Ch. 6 Immunologic Disorders: Primary Immunodeficiency

Question 1

which causes of SCID lead to isolated CD8 T cell lymphopenia, but preserved CD4 T cells?

Answer 1

MHC class I deficiency (TAP1/TAP2 or tapasin); ZAP 70 (imp for CD8 signaling)

Question 2

which causes of SCID lead to isolated CD4 T cell lymphopenia, but preserved CD8 T cells?

Answer 2

Bare lymphocyte syndrome (MHC II deficiency), Lck deficiency. Also think about HIV

Question 3

There is an x-linked and AR SCID that have an identifical phenotype? What are they and why are they the same?

Answer 3

X-linked SCID=common gamma chain; AR SCID= JAK3 mutation; Jak3 is the signaling protein for the common gamma chain; T-B+NK-

Question 4

what are the radiosensitive SCIDs?

Answer 4

artermis, cernunnos, ligase IV, Nijmegen breakage syndrome (also ATM which isn’t SCID)

Question 5

why are RAG1/RAG2 mutations not associated with radiosensitivity since they are DNA repair genes?

Answer 5

they are limited to immune cells, unlike artemis, cernunnos, ligase IV, etc

Question 6

what is the mutated gene/protein in ataxia telangiectasia?

Answer 6

ATM, which is a PI3 kinase that is responsible for DNA ds breaks

Question 7

what viral infection is fatal in XLP?

Answer 7

EBV-becomes fulminant and activates CTLs and macrophages which can lead to HLH

Question 8

what is the mutation in XLP1? XLP2?

Answer 8

SH21A encodes SAP; XIAP in XLP-2

Question 9

what is the mutation, inheritance and clinical presentation of Wiskott Aldrich?

Answer 9

WASp; inherited X-linked recessive; present with diarrhea/recurrent infections, FTT, eczema and thrombocytopenia; WAS is involved in intracellular trafficking; platelets are affected; NK cell can also be affected

Question 10

what is AD Hyper IgE

Answer 10

mutation in STAT3; recurrent infections pyogengic and mucocutaneous (due to absent Th17); pneumatoceles; skeletal abnormalities, joint extensibility, fracture risk, retained primary teeth, abnormal facies, eczema and IgE>2000

Question 11

what is AR hyper IgE

Answer 11

mutation in DOCK8; severe and difficult to treat viral infections; more prominent eos; no skeletal issues. Tyk2 is absent protein expression and is similar phenotype to DOCK8

Question 12

severe enteroviral infections

Answer 12

think XLA; also ECHO viruses

Question 13

what are some of the AR forms of agammaglobulinemia with essentially same phenotype as XLA?

Answer 13

surrogate light chain (V pre-B; lambda5); mu IgM heavy chain (constant) Iga, IgB, BLNK. of these IgM heavy chain is most common

Question 14

what is kabuki syndrome

Answer 14

mutation in KMT2D (histone methylation?); clinically: hypogamm, cleft palate, abnormal facies and DD

Question 15

what does reduced memory B cells (CD27) help you in management of CVID?

Answer 15

shown to be associated with certain NON-infectious complications (esp hematologic autoimmunity)

Question 16

what is WHIM and the pathophysiology?

Answer 16

Warts, Hypogamm, infections and myelokathexis (retention of mature neutrophils in bone marrow which can lead to neutropenia). AD GOF mutation in CXCR4 which is important for bone marrow homing; ligand for CXCR4 is CXCL12 (expressed on leukocytes)

Question 17

what are the mutations associated with Severe congenital neutropenia?

Answer 17

Hax-1 (Kostmann’s)-AR; ELA-2 (elastase)- AD

Question 18

LAD type I is a defect in what?

Answer 18

CD18; recall binds to variable alpha chains (CD11a=LFA1; CD11b=LFA2; CD11c p150,95) results in recurrent infections, delayed wound healing, impaired pus production, gingival issues, omphalitis or delayed cord release; detected by decreased CD18 on flow

Question 19

LAD 2 is a defect in what? clinical phenotype?

Answer 19

mutation in FUCT1 (absence of fucosylation) -no Sialyl Lewis x (CD15a) that typically binds p-selectin; less severe infections; also associated with developmental delay, microcephaly, short stature and Bombay phenotype (unable to form blood group A, B or O)

Question 20

LAD3 clinical phenotype

Answer 20

like LAD1 + bleeding diathesis; issue with inside out signaling

Question 21

Chediak -Higashi

Answer 21

mutations in LYST; giant lysosomal granules in PMNs poor NK cytotoxicity; clinically have oculocutaneous albinism, recurrent infections, bleeding, neuro deficits; at risk for HLH

Question 22

what are the 5 key infectious organisms to recall in CGD?

Answer 22

Staph, Burkholderia, Serratia, Nocardia and Aspergillus;

Question 23

what are the enzymes defective in CGD?

Answer 23

PHOX (phagocytic NADPH oxidase system) >50% g91phox (x-linked); p47; p 67 and p22 (AR)

Question 24

which of the complement deficiencies inherited x-linked? What is the inheritance pattern of the other complement deficiencies?

Answer 24

properidin deficiency is x-linked; the others are AD