Molecular Cell Biology and Immunology
Lecture 6. Primary immunodeficiencies: inborn errors of immunity
INDEX
1. Immunodeficiencies – Introduction ............................................................................................................................................................. 1
1.1. Primary immunodeficiencies .............................................................................................................................................................. 1
2. Genetic aetiology of PID ............................................................................................................................................................................. 1
2.1. Consanguineous families .................................................................................................................................................................... 1
2.2. Variable presentation of monogenic PIDs ........................................................................................................................................... 2
2.3. Non-monogenic diseases and unknown aetiologies ............................................................................................................................ 2
2.4. Known PIDs ........................................................................................................................................................................................ 2
3. How do we find the genetic mutations in the PID patients? ........................................................................................................................ 2
3.1. Why look for causative mutations in PID patients? ............................................................................................................................. 2
3.2. Finding genetic mutations in PID patients ........................................................................................................................................... 2
3.2.1. Next generation sequencing ................................................................................................................................................................ 3
3.2.2. Identifying mutations ........................................................................................................................................................................... 3
3.2.3. Mutations found in the RIPK1 gene ..................................................................................................................................................... 3
4. PID classification ........................................................................................................................................................................................ 3
4.1. Antibody deficiencies ......................................................................................................................................................................... 4
4.2. Diseases caused by intrinsic T cell defect ............................................................................................................................................ 4
5. Severe combined immunodeficiencies (SCID) .............................................................................................................................................. 4
5.1. Immunological mechanisms of SCID.................................................................................................................................................... 4
5.2. SCID-X1 ............................................................................................................................................................................................... 4
5.2.1. David Vetter, the Bubble boy ............................................................................................................................................................... 5
5.3. SCID patient numbers ......................................................................................................................................................................... 5
6. Atypical leaky SCIDs.................................................................................................................................................................................... 5
6.1. Omen syndrome ................................................................................................................................................................................. 5
7. Combined immunodeficiencies (CIDs) ......................................................................................................................................................... 5
7.1. Diagnostics of combined immunodeficiencies ..................................................................................................................................... 5
8. Treatment of SCID ...................................................................................................................................................................................... 6
8.1. Hematopoietic stem-cell transplantation (HSCT)................................................................................................................................. 6
8.2. Gene therapy ...................................................................................................................................................................................... 6
9. Predominantly antibody deficiencies .......................................................................................................................................................... 7
9.1. Group 1. antibody deficiencies ........................................................................................................................................................... 7
9.2. Group 3. Hyper IgM – class switch recombination defect .................................................................................................................... 8
9.3. Diagnostic of antibody deficiencies ..................................................................................................................................................... 8
9.4. Treatment .......................................................................................................................................................................................... 8
, Patterns in case study: they all had mutations in the RIPK1 gene, a primary immunodeficiency.
1. IMMUNODEFICIENCIES – INTRODUCTION
They are disorders of the immune system that manifest with increased susceptibility to infection. we are all susceptible to infection but our IS
gets us through it, in the case of immunodeficiencies there is an impairment of the IS and they suffer recurrent or more severe infections by
common or unusual pathogens. In addition, immunodeficiencies might be associated with autoinflammatory or autoimmune manifestations.
We can distinguish two types of immunodeficiencies:
- Primary (PIDs): they are inborne errors caused by genetic mutations.
- Secondary (SIDs): caused by secondary factors (HIV, chemotherapy, leukemia, diabetes, etc.).
1.1. PRIMARY IMMUNODEFICIENCIES
PIDs are an extremely heterogeneous group of diseases, there are more than 450 types identified and the numbers increase. A classification in
published every 2 years, where new diseases are included.
Most PIDs are rare diseases, there are hundreds of patients known in the population and in some of them, only a few patients have been
reported. They are rare but there has to be reported, as new patients can be identified later. They also help learn about the IS.
The prevalence varies in different countries: in UK is 5.9/100,000, in Turkey 30.5/100,000, etc. They are underestimated, specially in countries
where the diagnostics is difficult.
Raising awareness about PIDs in clinicians, patients and families is important to identify the
patients and get a correct treatment. → Jeffrey Modell foundation is a foundation generated
by a family that had a son with PID. They have contributed a lot in raising awareness. Together
with clinicians they came up with a list of 10 warning signs of these PIDs: 4 or more infections
within one year, etc.
If there are 2 or more signs, the parents have to speak to the physician about a possible PID.
It gives an idea of how a PID can manifest early in life.
PIDs are inborn errors of the IS, this makes it that
many of them are diagnosed in children.
Surprisingly, 50% of PIDs are diagnosed in adults.
There are some warning signs per adults also.
Early PID diagnostics is critical, this leads to:
- Better and more adequate treatment.
- Increases prognosis and reduces mortality.
- Reduces the cost of treatment. Treating undiagnosed PID patients are much higher than the cost of treating a diagnosed PID.
There are environmental factors that impact the manifestation of the PID in some patients.
2. GENETIC AETIOLOGY OF PID
Most of them are caused by monogenic diseases, they are caused by rare mutations that have a big impact on the immune system. A single
mutation is enough to cause the disease, they can be recessive, dominant, or X-chromosome-linked genes. The ones carried in the X gene are
more predominantly seen in boys and girls will be carriers.
The recessive mutations are seen in families where the parents are related with each other.
2.1. CONSANGUINEOUS FAMILIES
There was a paper in nature communications of people that were probable of being affected in consanguineous families. They can be present
in the old or new times. Nowadays whole genome data has allowed to find the frequency of this mutations in the population: 1 in 360,000
people.
1
Lecture 6. Primary immunodeficiencies: inborn errors of immunity
INDEX
1. Immunodeficiencies – Introduction ............................................................................................................................................................. 1
1.1. Primary immunodeficiencies .............................................................................................................................................................. 1
2. Genetic aetiology of PID ............................................................................................................................................................................. 1
2.1. Consanguineous families .................................................................................................................................................................... 1
2.2. Variable presentation of monogenic PIDs ........................................................................................................................................... 2
2.3. Non-monogenic diseases and unknown aetiologies ............................................................................................................................ 2
2.4. Known PIDs ........................................................................................................................................................................................ 2
3. How do we find the genetic mutations in the PID patients? ........................................................................................................................ 2
3.1. Why look for causative mutations in PID patients? ............................................................................................................................. 2
3.2. Finding genetic mutations in PID patients ........................................................................................................................................... 2
3.2.1. Next generation sequencing ................................................................................................................................................................ 3
3.2.2. Identifying mutations ........................................................................................................................................................................... 3
3.2.3. Mutations found in the RIPK1 gene ..................................................................................................................................................... 3
4. PID classification ........................................................................................................................................................................................ 3
4.1. Antibody deficiencies ......................................................................................................................................................................... 4
4.2. Diseases caused by intrinsic T cell defect ............................................................................................................................................ 4
5. Severe combined immunodeficiencies (SCID) .............................................................................................................................................. 4
5.1. Immunological mechanisms of SCID.................................................................................................................................................... 4
5.2. SCID-X1 ............................................................................................................................................................................................... 4
5.2.1. David Vetter, the Bubble boy ............................................................................................................................................................... 5
5.3. SCID patient numbers ......................................................................................................................................................................... 5
6. Atypical leaky SCIDs.................................................................................................................................................................................... 5
6.1. Omen syndrome ................................................................................................................................................................................. 5
7. Combined immunodeficiencies (CIDs) ......................................................................................................................................................... 5
7.1. Diagnostics of combined immunodeficiencies ..................................................................................................................................... 5
8. Treatment of SCID ...................................................................................................................................................................................... 6
8.1. Hematopoietic stem-cell transplantation (HSCT)................................................................................................................................. 6
8.2. Gene therapy ...................................................................................................................................................................................... 6
9. Predominantly antibody deficiencies .......................................................................................................................................................... 7
9.1. Group 1. antibody deficiencies ........................................................................................................................................................... 7
9.2. Group 3. Hyper IgM – class switch recombination defect .................................................................................................................... 8
9.3. Diagnostic of antibody deficiencies ..................................................................................................................................................... 8
9.4. Treatment .......................................................................................................................................................................................... 8
, Patterns in case study: they all had mutations in the RIPK1 gene, a primary immunodeficiency.
1. IMMUNODEFICIENCIES – INTRODUCTION
They are disorders of the immune system that manifest with increased susceptibility to infection. we are all susceptible to infection but our IS
gets us through it, in the case of immunodeficiencies there is an impairment of the IS and they suffer recurrent or more severe infections by
common or unusual pathogens. In addition, immunodeficiencies might be associated with autoinflammatory or autoimmune manifestations.
We can distinguish two types of immunodeficiencies:
- Primary (PIDs): they are inborne errors caused by genetic mutations.
- Secondary (SIDs): caused by secondary factors (HIV, chemotherapy, leukemia, diabetes, etc.).
1.1. PRIMARY IMMUNODEFICIENCIES
PIDs are an extremely heterogeneous group of diseases, there are more than 450 types identified and the numbers increase. A classification in
published every 2 years, where new diseases are included.
Most PIDs are rare diseases, there are hundreds of patients known in the population and in some of them, only a few patients have been
reported. They are rare but there has to be reported, as new patients can be identified later. They also help learn about the IS.
The prevalence varies in different countries: in UK is 5.9/100,000, in Turkey 30.5/100,000, etc. They are underestimated, specially in countries
where the diagnostics is difficult.
Raising awareness about PIDs in clinicians, patients and families is important to identify the
patients and get a correct treatment. → Jeffrey Modell foundation is a foundation generated
by a family that had a son with PID. They have contributed a lot in raising awareness. Together
with clinicians they came up with a list of 10 warning signs of these PIDs: 4 or more infections
within one year, etc.
If there are 2 or more signs, the parents have to speak to the physician about a possible PID.
It gives an idea of how a PID can manifest early in life.
PIDs are inborn errors of the IS, this makes it that
many of them are diagnosed in children.
Surprisingly, 50% of PIDs are diagnosed in adults.
There are some warning signs per adults also.
Early PID diagnostics is critical, this leads to:
- Better and more adequate treatment.
- Increases prognosis and reduces mortality.
- Reduces the cost of treatment. Treating undiagnosed PID patients are much higher than the cost of treating a diagnosed PID.
There are environmental factors that impact the manifestation of the PID in some patients.
2. GENETIC AETIOLOGY OF PID
Most of them are caused by monogenic diseases, they are caused by rare mutations that have a big impact on the immune system. A single
mutation is enough to cause the disease, they can be recessive, dominant, or X-chromosome-linked genes. The ones carried in the X gene are
more predominantly seen in boys and girls will be carriers.
The recessive mutations are seen in families where the parents are related with each other.
2.1. CONSANGUINEOUS FAMILIES
There was a paper in nature communications of people that were probable of being affected in consanguineous families. They can be present
in the old or new times. Nowadays whole genome data has allowed to find the frequency of this mutations in the population: 1 in 360,000
people.
1
