Immunodeficiencies

Question 1

X-linked (Bruton) agammaglobulinemia, Selective IgA deficiency, Common variable immunodeficiency & X-linked hyper IgM syndrome are immunodeficiencies of which cell type?

Answer 1

B cell

Question 2

Thymic aplasia, IL-12 receptor deficiency, Autosomal dominant hyper-IgE syndrome (Job syndrome) & Chronic mucocutaneous candidiasis are immunodeficiencies of which cell type?

Answer 2

T cell

Question 3

B cell immunodeficiencies?

Answer 3

X-linked (Bruton) agammaglobulinemia

Selective IgA deficiency

Common variable immunodeficiency

X-linked hyper IgM syndrome

Question 4

T cell immunodeficiencies?

Answer 4

12CAT

IL-12 receptor deficiency

Chronic mucocutaneous candidiasis

Autosomal dominant hyper-IgE syndrome (Job syndrome)

Thymic aplasia

Question 5

What is the defect in Bruton’s disease?

Answer 5

BTK
Bruton tyrosine kinase

defective tyrosine kinase gene → no B-cell maturation

Question 6

Which B cell immunodeficiency is seen ↑ in boys?

Answer 6

X-linked (Bruton) agammaglobulinemia

Question 7

Sign/symptoms of Bruton’s disease?

Answer 7

• Recurrent encapsulated pyogenic bacterial and enteroviral infections after 6 months (↓ maternal IgG)
• ↓ immunoglobulins of all isotypes
• ↓ or no circulating B cells in peripheral blood
• ↓ or small or no lymph nodes & tonsils (1° follicles & germinal centers absent)

Question 8

Sign/symptoms of X-linked agammaglobulinemia?

Rx considerations?

Answer 8

• Recurrent encapsulated pyogenic bacterial and enteroviral infections after 6 months (↓ maternal IgG)
• ↓ immunoglobulins of all isotypes
• ↓ or no circulating B cells in peripheral blood
• ↓ or small or no lymph nodes & tonsils (1° follicles & germinal centers absent) → live vaccines
  contraindicated

Rx
Monthly gamma-globulin replacement
Antibiotics for infections

Question 9

Why do patients with Bruton’s disease have recurrent encapsulated pyogenic bacterial and enteroviral infections after 6 months?

Answer 9

↓ maternal IgG

Defective BTK tyrosine kinase gene → no B-cell maturation

After initial maternal Ig protection there is no development of B cell to maintain self cell-mediated immunity

Question 10

Sign/symptoms of selective IgA deficiency?

Answer 10

Presentation:

• Majority Asymptomatic
• Repeated Airway (sinopulmonary) and GI infections
• ↑ Atopy
• Autoimmune disease
• Anaphylaxis to IgA in blood products

Findings:

• ↓ IgA
• Normal IgG, IgM
• ↑IgE
• ↑ susceptibility to giardiasis
• Can cause false-negative celiac disease test

Question 11

Sign/symptoms of common variable immunodeficiency?

Answer 11

Presentation:
May present in childhood but usually diagnosed after puberty (late teens, early 20s)
↑ risk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections

Findings:
B cells in peripheral blood
↓ plasma cells
↓ immunoglobulin levels with time

Question 12

What is the defect in thymic aplasia?

Answer 12

22q11 heterozygous microdeletion

Failure to develop 3rd and 4th pharyngeal pouches
→ absent thymus and parathyroids

Question 13

Failure to develop 3rd and 4th pharyngeal pouches results in which immunodeficiency disease?

Answer 13

Thymic aplasia

Question 14

DiGeorge syndrome is an immunodeficiency of which cell type?

Answer 14

T cell

Thymic aplasia

Question 15

Velocardiofacial syndrome is an immunodeficiency of which cell type?

Answer 15

T cell

Thymic aplasia

Question 16

What is the defect in DiGeorge syndrome?

Answer 16

22q11 heterozygous microdeletion

Failure to develop 3rd and 4th pharyngeal pouches
→ absent thymus and parathyroids

along with cardiac defects

Question 17

How does thymic aplasia present?

What are the findings?

Answer 17

CATCH-22:

Cardiac defects (conotruncal abnormalities
[eg, tetralogy of Fallot, truncus arteriosus])

Abnormal facies (fish lips)

Thymic hypoplasia → T-cell deficiency (recurrent viral/ fungal infections)

Cleft palate

Hypocalcemia 2° to parathyroid aplasia → tetany

(only IgM → no class switching)

Findings:
↓ T cells
↓ PTH
↓ Ca2+
Thymic shadow absent on CXR

Question 18

What is the defect in velocardiofacial syndrome?

Answer 18

22q11 heterozygous microdeletion

Failure to develop 3rd and 4th pharyngeal pouches
→ absent thymus and parathyroids

along with palate, facial & cardiac defects

Question 19

What is the defect in IL-12 receptor deficiency?

Answer 19

↓ Th1 response

autosomal recessive

Question 20

How does IL-12 receptor deficiency present?

What are the findings?

Answer 20

Presentation:

• Disseminated mycobacterial and fungal infections
• may present after administration of BCG vaccine

Findings:
↓ IFN-γ
Most common cause of Mendelian susceptibility to mycobacterial diseases (MSMD)

Question 21

What is the defect in Jobs syndrome?

Answer 21

Deficiency of Th17 cells due to STAT3 mutation → impaired recruitment of neutrophils to sites of infection → ↓ IFN-γ

Question 22

What is the defect in autosomal dominant hyper-IgE syndrome?

Answer 22

Jobs syndrome

Deficiency of Th17 cells due to STAT3 mutation → impaired recruitment of neutrophils to sites of infection

Question 23

How does Jobs syndrome present?

What are the findings?

Answer 23

A - Abscesses: cold (noninflamed) staphylococcal severe, recurrent infections

B- retained Baby (primary) teeth

C - Coarse facies

D - Dermatologic problems (eczema) (JOB-Yaqub A.S)

E - ↑ IgE

F - bone Fractures from minor trauma

Findings:
↑ IgE
↑ eosinophils

Question 24

What is the defect in chronic mucocutaneous candidiasis?

Answer 24

• T-cell dysfunction
• Impaired cell-mediated immunity against Candida sp
• Classic form caused by defects in AIRE (autoimmune regulator protein)

Question 25

How does chronic mucocutaneous candidiasis present? What are the findings?

Answer 25

Persistent noninvasive Candida albicans infections of skin and mucous membranes Findings: - Absent in vitro T-cell proliferation in response to Candida antigens - Absent cutaneous reaction to Candida antigens

Question 26

Persistent Candida albicans infections of skin and mucous membranes are characteristic of which immunodeficiency? Which immune cells are affected?

Answer 26

Chronic mucocutaneous candidiasis T cells

Question 27

What is the defect in severe combined immunodeficiency (SCID)?

Answer 27

- Defective IL-2 receptor gamma chain (X-linked recessive) most common - adenosine deaminase deficiency (autosomal recessive) (boy in a bubble) - recombinase gene RAG mutation → VDJ recombination defect

Question 28

Presentation of severe combined immunodeficiency (SCID)?

Answer 28

- Failure to thrive - chronic diarrhea - Bad diaper rashes - Thrush - Recurrent viral, bacterial, opportunistic fungal, and protozoal infections

Question 29

Common findings in severe combined immunodeficiency (SCID)?

Answer 29

↓ T-cell receptor excision circles (TRECs) (assessment of thymic function > TRECs are expressed only in T cells of thymic origin) ↓ levels of circulating lymphocytes ``` Part of newborn screening for SCID Absence of thymic shadow (CXR), germinal centers (lymph node biopsy) T cells (flow cytometry) ```

Question 30

What is the defect in ataxia-telangiectasia?

Answer 30

Defects in ATM kinase gene → failure to detect DNA damage → failure to halt progression of cell cycle → mutations accumulate Autosomal recessive

Question 31

Presentation of ataxia-telangiectasia?

Answer 31

Triad: - Cerebellar defects (Ataxia) - Spider Angiomas (telangiectasia) - IgA deficiency ↑↑ sensitivity to radiation (limit x-ray exposure)

Question 32

Common findings in ataxia-telangiectasia?

Answer 32

↑ AFP (alpha-fetoprotein) ↓ IgA, IgG, and IgE Lymphopenia cerebellar atrophy ↑ risk of lymphoma and leukemia

Question 33

What is the defect in hyper-IgM syndrome?

Answer 33

``` Most commonly due to defective CD40L on Th cells → IgM only → class switching doesn't occur → can't make IgG, A, E ``` X-linked recessive

Question 34

Presentation of hyper-IgM syndrome? Findings?

Answer 34

Severe pyogenic infections early in life; opportunistic infection with Pneumocystis, Cryptosporidium, CMV Findings: - Normal or ↑ IgM - ↓↓ IgG, IgA, IgE - Failure to make germinal centers

Question 35

What is the defect in Wiskott-Aldrich syndrome (WAS)?

Answer 35

Mutation in WAS gene leukocytes and platelets unable to reorganize actin cytoskeleton → defective antigen presentation X-linked recessive

Question 36

Presentation of Wiskott-Aldrich syndrome? Common findings?

Answer 36

Presentation: - Thrombocytopenia - Eczema - Recurrent (pyogenic) infections - ↑ risk of autoimmune disease and malignancy Findings: - ↓ to normal IgG, IgM - ↑ IgE, IgA - Fewer and smaller platelets

Question 37

What is the defect in leukocyte adhesion deficiency (type 1)?

Answer 37

Defect in LFA-1 integrin (CD18) protein on phagocytes; impaired migration and chemotaxis Autosomal recessive ``` *CD18 - common β chain of the leukocyte integrins The 3 integrins that contain CD18: LFA-1 MAC-1 gp150/95 ```

Question 38

Presentation of leukocyte adhesion deficiency? Findings?

Answer 38

Late separation (>30 days) of umbilical cord (Omphalitis) No pus (d/t lack of adhesion-dependent leukocyte migration into sites of inflammation) Gum infections (d/t antigen in mouth) dysfunctional neutrophils → ↑ recurrent skin and mucosal bacterial infections Findings ↑ neutrophils in blood but absence of neutrophils at infection sites → impaired wound healing

Question 39

What are the 3 integrins that contain CD18? Defect in which integrin causes LAD type 1?

Answer 39

LFA-1 - causes leukocyte adhesion deficiency LAD MAC-1 gp150/95

Question 40

What is the defect in Chédiak-Higashi syndrome?

Answer 40

Nonsense mutation in lysosomal trafficking regulator gene (LYST) → Microtubule dysfunction → error in phagosome-lysosome vesicle fusion Autosomal recessive

Question 41

Presentation of Chédiak-Higashi syndrome? Findings?

Answer 41

Immunodeficient albino ``` PLAIN: Progressive neurodegeneration, Lymphohistiocytosis Albinism (partial) Infections recurrent pyogenic Neuropathy peripheral ``` ``` Findings: Giant granules in granulocytes and platelets Pancytopenia Mild coagulation defects No NK activity ```

Question 42

What is the defect in chronic granulomatous disease?

Answer 42

Defect of NADPH oxidase → ↓ reactive oxygen species (eg, superoxide) and ↓ respiratory burst in neutrophils; X-linked form most common

Question 43

Presentation of chronic granulomatous disease? Findings?

Answer 43

↑ susceptibility to catalase ⊕ organisms Recurrent infections and granulomas *catalase ⊕ bacteria & fungi destroy H202 → patient cannot produce .02, .OH, 1O2 & is left with only O2 independent lysosomal mechanism that is inadequate to control rampant infection Findings: DHR test: Abnormal DHR (dihydrorhodamine) (flow cytometry) test (↓green fluorescence) Nitroblue tetrazolium dye reduction test (obsolete) fails to turn blue

Question 44

Why is patient with chronic granulomatous disease not affected by catalase ⊖ organisms?

Answer 44

Because the waste product produced by the bacterium can be used as substrate for the alternative myeloperoxidase killing mechanism *catalase ⊕ bacteria & fungi destroy H202 → patient cannot produce .02, .OH, 1O2 & is left with only O2 independent lysosomal mechanism that is inadequate to control rampant infection *O2 independent killing Lysosomes O2 independent killing Myeloperoxidase + H2O2 + HOCl

Question 45

What is the outcome of bacterial pathogen when there are ↓T cells?

Answer 45

Sepsis

Question 46

↓ B cell immunodeficiency leads to susceptibility of which type of bacterial pathogen?

Answer 46

``` Encapsulated (Please SHINE my SKiS): Pseudomonas aeruginosa Streptococcus pneumoniae Haemophilus Influenzae type b, Neisseria meningitidis, Escherichia coli, Salmonella, Klebsiella pneumoniae, group B Streptococcus ```

Question 47

Granulocyte deficiency leads to susceptibility of which type of bacterial pathogen?

Answer 47

``` Some Bacteria Produce No Serious granules: Staphylococcus, Burkholderia cepacia, Pseudomonas aeruginosa, Nocardia, Serratia ```

Question 48

Complement deficiency leads to susceptibility of which type of bacterial pathogen?

Answer 48

Encapsulated species with early complement deficiencies Neisseria with late complement (C5–C9) deficiencies

Question 49

T cell immunodeficiency leads to susceptibility of which type of viruses?

Answer 49

CMV EBV JC virus (Human polyomavirus 2/ John Cunningham virus) VZV chronic infection with respiratory/GI viruses

Question 50

B cell deficiency leads to susceptibility of which type of viruses?

Answer 50

Enteroviral encephalitis poliovirus (live vaccine contraindicated)

Question 51

Which type of infections are associated with B & T cell deficiencies?

Answer 51

B-cell deficiencies → recurrent bacterial infections T-cell deficiencies → fungal and viral infections

Question 52

T cell immunodeficiency leads to susceptibility of which type of fungi/parasites?

Answer 52

Candida (local), PCP, Cryptococcus

Question 53

B cell immunodeficiency leads to susceptibility of which type of fungi/parasites?

Answer 53

GI giardiasis (no IgA)

Question 54

Granulocyte deficiency leads to susceptibility of which type of fungi/parasites?

Answer 54

Candida (systemic), Aspergillus, Mucor

Question 55

What is the deficiency of Th17 cells due to STAT3 mutation which impairs recruitment of neutrophils to sites of infection and ↓ IFN-γ?

Answer 55

Jobs syndrome | Autosomal dominant hyper-IgE syndrome