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p. 463. Ch. 20. AIDS and Other Immunodeficiencies. Primary: affects either adaptive or innate immunity inherited developmental Secondary: exposure to viruses and other agents Consequence: infection, life-threatening . p. 494. Severity depends on the number and type of - PowerPoint PPT Presentation
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Ch. 20
p. 463
Ch. 20
Ch. 20. AIDS and Other Immunodeficiencies
Primary: affects either adaptive or innate immunityinheriteddevelopmental
Secondary:exposure to viruses and other agents
Consequence: infection, life-threatening
Ch. 20
p. 494
Ch. 20
Severity depends on the number and type ofimmune system aspects involved
Earlier developmental defects are more severe
Reticular dysgenesis- cells do not differentiateduring hematopoiesis
No lymphocytes
No phagocytes
Ch. 20
p. 495
Ch. 20
SCID: Severe Combined Immunodeficiency
Lymphoid cells are depleted
Thymus does not develop
Usually fatal without intervention
Ch. 20
Several causes of SCID
Lack of chain of IL-2 receptoralso affects signaling through IL-4,-7,-9,-15
ADA (adenosine deaminase) deficiency
Defects in signal transduction or transcription
Deficiencies in MHC Class I or Class II synthesis
Ch. 20
p. 497
Ch. 20
Ch. 20
p. 496
Ch. 20
Specialized immunodeficiencies
Phagocytic
fewer phagocytes or reduction in function(chemotaxis, extravasation, killing)
Increased susceptibility to infectionsS. aureus, S. pneumoniae, E. coli,Pseudomonas, Candida, Aspergillus
Ch. 20
Neutrophil reduction
Neutropenia and worsecongenital or acquiredradiation or drugsautoimmune syndromes (e.g., SLE)can be temporaryneonatal neutropenia – Ab’s from mother
Ch. 20
Loss of function
LAD (leukocyte adhesion deficiency)
cells cannot adhere to endothelial cellskiller cells (CTL, NK) can’t adhere to
targetsTh and B cells can’t form conjugates
Defect in synthesis of beta-chain of integrinadhesion molecules
Lazy-leukocyte syndrome
Ch. 20
Killing defects
Chronic granulomatous disease (X-linked)(CGD)
Neutrophils can phagocytose bacteria but can’t kill them
Defect in oxygen metabolism; can’t produceH2O2
Ch. 20
Humoral deficiencies
X-linked agammaglobulinemia (XLA)first immunodeficiency defined
Pre-B cells do not progress to mature B cellsall isotypes affected
Defect in Bruton’s tyrosine kinaseheavy-chain genes are rearranged butlight chain genes are not
Ch. 20
Diagnosed by serum electrophoresis(gamma-globulin is severely reduced)
Treated with gamma-globulin
Still susceptible to pulmonary infections;lack of secretory IgA
Ch. 20
X-linked hyper-IgM
Lack of CD40L on their Th cells
CD40-CD40L interaction required for B cellresponse to T-dependent antigens
no class switching no memory cells no germinal centers in lymphoid organs
Ch. 20
Late-onset problems: various possible causes
Inability to switch from membrane-bound to secreted form
Structural defect in antibody
B cells do not respond to cytokines
Ch. 20
p. 499
Ch. 20
Selective IgA deficiency very common (1:600-800)
Asymptomatic or
Recurrent GI and respiratory infections
Tend to have more allergic reactions
Complement deficiencies result in either:Immunodeficiency (infections) and/or immune complex disease
Ch. 20
Cell-mediated deficiencies
Increased susceptibility to viral, protozoan,fungal diseases
Usually innocuous microbes can become life-threatening
Tend to affect humoral responses, too
Ch. 20
DiGeorge syndrome
Lack of thymus (also defects in parathyroidand aortic arches)
Diagnosis: low T cell count, no DTH, decreased T cell activity
Treatment: fetal thymus grafts
Ch. 20
p. 500
Ch. 20
p. 503
Ch. 20
Nude mice: no CMI
Little antibody response
Death within 6 months
Can tolerate grafts
Thymus transplants can restoreimmune competence
Ch. 20
To summarize, treatments for immunodeficiencies:replacement of defective element:
* missing protein* missing cell type or lineage * missing or defective gene
Ch. 20
Thus, pooled human gamma-globulin (Ab’s) for agammaglobulinemia
Recombinant gamma-interferon for CGDRecombinant IL-2 for AIDS patientsRecombinant ADA for ADA-deficient SCID patients
Gene therapy for ADA-deficiency and CGD, p67phox-deficiency: CD34+ stem cells from pt. transfected with normal copy of defective gene)
Cell replacement: bone marrow transplantation CD34+ stem cells from HLA-matched donor
Ch. 20
SCID mice- autosomal recessive mutationno B or T cells, other cells functionalcan be cured with bone marrow transplant
RAG knockout mice have also been developed
Knockout mice can be “designed” with specificimmune deficiencies
SCID-hu mouse is engrafted with human fetal liver,adult thymus and lymph nodes
Ch. 20
SCID-hu Mice – discussed on p. 504
Ch. 20
Secondary immunodeficiencies
Acquired hypogammaglobulinemia
Immune suppressionAgent-induced immunodeficiency
AIDS, caused by HIV-1 retrovirus
Ch. 20
p. 505
Ch. 20
p. 506
Ch. 20p. 508
Ch. 20
Ch. 20
p. 509
Ch. 20
p. 510
Ch. 20
Ch. 20
p. 511
Ch. 20
Ch. 20
Ch. 20
p. 512
Ch. 20
p. 513
Ch. 20 p. 516
Ch. 20
Ch. 20p. 515
Ch. 20
p. 516
Ch. 20
Categories of drugs – p. 517
Reverse transcriptase inhibitorsnucleoside analogsnonnucleoside analogs
Protease inhibitors
Fusion inhibitor
Lots of drugs, lots of side effects
Combinations lower viral load
Ch. 20
p. 517
Ch. 20
p. 519
Ch. 20
Summary
Immune deficiencies are either primary(genetic, developmental)
Or acquired (infection, radiation, HIV, immunosuppressive treatment)
Classified by type of cell(s) compromised
Treatments:replacement: bone marrow, gene therapyless extreme: antibody therapy, drugs