PrimaryImmunodeficienciesforUSMLEStepOne
JohnBarber,Classof2019www.12DaysinMarch.com
E-mail:[email protected]
PartI PartII
LymphocyteDisorders:SCID
Bruton’sX-LinkedAgammaglobulinemiaCVID
Wiskott-AldrichNeutrophilDisorders
ChronicGranulomatousDiseaseChediak-Higashi
LeukocyteAdhesion Deficiency
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
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
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
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
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
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
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
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
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
Eczema:InadequateT-cellRegulation
Cytoskeleton ofhematopoieticcell:PLTSFewinnumber andsize
WASprotein→BaldLymphocytes
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
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
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
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
Chediak-HigashiLYST:Lysosomaltransportdisorder
Nophagolysosome
Melanin CytoplasmicGranules Schwann
CaliforniaHighwaySystem(CHS)TrafficinLosAngeles
LeukocyteAdhesionDefect
• Background:• Neutrophil,FailureofMigration.‘Can’tgettherefromhere’
• Pathogenesis• DefectiveleukocyteadhesionduetomutationsinbetachainofCD11/18integrins.
• DistinguishingClinicalFeatures [skin(bacterialinfections),mucosa,respiratory]• PoorWoundHealing:failureofumblicalcordseparation(omphalitis)• Hallmark:Absenceofpusformationatsitesofinfection• Neutrophilia:theyarepresent,justcan’tgettherefromhere.
Omphalitis
Infection
Nopus
PrimaryImmunodeficienciesforUSMLEStepOne
JohnBarber,Classof2019www.12DaysinMarch.com
E-mail:[email protected]
PartI PartII
LymphocyteDisorders:SCID
X-LinkedAgammaglobulinemiaCVID
Wiskott-AldrichNeutrophilDisorders
ChronicGranulomatousDiseaseChediak-Higashi
LeukocyteAdhesion Deficiency