Exam 3: Immunodeficiencies Flashcards
What are the two types of immunodeficiencies?
- Primary (genetic/inherited)
2. Secondary (acquired)
What is immmunosupression?
Intentional induction of an immunodeficiency as a treatment to autoimmune disease
What things can detect immunodeficiency?
Generally found during childhood
- Recurrent infection
- Test for presence or test function of implicated components of immune system
Types of immunodeficiencies?
- COmplement protein deficiencies
- B cell deficiencies
- T cell deficiencies
- Phagocyte deficiencies
- NK deficiencies
Describe Complement protein deficiencies
- Mutation in gene for specific complement component
- most affect opsonin function- susceptible to pus-causing 9(PYOGENIC) extracellular bacteria such as Streptococcus spp. and Staphylococcus spp. (C3b, Factor D, Factor P)
- Defects in MAC components (C5-C9 lead to selective susceptibility to Neisseria spp. infections
In the classical pathway, deficiencies in C1, C2, and C4 lead to what type of hypersensitivity?
TYPE III –> buildup of immune complexes as Ag-Ab are not cleared
What do alternative pathway and C3b deficiencies make you susceptible to?
Pyogenic bacteria such as Streptococcus spp. and Staphylococcus spp.
Describe B Cell/Antibody Deficiencies
defects in responses to extracellular bacteria and viruses
- Btk mutation –> Bruton’s X-linked Agammaglobulinemia
- Hyper-IgM syndromes
- Selective IgA deficiency, common variable immunodeficiencies (Igm, IgG, IgA deficiencies
Describe Bruton’s X linked Agammaglobulinemia
BLOCK IN B CELL DEVELOPMENT, no peripheral B cells, no serum Ig
Describe Hyper-IgM syndromes
DEFECT IN B CELL ACTIVATION AND CLASS SWITCHING
lots of IgM but little or no IgA, IgG, or IgE
X-linked version caused by CD40L mutation –> T and macrophage defects as CD40L involved in activation of these
Autosomal version caused by mutation in AID which is involved in class switching and somatic hypermutation
Describe T cell deficiencies
often lead to Severe Combined Immunodeficiencies (SCIDs) –> increased susceptibility to all classes of pathogen
What is X-linked scid
early block in T cell development, so no peripheral T cells (do have B cells though)
What is Bare Lymphocyte Syndrome
loss of MHC molecules –> defects in TAP genes cause loss of MHC I expression so no CD8+ T cells
mild immunodeficiency
defects in TF’s controlling MHC II gene expression (CIITA, RFXANK, RFX5, RFXAP)–> block CD4+ T cell development and results in SCID
What is DiGeorge’s Syndrome
TBX1 deletion–> single-copy deletion of TF T-Box1–? defect in thymic epithelium development (Haploinsufficiency)
Other forms of T cell deficiencies besides X-linked scid, Bare Lymphocyte Syndromes, and DiGeorge’s syndrome include __
Defects in T cell signaling molecules like CD3 and ZAP-70
Defections in cytokine expression, cytokine receptors, or cytokine signaling molecules ( IL-7)
CD3 leads to
scid and MHC defect
B/T Cell Deficiencies
some forms of SCID that result in lack of B and T cells
Mutations/defects in what enzymes lead to B/T cell deficiencies
ADA and PNP lead to autosomal SCIDS
RAG1/RAG2 defects lead to what?
B/T Cell Deficiency
Autosomal scid lead to unrepaired double-strand breaks during TCR and BCR locus rearrangement. What happens
B and T cell precursors die
taxia telangiectasia (ATM defect) (B/T Cell deficiency)
protein involved in signaling presence of DNA double-strand breaks –> failure to induce DNA repair during T and B cell development
Describe Phagocyte Deficiencies
Phagocytes important to initial responses to bacteria sp deficiency leads to susceptibility to bacterial infections
What is Neutropenia?
Reduced # of Neutrophils
2 types of Neutropenia
- Severe congenital neutropenia–> dominant or recessive (exhibit <10% of normal neutrophil count and is fatal without bone marrow transplant)
- Cyclic neutropenia –> neutrophil #’s fluctuate over 21 day period from normal to low/none
Leukocyte adhesion deficiency syndrome is what type of deficiency
Phagocyte (defect in integrin common beta2 subunit CD18)
leads to widespread pyogenic bacterial infections that are dependent on macrophage phagocytosis
What are some disorders associated with defects in intracellular killing mechanisms of phagocytes?
- Chronic granulomatous disease -> defect in NADPH oxidase system (failure to make superoxide radical) really hard to kill intracellular bacteria leading to granulomas against bacteria that normally are uptaken by macrophages
- G6PD deficiency–> chronic infection from defective respiratory burst
- Myeloperoxidase deficiency–> Defective intracellular. killing. chronic infection
- Chediak-Higashi syndrome
- -> defect. in lysosome-phagosome
What do integrins facilitate
Cell adhesion molecules
What type of immunodeficiency? Chronic granulomatous disease
Phagocyte
What type of immunodeficiency?
G6PD deficiency
Phagocyte
What type of immunodeficiency?
Myeloperoxidase deficiency
Phagocyte
What type of immunodeficiency?
Chediak-Higashi syndrome
Phagocyte
What type of immunodeficiency?
Neutropenia
Phagocyte
What type of immunodeficiency? taxia telangiectasia (ATM defect)
T/B cell
What type of immunodeficiency?
RAG1/RAG2 defects
T/B cell
What type of immunodeficiency?
Bruton’s X linked Agammaglobulinemia
B cell
What type of immunodeficiency?
Hyper-IgM syndromes
B cell
What type of immunodeficiency?
elective IgA deficiency, common variable immunodeficiencies (Igm, IgG, IgA deficiencies
B cell
What type of immunodeficiency?
SCIDs
T cell
What type of immunodeficiency?
X-linked scid
T cell
What type of immunodeficiency?
Bare Lymphocyte Syndrome
T cell
What type of immunodeficiency?
DiGeorge’s Syndrome
T cell
What type of immunodeficiency?
CD3 and ZAP-70
T cell
What type of immunodeficiency?
Defections in cytokine expression, cytokine receptors, or cytokine signaling molecules ( IL-7)
T cell
What type of immunodeficiency?
ADA and PNP enzyme defect
T/B cell
What type of immunodeficiency? taxia telangiectasia (ATM defect)
t/B cell
Which cytokine defects lead to susceptibility to otherwise non-pathogenic intracellular. bacteria. like Mycobacterium. spp. and Salmonella spp.
IL-12, IL-12R or IFN-gammaR
(TH1) responses
What immunodeficiency leads to defective control of Epstein-Barr virus?
X-linked lymphoproliferative syndrome (SAP defect)
SAP important for B cell/T cell adhesion
What does Epsetin-Barr virus infect?
B cells; cause mono
SAP defect leads to what effect of B cells?
B cell hyperproliferation coupled with insufficient T cells as SAP is involved in regulating IFN-gamma;
CD8+ T cells must kill B cells
What is the main treatment for immunodeficiencies?
Bone-marrow transplantation (BMT)–> this requires at least one MHC allele in common between graft and patient
What are some potential problems with bone marrow. transplant?
- GVHD (Graft vs Host Disease)–> mature T cells in bone marrow graft attack the patient’s tissues (alloreactivity); (Graft rejects patient)
- HVGD (Host vs Graft disease) –> patient’s mature T cells and/or NK cells rejects graft
T/F GVHD is a systemic immune disease
T; Graft can attack any lymphocytes in any tissue in patient
What is another treatment for immunodeficiencies besides BMT?
Gene therapy
What is the goal of gene therapy?
Fix mutation causing immunodeficiency. Take bone marrow out of patient and fix it in lab
Which deficiencies show more successful treatment via gene therapy?
X-linked scid and retroviral transduction
however–> leukemia risk
Why is there limited success with ADA gene therapy using mature lymphocytes or cord blood (HSCs) in autosomal scid
Can inject correct enzyme ADA into patient but have to do it all the time
Only bone marrow treatment shows prolonged treatment
Secondary immunodeficiencies most common cause?
MALNUTRITION
