Primary Immunodeficiency

Question 1

Female infant with low T and NK cells but normal B cell numbers, also has diarrhea, FTT, pneumonia. What gene mutation is most likely?

Answer 1

JAK3 mutation (T-/B+NK- SCID: common gamma chain is X-linked whereas JAK3 is autosomal recessive)

Question 2

Which PID is associated with increased alpha fetoprotein (AFP) after 12 months?

Answer 2

Ataxia Telangiectasia

Question 3

Which PID is most likely with recurrent sinopulmonary infections and neutropenia?

Answer 3

CD40L (X-linked) or CD40 (AR) –> Hyper-IgM syndrome

Question 4

Which PID presents with early onset enteropathy (diarrhea), eczema/rash (dermatitis), early onset type 1 diabetes?

Answer 4

IPEX (FOXp3 mutation on X chromosome leading to defective Tregs)

CD25 (IL2 receptor alpha subunit) and STAT5B (autosomal recessive) mutations can also cause IPEX-like presentation.

Question 5

What are the 4 different Autosomal Recessive mutations that cause agammaglobulinemia?

Answer 5

Mu heavy chain - most common
Surrogate light chain, lambda5
Ig-alpha or Ig-beta
BLNK

(BTK causes X-linked agammglobulinemia)

Question 6

What is Good Syndrome?

Answer 6

Adult onset hypogammaglobulinemia with thymoma. Infections (no B cells, low T cells 75%), autoimmunity, diarrhea. Thymectomy may improve autoimmunity but not immunodeficiency.

Question 7

Infection caused by Staph, Serratia, Burkholderia, Nocardia, Aspergillus, Chromobacterium violaceum, Francisella philomiragia, Granulibacter bethesdensis suggest which immunodeficiency?

Answer 7

Chronic Granulomatous Disease

Question 8

Which of the following can cause developmental abnormalities?

1) LAD type 1
2) LAD type 2
3) LAD type 3

Answer 8

LAD type 2 - mutation in GDP-fucose transp. FUCT1 = trouble with fucosylation and glycosylation; fucose on CD15s (Sialyl-Lewis X), no fucose = no binding of neutrophils to endothelium. Fucosylation of other proteins also impaired = developmental defects.

Question 9

Which immunodeficiency causes delayed primary dental deciduation, wide nasal bridge, scoliosis + fractures, hyper-extensible joints, eczema, recurrent staph abscesses that lack typical inflammation, lung infections that turn into pneumatoceles

Answer 9

Job’s Syndrome (Hyper-IgE Syndrome)
STAT3 autosomal dominant negative mutation (1 nml and 1 mutant allele)
Impaired Th17 pathway can lead to chronic mucocutaneous candidiasis

Question 10

Which immunodeficiency has severe HPV (warts all over fingers), molluscum contagiosum, high IgE, lots of atopic disease

Answer 10

DOCK8 deficiency (AR)
don't get lung disease that happens in HIES

Question 11

Name the cytokines that are important for control of mycobacterial diseases.

Answer 11

IL-12, IL-23, and Interferon-gamma

Question 12

What mutations lead to mendelian susceptibility to mycobacterial diseases (MSMD)?

Answer 12

• IL-12R-beta1 deficiency
• IL-12p40 deficiency (p40 shared by IL-12 and IL-23)
• IFN gamma R1 and R2 mutations (mycobacterial osteo pathognomonic for IFNGR1)
• GATA2 - “MonoMAC”, bad warts, lymphedema
• STAT1 mutations (GOF or deficiency)
• IRF8 deficiency (AR biallelic complete or AD partial)
• ISG15 deficiency (potent inducer of IFN-gamma synthesis)
• NEMO
• CYBB

Question 13

What gene mutations cause MHC I deficiency? How do you treat MHC I deficiency?

Answer 13

TAP1, TAP2, tapasin, B2M.

Cannot HSCT because not restricted to hematopoietic cells. Instead, manage pulmonary infections like a CF patient.

Question 14

What gene mutations cause MHC II deficiency? What abnormality would you see on lymphocyte subsets? How do you treat MHC II deficiency?

Answer 14

RFXANK most common, CIITA, RFXAP, RFX5
CD4 lymphopenia (CD4:CD8 ratio reversed)
Tx = HSCT

Question 15

Mutations in Fas or FasL cause what disease? What other mutation can cause this disease?

Answer 15

Autoimmune Lymphoproliferative syndrome (ALPS). Caspase 10 mutation can also cause ALPS.
-alpha-beta TCR double-negative T cells high
-defect in FAS ~60-70%
FASLG, CASP10 <2%
Unknown defect ~25%
-non-malignant LAD, but increased risk for lymphoma
-increased B12, IL-10, soluble FasL

Question 16

What symptoms are seen in X-linked lymphoproliferative syndrome (XLP)? What mutations cause XLP?

Answer 16

XLP
-EBV driven
-lymphoma, autoimmunity
-HLH
XLP1 - SAP or SH2D1A mutation interrupts SLAM family receptor signal, includes 2B4 (CD244) which is NK + T cell receptor for CD48 ligand that is induced on EBV-infected cells
XLP2 - XIAP mutation (X-linked inhibitor of apoptosis, needed for survival of cytolytic lymphocytes)

Question 17

ZAP-70 deficiency causes SCID-like symptoms. What do the lymphocyte and NK counts look like in this condition?

Answer 17

NO CD8 T cells. CD4 T cells are present but not functional. Normal B and NK cells.

Question 18

What type of infections occur in IRAK4 deficiency?

Answer 18

pyogenic infections, especially with strep pneumo

Question 19

What immunodeficiencies are known primarily for susceptibility to HSV encephalitis?

Answer 19

• TLR 3 deficiency (also VZV cerebritis)
• UNC93B1 deficiency (normal function is to load endosome)
• TRIF/TRAF3/TBK1/IRF3 deficiency (these are all MyD88 independent pathway so similar to TLR 3 defic)

Question 20

What is the defect in type 1 leukocyte adhesion deficiency?
a. Inability to encode the beta subunit of LFA-1 and MAC-1
b. Error in encoding ICAM-1, ICAM-2, and ICAM-3
c. Lack of the Golgi GDP-fucose transporter needed to express the carbohydrate ligands for E-selectin
and P-selectin
d. Mutation in the signaling pathways linking chemokine receptors to integrin activation

Answer 20

a. Inability to encode the beta subunit of LFA-1 and MAC-1.
Type 1 leukocyte adhesion disorder is due to an inability to encode the beta2 subunit of LFA-1 and MAC-1. It is an autosomal recessive inherited deficiency in the CD18 gene (ITGB2).

Question 21

X-linked Lymphoproliferative syndrome caused by mutations in SAP (SH2D1A) causes defective signaling through which receptor that is found on NK + T cells? This receptor binds to CD48 ligand that is upregulated on EBV-infected cells.

Answer 21

2B4 (CD244)

Question 22

AID and UNG deficiency are HIGM2 and HIGM4, respectively. Clinically how are patients with AID/UNG deficiency different from patients with CD40L/CD40 deficiency?

Answer 22

1. Do NOT have opportunistic infections because T cells can still interact with macrophages and dendritic cells through intact CD40L/CD40 interactions
2. Get GIANT germinal centers and lymphadenopathy because cells are trying hard to activate B cell class switch through intact CD40L/CD40 interaction (but can’t). CD40L/CD40 deficiency presents with ABSENT germinal centers!

Question 23

What type of mutations cause severe congenital neutropenia/cyclic neutropenia?

Answer 23

Autosomal dominant mutations in Elastase (ELA-2); or autosomal recessive mutations in HAX1 (Kostmann syndrome)

Question 24

A patient presents with marked peripheral eosinophilia (>1500/mm3) on two separate occasions and has been having frequent recurring asthma exacerbations treated in the ED with breathing treatments and corticosteroids over the past 4 months. A diagnosis is made based on identification of a constitutively active fusion protein–what is this fusion protein? What treatment should be initiated in this patient based on this fusion protein?

Answer 24

PDGFRA-FIP1L1 constitutively active fusion protein tyrosine kinase, causes myeloproliferative hypereosinophilic syndrome (m-HES).

Treatment: SENSITIVE TO IMATINIB (tyrosine kinase inhibitor)

• PDGFRB also sensitive to imatinib
• FGFR1 and JAK2 mutations not sensitive to imatinib

Question 25

A diagnosis of systemic mastocytosis can be made if one major + one minor, OR three minor criteria, are met. What are the major and minor criteria?

Answer 25

Major criteria: biopsy with multifocal, dense infiltrates of mast cells (>15 MCs in aggregates)

Minor criteria:

• biopsy with more than 25% of mast cells having spindle-shaped or atypical morphology
• KIT point mutation at codon 816 (D816V)
• CD2 and/or CD25 on CD117+ mast cells
• Total serum tryptase > 20 ng/mL

Question 26

What are the diagnostic criteria for ALPS?

Answer 26

Required criteria:

1. > 6mo lymphadenopathy or splenomegaly not caused by infection/malignancy
2. elevated αβ double-neg T cells ≥ 1.5% total lymphocytes OR ≥ 2.5% of CD3+ lymphocytes

Primary accessory criteria:

• defective Fas-mediated apoptosis (in 2 separate assays)
• mutation in FAS, FASLG, CASP10

Secondary accessory criteria:

• elevated FAS ligand, IL-10, vit B12, IL-18 levels
• typical pathology
• autoimmune cytopenias and elevated IgG
• family history

DEFINITE DIAGNOSIS = Both required criteria + 1 primary accessory criterion
PROBABLE DIAGNOSIS = Both required criteria + 1 secondary accessory criterion