L18 - Primary Immune Deficiancy

Q: What are primary immunodeficiencies?

A: Inherited/genetic defects of the immune system that can affect innate immunity, adaptive immunity, or both.

Q: When are primary immunodeficiencies commonly diagnosed?

A: Often during childhood, especially when a child develops recurrent infections.

Q: Why are males more susceptible to many primary immunodeficiencies?

A: Many are caused by X-linked recessive mutations, so males are more likely to express the defective gene.

Q: What components of the immune system can be defective in primary immunodeficiencies?

A: Phagocytes, B cells/antibody production, isotype switching, T cells, complement, cytokines/cytokine receptors, and MHC I or MHC II.

Q: What is the difference between primary and secondary immunodeficiency?

Primary = inherited/genetic.
Secondary = acquired later in life.

Q: What types of pathogens are phagocytes especially important for clearing?

A: Extracellular pathogens, especially bacteria and fungi.

Q: What infections are common in patients with phagocyte deficiencies?

A: Recurrent bacterial and fungal infections.

Q: Why can complement deficiencies cause persistent immune complexes?

A: Complement normally binds/tags immune complexes → allows their transport and recognition by complement receptors → promotes their clearance and degradation.

Q: Why can defects in the classical complement pathway increase susceptibility to extracellular bacterial infections?

A: There is decreased clearance of opsonized bacteria, making bacterial elimination less effective.

Q: What are two major problems associated with complement deficiencies in this lecture?

A: Poor clearance of extracellular pathogens and poor clearance of immune complexes.

Q: What happens to B cells after encountering their specific antigen and receiving CD4+ T-cell help?

A: They can differentiate into antibody-secreting plasma cells.

Q: What are three important antibody functions for clearing extracellular pathogens?

A: Neutralization, opsonization, and antibody-dependent cellular cytotoxicity (ADCC).

Q: What antibody is especially important for opsonizing encapsulated bacteria?

IgG

Q: Why can antibody deficiencies increase susceptibility to extracellular infections?

A: Without sufficient antibodies, there is decreased neutralization and opsonization, making extracellular pathogens harder to eliminate.

Q: What can severe T-cell deficiencies lead to?

A: Forms of severe combined immunodeficiency (SCID).

Q: Why are MHC molecules important for T-cell development?

A: Developing T cells must recognize MHC molecules during positive selection in the thymus to survive.

Q: What happens if MHC I expression is deficient?

A: There is a deficiency of the corresponding CD8+ T-cell population.

Q: What happens if MHC II expression is deficient?

A: There is a deficiency of the corresponding CD4+ T-cell population.

Q: How can some defects in humoral immunity be treated?

A: With intravenous immunoglobulin (IVIG), which provides preformed IgG antibodies.

Q: Is IVIG active or passive immunity?

A: Passive immunity, because the patient receives preformed antibodies rather than producing them themselves.

Immune deficiency → ask what part is missing → predict the consequence:

? → bacterial/fungal infections
? → poor opsonization/immune-complex clearance
? → poor extracellular pathogen defense
? → CD8 T cells ↓
? → CD4 T cells ↓

Phagocyte ↓ → bacterial/fungal infections
Complement ↓ → poor opsonization/immune-complex clearance
Antibody/B cell ↓ → poor extracellular pathogen defense
MHC I ↓ → CD8 T cells ↓
MHC II ↓ → CD4 T cells ↓

Q: What causes inherited (primary) immune deficiencies?

A: Genetic defects, often involving recessive mutations.

Q: Why are males more susceptible to many inherited immune deficiencies?

A: Many of the mutations are X-linked recessive, so males are more likely to express the disorder.

Q: What major components of the immune system can be affected by inherited immune deficiencies?

A: Phagocytes, antibodies, B cells, T cells, complement, and MHC I or MHC II.

Q: What can a defect in phagocytes cause?

A: Impaired pathogen killing/clearance, especially increasing susceptibility to bacterial and fungal infections.

Q: What can defects in antibody production or isotype switching cause?

A: Impaired humoral immunity, resulting in decreased ability to neutralize and opsonize extracellular pathogens.

Q: What lymphocytes can be affected by inherited immune deficiencies?

A: B cells and T cells.

Q: What can complement deficiencies cause?

A: Impaired pathogen clearance and impaired immune-complex clearance.

Q: What happens when MHC I is deficient?

A: ↓ CD8+ T-cell development because CD8+ T cells require MHC I for positive selection.

(MHC I → CD8)

Q: What happens when MHC II is deficient?

A: ↓ CD4+ T-cell development because CD4+ T cells require MHC II for positive selection.

(MHC II → CD4)

Q: What is the defect in chronic granulomatous disease (CGD)?

A: A defect in NADPH oxidase.

Q: What are neutrophils unable to properly produce in chronic granulomatous disease?

A: Superoxide radicals, resulting in impaired microbial killing.

Q: What is the consequence of NADPH oxidase deficiency in chronic granulomatous disease?

A: ↓ superoxide production → ↓ bactericidal activity → recurrent bacterial and fungal infections.

Q: What types of infections are associated with chronic granulomatous disease?

A: Recurrent bacterial and fungal infections.

Q: What is the defect in myeloperoxidase (MPO) deficiency?

A: A deficiency/defect in myeloperoxidase, an enzyme found in phagocyte granules.

Q: What reaction is impaired in myeloperoxidase deficiency?

A: The conversion of hydrogen peroxide (H₂O₂) → hypochlorite (HOCl) is impaired.

Q: Why is hypochlorite important in phagocytes?

A: It is a powerful antimicrobial substance used to kill engulfed microorganisms.

Q: What infections can occur with myeloperoxidase deficiency?

A: Bacterial infections can occur, although some individuals have few or no symptoms.

_____ = can't make superoxide
______ = can't efficiently turn H₂O₂ into hypochlorite

CGD

MPO deficiency

In Chronic granulomatous disease ______ cannot produce the superoxide radical (due to a defect in NADPH oxidase); therefore, their ______ activity is reduced

What happens as a result of this?

neutrophils; bactericidal

Recurrent infection with bacteria and fungi

In Myeloperoxidase deficiency, a defect in myeloperoxidase (in granules) affects the ability to convert ?

What is the result of this?

hydrogen peroxide to hypochlorite 

Bacterial infection is common.  (in some individuals there are few symptoms of this immune deficiency)

Q: What are two major consequences of complement deficiencies?

A: Impaired defense against pathogens and impaired clearance of immune complexes.

Q: Why can complement deficiency cause immune complexes to persist?

A: Complement normally binds/tags soluble immune complexes → helps transport them to phagocytes → complexes are ingested and degraded.

Patients with mutations in the classical pathway are more susceptible to _______ due to a lack of clearance of ?

extracellular pathogens; opsonized bacteria

_________ attach to soluble immune complexes and allow them to be transported, ingested and degraded by cells with complement receptors

Complement components

immune complexes are generally normal, however if somone has a deficiency where they can cleat these than what can happen?

inflammation and tissue damage (via phagocytosis)

Q: What happens when early complement components are deficient?

A: Immune complexes are not efficiently cleared → complexes deposit in tissues → inflammation and tissue damage.

Q: Why can classical complement pathway deficiencies increase susceptibility to extracellular pathogens?

A: There is decreased opsonization and clearance of bacteria, making phagocytosis less effective.

Q: What is opsonization?

A: Coating/tagging a pathogen to make it easier for phagocytes to recognize and destroy it.

Q: How can persistent immune complexes cause tissue damage?

A: Immune complexes deposit in tissues → activate phagocytes/inflammation → tissue damage.

Q: What happens when membrane attack complex (MAC) formation is defective?

A: There is impaired defense against Neisseria species.

Q: What type of infection should make you think of a terminal complement/MAC deficiency?

A: Recurrent Neisseria infections.

Q: What type of pathogens are patients with antibody deficiencies especially unable to clear?

A: Extracellular bacteria.

Q: What is defective in Bruton’s X-linked agammaglobulinemia (XLA)?

A: Bruton’s tyrosine kinase (BTK), a protein important for B-cell development.

Q: What happens to B-cell development in Bruton’s X-linked agammaglobulinemia?

A: B-cell maturation stops at the pre-B-cell stage → very few/absent mature B cells → severely decreased antibodies.

Q: Why does XLA result in recurrent infections?

A: ↓ mature B cells → ↓ antibodies → impaired clearance of extracellular bacteria.

Q: What is defective in X-linked hyper-IgM syndrome?

A: CD40 ligand (CD40L) on activated T cells.

Q: What normally happens when CD40L on a T cell binds CD40 on a B cell?

A: It provides a signal necessary for B-cell isotype/class switching.

Q: What happens when CD40L is defective in X-linked hyper-IgM syndrome?

A: T cells cannot properly signal B cells through CD40 → no effective isotype switching → predominantly IgM is produced.

in X linked hyper-IgM syndrome, the -cells are normal, but the ____ ligand is altered - What does this result in?

B; CD40

There is no T-dependent B cell activation, resulting in no isotype switching and only IgM is produced

Q: Are the B cells themselves abnormal in X-linked hyper-IgM syndrome?

A: According to this lecture, the B cells are normal; the major defect is CD40L on activated T cells.

Q: What immunoglobulin is deficient in selective IgA deficiency?

A: IgA.

Q: What is an important normal function of IgA?

A: It provides mucosal immunity, particularly in the respiratory and gastrointestinal tracts.

Q: What problem can be associated with selective IgA deficiency according to this lecture?

A: Patients tend to have increased chronic respiratory/lung disease.

? → BTK defect → B-cell maturation fails → ↓ all antibodies

? → CD40L defect → no class switching → mainly IgM

? → ↓ IgA → impaired mucosal protection

Brutons XLA → BTK defect → B-cell maturation fails → ↓ all antibodies

X-linked Hyper-IgM → CD40L defect → no class switching → mainly IgM

Selective IgA deficiency → ↓ IgA → impaired mucosal protection

Q: What is severe combined immunodeficiency (SCID)?

A: A severe immune deficiency involving T-cell dysfunction, which can also compromise B-cell function.

Q: Why can a T-cell defect also impair B-cell function in SCID?

A: CD4+ helper T cells are needed for effective B-cell activation, so defective T cells can also impair antibody responses.

Q: What happens with RAG-1 or RAG-2 deficiency?

A: TCR and BCR development fails → both T-cell and B-cell responses are impaired.

Q: Why does RAG-1/2 deficiency affect both T cells and B cells?

RAG proteins are required to generate:

• TCRs on T cells

• BCRs on B cells

RAG deficiency → no functional ______ → impaired ______

TCR/BCR; T + B cells

Q: How can cytokine receptor mutations cause T-cell deficiency?

A: Certain cytokine signals are required for T-cell development, so defective cytokine receptors can prevent T cells from developing normally.

Q: What is defective in the form of bare lymphocyte syndrome described in this lecture?

A: MHC II expression is deficient.

Q: Why does MHC II deficiency cause a CD4+ T-cell deficiency?

A: CD4+ T cells require MHC II for positive selection in the thymus.

Q: What happens to CD8+ T cells in MHC II bare lymphocyte syndrome?

A: CD8+ T-cell function is preserved, because CD8+ T cells undergo positive selection using MHC I.

No MHC II → no proper____ selection → ↓ in ?

CD4; CD4 T cells

Q: What is the major immune-system defect in DiGeorge syndrome?

A: Abnormal development of the thymus/thymic epithelium → impaired T-cell development.

Q: Why does DiGeorge syndrome cause T-cell deficiency?

A: The thymus is required for T-cell development and maturation, so abnormal thymic development prevents normal T-cell development.

what happens to CD4+ and CD8+ T cells in severe DiGeorge syndrome?

A: Both CD4+ and CD8+ T cells are deficient/absent.

Q: Why can B-cell responses also be impaired in DiGeorge syndrome?

A: ↓ CD4+ helper T cells → ↓ T-dependent B-cell activation, so antibody responses can also be impaired.

_______ → no proper TCR/BCR → T cells ↓ + B cells ↓

_______ → CD4 ↓, CD8 preserved

_______ → thymus abnormal → CD4 ↓ + CD8 ↓ → impaired T-dependent B-cell activation

RAG-1/2 deficiency

Bare lymphocyte syndrome (MHC II deficiency)

DiGeorge syndrome

•_________ can result from T cell mutations that, in turn, compromise B cells

Severe combined immune deficiency (SCID)

•__________ lead to failed T and B cell responses due to a lack of TCR or BCR development

Deficiencies in RAG-1/2

•T cells can fail to develop due to mutations in _____ receptors that drive development 

cytokine

•In _________, the lack of MHC II products on cells inhibits positive selection of CD4 T cells.  Patients still have proper CD8 T cells function

Bare lymphocyte syndrome

•In ______, thymic epithelium develops abnormally, and T cells fail to develop properly.  There are no CD4 or CD8 T cells and impaired T-dependent B cell activation.

Di George syndrome

Q: When are inherited immune deficiencies usually diagnosed?

A: Usually in childhood, after the patient presents with recurrent infections.

Q: What is a major clue that a child may have an inherited immune deficiency?

A: Repeated/recurrent infections.

Q: What treatments can be used for patients with immune deficiencies?

A: Intravenous immunoglobulin (IVIG) and antimicrobial treatments, depending on the specific deficiency.

Q: Why can IVIG be useful in patients with certain immune deficiencies?

A: IVIG provides preformed antibodies (mainly IgG) to patients who cannot produce adequate antibodies themselves.

Q: What type of immunity does IVIG provide?

A: Passive immunity, because the patient receives preformed antibodies.

Q: What treatment may be used for severe immune deficiencies such as SCID?

A: Bone marrow/hematopoietic stem cell transplantation.

Q: Why can a bone marrow transplant help treat severe immune deficiencies such as SCID?

A: It can provide healthy hematopoietic stem cells → development of functional immune cells → restoration of immune function.

? → IVIG
? → antimicrobials
? → bone marrow/stem cell transplant

Antibody deficiency → IVIG
Infections → antimicrobials
Severe SCID → bone marrow/stem cell transplant