Clinical Immunology Evelien Floor
HC2 Immune deficiencies
Primary immune deficiencies
The innate immune system is non-specific and
phylogenetically the oldest part of the immune
system. It is present in all organisms and comprises
among others of myeloid cells, NK-cells and
complement. The adaptive immune system is
specific and phylogenetically the youngest part of
the immune system. It is present in only jawed
vertebrates and comprises of T and B cells. The
adaptive immune system consists of a memory, this
is also why people get vaccinated.
Primary immune deficiencies are caused by inborn mutations in genes involved in production of
components of the immune system. If the mutation takes place in the active site of an enzyme this can
result in an immune deficiency, but if the mutation is in a non-functional domain this will not lead to
any consequences. Deficiency means a paucity of cells and/or inherent effect.
As a result of primary immune deficiencies recurrent infections will take place. In case of B cell
deficiency recurrent bacterial infections will occur. In case of T cell deficiency recurrent parasitic, viral
and fungal infections will occur. In addition, phagocytic deficiencies can take place, in that case
recurrent skin and oral bacterial infections take place, but also fungal infections and granuloma
formation. Lastly, combined immune deficiencies can occur, this means that more parts of the immune
system are affected.
Primary immune deficiencies are mostly inherited single-gene disorders. The deficiencies are very
informative as ‘experiments of nature’. They are classified according to which component is faulty:
• B cell defects (adaptive): 50%
• T cell defects (adaptive): 30%
• Phagocytic deficiencies (innate): 18%
• Complement deficiencies (innate): 2%
The incidence of primary immune deficiencies
is very rare: 1/10.000. Diagnosis takes place in
patients under 20 years old because it is an
inherited or congenital disease. Most of
primary immune deficiencies (70%) occur in
males because of the X-linked inheritance
(hemizygosity). Only one X chromosome in
males has to be affected to develop a primary
immune deficiency. Many immune system
related genes are on the X chromosome.
Most primary immune deficiencies are autosomal recessive. If both parents carry the mutation, their
offspring have 25% chance of getting the disease. Therefore, it is important to know whether there is
consanguinity in the family or not.
Normal people get 6 to 8 upper respiratory infections per year. This can be more frequent because of
daycare, smoking, and allergies and asthma. Recurrent infections are more than 10 times of otitis
media per year and more than 2 times pneumonia per year. This is severe if there are more than 2 life-
threatening infections per lifetime. Suspicion of a primary immune deficiency starts after infection with
unusual organisms or an unusual response to an organism (sometimes after vaccination).
1
, Clinical Immunology Evelien Floor
Phagocytic disorders
Phagocytic disorders belong to the rare immune deficiencies: 1:200.000 births. Infections with
Mycobacteria, Aspergillus, Candida, and catalase-positive microorganism take place. Symptoms are
then: poor wound healing, abscesses, chronic gingivitis (inflammation of the gums), oral ulcers, and
periodontal disease.
Examples of phagocytic disorders:
• Chronic granulomatous disease
• Leukocyte adhesion defect
• (Congenital neutropenia (G-CSFR))
Chronic granulomatous disease
Chronic granulomatous disease is for 70% X-linked and occurs 1 in 250.000 births. It is caused by a
defect in NADPH oxidase. Therefore, the neutrophil is not capable to form reactive oxygen species
(ROS) that activate granule proteases. Patients are susceptible to catalase positive bacteria.
Leukocyte adhesion defect
In case of an infection, it is important that leukocytes travel from the bloodstream to the site of
infection (extravasation). Adhesion molecules (selectins) are expressed on the endothelium in the
capillaries. Neutrophils can bind to these molecules which results in loose binding to the endothelial
cell wall, the neutrophils start rolling. The endothelial cells get activated by chemokines from the site
of infection, this also activates integrins on leukocytes. Integrins can now bind to their ligand ICAM,
this is a high affinity interaction. The leukocytes adhere firmly to the endothelium and transmigrate to
the site of infection.
Problems can occur during this process because of the absence or disfunction of one of those adhesion
proteins. In that case, leukocytes can’t enter the site of infection and remain in the bloodstream
(leukocytosis). Symptoms of LAD:
• Recurrent skin infections (occasionally internal infections)
• Severe periodontal disease (up to tooth loss)
• Delayed wound healing (delayed umbilical cord separation)
• Candidiasis
• Leukocytosis (because they can’t leave the bloodstream)
Different forms of LAD:
• LADI
o Mutation in the beta chain (CD18) of the integrin LFA-1 (CD11a/CD18); reduced
binding of mononuclear cells to blood vessel endothelial cells which results in a
consequent reduced extravasation
2
HC2 Immune deficiencies
Primary immune deficiencies
The innate immune system is non-specific and
phylogenetically the oldest part of the immune
system. It is present in all organisms and comprises
among others of myeloid cells, NK-cells and
complement. The adaptive immune system is
specific and phylogenetically the youngest part of
the immune system. It is present in only jawed
vertebrates and comprises of T and B cells. The
adaptive immune system consists of a memory, this
is also why people get vaccinated.
Primary immune deficiencies are caused by inborn mutations in genes involved in production of
components of the immune system. If the mutation takes place in the active site of an enzyme this can
result in an immune deficiency, but if the mutation is in a non-functional domain this will not lead to
any consequences. Deficiency means a paucity of cells and/or inherent effect.
As a result of primary immune deficiencies recurrent infections will take place. In case of B cell
deficiency recurrent bacterial infections will occur. In case of T cell deficiency recurrent parasitic, viral
and fungal infections will occur. In addition, phagocytic deficiencies can take place, in that case
recurrent skin and oral bacterial infections take place, but also fungal infections and granuloma
formation. Lastly, combined immune deficiencies can occur, this means that more parts of the immune
system are affected.
Primary immune deficiencies are mostly inherited single-gene disorders. The deficiencies are very
informative as ‘experiments of nature’. They are classified according to which component is faulty:
• B cell defects (adaptive): 50%
• T cell defects (adaptive): 30%
• Phagocytic deficiencies (innate): 18%
• Complement deficiencies (innate): 2%
The incidence of primary immune deficiencies
is very rare: 1/10.000. Diagnosis takes place in
patients under 20 years old because it is an
inherited or congenital disease. Most of
primary immune deficiencies (70%) occur in
males because of the X-linked inheritance
(hemizygosity). Only one X chromosome in
males has to be affected to develop a primary
immune deficiency. Many immune system
related genes are on the X chromosome.
Most primary immune deficiencies are autosomal recessive. If both parents carry the mutation, their
offspring have 25% chance of getting the disease. Therefore, it is important to know whether there is
consanguinity in the family or not.
Normal people get 6 to 8 upper respiratory infections per year. This can be more frequent because of
daycare, smoking, and allergies and asthma. Recurrent infections are more than 10 times of otitis
media per year and more than 2 times pneumonia per year. This is severe if there are more than 2 life-
threatening infections per lifetime. Suspicion of a primary immune deficiency starts after infection with
unusual organisms or an unusual response to an organism (sometimes after vaccination).
1
, Clinical Immunology Evelien Floor
Phagocytic disorders
Phagocytic disorders belong to the rare immune deficiencies: 1:200.000 births. Infections with
Mycobacteria, Aspergillus, Candida, and catalase-positive microorganism take place. Symptoms are
then: poor wound healing, abscesses, chronic gingivitis (inflammation of the gums), oral ulcers, and
periodontal disease.
Examples of phagocytic disorders:
• Chronic granulomatous disease
• Leukocyte adhesion defect
• (Congenital neutropenia (G-CSFR))
Chronic granulomatous disease
Chronic granulomatous disease is for 70% X-linked and occurs 1 in 250.000 births. It is caused by a
defect in NADPH oxidase. Therefore, the neutrophil is not capable to form reactive oxygen species
(ROS) that activate granule proteases. Patients are susceptible to catalase positive bacteria.
Leukocyte adhesion defect
In case of an infection, it is important that leukocytes travel from the bloodstream to the site of
infection (extravasation). Adhesion molecules (selectins) are expressed on the endothelium in the
capillaries. Neutrophils can bind to these molecules which results in loose binding to the endothelial
cell wall, the neutrophils start rolling. The endothelial cells get activated by chemokines from the site
of infection, this also activates integrins on leukocytes. Integrins can now bind to their ligand ICAM,
this is a high affinity interaction. The leukocytes adhere firmly to the endothelium and transmigrate to
the site of infection.
Problems can occur during this process because of the absence or disfunction of one of those adhesion
proteins. In that case, leukocytes can’t enter the site of infection and remain in the bloodstream
(leukocytosis). Symptoms of LAD:
• Recurrent skin infections (occasionally internal infections)
• Severe periodontal disease (up to tooth loss)
• Delayed wound healing (delayed umbilical cord separation)
• Candidiasis
• Leukocytosis (because they can’t leave the bloodstream)
Different forms of LAD:
• LADI
o Mutation in the beta chain (CD18) of the integrin LFA-1 (CD11a/CD18); reduced
binding of mononuclear cells to blood vessel endothelial cells which results in a
consequent reduced extravasation
2
