primary immunodeficienciesfor usmle step...
TRANSCRIPT
PrimaryImmunodeficiencies forUSMLEStepOne
JohnBarber,Classof2019www.12DaysinMarch.com
E-mail:[email protected]
PartI PartII
LymphocyteDisorders:SCID
Bruton’sX-LinkedAgammaglobulinemiaCVID
Wiskott-AldrichNeutrophilDisorders
ChronicGranulomatousDiseaseChediak-Higashi
LeukocyteAdhesion Deficiency
thePrimaryImmunodeficiencySyndromes
• Lymphocyte-predominantdefect• SCID:SevereCombinedImmunodeficiency(T→B)• Bruton’s(X-linked)Agammaglobulinemia(BTK→B-maturation)• CVID:CommonVariableImmunodeficiency(B-differentiation)
• Cytoskeletondefect• Wiskott-Aldrich(𝚽 actinpolymerization→failureof‘immunologicsynapse’)
• Neutrophil-predominantdefect• CGD:ChronicGranulomatousDefect(Enzymedeficiency,NADPHoxidase)• Chediak-Higashi (Lysosomaltransportdefect;LYST)• LAD:LeukocyteAdhesionDeficiency(Integrinfailure;βchain- CD11/18)
Severe Combined Immunodeficiency(SCID)
• Background:• CharacteristicFeature:FailureofLymphocyteProgenitor(Pro-T)Cellwith profoundsusceptibilitytoinfection
• Pathogenesis• Multiplemutations:failuretodevelopTandconsequentlyBlymphocytes.
• Subtype:Adenosinedeaminase(ADA) deficiencyleadstoaccumulationofadenosine,toxictolymphocytes.
• ClinicalFeaturesofProfoundLymphocyteFailure• Failuretothrive/ChronicDiarrhea(2° toperistenceofenteropathogens)• Infections:fungal (mucocutaneouscandidiasis→thrush/diaperrash,Pneumocystis);bacteria/viral
• DistinguishingFeatures• AbsenceofT-cellsandthymicshadow.
• Therapy:• Bonemarrowtransplant(hematopoieticstemcells)– norejection• Gene/Replacementtherapy:Adenosinedeaminase
SevereCombined Immunodeficiency (SCID)
Candida:GermTubes(37°)
Pneumocystis jiroveci
SCID:Absenceofthymicshadow.
Bruton’s (X-linked)Agammaglobulinemia
• Background• FailureofB-cellprecursorstodevelopintomatureB-cells(noplasmacells,noglobulins).
• Pathogenesis• Tyrosinekinasedeficiency(Btk)
• Nonreceptor(protein)TK:involvedinsignaltransductionrequiredinallstagesofB-celldevelopment.MaturationceasesintheabsenceofTKsignalling.
• DistinguishingFeaturesofB-lymphocyteFailure(i.e.agammaglobulinemia)• NoB-cells:noCD19,underdevelopedGerminalCenter,noplasmacellsorhumoralimmunity• Respiratory:pyogenicinfections(encapsulatedorganisms;lossofopsonizingaby)• GI:especiallyenterovirusandGiardia(lowIgA)
• Rx:IVIG• Notes:
• InitialprotectionfrommaternalIgG.• AssociationwithhemeandGImalignancies• NormalT-cells:TypeIVhypersensitivityintact,fungalinfectionuncommon
Bruton’s (X-linked)Agammaglobulinemia
• Background• FailureofB-cellprecursorstodevelopintomatureB-cells(noplasmacells,noglobulins).
• Pathogenesis• Tyrosinekinasedeficiency(Btk)
• Nonreceptor(protein)TK:involvedinsignaltransductionrequiredinallstagesofB-celldevelopment.MaturationceasesintheabsenceofTKsignalling.
• DistinguishingFeaturesofB-lymphocyteFailure(i.e.agammaglobulinemia)• NoB-cells:noCD19,underdevelopedGerminalCenter,noplasmacellsorhumoralimmunity• Respiratory:pyogenicinfections(encapsulatedorganisms;lossofopsonizingaby)• GI:especiallyenterovirusandGiardia(lowIgA)
• Rx:IVIG• Notes:
• InitialprotectionfrommaternalIgG.• AssociationwithhemeandGImalignancies• NormalT-cells:TypeIVhypersensitivityintact,fungalinfectionuncommon
Agammaglobulinemia
Bruton’s (X-linked)Agammaglobulinemia
• Background• FailureofB-cellprecursorstodevelopintomatureB-cells(noplasmacells,noglobulins).
• Pathogenesis• Tyrosinekinasedeficiency(Btk)
• Nonreceptor(protein)TK:involvedinsignaltransductionrequiredinallstagesofB-celldevelopment.MaturationceasesintheabsenceofTKsignalling.
• DistinguishingFeaturesofB-lymphocyteFailure(i.e.agammaglobulinemia)• NoB-cells:noCD19,underdevelopedGerminalCenter,noplasmacellsorhumoralimmunity• Respiratory:pyogenicinfections(encapsulatedorganisms;lossofopsonizingaby)• GI:especiallyenterovirusandGiardia(lowIgA)
• Rx:IVIG• Notes:
• InitialprotectionfrommaternalIgG.• AssociationwithhemeandGImalignancies• NormalT-cells:TypeIVhypersensitivityintact,fungalinfectionuncommon
Agammaglobulinemia
NoGerminalCenters
FailureofHumoral Immunity
Bruton’s (X-linked)Agammaglobulinemia
• Background• FailureofB-cellprecursorstodevelopintomatureB-cells(noplasmacells,noglobulins).
• Pathogenesis• Tyrosinekinasedeficiency(Btk)
• Nonreceptor(protein)TK:involvedinsignaltransductionrequiredinallstagesofB-celldevelopment.MaturationceasesintheabsenceofTKsignalling.
• DistinguishingFeaturesofB-lymphocyteFailure(i.e.agammaglobulinemia)• NoB-cells:noCD19,underdevelopedGerminalCenter,noplasmacellsorhumoralimmunity• Respiratory:pyogenic infections (encapsulatedorganisms;lossofopsonizingaby)• GI:especiallyenterovirusandGiardia(lowIgA)
• Rx:IVIG• Notes:
• InitialprotectionfrommaternalIgG.• AssociationwithhemeandGImalignancies• NormalT-cells:TypeIVhypersensitivityintact,fungalinfectionuncommon
BTK‘complex’ involvedinsignalingandB-celldevelopment
NoGerminalCenter
NoImmunoglobulins
Nosignaltransduction forB-celldevelopment
CD19
CommonVariable Immunodeficiency
• Background• Defect:impairedB-celldifferentiationintoplasmacellswithimpairedIgsecretion/production→
hypogammaglobulinemia• Variable
• Variablephenotypicexpression• Variablegeneticdefects(i.e.groupofdisorderssharinglowglobulinsincommon)• Variable=Lousyboardderivatives
• Presentation:20-45yrsold• Pulmonary:PNA,sinusitis/otitis,bronchietasis• GI:viral,parasite,bacteria
• Dx:IglevelsandIgGresponsetovaccines(tetanus,diptheria,PVX)• B-cellnumberisnormalbutdecreaseinisotype-switchedmemoryBcells.
• Rx:IVIG• Notes:
• Immunedysregulation→autoimmunity(AIHA,ITP;RA)• Malignancy(lymphoma)
PrimaryImmunodeficienciesforUSMLEStepOne
JohnBarber,Classof2019www.12DaysinMarch.com
E-mail:[email protected]
PartI PartII
LymphocyteDisorders:SCID
Bruton’sX-LinkedAgammaglobulinemiaCVID
Wiskott-AldrichNeutrophilDisorders
ChronicGranulomatousDiseaseChediak-Higashi
LeukocyteAdhesion Deficiency