Due to defect in isotype switching
Recurrent respiratory, gastrointestinal and/or
genitourinary infection
Selective Ig class deficiency
X-linked Agammaglobulinemia (x-LA)
Pre B
cells
Mature B
cells
x-LA
Proliferation
Differentiation
Isotype
switchingCVD
IgA def.
Plasma
cells
IgM

19. Common Variable Immunodeficiency
B cells are normal
Defect in maturation to plasma cells
Decreased IgM, IgG and IgA or only IgG and IgA
Susceptible to bacterial (e.g. pneumococci) infections
Low Ab titers against DPT or MMR Vaccines
Usually not detected in children because of
maternal Abs
Also called Late-onset hypogammaglobulinemia,
Adult-onset agammaglobulinemia or Acquired
agammaglobulinemia
Ig replacement therapy and antibiotics
Pre B
cells
Mature B
cells
x-LA
Proliferation
Differentiation
Isotype
switchingCVD
IgA def.
Plasma
cells
IgM

20. Other Immunodeficiencies
Bare lymphocyte syndrome:
Lack MHC class II on B cells, macrophages and dendritic
cells
Complement Deficiency

21. x-linked
aγglobulinemia
xLA DiGeorge
Syndrome d
Common Variable Hypoγglobulinemia
/ x-linked hyperIgM syndrome/Selective Ig
deficiency
Primary ImmunodeficienciesStem Cell
Myeloid
Progenitor
Lymphoid
Progenitor
Neutrophil Monocyte Pre-B Pre-T
Mature B
Plasma
Cell Memory B
Thymus
Reticular Dysgenesis
Severe combined
Immunodeficiency
SCID
Congenital
Agranulocytosis
Chronic
Granulomatous
Disease (x or r)
Bare Lymphocyte
Syndrome
Mature
T

22. 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