Primary Immunodeficiency

Question 1

What are primary immunodeficiencies

Answer 1

Congenital, resulting from genetic defects—hereditary.

Question 2

What is secondary immunodeficiencies

Answer 2

Acquired, resulting from other diseases or conditions.

Question 3

What are examples of causes of secondary immunodeficiency?

Answer 3

HIV infection.
Malnutrition.
Immunosuppression.

Question 4

What underlies the cause of primary immunodeficiencies?

Answer 4

Primary immunodeficiencies are due to genetic defects and are inherited.

Question 5

What are some characteristics of primary immunodeficiencies?

Answer 5

Commonly present as recurrent infections in the young.
May also involve allergy, autoimmunity, abnormal lymphocyte proliferation, and cancer.

Question 6

What has the study of primary immunodeficiencies taught us?

Answer 6

Knowledge about the nature of immunodeficiencies.
Insights into how the immune system works, including T and B cell interactions.
Differences in immune system functioning between mouse models (knockout mice) and humans.

Question 7

Give examples of classes of primary immunodeficiencies and their susceptibilities.

Question 8

B lymphocytes/antibody defects susceptibilities

Answer 8

Susceptible to bacterial infections.

Question 9

T and B combined defects susceptibilities

Answer 9

Susceptible to viral, fungal, and protozoal infections.

Question 10

T lymphocytes defects susceptibilities

Answer 10

Susceptible to viral, fungal, and protozoal infections.

Question 11

Phagocytes defects susceptibilities

Answer 11

Susceptible to bacterial infections.

Question 12

Complement defects susceptibilities

Answer 12

Susceptible to bacterial infections and autoimmunity

Question 13

What are the treatments for different classes of primary immunodeficiencies?

Question 15

T and B combined defects treatments

Answer 15

Immunoglobulin injections.

Question 16

T lymphocytes defects treatments

Answer 16

Bone marrow transplant.

Question 17

Phagocytes defects treatments

Answer 17

Antibiotics, cytokines.

Question 18

Complement defects treatments

Answer 18

Infusions of complement components

Question 19

Recessive inheritance patterns in primary immunodeficiencies?

Answer 19

Disease manifests if the individual has two copies of the defective gene (nn).

Question 20

Dominant inheritance patterns in primary immunodeficiencies?

Answer 20

Disease manifests if the individual has at least one copy of the defective gene (Dd or DD).

Question 21

What are the different immune cell defects involved in primary immunodeficiencies?

Answer 21

Humoral Defect (B cell and Antibodies)
Combined Humoral and cellular immunodeficiencies (B and T cells)
Defect of cell-mediated immunity (T cells)
Phagocytic Dysfunction (PMNs)
Complement Deficiency
Defects in cytokines, receptors, and molecules.

Question 22

What is significant about the overlap and variability among immunodeficiency syndromes?

Answer 22

There is a significant overlap among syndromes, with great variability in severity, ranging from mild to fatal.

Question 23

How has gene sequencing impacted the understanding of primary immunodeficiencies?

Answer 23

whole exome and genome sequencing, have greatly enhanced the ability to identify gene defects in affected families and individuals.

Question 24

What are the categories of immunodeficiencies according to the IUIS Expert Committee?

Answer 24

Combined Immunodeficiencies
Combined, with syndromic features
Antibody deficiencies
Immune dysregulation
Phagocyte defects
Defects in innate immunity
Autoinflammatory disorders
Complement deficiencies
Phenocopies of PID

Question 25

List examples of combined immunodeficiencies without syndromic features.

Answer 25

T-B+ severe combined immunodeficiency (e.g., common gamma chain deficiency)
T-B- SCID (e.g., Adenosine deaminase deficiency – ADA-SCID)
Less profound combined immunodeficiencies (e.g., CD40L deficiency)

Question 26

What is X-linked SCID and what is it commonly known as?

Answer 26

X-linked SCID is a severe immunodeficiency caused by mutations in cytokine receptors. It is commonly known as “Bubble boy” disease due to the famous case of David Vetter

Question 27

What is X-linked SCID and what genetic mutations cause it?

Answer 27

“Bubble boy” disease, is caused by mutations in cytokine receptors, specifically the IL-2Rγ chain, affecting a group of interleukins (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21). It results in the failure of T cells and NK cells, while B cells are normal but cannot mount efficient antibody responses due to lack of T cell help.

Question 28

What is ADA-SCID and how is it treated?

Answer 28

deficiency caused by mutations in the enzyme adenosine deaminase, leading to the depletion of T, B, and NK cells. There are 70 different mutations identified, mostly recessive. Treatment includes bone marrow stem cells from a suitable donor, and gene therapy with Strimvelis

Question 29

What characterizes Hyper IgM Syndrome and where does the genetic fault lie?

Answer 29

Hyper IgM Syndrome is characterized by high levels of IgM and low levels of other immunoglobulins, caused by a defect in class switching. It makes individuals susceptible to infection. The fault lies in the CD40L molecule on T cells, and the condition is classified in groups 1 and 3.

Question 30

Describe combined immunodeficiencies with syndromic features and give an example.

Answer 30

immunodeficiencies that include additional clinical features beyond the immune defect. An example is FoxN1 deficiency, which leads to athymia and alopecia (lack of any hair), due to the failure of thymic epithelium development resulting in no T cell production. B cells are normal but lack T cell assistance.

Question 31

Give examples of predominantly antibody deficiencies

Answer 31

Bruton’s tyrosine kinase deficiency, which impairs B cell development, CD40L deficiency which affects T cell help for B cells, and IgA deficiency, the most common immunodeficiency, which often presents with recurrent infections of the airways and digestive tract.

Question 32

What are the characteristics of Humoral/B-cell defects?

Answer 32

Lack of antibodies leading to recurrent infections.
Frequent episodes of sepsis, often originating from the airways.
Persistent bacterial infections and chronic gastroenteritis.
May result in failure to thrive in children.

Question 33

How common are Humoral defects as a cause of primary immunodeficiency?

Answer 33

Humoral defects are the most common cause of primary immunodeficiency. Presentation can vary; some individuals are asymptomatic while others may improve over time

Question 34

What is Bruton’s Agammaglobulinemia and what causes it?

Answer 34

A genetic immunodeficiency caused by a mutation in the Bruton’s tyrosine kinase gene.
It prevents B cell development from the pro-B to the pre-B stage, leading to few follicles in lymph nodes and low serum antibody levels.
Notably, it is X-linked.

Question 35

What is IgA Deficiency and its prevalence?

Answer 35

IgA Deficiency is the most common immunodeficiency syndrome, with a higher prevalence in Arabic countries (1:142) compared to Japan (1:18,000).
It is possibly related to an interleukin deficiency where cytokines are needed to mature B lymphocytes into IgA-secreting plasma cells.

Question 36

What are the manifestations of IgA Deficiency?

Answer 36

Many individuals are asymptomatic (85-90%).
Some children with a mild deficiency may outgrow it (up to 50% in some studies), while others do not.

Question 37

What are examples of diseases that involve immune dysregulation?

Answer 37

Immune dysregulation with colitis due to IL-10/10R deficiencies.
Genetic defects of regulatory T cells (Tregs) leading to conditions like IPEX syndrome.
Autoimmune lymphoproliferative syndrome (ALPS) due to CD95/Fas deficiency.

Question 38

List examples of congenital defects of phagocyte number or function.

Answer 38

Defects in the respiratory burst, such as Chronic Granulomatous Disease (CGD).
Mendelian susceptibility to mycobacterial diseases (MSMD), involving deficiencies in IFNR or IRF8 genes.

Question 39

What are the consequences of phagocyte deficiencies?

Answer 39

Phagocyte-mediated killing is crucial for immune defense.
Defects in phagocyte function can lead to a number of rare diseases.
Individuals with these deficiencies may experience recurrent, often fatal bacterial infections.

Question 40

What is DC Deficiency and what are the susceptibilities?

Answer 40

diagnosed before 3 months of age and results in increased susceptibility to infections by mycobacteria, fungi, and viruses due to a lack of functional dendritic cells which are crucial for initiating the immune response.

Question 41

What is Chronic Granulomatous Disease and its cause?

Answer 41

CGD is characterized by the absence of the superoxide burst needed to kill bacteria. It leads to the formation of multiple granulomas due to defective bacterial elimination and is caused by defects in the NADPH oxidase complex.

Question 42

CGD is an autosomal recessive disorder. Patients with CGD are particularly susceptible

Answer 42

CGD is an autosomal recessive disorder. Patients with CGD are particularly susceptible to fungal infections like Aspergillus fumigatus and to certain bacterial infections such as Absidia corymbifera pneumonitis.

Question 43

Give examples of defects in innate immunity.

Answer 43

Myd88 deficiency, which can lead to severe bacterial infections.
Chronic mucocutaneous candidiasis due to deficiencies in the IL-17 pathway, specifically IL-17RA, IL-17F, or CARD9 deficiencies.

Question 44

What are some examples of autoinflammatory disorders?

Answer 44

Disorders like Familial Mediterranean Fever involve defects affecting the inflammasome.
IL-10/10R deficiency is another condition where immune dysregulation leads to chronic inflammation

Question 45

Describe Familial Mediterranean Fever and its response to treatment.

Answer 45

In FMF, the inflammasome which converts pro-IL-1 to IL-1 is dysregulated due to mutations in inflammasome regulators. This leads to excessive activation of the inflammasome and elevated levels of IL-1, resulting in acute inflammatory episodes. Anti-IL-1 therapy can be effective in managing the inflammation in FMF.

Question 46

What is DC Deficiency and what are the susceptibilities?

Answer 46

DC Deficiency is typically diagnosed before 3 months of age and results in increased susceptibility to infections by mycobacteria, fungi, and viruses due to a lack of functional dendritic cells which are crucial for initiating the immune response.

Question 47

What is complement deficiency and its significance?

Answer 47

the rarest form of immunodeficiencies. The symptoms vary depending on where in the complement pathway the defect occurs, which may involve regulatory proteins. It can lead to increased susceptibility to infections and autoimmune diseases.

Question 48

List diseases associated with complement control defects

Answer 48

Paroxysmal nocturnal hemoglobinuria (defects in DAF or CD59).
Factor I deficiency.
Atypical hemolytic uremic syndrome (defects in MCP, factor I, or factor H).
Age-related macular degeneration (polymorphisms in factor H).
Hereditary angioedema (C1 inhibitor deficiency).

Question 49

What are the causes of secondary immunodeficiency?

Answer 49

HIV infection leading to depletion of CD4+ T cells.
Protein-calorie malnutrition.
Chemotherapy and radiation treatments for cancer.
Cancer metastasis to the bone marrow.
Removal of the spleen affecting phagocytosis of microbes

Question 50

What is the global impact of HIV/AIDS?

Answer 50

2 million deaths annually world wide

Question 50

How do immunosuppressants affect patients with inflammatory diseases

Answer 50

mitigate inflammation but also impair the immune system, potentially making patients more susceptible to infections and affecting their overall immune response. The specific effects depend on the medication used.

Question 51

How is ANCA-Associated Vasculitis (AAV) treated and what are the considerations for patients with kidney disease?

Answer 51

AAV is treated with immunosuppressants, which can also be used in inflammatory arthritis and in patients with end-stage kidney disease requiring hemodialysis. The degree of immunosuppression must be carefully balanced to manage the disease without overly compromising the immune system.

Question 52

Summarize primary and secondary immunodeficiency.

Answer 52

Primary immunodeficiencies are mainly genetic and result in an intrinsic defect within the immune system. Secondary immunodeficiencies are acquired and occur due to external factors like infections, malnutrition, or medical treatments.

Question 53

Provide examples of primary and secondary immunodeficiencies.

Answer 53

primary immunodeficiencies include X-linked agammaglobulinemia and common variable immunodeficiency. Secondary examples include AIDS from HIV infection and immunosuppression due to medical treatments like chemotherap

Question 54

What are some causes and consequences of immunodeficiencies?

Answer 54

Causes range from genetic mutations in primary immunodeficiencies to viruses and lifestyle factors in secondary forms. Consequences include increased susceptibility to infections, autoimmune disorders, and in severe cases, death.