primary immunodeficiencies for usmle step...

PrimaryImmunodeficienciesforUSMLEStepOne

JohnBarber,Classof2019www.12DaysinMarch.com

E-mail:Howard@12daysinmarch.com

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:Howard@12daysinmarch.com

PartI PartII

LymphocyteDisorders:SCID

X-LinkedAgammaglobulinemiaCVID

Wiskott-AldrichNeutrophilDisorders

ChronicGranulomatousDiseaseChediak-Higashi

LeukocyteAdhesion Deficiency