p. 463
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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 PresentationTRANSCRIPT
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Ch. 20
p. 463
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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
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Ch. 20
p. 494
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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
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Ch. 20
p. 495
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Ch. 20
SCID: Severe Combined Immunodeficiency
Lymphoid cells are depleted
Thymus does not develop
Usually fatal without intervention
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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
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Ch. 20
p. 497
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Ch. 20
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Ch. 20
p. 496
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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
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Ch. 20
Neutrophil reduction
Neutropenia and worsecongenital or acquiredradiation or drugsautoimmune syndromes (e.g., SLE)can be temporaryneonatal neutropenia – Ab’s from mother
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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
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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
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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
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Ch. 20
Diagnosed by serum electrophoresis(gamma-globulin is severely reduced)
Treated with gamma-globulin
Still susceptible to pulmonary infections;lack of secretory IgA
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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
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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
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Ch. 20
p. 499
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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
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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
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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
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Ch. 20
p. 500
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Ch. 20
p. 503
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Ch. 20
Nude mice: no CMI
Little antibody response
Death within 6 months
Can tolerate grafts
Thymus transplants can restoreimmune competence
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Ch. 20
To summarize, treatments for immunodeficiencies:replacement of defective element:
* missing protein* missing cell type or lineage * missing or defective gene
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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
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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
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Ch. 20
SCID-hu Mice – discussed on p. 504
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Ch. 20
Secondary immunodeficiencies
Acquired hypogammaglobulinemia
Immune suppressionAgent-induced immunodeficiency
AIDS, caused by HIV-1 retrovirus
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Ch. 20
p. 505
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Ch. 20
p. 506
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Ch. 20p. 508
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Ch. 20
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Ch. 20
p. 509
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Ch. 20
p. 510
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Ch. 20
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Ch. 20
p. 511
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Ch. 20
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Ch. 20
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Ch. 20
p. 512
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Ch. 20
p. 513
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Ch. 20 p. 516
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Ch. 20
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Ch. 20p. 515
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Ch. 20
p. 516
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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
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Ch. 20
p. 517
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Ch. 20
p. 519
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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