Immunodeficiencies Flashcards
X-linked (Bruton) agammaglobulinemia, Selective IgA deficiency, Common variable immunodeficiency & X-linked hyper IgM syndrome are immunodeficiencies of which cell type?
B cell
Thymic aplasia, IL-12 receptor deficiency, Autosomal dominant hyper-IgE syndrome (Job syndrome) & Chronic mucocutaneous candidiasis are immunodeficiencies of which cell type?
T cell
B cell immunodeficiencies?
X-linked (Bruton) agammaglobulinemia
Selective IgA deficiency
Common variable immunodeficiency
X-linked hyper IgM syndrome
T cell immunodeficiencies?
12CAT
IL-12 receptor deficiency
Chronic mucocutaneous candidiasis
Autosomal dominant hyper-IgE syndrome (Job syndrome)
Thymic aplasia
What is the defect in Bruton’s disease?
BTK
Bruton tyrosine kinase
defective tyrosine kinase gene → no B-cell maturation
Which B cell immunodeficiency is seen ↑ in boys?
X-linked (Bruton) agammaglobulinemia
Sign/symptoms of Bruton’s disease?
- 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)
Sign/symptoms of X-linked agammaglobulinemia?
Rx considerations?
- 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
Why do patients with Bruton’s disease have recurrent encapsulated pyogenic bacterial and enteroviral infections after 6 months?
↓ 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
Sign/symptoms of selective IgA deficiency?
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
Sign/symptoms of common variable immunodeficiency?
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
What is the defect in thymic aplasia?
22q11 heterozygous microdeletion
Failure to develop 3rd and 4th pharyngeal pouches
→ absent thymus and parathyroids
Failure to develop 3rd and 4th pharyngeal pouches results in which immunodeficiency disease?
Thymic aplasia
DiGeorge syndrome is an immunodeficiency of which cell type?
T cell
Thymic aplasia
Velocardiofacial syndrome is an immunodeficiency of which cell type?
T cell
Thymic aplasia
What is the defect in DiGeorge syndrome?
22q11 heterozygous microdeletion
Failure to develop 3rd and 4th pharyngeal pouches
→ absent thymus and parathyroids
along with cardiac defects
How does thymic aplasia present?
What are the findings?
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
What is the defect in velocardiofacial syndrome?
22q11 heterozygous microdeletion
Failure to develop 3rd and 4th pharyngeal pouches
→ absent thymus and parathyroids
along with palate, facial & cardiac defects
What is the defect in IL-12 receptor deficiency?
↓ Th1 response
autosomal recessive
How does IL-12 receptor deficiency present?
What are the findings?
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)
What is the defect in Jobs syndrome?
Deficiency of Th17 cells due to STAT3 mutation → impaired recruitment of neutrophils to sites of infection → ↓ IFN-γ
What is the defect in autosomal dominant hyper-IgE syndrome?
Jobs syndrome
Deficiency of Th17 cells due to STAT3 mutation → impaired recruitment of neutrophils to sites of infection
How does Jobs syndrome present?
What are the findings?
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
What is the defect in chronic mucocutaneous candidiasis?
- T-cell dysfunction
- Impaired cell-mediated immunity against Candida sp
- Classic form caused by defects in AIRE (autoimmune regulator protein)
How does chronic mucocutaneous candidiasis present?
What are the findings?
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
Persistent Candida albicans infections of skin and mucous membranes are characteristic of which immunodeficiency?
Which immune cells are affected?
Chronic mucocutaneous candidiasis
T cells
What is the defect in severe combined immunodeficiency (SCID)?
- 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
Presentation of severe combined immunodeficiency (SCID)?
- Failure to thrive
- chronic diarrhea
- Bad diaper rashes
- Thrush
- Recurrent viral, bacterial, opportunistic fungal, and protozoal infections
Common findings in severe combined immunodeficiency (SCID)?
↓ 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)
What is the defect in ataxia-telangiectasia?
Defects in ATM kinase gene → failure to detect DNA damage → failure to halt progression of cell cycle → mutations accumulate
Autosomal recessive
Presentation of ataxia-telangiectasia?
Triad:
- Cerebellar defects (Ataxia)
- Spider Angiomas (telangiectasia)
- IgA deficiency
↑↑ sensitivity to radiation (limit x-ray exposure)
Common findings in ataxia-telangiectasia?
↑ AFP (alpha-fetoprotein)
↓ IgA, IgG, and IgE
Lymphopenia
cerebellar atrophy
↑ risk of lymphoma and
leukemia
What is the defect in hyper-IgM syndrome?
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
Presentation of hyper-IgM syndrome?
Findings?
Severe pyogenic infections early in life; opportunistic infection with Pneumocystis, Cryptosporidium, CMV
Findings:
- Normal or ↑ IgM
- ↓↓ IgG, IgA, IgE
- Failure to make germinal centers
What is the defect in Wiskott-Aldrich syndrome (WAS)?
Mutation in WAS gene
leukocytes and platelets unable to reorganize actin cytoskeleton → defective antigen presentation
X-linked recessive
Presentation of Wiskott-Aldrich syndrome?
Common findings?
Presentation:
- Thrombocytopenia
- Eczema
- Recurrent (pyogenic) infections
- ↑ risk of autoimmune disease and malignancy
Findings:
- ↓ to normal IgG, IgM
- ↑ IgE, IgA
- Fewer and smaller platelets
What is the defect in leukocyte adhesion deficiency (type 1)?
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
Presentation of leukocyte adhesion deficiency?
Findings?
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
What are the 3 integrins that contain CD18?
Defect in which integrin causes LAD type 1?
LFA-1 - causes leukocyte adhesion deficiency LAD
MAC-1
gp150/95
What is the defect in Chédiak-Higashi syndrome?
Nonsense mutation in lysosomal trafficking regulator gene (LYST) → Microtubule dysfunction → error in phagosome-lysosome vesicle fusion
Autosomal recessive
Presentation of Chédiak-Higashi syndrome?
Findings?
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
What is the defect in chronic granulomatous disease?
Defect of NADPH oxidase → ↓ reactive oxygen species (eg, superoxide) and ↓ respiratory burst in neutrophils; X-linked form most common
Presentation of chronic granulomatous disease?
Findings?
↑ 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
Why is patient with chronic granulomatous disease not affected by catalase ⊖ organisms?
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
What is the outcome of bacterial pathogen when there are ↓T cells?
Sepsis
↓ B cell immunodeficiency leads to susceptibility of which type of bacterial pathogen?
Encapsulated (Please SHINE my SKiS): Pseudomonas aeruginosa Streptococcus pneumoniae Haemophilus Influenzae type b, Neisseria meningitidis, Escherichia coli, Salmonella, Klebsiella pneumoniae, group B Streptococcus
Granulocyte deficiency leads to susceptibility of which type of bacterial pathogen?
Some Bacteria Produce No Serious granules: Staphylococcus, Burkholderia cepacia, Pseudomonas aeruginosa, Nocardia, Serratia
Complement deficiency leads to susceptibility of which type of bacterial pathogen?
Encapsulated species with early complement deficiencies
Neisseria with late complement (C5–C9) deficiencies
T cell immunodeficiency leads to susceptibility of which type of viruses?
CMV
EBV
JC virus (Human polyomavirus 2/ John Cunningham virus)
VZV
chronic infection with respiratory/GI viruses
B cell deficiency leads to susceptibility of which type of viruses?
Enteroviral encephalitis
poliovirus
(live vaccine contraindicated)
Which type of infections are associated with B & T cell deficiencies?
B-cell deficiencies → recurrent bacterial infections
T-cell deficiencies → fungal and viral infections
T cell immunodeficiency leads to susceptibility of which type of fungi/parasites?
Candida (local), PCP, Cryptococcus
B cell immunodeficiency leads to susceptibility of which type of fungi/parasites?
GI giardiasis (no IgA)
Granulocyte deficiency leads to susceptibility of which type of fungi/parasites?
Candida (systemic), Aspergillus, Mucor
What is the deficiency of Th17 cells due to STAT3 mutation which impairs recruitment of neutrophils to sites of infection and ↓ IFN-γ?
Jobs syndrome
Autosomal dominant hyper-IgE syndrome
