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LECTURE 12
PRIMARY (INBORN) AND
SECONDARY (ACQUIRED)
IMMUNODEFICIENCIES (ID)
Jan Żeromski
2007/2008
PRIMARY ID:
GENERAL DATA
• Relatively infrequent (average 1 per 100.000)
• Lack or improper function of one or more
elements of immune system
• Increased susceptibility for infections but
other follow ups include autoimmunity,
hypersensitivity and malignancy
• Are hereditary, with familiar trait, often linked
to X chromosome
PRIMARY IDs
(ACCORDING TO WHO-1999)
• Combined
• Other well
characterized
• Disturbances of
antibody biosynthesis
• Defects of fagocytosis
• Syndromes of
chromosomal
instability
• Deficits of
complement
components
• Appear with other
inborn defects
• Co-existing with
defects of
lymphoproliferation
• Other
SEVERE COMBINED IMMUNODEFICIENCY (SCID)
DISEASE
MECHANISM
1. Severe (T-B-SCID) Reticular Defects of stem cells and genes
dysgenesis Deficiencyfor Ig and TCR
RAG1,RAG2
(recombinations)
2. Defective purine metabolism Toxic metabolites for
deficiency of ADA and PNP lymphocytes
3. Lack of expression of MHC
antigens, class I and/or
class II
Lack of gene transcription for
MHC and TAP proteins
4. Hyper IgM syndrome
Lack of CD40L signal from
T to B cell
5. CD3 deficiency
Defect of CD3-TCR proteins
6. Omenn syndrome (SCID
with hypereosinophilia)
RAG1 and RAG2 mutations
COMBINED SCID
Disease
Mechanism
• Severe (T-B-SCID)
Reticular dysgenesis
Deficiency-RAG1,RAG2
• Defective purine
metabolism deficiency
of ADA and PNP
• Lack of expression of
MHC antigens, class I
and/or class II
• Defects of stem cells
and genes for Ig and
TCR (recombinations)
• Toxic metabolites for
lymphocytes
• Lack of gene
transcription for MHC
and TAP proteins
COMBINED SCID-contd.
Disease
• Hyper IgM
syndrome
• CD3 deficiency
• Omenn syndrome
(SCID with
hypereosinophilia)
Mechanism
• Lack of CD40L
signal from T to B
cell
• Defect of CD3-TCR
proteins
• RAG1 and RAG2
mutations
B CELL DEFICIENCIES
• X-linked agammaglobulinemia (Bruton
disease) – lack of Btk kinase necessary for B
cell formation;
• Common variable ID(CVID) – defects of T
lymphocyte signaling to B cell;
• IgA deficiency defect of Ig class switch;
• Selective Ig subclass deficiency;
• Transient hypogammaglobulinemia of infants
– maturation defect of Th cell function.
OTHER WELL CHARACTERIZED
SYNDROMES OF ID
1. Wiskott-Aldrich syndrome (WAS)
mutation of Xp11.22 gene encoding WASP protein
results in defects of cytoskeleton
of T cells (faulty collaboration among
T and B cells)
Symptoms: thrombocytopenia, eczema,
infections, variations in Ig levels, risk of lymphoma
OTHER WELL CHARACTERIZED
SYNDROMES OF ID (cont.)
2. DiGeorge syndrome (DGS)
congenital defect in the organs derived from
third and fourth pharyngeal pouches
(lack of thymus and parathyroids, malformations
of the heart and/or aortic arch)
Symptoms: viral and fungal infections,
neonatal tetany, distinctive facial features
SYNDROMES OF CHROMOSOMAL
INSTABILITY
1. Hereditary ataxia-teleangiectasia (AT)
lack of ATM kinase involved in repair of doublestrand breaks of DNA;
defects of cell cycle control
Symptoms: as in the name, severe sinus and lung
infections, T cell and B cell deficiencies
2. Nijmegen breakage syndrome (NBS)
defects of rearrangement of Ig genes,
faulty DNA reparation (mutation of NBS1 gene)
Symptoms: microcephaly, developm. retardation, Ig
deficiencies,T cell-lymphocytopenia
HEREDITARY PHAGOCYTE FUNCTION
DEFICIENCIES
1. Chronic granulomatous disease (CGD)
comprises a group of 4 disorders with a common
phenotype. Deficient superoxide (0-2) generation via
the phagocyte NADPH oxidase
Symptoms: recurrent infections, abscesses,
granuloma formation
2. Chediak-Higashi syndrome
defect of lysosome formation; mutation of
CHS1 gene
Symptoms: albinism, infections, photophobia,
pancytopenia, lack of NK cell activity
DISORDERS OF PHAGOCYTE NUMBER
1.Kostman syndrome
infantile agranulocytosis
Symptoms: severe infections, sepsis already
at the newborn period
2.Cyclic neutropenia
periodic (every 2-3 weeks) fall of neutrophil
number
3.Shwachman syndrome
neutropenia, defects of chemotaxis and
bacterial killing
4.Chronic mild familiar neutropenia
HEREDITARY LEUKOCYTE FUNCTION
DEFICIENCIES
Leukocyte adhesion deficiency (LAD)
LAD1
defect of CD11/CD18 integrin  chain (CD18)
biosynthesis.
Symptoms: recurrent necrotizing infections,
failure to form pus
LAD2
defect of sialyl Lewis (CD15s) ligand for
the selectin family.
Symptoms: growth and mental retardation,
hypotonia, seizures, persistent periodontitis
Leukocyte adhesion deficiency (LAD-1)
• Is due to integrin gene defects – deficiency of
CD18, forming 3 important molecules:
CD18/CD11a (LFA-1), CD18/CD11b (Mac-1 or
CR3, and CD18/CD11c (CR4 or p150,95)
• These molecules are expressed on different classes
of leukocytes and mediate their adhesion to
endothelium
Leukocyte adhesion deficiency (LAD-1) - 2
• Leukocytes show defective chemotaxis and
adherence,
• T lymphocytes and NK cells have impaired
cytotoxic activity,
• Infants show delayed umbilical cord
separation, persistent leukocytosis,
destructive peridontitis, recurrent infections
(S. aureus, Pseudomonas, Klebsiella)
LAD type 2
• Leukocytes cannot roll on endothelial surface
• Rolling is due to selectins, which react with
glycoproteins containing fucosylated shugars
• Genetic defect in conversion of mannose to fucose
results in failure of normal synthesis of these
selectin ligands, such as blood group sialyl Lewisx
• Sialyl Lewisx is defective (hypofucosylated)
LAD type 2 - 2
• Leukocytes cannot roll, so their export from
vessel lumen is considerably retarded
• Clinical features: growth and mental
retardation,strabismus, dysmorphia,
persistent peridontitis
• Leukocytosis in absence of infection
• Wound healing is not impaired
DEFICIENCIES OF COMPLEMENT
COMPONENTS – 1% of ID
1. Deficits of classical pathway of activation
2. Deficits of C3 and of proteins of alternative
pathway
3. Deficits of components of lectin pathway
4. Deficits of membrane attack complex
(MAC) C5 –C9
5. Deficits of C1 inhibitor
OTHER PRIMARY ID
1. Job syndrome (hyper IgE):
- faulty chemotaxis, high IgE
Symptoms: recurrent infections, severe
eczema, facial and skeletal abnormalities,
eosinophilia
1. Duncan disease:
- X-linked lympho-proliferative syndrome
2. Failure of tubercle bacilli killing:
- defect of IFN-R and /or IL-12R
3. Chronic muco-cutaneous candidiasis
4. T CD4+ cell lymphopenia
TEN WARNING SYMPTOMS OF ID
1. Six or more infections per year
2. Two or more severe sinusitis per
year
3. Antibiotic treatment lasting 2
months or longer without visible
effect
4. Two or more pneumonias per
year
5. Retardation of growth and
development of child
TEN WARNING SYMPTOMS OF ID
(CONTINUED)
6. Recurrent deep skin or organ
abscesses
7. Persistent mycosis of oral cavity
and skin in a child >1 year old
8. Necessity of long lasting
application of intravenous
antibiotics to control infection
9. Two or more severe infections
such as encephalitis, osteitis,
dermatitis, myositis, sepsis
10.Family history indicating primary ID
SECONDARY ID - CAUSES
1. Glycocorticoids:
lympho- and monocytopenia, inhibition of T
cell activation, IL-1 and TNF synthesis;
2. Cytostatics:
act mainly on DNA and its synthesis;
3. Malnutrition;
4. Deficits of elements (selene, magnesium,
iron etc.);
5. Deficits of vitamins (A, C, D, B6, folic acid);
6. AIDS;
7. Other viral infections (mainly of herpes
group).
ACQUIRED IMMUNODEFICIENCY SYNDROME
(AIDS) – GENERAL DATA
• Etiology: HiV-1 and HIV-2 retrovirus (RNA)
• M-tropic and T-tropic viruses (the latter
worse)
• T-tropic form syncytia from infected and
non-infected cells, what results in rapid cell
destruction
• HIV receptors: CD4 and chemokine
receptors (CCR5, CCR3, CXCR4)
• Main reservoir of virus – lymphatic tissue
AIDS PATHOGENESIS
• Early period: fall of CD4+ cells, viremia, lack
of immune response;
• Fall of viremia, an increase of TCD8+ cell
number able to kill infected cells;
• Appearance of anti-HIV antibodies;
• Growth of virus mutagenicity;
• Dysfunction and decline of Th1 CD4+ cell
number with parallel increase of Th2 cells;
• Development of symptomatic AIDS.
THANK YOU
GOOD LUCK