9. Immunodeficiencies Flashcards
What causes primary immunodeficiency diseases?
What is the heredity?
Recessive mutations in a single gene
Often X Linked, sometimes autosomal
What is SCID?
Severe Combined Immunodeficiency
A defect in the progenitors for both T and B cells.
What cytokine stimulates differentiation into the early lymphoid lineage?
IL-7
Production of what three products is necessary to move from Pro-B cell into the Pre-B cell stage?
RAG1, RAG2
Artemis
What is necessary to move from Pre-B cells to immature B Cells?
BTK
Why do B Cell defects manifest sx later than T Cell defects?
Because the child is still receiving maternal antibodies while their T Cells are developing.
How is SCID classified?
Since T Cell function is always impared in SCID, the classification is based on whether or not B Cell function is also impared.
Also may have NK cells absent if, say, IL7 is absent
(B lyphocyte + / B lymphocyte -)
What do you typically see in kids with infections, that you don’t see in kids with SCID who have infections?
Lymphadenopathy
What is the most common inheritance pattern and phenotype for SCID?
What is the name of this disease?
X Linked Recessive (~50%)
T- B+ NK- phenotype
Common γ Chain Deficiency
What is the mutation in the most common form of SCID?
Mutation in the common IL receptor gamma chain.
ILRγ
What is the phenotype of JAK3 deficiency SCID?
What is JAK3 responsible for?
T- B+ NK-
IL-2 receptor signaling
What other form of SCID does JAK3 deficiency resemble and why?
X linked / Common γ Chain Deficiency SCID
Because JAK3 is a tyrosine kinase that associates with the common γ chain of the IL2 receptor, so when it’s deficient, it’s as if the γ chain itself is deficient.
(Even has the same phenotype)
What happens in purine salvage pathway / Adenosine Deaminase Deficiency (ADA) SCID?
What is the phenotype?
Purine salvage pathway doesn’t work, so we have accumulation of toxic metabolites in all cells.
T- B- NK-
What happens in RAG1/RAG2 SCID?
What is the phenotype?
RAG1 / RAG2 is deficient, so immunoglobulin rearrangement cannot occur. As a result we see absent T and B cell function, but not NK cell function, because it doesn’t use RAG. Can’t get past the Pro- stage.
T- B- NK+
What is another name for X Linked Agammaglobulinemia?
What happens?
Bruton’s Syndrome
BTK doesn’t develop and the B Cell cannot pass the pre-B cell stage and are stuck there.
What is the most common immunodeficiency in the world?
Selective IgA deficiency
What compensates for a lack of IgA in selective IgA deficiency, and is therefore present in higher than normal amounts?
IgM
It too can enter the mucosa.
What kind of infection is more likely in patients with IgA deficiency?
Respiratory (especially sinus) infections
Pyogenic bacterial infections
What is the main issue pts face in Digeorge Syndrome?
The embryonic pouch that forms the Thymus, Thyroid, and Heart doesn’t develop properly. Thus pts have issues with Thymic hypoplasia / aplasia, hypoparathyroidism, and cardiac malformation.
Why do pts with Digeorge Syndrome have infections so soon after birth?
They cannot educate T Cells, and don’t have a reservoir from the mother to use as one might for a humoral immunodeficiency.
What happens in X-Linked Hyper IgM syndrome?
Patients lack CD40L or AID, and as a result, no isotype switching is possible. As a result you see an increase in IgM, but low IgA, IgG, and IgE.
Virtually no response to T Dependent antigens
Pts have a high incidence of pyogenic bacteria.
What is the general affect of the Common Variable Immunodeficiency collection of disorders?
B cell maturation defects leading to hypogammaglobulinemia.
B Cells fail to become plasma cells
Thus, serum IgG, IgA, and IgM levels are low, but B Cell levels are normal
We see generalized lymphadenopathy and splenomegaly
What happens in Wiskott Aldrich syndrome?
What is the “Clinical Triad”?
WASp (Wiskott-Aldrich Syndrome protein) is defective, leading to a defect in the immune synapse. This affects macrophages (encapsulated organisms) and CD8+ T Cells (viruses)
Eczema, thrombocytopenia (platelet dysfunction generally), and immune deficiency.
What is the phenotype for Bare Lymphocyte Syndrome?
T- B+ NK+
