Flashcards in 33. Immunodeficiencies Deck (104):
Generally, T - cells deficiencies vs B cell deficiencies according to risk for infenctions
generally, B- celles deficii cell disorders
4. phagocyte dysfunctiononenceis --> reurrent bacterial infenction
generally, T cells deficiencies --> fungal and viral infenct
Immunodeficiencies are divided to
1. B-cells disorders
2. T cells disorders
3. B and T disorders
4. Phagocyte dysfunction
Immunodeficiencies - B cells disorders type
1.X- linked (Bruton ) agammaglobulinemia
2. Selective IgA deficiency
3. Common variable immunodeficiency
X-linked (bruton) agammaglobunimenia - defect
Defect in BTK, a tyrosine kinase gene -> no B cell maturation
X-linked ---> boys
X-linked (bruton) agammaglobunimenia -mechanism of inheritance
x-linked recessive--> boys
X-linked (bruton) agammaglobunimenia - presentation
Recurrent bacterial and enteroviral infenction after 6 months ( after maternal IgG protections
X-linked (bruton) agammaglobunimenia - findings
Absent B cells in perippheral blood
2. Low Ig of classes
3. Absent / scanty lymph nodes and tonsils
Selective IgA deficiency - defect
Selective IgA deficiency - presentation
airway and Gi infenctions
Anaphylaxis to IgA-containing products
Selective IgA deficiency - findings
1. Low IgA
2. normal IgG, IgM levels
Common variable immunodeficiency - defect
defect in B cells differentiation (many causes)
Common variable immunodeficiency - presentation
Can be acquired in 20-30
Common variable immunodeficiency - findings
1. low plasma cells
2. low immunoglobulins
T-cell disorders - types
1. thymus aplasia (diGeorge syndrome)
2. IL-12 receptor deficiency
3. Autosomal dominant hyper IgE syndrome (Job syndrome)
4. Chronic mucocutaneous candidiasi
Thymus aplasia is AKA
Di George syndrome
Thymus aplasia (DiGeorge syndrome ) - defect
22q11 deletion --> failure to develop 3rd and 4th pharyngeal pouches --> absent thymus and parathyroids
Thymus aplasia (DiGeorge syndrome ) - presentation
1. Tetany (hypocalcemia)
2. Recurrent viral/ fungal infenction
3. conotruncal abnormalities ( ef tetralogy of Fallot, truncus arteriosus)
Thymus aplasia (DiGeorge syndrome ) - findings
1. decreased T-cells
2. decreased Parathormone --> decreased calcium
3. absent thymic shadow on CXR
4. 22q11 deletion detected by FISH
5. not well developed lymph node paracortex
Il-12 receptor deficiency - defect
low Th1 response
Il-12 receptor deficiency - mode of inheritance
Il-12 receptor deficiency - presentation
Disseminated mycobacterial and fugal infenctions - may present after BCG vaccine administration
Il-12 receptor deficiency - may present after
BCG vaccine administration
Il-12 receptor deficiency - findings
INF-γ is secreted by .../ actions
it is secreted by NK cells and T cells in response to il-12 from macrophages. actions
1. stimulates macrophages to kill phagocytosed pathogens
2. Inhibits differentiation of Th2
3. Activates NK cells to kill virus infected -cells
4. increases MHC expression and antigen presentation by all cells
Autosomal dominant hyper-IgE syndrome is also called
Autosomal dominant hyper-IgE syndrome ( Job synrome)- defect / mode of inheritance
Deficiency of Th17 cells due to STAT3 mutation --> impaired recruitment of neutrophils to site of mutation
Autosomal dominant hyper-IgE syndrome ( Job synrome)- presentation
1. coarse facies
2. cold (non inflammed ) staphylococcal Abscess
3. retained primary teeth
5. Dermatologic problems (eczema)
Autosomal dominant hyper-IgE syndrome ( Job synrome) - findings
Chronic mucocutaneous candidiasis - defect
T- cell dysfunction (many causes
Chronic mucocutaneous candidiasis - presentation
Noninvasive Candida albicans infenction of skin and mucous membranes
Chronic mucocutaneous candidiasis - findings
1. absent in vitro T-cell proliferation in response to Candida ablicans
2. Absent cutaneous reaction to Candida ablicans
B and T cell disorders types
1. Severe combined immunodeificiency
2. Ataxia - telangiectasia
3. Hyper - IgM syndrome
4. Wiskott- Aldrich syndrome
Severe combined immunodeficiency-defect
a. defective IL-2R gamma chain (MC, X-linked)
b. adenosine deaminasi deficiency (AR)
Severe combined immunodeficiency - presentation
1. failure to thrive
2. chronic diarrhea
4. Recurrent viral, bacterial, fungal and protozoal infenction
Severe combined immunodeficiency - treatment
bone marrow transplant (no cocern for rejection)
Severe combined immunodeficiency - findings
1. decreased T-cell rceptor excision circles ( TRECs)
2. absence of thymic shadow on CXR
3. absent of germinal centers (lymph node biopsy)
4. absence of T cells (flow cytometry)
T cell receptor excision circles (TRECs) are
small circles created in T-cells during their passage through the thymus as they rearrange their TCR genes --> indication of T-cell maturation
Ataxia - telegectasia - defect
defects in ATM gene --> failure to repair DNA double strand breaks --> cell cycle arrest
Ataxia - telegectasia - presentation
1. cerebellar defects ( Ataxia)
2. spider angiomas (telangiectasia)
3. IgA deficiency
Ataxia - telegectasia - findings
1. increased AFP
2. low IgA, IgG and IgE
4. cerebellar atrophy
5. Normal Level of IgM
Hyper- IgM syndrome-defect
MC due to defective CD40L on Th cells --> class switching defect
Hyper- IgM syndrome -mode of inheritance
Hyper- IgM syndrome - presentation
1. severe pyogenic infenction early in life
2. oppurtunistic infenction with Pneumocystis, Cryptosporidium, CMV
Hyper- IgM syndrome -oppurtunistic infenction
Pneumocystis, Cryptosporidium, CMV
Hyper- IgM syndrome- findings
1. normal or increased Igm
2. low IgG, IgA, IgE
Wiskott-Aldrich syndrome - defect
mutation of WAS gens - cells unable to reorganize actin cytoskeleton
Wiskott-Aldrich syndrome - mode of inheritance
Wiskott-Aldrich syndrome -presentation
Mnemonic: WATER + autoimmune +malignancy
3. Recurrent infenction
4. High risk of autoimmune disease and malignancy
Wiskott-Aldrich syndrome - findings
1. low / normla IgG, Igm
2. High IgE, IgA
3. Fewer and smaller platelets
B and T cell disorders - types and mode of inheritance
1. Sever combimed immunodeficiency --> X or AR
2. Ataxia - telagiectasia--> -
3. Hyper Igm syndrome -->XR
4. Wiskott - Aldrich syndrome --> XR
Phagocyte dysfunction- type and mode of inheritance
1. Phagocyte adhesion deficiency 9type 1) ---> AR
2. Chediak- Higashi --> AR
3. Chronic granulomatous disease --> XR
Leukocyte adhession deficiency (type 1) - defect
defect in LFA-1 intergrin (CD18) protein on phagocytes --> impaired migration and chemotaxis
Leukocyte adhession deficiency (type 1) - mode of inheritance
Leukocyte adhession deficiency (type 1) - presentation
1. recurrent bacterial skin and mucosa infenction
2. Absent pus formation
3. impaired wound healing
4. delayed separation of umbilical cord (>30days)
Leukocyte adhession deficiency (type 1) -findings
1. increased neutrophils
2. no neutrophils at infenction site
Chediak- Hisgashi syndrome -mechanis
defect in lysosomal traficking regulation gene (LYST) --> microtubule dysfunction in phagosome-lysosome fusion
Chediak- Hisgashi syndrome - mode of inheritance
Chediak- Hisgashi syndrome - presentation
recurrent pogenic infenction by straps and steps
2. partial albinism
3. peripheral neurpathy
4. progressive neurodegenaration
Chediak- Hisgashi syndrome - findings
1. giant granules in granulocytes and platelets
3. Mild coagulation defects
Chronic granulomatous disease - mechanism
Defect of NADPH oxiades --> decreased ROS and respiratory burst in neutrophils
Chronic granulomatous disease -mode of inheritance
Chronic granulomatous disease
high susceptibility to CAT + organism
CAT + bugs?
CAT Need PLACESS to Belch their Hairballs
Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E. coli, Staphylococci, Serratia, B.cepacia. H.pylori
Chronic granulomatous disease
Abnormal dihydrorhodamine (flow cytometry test (decreased green fluorescence)
Nitroblue tetrazolium dye reduction test obsolete (if + --> less blue
Selective IgA deficieny
• An 8-month-old boy has 2 months of recurrent bacterial infections and suspected immunodeficiency. Explain the timing of presentation.
Maternal IgG depletion after 6 months (he has Bruton agammaglobulinemia with ineffective maturation and low B cells and immunoglobulins)
• A woman has balance problems, web-like angiomas on her face, and low IgA levels. What is the pathogenesis? What are some lab findings?
Ataxia-telangiectasia due to ATM gene defects encoding DNA repair enzymes; high α-fetoprotein; low-levels of IgG/IgA/IgE & lymphocytes
• Bruton agammaglobulinemia is a(n) ____-recessive disorder caused by a defect in ____ kinase, preventing ____ (B-/T-) cell maturation.
X-linked (affects Boys), tyrosine (BTK), B- (B cell)
• A 6-m/o boy has a normal CD19+ B-cell count. He has no B cells in peripheral blood, low immunoglobulins, and scanty tonsils. Diagnosis?
A boy has an X-linked recessive WAS gene mutation. What triad of symptoms may he experience?
Wiskott-Aldrich triad of Thrombocytopenia, Eczema, & Recurrent infections (WATER)
• A boy w/recurrent viral illnesses, ASD, and tetany has low Ca2+ & PTH. CXR shows an absent thymic shadow. What test confirms diagnosis?
FISH for 22q11 deletion (this is DiGeorge syndrome with thymic aplasia [a lack of thymus/parathyroid glands from third/fourth pouches])
• A boy has thrombocytopenic purpura, eczema, and recurrent infections. What gene is affected? Which conditions is he at higher risk for?
WAS gene mutation (X-linked recessive); increased risk of cancer and autoimmune disease (this is Wiskott-Aldrich syndrome)
• A boy gets a BCG vaccine, soon after he develops a disseminated mycobacterial infection. Diagnosis? What cells and cytokines are implicated?
This is IL-12 receptor deficiency; decreased activation of Th1 cells (from decreased interferon-γ)
• A blonde boy with very white skin has recurrent pyogenic infections, numbness, and tingling in his hands. Diagnosis, & mechanism of action?
Chédiak-Higashi syndrome; defect in lysosomal trafficking regulator gene (LYST), microtubule dysfunction in phagosome-lysosome fusion
• A boy has retained primary teeth, eczema, and recurrent abscesses; labs show elevated IgE and eosinophilia. What is the diagnosis and cause?
Hyper-IgE (Job) syndrome; autosomal dominant STAT3 mutation causes Th17 deficiency & abnormal neutrophil recruitment
• A pale blonde has recurrent staphylococcal and streptococcal infections. Name the disorder. Its mode of inheritance? Three lab findings?
Chédiak-Higashi syndrome; autosomal recessive; pancytopenia, mild coagulation defects, and giant granules in platelets/neutrophils
• List the symptoms of hyper-IgE (Job) syndrome using the mnemonic FATED.
Coarse Facies, noninflamed staphylococcal Abscesses, retained primary Teeth, high Ig E, Dermatologic issues
• What is the pathogenesis of chronic granulomatous disease?
Neutrophils have reduced microbicidal capability due to a lack of NADPH oxidase, increasing susceptibility to catalase-positive organisms
A boy has recurrent abscesses and elevated IgE. Which cells are dysfunctional? Are levels of interferon-γ increased or decreased?
Neutrophils; decreased (this is autosomal dominant hyper-IgE syndrome [Job syndrome])
• A boy has recurrent S. aureus, E. coli, and Aspergillus infections (all catalase positive). Results of which two tests confirm his diagnosis?
Negative nitroblue-tetrazolium dye reduction test, abnormal flow cytometry dihydrorhodamine test (testing for chronic granulomatous disease)
• A patient has recurrent skin and mucous membrane Candida infections. Which immunodeficiency is this? Which cells are dysfunctional?
Chronic mucocutaneous candidiasis due to T-cell dysfunction (many causes)
• What are two possible causes of severe combined immunodeficiency and their modes of inheritance? Which is most common?
Autosomal recessive (adenosine deaminase deficiency) and X-linked (most common due to defective IL-2R gamma chain)
• What is the most common primary immunodeficiency? What are the symptoms?
Selective IgA deficiency (most have Asymptomatic Airway & GI infections, Autoimmune disease); Atopy, Anaphylaxis to IgA-containing products
• A boy has recurrent infections (viral, bacterial, protozoal), faulty IL-2 receptors, and no germinal centers in lymph nodes. Treatment?
Treatment of choice is bone marrow transplantation (no allograft rejection) for this patient with severe combined immunodeficiency
• Which immune deficiency disease presents with normal numbers of circulating B cells but a decreased number of plasma cells?
Common variable immunodeficiency
• A boy has SCID. What do T-cell receptor excision circles, chest x-ray, flow cytometry, and lymph node biopsy show, respectively?
Lower T-cell receptor excision circles (TRECs), no thymic shadow, no T cells, and no germinal centers
• A man has thrombocytopenia, recurrent infections, and eczema similar to his maternal grandfather. What lab findings do you expect to see?
High IgA/IgE and low–normal IgM/IgG, decreased platelet size/number (this is Wiskott-Aldrich syndrome)
• A woman has common variable immunodeficiency. What is her likely age? Which four noninfectious conditions is she at increased risk for?
Presents in 20s–30s; autoimmune disease, bronchiectasis, lymphoma, and sinopulmonary infections
• The umbilical cord of a neonate with neutrophilia fails to separate normally. What is the diagnosis? What is its pathophysiology?
Leukocyte adhesion deficiency type 1; lack of phagocyte LFA-1 integrin (CD18) leads to recurrent bacterial skin and mucosal infections
• A man has common variable immunodeficiency. Which type of infections will he present with? Which type of cell has defective maturation?
Sinopulmonary infections; B cell (many causes)
• A 2-y/o child has recurrent severe pyogenic bacterial infections, high IgM, and low levels of all other immunoglobulins. Pathophysiology?
Defective CD40L on Th cells, which is the necessary second signal for B-cell class switching (this is hyper-IgM syndrome)
• A girl has recurrent bacterial skin infections. No pus comes out of her wounds. Characterize the number and localization of neutrophils.
Neutrophil levels increase; there are no neutrophils at infection sites due to impaired chemotaxis in type 1 leukocyte adhesion deficiency
• A man has recurrent disseminated mycobacterial infections. What immune deficiency does he most likely have?
Interleukin 12 (IL-12) receptor deficiency, causing decreased Th1 response and interferon-γ
• A man has no symptoms but is found to have selective immunoglobulin (Ig) deficiency. What levels of IgA, IgM, and IgG would you find?
• A 5-month-old child with high IgM and low IgG, IgA, and IgE has a severe Pneumocystis infection. What is defective? How is it inherited?
CD40L on Th cells is abnormal, leading to class switching defect; X-linked recessive (hyper-IgM syndrome is example of B- & T-cell disorder)
• A 25-y/o has frequent sinus infections and defective B-cell differentiation. Do plasma cell and immunoglobulin levels increase or decrease?
Plasma cell and immunoglobulin levels decrease (this describes common variable immunodeficiency)
• A boy has defective NADPH oxidase; his neutrophils produce fewer reactive oxygen species. Which organism(s) is he most susceptible to?
Catalase-positive bugs (Nocardia,Pseudomonas,Listeria,Aspergillus,Candida,E.coli,Staphylococcus aureus,Serratia [Need PLACESS])(this is CGD)
• A man has many oral yeast infections. Would he have a cutaneous reaction to Candida antigens? Would his T cells respond in vitro to Candida?
No; no (the patient has chronic mucocutaneous candidiasis, with T-cell dysfunction and recurrent skin/mucous membrane Candida infections)
Which cell is most affected in leukocyte adhesion deficiency (type I), Chédiak-Higashi syndrome, and chronic granulomatous disease?
• A boy's disorder leads to recurrent DNA double-strand breaks. Diagnosis? What physical exam, lab, and imaging findings might be present?
Ataxia-telangiectasia; exam = Ataxia, spider Angiomas, lab = increased AFP, decreased IgA/IgG/IgE, lymphopenia, imaging = cerebellar atrophy
• Patients with hyper-IgM syndrome are more susceptible to infection by which opportunistic organisms?
Pneumocystis, Cryptosporidium, CMV
• Name four inherited immunodeficiencies that are more common in boys. Why is this the case?
Hyper-IgM syndrome, Wiskott–Aldrich syndrome, chronic granulomatous disease, & Bruton agammaglobulinemia; all are X-linked recessive
• Bruton agammaglobulinemia, selective IgA deficiency, and common variable immunodeficiency are disorders of which type of cell?