Understanding Immunodeficiency: Genetic and Acquired Defects

1. Dr. Seelke, may we have our exams back????

2. Chapter 20- Immunodeficiency • Where we’re going- Briefly! • A few categories of immunodeficiencies-genetic and acquired (primary and secondary) • A brief look at AIDS

3. A very sad, immunodeficient, nude mouse  Think about all the steps involved in a typical immune response, all the signals, molecules…. All these are coded by genes, and thus recessive genetic defects can occur to cause immunodeficiencies.

4. Some categories & general comments • Primary vs secondary immunodeficiencies • Primary: genetic or developmental ? • Secondary- drug treatment, AIDS • Primary- Depending upon where they hit, they can affect one or more areas. The earlier in the developmental path, the more severe.

5. The consequences (very broadly): • Phagocytic- bacterial infections • Humoral- bacterial infections • Cell-mediated- viral infections • T-cell problems often also result in B-cell problems, due to T-dependent Ag’s. • Both, or all-  bacterial, viral, problems with commensals, etc.

9. Neutrophil abuse! http://www.youtube.com/watch?v=ZUUfdP87Ssg ARP2/3 breaks off, binds to the newly formed actin

10. We’ll go from worst to least- and a few key defects • SCID- RAG’s are bad; nucleotide metabolism’s bad; Signaling receptors (JAK, IL2 receptor) are bad; no MHC II. • One type is mildly famous- 1st gene therapy treatment- Adenosine deaminase, toxic levels of deoxyadenosine (which results in feedback control effects )

12. B cell deficiencies • Agammaglobulinemia- NO humoral branch!- frequent bacterial infections. • Defective tyrosine kinase that’s part of Signal 1- Bruton’s TK. • X-linked hyper-IgM- a T cell defect! Signal 2- CD40/CD40L- CD40L, on the T cell, is bad- no signal 2, so you just get a T-independent response, thus the IgM

13. T-Cell deficiencies • DiGeorge Syndrome- developmental problem early, no thymus, bunch of other problems

14. Phagocyte defects • No neutrophils- sometimes disease/toxins causes neutropenia; we’re describing genetic problems. • Oxidative pathway can have problems (chronic granulomatous disease), targeting proteins to lysosomes can be a problem, or bad cell surface proteins inhibit phagocytosis or extravasation.

15. Things to know- • Associate defects with immunodeficiency- • RAG1,2- JAK, ADA defects-SCID • Bruton’s tyrosine kinase- agammaglobulinemia- • CD40L defect on Thelper cells= hyper IgM • DiGeorge syndrome- no thymus= no Tcells • Oxidase defects- Chronic granulomatous disease

16. AIDS • Very Briefly! • Replication • Key immune responses • Why a vaccine’s so hard

19. T cell, vs monocyte, infection- don’t get your hopes up for an AIDS cure based on deletion CCR5 from target cells

20. Slow, progressive destruction of Th cells. Most of the problems are with cell-mediated, since some humoral response remains- mostly T independent

25. 2 different ways- nucleoside analogs and RT inhibitors Not out- I think some are in clinical trials Inhibit fusion!

27. Things to know-AIDS • Life cycle • Cells infected • Slowly grinds down the Th level • Effects as expected- cell-mediated response, particularly Tdth, later effects on Tc response; • Treatment targets • Why vaccine is a problem