Lecture 13: Failures in Host Defense...
Transcript of Lecture 13: Failures in Host Defense...
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Lecture 13: Failures in Host Defense Mechanisms
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Questions to Consider
What insights into the working of the immune system can we learn from patients?
How does one elicit and utilize clinical history to diagnose the etiology of a congenital immunodeficiency?
How can ignorance of immunology kill your patients?
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“Bubble Boy”- Patient Without T and B Cell Immunity Needs Isolation to Protect From Infection
Clin Immunol Immunopathol. 1986;40:128-35
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Clin Immunol Immunopathol. 1986;40:128-35
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Scientific American
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Etiology of Immunodeficiency
B and T cell23%
Phagocytic
14%
Misc.10%
B cell53%
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Evaluation of Immunodeficiency
Complaint
increased frequency of infections
inability to clear infection
infection with opportunistic pathogens
Age of presentation
< 6 months suggests cellular defect
> 6 months indicates antibody deficiency
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Maternal IgG Crosses the Placenta Providing Newborns With IgG Levels Equivalent to Those Present in the Mother
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Evaluation of Immunodeficiency
Complaint
increased frequency of infections
inability to clear infection
infection with opportunistic pathogens
Age of presentation
< 6 months suggests cellular defect
> 6 months indicates antibody deficiency
Infections
Viruses/Fungii- T cell defect
Bacteria- Antibody deficiency
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Hematopoietic Lineage
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Leukocytes Can be Identified by Flow Cytometric Analysis
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Leukocytes Can be Identified by Flow Cytometric Analysis
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Severe Combined Immunodeficiency
Cellular: T cells, to normal B cells
Humoral: immunoglobulins
Presentation: After birth
Pathogens: Bacterial, viral, fungal
Etiology: mutation
Therapy: Bone marrow transplant,
gene therapy
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X-linked SCID is Associated With Defective Maturation of Lymphocytes
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The Interleukin 2 Receptor Complex Includes a Gamma Chain Utilized for Signal Transduction
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The Same -chain is Used by Multiple Cytokine Receptors For Signal Transduction
Nat Rev Immunol. 2005 Sep;5(9):688-98
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Mutation of the Common -chain Causes Almost 50% of SCID Cases
NEJM 2000;343:1313
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Severe Combined Immunodeficiency
Cellular: T cells, to normal B cells
Humoral: immunoglobulins
Presentation: months to years after
birth
Pathogens: Bacterial, viral, fungal
Etiology: Adenosine deaminase
deficiency
Therapy: Bone marrow transplant
Rosen/Geha- Case 14
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Absence of Adenosine Deaminase Prevents Elimination of Adenosine
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Inosine
Adenosine Kinase
Adenosine Deoxyadenosine
Adenosine monophophate Deoxyadenosine monophosphate
No Enzyme for Deamination of dAMP
Deoxycytidine Kinase
AdenylateDeaminase
Inosine Phosphatase
Inosine monophosphate
`
`
STOP
Alternate Pathway for Metabolism of Adenosine
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Deoxyadenosine
dATP
Deoxycytidine Kinase5'-Nucleotidase
1. Inhibition of Ribonucleotide Reductase RESULT: Decreased pools of dNTP's
2. Inhibition of Endogenous DNA Repair
RESULT: Build up of DNA nicks- mRNA
3. Activation of poly-(ADP-ribose) polymerase
RESULT: Decrease NAD and ATP
TOXICITY OF ELEVATED LEVELS dATP
Elevated Level of Deoxycytidine Kinase in LymphocytesPhosphorylates dATP Which Builds Up In the Cell
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Severe Combined Immunodeficiency
Cellular: T cells, to normal B cells
Humoral: immunoglobulins
Presentation: After birth
Pathogens: Bacterial, viral, fungal
Etiology: JAK/STAT defect
Therapy: Bone marrow transplant
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Signal Transduction by Heterodimeric Cytokine Receptors is Mediated by JAK/STAT Pathway
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SCID Can be Caused by Mutation of the Cytokine Receptor Transduction Molecule, Jak3
NEJM 2000;343:1313
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Use of Gene Therapy for SCID
In 1990- 1st gene therapy trial the NIH in a four year old girl with adenosine deaminase (ADA) deficiency. Of two patients treated, the peripheral blood T cell counts in patient 1 rapidly increased until they reached the normal range where they have remained and patient 2 also showed an increase in the number of T cells.
In 2002-3, nine of eleven children with SCID due to - chain receptor mutation have been successfully treated with hematopoietic stem cell therapy.
However, four have developed leukemia due to insertional mutagenesis.
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DiGeorge Syndrome
Cellular: Decreased T cells, normal B cells
Humoral: Decreased IgG
Presentation: Hypocalcemia, seizures
Pathogens: Bacterial, viral, fungal
Etiology:
Genetic: A large deletion from chromosome 22q11, produced by an error in recombination at meiosis, variation in symptoms is related to the amount of genetic material lost in the chromosomal deletion.
Anatomic: Anomalous development of the 3rd and 4th brachial pouches
Therapy: Thymic transplant
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Lateral Chest X-ray in DiGeorge SyndromeDiGeorge SyndromeNormal
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Roitt, Immunology
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Absent T cells Cause Functional Antibody Deficiency Because T Cell Help is Required for IgG Production
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X-linked agammaglobinemia
Cellular- Decreased B cells
and normal T cell numbers
Humoral- Absent Ig
Presentation- After 6 months old
Pathogens- Bacterial
Etiology- Defective Btk (Bruton’s
tyrosine kinase)
Therapy- IV gammaglobulin
Rosen/Geha- Case 10
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Hyper-IgM Syndrome
Cellular: Normal T cells and B cells
Humoral: IgM, IgG and IgA
Presentation: After 6 months
Pathogens: Bacterial
Etiology: Absence of CD40 ligand
or AID cytidine deaminase
Therapy: Intravenous gammaglobulin
Rosen/Geha- Case 11 and 12
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CD40 Ligand-CD40 Interaction is Required for Isotype Switching
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IgG Subclass Deficiencies
Cellular- Normal B and T cell
numbers
Humoral- Decreased IgG subclass
(sometimes IgA also)
Presentation- After 6 months old
Pathogens- Bacterial
Etiology- unknown
Therapy- IV gammaglobulin
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IgA Deficiency
Cellular: Normal T cells and B cells
Humoral: Decreased IgA
Presentation: sinopulmanry
infections, allergic
Pathogens: Bacterial
Etiology: Failure of isotope switch
Therapy: None
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Bare Lymphocyte Syndrome
Cellular: T cells, normal B cells
Humoral: IgG deficiency
Presentation: After birth
Pathogens: Bacterial, viral, fungal
Etiology: Mutation in MHCII promoter
Therapy: Bone marrow transplant
Rosen/Geha- Case 17 and 18
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Genetic Mutations of Different Transduction Molecules are Associated with Various Immunodeficiencies
NEJM 2000;343:1313
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Job’s Syndrome
Cellular: phagocytic chemotaxis
Humoral: IgE
Presentation: Childhood with cold
abcesses, eczema
Pathogens: Staph, strep, candida
Etiology: STAT3 dominant negative
mutation
Therapy: Antibiotic suppression
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Chronic Granulomatous Disease
Cellular: Ineffective phagocytosis
Humoral: Normal to increased IgG
Presentation: Hot abcesses
Pathogens: Staph, Candida
Etiology: Defective NADPH oxidase
gp91phox gene mutation.
Therapy: Antibiotics, interferon,
gene therapy
Rosen/Geha- Case 2
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Blockage at Discrete Differentiation Steps Prevents Downstream Maturation
Abbas- Cellular and Molecular Immunology
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Blockage at Discrete Differentiation Steps Prevents Downstream Maturation
Abbas- Cellular and Molecular Immunology
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Conclusions
Patients provide many insights into the working of the immune system
Clinical history helps diagnose the etiology of congenital immunodeficiency
Ignorance of immunology can kill your patients