Immunology

Question 1

Hyper-IGM syndrome:

• What is the immunodeficiency?
• Describe the phenotype

Answer 1

Combined B and T cell deficiency; no immunoglobulin class switching
Recurrent bacterial infections, opportunistic infections (PJP, histoplasmosis, cryptosporidium)

Question 2

Hyper-IgM syndrome: underlying gene defect and inheritance

Answer 2

CD40 ligand gene

XL

Question 3

Hyper-IgM syndrome: treatment

Answer 3

HSCT

Question 4

Wiskott-Aldrich syndrome:

• Associated mutation
• Inheritance

Answer 4

• WAS gene, encoding WASP

- XL

Question 5

Describe the immunodeficiency reported with WAS

Answer 5

Combined T and B (usually worse) defect
T: abnormal proliferation to antigen and mitogen
B: decreased production of specific antibody; classically lacks responses to carbohydrates

Question 6

What is the classic triad of WAS?

Answer 6

• Immunodeficiency
• Microthrombocytopenia (typically have bloody diarrhea)
• Eczema

Question 7

What infections are commonly seen in WAS?

Answer 7

• Recurrent otitis media and sinopulmonary infections
• Staphylococcal skin superinfection
• Opportunistic infections

Question 8

What manifestations of auto-immunity are often seen in WAS?

Answer 8

• ITP, AIHA
• IBD
• Glomerulonephritis
• Vasculitis
• Dysimmunity: lymphoma, often EBV related

Question 9

What are possible mechanisms to explain the presence of Wiskott-Aldricht syndrome in a female?

Answer 9

• Extreme lyonization of the mutant X chromosome
• Random X chromosome inactivation
• WAS mutations on both chromosomes

Question 10

Management of Wiskott-Aldricht syndrome

Answer 10

• HSCT (ideally with MSD)
• Pre-transplant: regular infusions of IVIG, antibiotic prophylaxis, cautious use of safe blood product (CMV safe, irradiated)

Question 11

Name 3 SCID syndromes that are T-B-

Answer 11

1. ADA deficiency (NK-)
2. RAG1, RAG2 deficiency (NK+)
3. Artemis syndrome

(All are AR)

Question 12

Name 3 SCID syndromes that are T-B+

Answer 12

1. JAK3 mutation
2. IL7R alpha chain
3. Cytokine common gamma chain

Question 13

Describe the laboratory findings in SCID (4 features)

Answer 13

Usually decreased ALC (not always, since B cells can be normal)
Severely decreased IgA, IgG, IgM
Absent T cells on lymphocyte immunophenotyping (occasionally, some maternal T-cells can be seen)
Absent mitogen proliferation

Question 14

Describe the management of SCID (6 features)

Answer 14

• Urgent referral for allogeneic HSCT
• Protection against infections
• PJP prophylaxis
• Aggressive diagnosis and treatment of infections
• IVIG replacement
• If blood transfusion required, CMV (-)ve and irradiated

Question 15

Describe the management of ALPS?

Answer 15

• Mainstay of treatment: immunosuppression with steroids, sirolimus, MMF, etc.
• Monitoring for development of lymphoproliferation
• HSCT if very severe, refractory cases
• Avoid splenectomy; increased risk of infection and cytopenias usually improve over time

Question 16

Criteria ALPS

Answer 16

Required
1. Chronic (at least 6 months), nonmalignant, noninfectious lymphadenopathy and/or splenomegaly
2. Elevated CD3 TCR+ CD4-CD8- (DNT) cells (at least 1.5% of total lymphocytes or 2.5% of CD3 lymphocytes) in the setting of normal or elevated lymphocyte counts
Accessory
Primary
1. Defective lymphocyte apoptosis (in 2 separate assays)
2. Somatic or germline pathogenic mutation in FAS, FASLG, or CASP10
Secondary
1. Elevated plasma sFASL levels OR elevated plasma
interleukin-10 levels OR elevated serum or plasma vitamin B12 levels OR elevated plasma interleukin-18 levels
2. Typical immunohistological findings
3. Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, or neutropenia) AND elevated immunoglobulin G levels (polyclonal hypergammaglobulinemia)
4. Family history

Question 17

Typical mutations seen in ALPS (4)

Answer 17

• FAS
• FASLG
• CASP8 (not part of the official criteria)
• CASP10

Question 18

Name 3 hematological effects of HIV/AIDS

Answer 18

• Anemia
• Thrombopenia
• Neutropenia
• Immune dysfunction, including CD4 T-cells depletion, hyperactivation of B cells and hypergammaglobulinemia

Question 19

Name principal malignancies associated with HIV/AIDS

Answer 19

• NHL (systemic or primary CNS)
• Leiomyosarcoma and leiomyoma (mostly children)
• ALL
• Kaposi’s sarcoma (mostly adults)

Question 20

Name 3 AIDS defining malignancies and their associated virus

Answer 20

• Invasive cervical cancer (adults) - HPV
• Kaposi sarcoma - HHV6
• Lymphoma - EBV
• most common subtypes: Burkitt, immunoblastic, primary CNS lymphoma

Question 21

XLP: affected gene

Answer 21

SH2D1A gene (lack of expression of SAP protein)

Question 22

Difference between the CBC in infants comapred to older children?

Answer 22

Higher ALC (mostly 2nd to CD3+ and CD19+ cells)

Question 23

Normal values for ALC in infants?

Answer 23

3500-7500

Values less than 1000-2000 are highly suspicious for SCID