primary immunodeficiencies for usmle step...
TRANSCRIPT
![Page 1: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/1.jpg)
PrimaryImmunodeficienciesforUSMLEStepOne
JohnBarber,Classof2019www.12DaysinMarch.com
E-mail:[email protected]
PartI PartII
LymphocyteDisorders:SCID
Bruton’sX-LinkedAgammaglobulinemiaCVID
Wiskott-AldrichNeutrophilDisorders
ChronicGranulomatousDiseaseChediak-Higashi
LeukocyteAdhesion Deficiency
![Page 2: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/2.jpg)
Wiskott-Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoietic cells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelts; Presentation:bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema(dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearance
Failureofactinpolymerization
![Page 3: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/3.jpg)
Wiskott-Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoietic cells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelts; Presentation:bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema(dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearance
Failureof‘immunologic synapse’
Failureofthiscommunicationexplainstheimmunedysregulationassociatedwiththissyndrome
![Page 4: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/4.jpg)
Wiskott-(B)Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoietic cells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelts; Presentation:bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema(dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearanceActin-dependent villousprojections ‘Bald’Lymphocyte
![Page 5: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/5.jpg)
Wiskott-(B)Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoietic cells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelts; Presentation:bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema(dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearance
Failureof‘immunologic synapse’
Failureofthiscommunicationexplainstheimmunedysregulationassociatedwiththissyndrome
Eczema:InadequateT-cellRegulation
![Page 6: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/6.jpg)
Wiskott-(B)Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoietic cells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelts; Presentation:bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema(dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearance
Failureof‘immunologic synapse’
Failureofthiscommunicationexplainstheimmunedysregulationassociatedwiththissyndrome
Eczema:InadequateT-cellRegulation
Dry,Erythematous, Itchy
![Page 7: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/7.jpg)
Wiskott-(B)Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoietic cells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelts; Presentation:bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema(dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearance
Failureof‘immunologic synapse’
Eczema:InadequateT-cellRegulation
Tcell-dependentBcellactivation
![Page 8: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/8.jpg)
Wiskott-(B)Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoietic cells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelets→bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema(dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearance
Cytoskeleton ofhematopoieticcell:PLTSFewinnumber andsize
![Page 9: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/9.jpg)
Wiskott-(B)Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoietic cells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelets→bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema(dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearance
Cytoskeleton ofhematopoieticcell:PLTSFewinnumber andsize
![Page 10: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/10.jpg)
Wiskott-(B)Aldrich:Cytoskeleton
• Background• Defectincytoskeletonofhematopoieticcells
• T-cells: failureofimmunologicsynapse(withdendriticcells) immunodeficiency andimmunedysregulation(eczema)• Platelets: increasedclearance ofpunysizedplatelts; Presentation:bleeding
• Pathogenesis• WASp(Wiskott-Aldrichsyndromeprotein):geneticdefectleading tofailureofactinpolymerization/cytoskeleton rearrangement.• Lymphocytesaredescribedas‘bald’lackingprojections(filopodia)
• Distinguishing ClinicalFeatures• Immunedysregulation:Eczema (dry,pruritic,erythematous/papularrash)– face,diaperregion• ’Abnormalplateletmembrane’:increasedclearance ofsmallsizedplateletswithsignificantbleeding (<50k)• DysfunctionalT-cells (virus,fungus)failure toofB-cell (encapsulatedbugs)
• Dx:WASproteinscreening (flowcytometry)• Rx:
• Prophylactic/Supportive:Bactrim (PCP),acyclovir(virus),PLTtransfusion(bleeding),IVIG• HSCtransplant
• Notes:• CauseofDeath:Bleeding• ElevatedIgA/IgE:increasedsynthesisversusclearance
![Page 11: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/11.jpg)
Eczema:InadequateT-cellRegulation
Cytoskeleton ofhematopoieticcell:PLTSFewinnumber andsize
WASprotein→BaldLymphocytes
![Page 12: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/12.jpg)
ChronicGranulomatousDisease
• Background• Neutrophil,EnzymeFailure(NADPHoxidase)
• Pathogenesis• Failureof‘respiratoryburst’generationofROSandsubsequently HOCl• Implication:catalase(+)organisms
• Catalasemetabolizesbacteria/fungiderivedH2O2sohostmyeloperoxidasecan’tconverttoHOCL.• Hypochloriteisneedstofacilitatemicrobekillinginthephagolysosome.
• DistinguishingClinicalFeatures• Catalase(+)organisms:Staph,Serratia,Nocardia,Aspergillus,Burkholderia.• Granulomas:theyareresponsetoorganism,notthecause.
• Granulomas,however,aredestructive.
• Dx:NBT(nitroblue tetrazolium),DHF(dihydrorhodaminefluorescence)byflowcytometry• Notes:
• Normalhostresponsetoviralinfection;elevatedglobulins(humoralresponseintact)• Rx:antibioticandazole prophylaxis
![Page 13: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/13.jpg)
Chediak-HigashiSyndrome(CHS)
• Background:• Neutrophil,failureoftraffickingprotein(inlysosomalmembrane+);thinkgranules.
• Pathogenesis:• PMN:can’ttransportphagosometolysosome(nophagolysosometokillmicrobes);resultsingiantcytoplasmicgranules
• Melanocytes:can’ttransportmelanin• Nervoussystem:granuleaccumulationinSchwanncells
• DistinguishingClinicalFeatures• PMN:giantcytoplasmicgranules(pathognomonic)- infections,especiallyofskin• Skin:partialalbinism(oculocutaneous)
• Normalmelanoctyeswithfailureofmelanintransport• Neuro:Schwanncelldysfunctionyieldstoatrophyofbrain,spineandcranialneuropathies
• Rx:HSCtransplantCaliforniaHighwaySystem(CHS)
TrafficinLosAngeles
![Page 14: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/14.jpg)
Chediak-HigashiSyndrome(CHS)
• Background:• Neutrophil,failureoftraffickingprotein(inlysosomalmembrane+);thinkgranules.
• Pathogenesis(LYSTgenedefect):• PMN:can’ttransportlysosometophagosome(nophagolysosometokillmicrobes)• Melanocytes:can’ttransportmelanin• Nervoussystem:granuleaccumulationinSchwanncells
• DistinguishingClinicalFeatures• PMN:giantcytoplasmicgranules(pathognomonic)- infections,especiallyofskin• Skin:partialalbinism(oculocutaneous)
• Normalmelanoctyeswithfailureofmelanintransport• Neuro:Schwanncelldysfunctionyieldstoatrophyofbrain,spineandcranialneuropathies
• Rx:HSCtransplant
![Page 15: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/15.jpg)
Chediak-HigashiSyndrome(CHS)
• Background:• Neutrophil,failureoftraffickingprotein(inlysosomalmembrane+);thinkgranules.
• Pathogenesis(LYSTgenedefect):• PMN:can’ttransportlysosometophagosome(nophagolysosometokillmicrobes)• Melanocytes:can’ttransportmelanin• Nervoussystem:granuleaccumulationinSchwanncells
• DistinguishingClinicalFeatures• PMN:giantcytoplasmicgranules(pathognomonic)- infections,especiallyofskin• Skin:partialalbinism(oculocutaneous)
• Normalmelanoctyeswithfailureofmelanin transport• Neuro:Schwanncelldysfunctionyieldstoatrophyofbrain,spineandcranialneuropathies
• Rx:HSCtransplant
![Page 16: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/16.jpg)
Chediak-HigashiLYST:Lysosomaltransportdisorder
Nophagolysosome
Melanin CytoplasmicGranules Schwann
CaliforniaHighwaySystem(CHS)TrafficinLosAngeles
![Page 17: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/17.jpg)
LeukocyteAdhesionDefect
• Background:• Neutrophil,FailureofMigration.‘Can’tgettherefromhere’
• Pathogenesis• DefectiveleukocyteadhesionduetomutationsinbetachainofCD11/18integrins.
• DistinguishingClinicalFeatures [skin(bacterialinfections),mucosa,respiratory]• PoorWoundHealing:failureofumblicalcordseparation(omphalitis)• Hallmark:Absenceofpusformationatsitesofinfection• Neutrophilia:theyarepresent,justcan’tgettherefromhere.
![Page 18: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/18.jpg)
Omphalitis
Infection
Nopus
![Page 19: Primary Immunodeficiencies for USMLE Step One12daysinmarch.com/wp-content/uploads/2018/03/Immuno...Primary Immunodeficiencies for USMLE Step One John Barber, Class of 2019 E-mail:](https://reader030.vdocument.in/reader030/viewer/2022040405/5e986462315cdd228f286745/html5/thumbnails/19.jpg)
PrimaryImmunodeficienciesforUSMLEStepOne
JohnBarber,Classof2019www.12DaysinMarch.com
E-mail:[email protected]
PartI PartII
LymphocyteDisorders:SCID
X-LinkedAgammaglobulinemiaCVID
Wiskott-AldrichNeutrophilDisorders
ChronicGranulomatousDiseaseChediak-Higashi
LeukocyteAdhesion Deficiency