Inmunodeficiencia

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