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
DiGeorge syndrome
1) T cell immunodeficiency resulting from no thymus
2) No tissue to support T cell differentiation (no positive or negative selection = no T cells)
3) Normal B cells but do not produce Ab in response to immunization due to lack of T cell help
4) Treated via thymus transplant
Chronic granulomatous disease (CGD)
1) Mutation in various components of NADPH oxidase complex
2) Phagocytes can internalize pathogens but cannot kill them (unable to generate ROS)
3) Granuloma formation
4) Susceptibility to catalase positive pathogens (catalase neutralizes ROS)
Nitroblue-tetrazolium test (NBT)
Test for CDG
pink = lack of superoxide produced
blue = superoxide present
Leukocyte adhesion deficiency (LAD)
1) Phagocyte immunodeficiencies due to lack of CD18 and B2 integrin chain
2) CD18 required in formation of LFA1, Mac-1 (complement receptor CR3), gp150/95 (CR4), and adhesion molecules for leukocyte recruitment to sites of infection
HIV/AIDS
1) Infection with HIV, transmitted through bodily fluids
2) Initially, the immune system can control the infection through production of Ab against HIV p24 (prevents replication)
3) Tipping point eventually reached and infection progresses
4) Opportunistic infections
AZT drug
Reverse transcriptase inhibitor which prevents HIV replication and blocks maternal-child transmission
HAART drug
2 antiretrovirals and a protease inhibitor
