Immunodeficiencies Flashcards
What is the difference between engineering Abs from B cells and T cells
The T cell itself must be engineered, as opposed to just expressing the desired variable domain of the antibodies in B cells
Why can’t desired TCR genes be replaced in a new T cell?
-T cells must recognize self MHC molecules
-T cells must pass positive and negative selection during development
Chimeric Antigen Receptor (CAR)-T cells
1) TCR is removed from a T cell, with CD3s (intracellular signaling) remains
2) Single chain variable (ScV) region from Ag-specific Ab is attached to the signaling system
3) MHC molecules are not required to see Ags, and signaling can be induced
What are primary immunodeficiencies?
Congenital; caused by some genetic or developmental defect
What are secondary immunodeficiencies?
Acquired; resulting from exposure to some agent or insult
What are the types of primary immunodeficiencies?
1) Combined B/T-cell immunodeficiencies
2) Ab deficiencies
3) T-cell deficiencies (rare)
4) Myeloid deficiencies
5) Complement deficiencies
Severe Combined Immunodeficiency (SCID)
Combined B/T-cell immunodeficiency caused by:
1) Defect in DNA repair or RAG1-2
2) Defect in gamma chain of receptors for cytokines
3) ADA (adenosine deaminase deficiency)
4) PNP deficiency
Characterized by lymphopenia
ADA-deficiency
1) Inability to breakdown adenosine to inosine
2) Adenosine accumulation results in the inhibition of RNR (inhibits DNA replication and repair)
3) S-adenosylhomocysteine accumulation is cytotoxic
Autosomal SCID
1) Mutation in DNA repair or RAG-1/2
2) Failure to rearrange V(D)J genes
3) No functional BCR or TCR
4) Block in early lymphocyte development
X-linked SCID
1) Mutation in IL-R common gamma chain (IL-2, 4, 7, 9, 15,21)
2) Defect in cytokine signaling results in inhibited T cell development and proliferation (e.g., IL-2 is critical)
3) No T cell = no signaling for B cell proliferation/maturation
X-linked hyper-IgM syndrome
1) B cell immunodeficiency resulting from defect in CD40L (costimulatory molecule for B cells)
3) Reduced B cell activation in response to T-dependent antigens
4) No class-switch recombination, germinal rxn centers, reduced hypermutations, and few memory cells
5) Normal activation in response to T-independent antigens
Autosomal hyper-IgM syndrome
1) B-cell immunodeficiency resulting from defect in AID (required for class switching and hypermutation)
2) Germinal centers are formed but low affinity, non-class switched memory cells are produced
Why are there so few T-cell immunodeficiencies?
B cell deficiency is often secondary to T cell defects (involved in costimulation, germinal reaction centers, support, cytokine help)
Bare-lymphocyte syndrome
1) T-cell immunodeficiency resulting from defective expression of MHC II
2) Failed positive selection in thymus and no peripheral CD4+ T cells
3) Treated via BM transplant to replace APC
TAP-deficiency syndrome
1) T-cell immunodeficiency resulting from defective MHC I
2) Failure of positive selection in thymus and no peripheral CD8+ T cells
3) Susceptible to intracellular bacteria and viral infections
4) Not treatable with BM transplant as most nucleated cells express MHC I, not just blood cells
