I14

Question 1

People with asplenia are more susceptible to what kinds of infections? Why?

Answer 1

Regardless of the reason for the lack of a spleen (genetic or via splenectomy), these patients are significantly more susceptible to septic infections, especially with encapsulated bacteria. Macrophages in the spleen are important for recognizing and phagocytosing complement labeled or antibody opsonized bacteria from the bloodstream.

Question 2

What is the difference between ANKD, CNKD, and FNKD?

Answer 2

ANKD- ANKD involves either the complete absence of NK and NKT cells or total lack of NK cell functionCNKD- lack of NK cell and NK cell function but there is presence of NKT cellsFNKD- Normal/near normal NK cell numbers, but absent or severely decreased NK cell function. Patients with FNKD usually do have NKT cellsDiagnosis: difficult, but flow cytometry for NK and NKT cells helps

Question 3

The end result of all NK deficiency disorders is what?

Answer 3

The end result is susceptibility to viral infections.highly susceptible to opportunistic species of Mycobacterium (avid intercellulare); I assume that macrophages infected with these pathogens usually produce surface ligands for the NK cell activating receptors (e.g. MIC proteins) so that NK cells can participate in killing of infected cells.These patients are also susceptible to Tricophyton (a fungus commonly present on hair, skin, and nails).

Question 4

What is NEMO?

Answer 4

genetic defect in a protein (IKKg or NEMO) requires for NFkB activity. NFkB is important for transcription of genes (following PRR engagement; TLRs) that are involved in innate immune responses. Lack of expression of the cytokines/chemokines results in increased susceptibility to recurrent bacterial AND viral pathogens.

Question 5

NEMO is aka?

Answer 5

X-linked hypohydrotic ectodermal dysplasia and immunodeficiency

Question 6

What are the symptoms of NEMO?

Answer 6

deep-set eyes, space and/or fine hair, conical or missing teeth, and often incontinentia pigmenti (a skin condition that leads to unusual blistering and changes in skin color)

Question 7

What is the treatment for NEMO?

Answer 7

biweekly injections of gamma globulin from healthy donor or bone marrow transplant

Question 8

phagocytes are the primary mediator of immune killing of ___ and ___.

Answer 8

bacteria and fungi.

Question 9

What is Leukocyte adhesion deficiency caused by?

Answer 9

results from a genetic deficiency of functional CD18 (an integrin adhesion molecule normally expressed by phagocytes- binds to ICAM). Without this integrin, phagocyte migration into inflamed tissues is defective and the patient is susceptible to extracellular pathogens. Patients with this condition are especially sensitive to encapsulated bacterial pathogens.

Question 10

What is a main symptom in the diagnosis of Leukocyte adhesion deficiency?

Answer 10

Delayed detachment and sloughing of the umbilical cord because of defective tissue remodelingbacterial gingivostomatitis.

Question 11

What is Chronic granulomatous disease caused by?

Answer 11

results from defective NAPDH oxidase that results in phagocytes that cannot produce toxic oxygen intermediates. This impairs their ability to kill bugs they phagocytose. These patients suffer from chronic bacterial and fungal infections, and they make granulomas MORE readily than normal patients.

Question 12

The main genetic cause of CGD is? MOI?

Answer 12

usually inherited as an X-linked trait in autosomal recessive fashion; caused by a mutation resulting is non-functional gp91 protein (p91-PHOX)

Question 13

Which pathogens are patients with CGD most susceptible to?

Answer 13

There are several pathogens that these patients are especially sensitive to, including S. aureus, E. coli, Klebsiella, Aspergillus, Nocardia, Candida, and maybe most notably, Serratia marcescens. (E-SNACKS)Serratia is the most common infection that infants with CGD contract as infants (note that children with CGD are typically healthy at birth), and when this infection is observed in an infant, it is important to test the patient for this CGD.

Question 14

What is the (until recently) preferred diagnostic tool for diagnosing CGD and how does it work?

Answer 14

The nitroblue tetrazolium dye test.Normal phagocytes produce NADPH oxidase that gives rise to reactive oxygen species that oxidize the NTB, producing a blue color. Neutrophils from patients with CGD are unable to cause this color change. This test is no longer the preferred test, but you may still see it on step 1.

Question 15

What is the current preferred test for diagnosing CGD and how does it work?

Answer 15

The dihydrorhodamine test is a flow cytometric assay that determines whether neutrophils produce an oxidative burst that can reduce dihydrorhodamine to rhodamine (which fluoresces green). Patient’s that suffer from CGD lack the ability to produce sufficient respiratory burst to catalyze this conversion. This is now the assay that is typically used in clinical settings.Separated= normal

Question 16

What is the current treatment for CGD?

Answer 16

prophylactic clotrimoxazole, itraconazole (anti-fungal), IFN-y (unknown protective function)

Question 17

What is Chediak-Higashi Syndrome?

Answer 17

caused by a genetic defect of the gene that encodes a protein that is involved in intracellular vesicle formation, known as the LYST protein. Phagocytes from one of these patients are unable to fuse lysosomes with phagosomes, therefore, they cannot efficiently kill bugs that they have phagocytosed.

Question 18

How does Chediak-Higashi syndrome present clinically?

Answer 18

(1) Partial albinism: remember that melanosome formation is also dependent on the LYST protein(2) recurrent pyogenic infections, especially with S. aureus and S. pyogenes (and Pneumococcus). Infections of the respiratory tract and lungs as well as the skin are the most common in these patients.(3) Neurological disorders

Question 19

Diagnosis of Chediak-Higashi syndrome?

Answer 19

genetic testing and appearance of neutrophils (poorly organized and larger than normal azurophilic granules are evident). Due to their inability to correctly form intracellular vesicles, their granules appear quite large and irregularly shaped.

Question 20

Treatment of Chediak-Higashi?

Answer 20

Treatment of this condition requires a bone marrow transplant. Patients that do not receive this treatment very often succumb to a lymphoma-like lymphoproliferative condition relatively early in life.

Question 21

What is neutropenia?

Answer 21

low neutrophil counts. People suffering from this condition are susceptible to bacterial and fungal infections, including normal flora microbes.Usually defined by a neutrophil count of less than 500 cell/ul (normal is more than 2000 cells/ul)

Question 22

What are the three most common types of neutropenia?

Answer 22

1) severe congenital neutropenia (Kostmann syndrome)2) cyclic neutropenia3) benign chronic neutropenia

Question 23

What is Kostmann syndrome?

Answer 23

an AR disease associated with a gene abnormality of granulocyte colony stimulating factor (G-CSF) or its receptor (G-CSFR); G-CSF stimulates granulocyte growth

Question 24

What is cyclic neutropenia?

Answer 24

an AD disorder in which the neutropenia occurs every 2 to 4 weeks and lasts about a week. It is associated with a gene defect termed ELA-2 (this gene encodes elastase)

Question 25

What is begin chronic neutropenia?

Answer 25

low but not life-threatening neutropenia and is often asymptomatic

Question 26

Several immunodeficiencies are complicated by neutropenia. Some of these patients produce autoantibodies that are specific for neutrophil determinants that result in decreased neutrophil numbers. Examples?

Answer 26

X-linked hyper IgM syndrome, X-linked agammaglobulinemia, WHIM syndrome, Griselli syndrome.

Question 27

Patients with complement deficiencies that reduce deposition of C3b are significantly more susceptible to ___ infections.

Answer 27

bacterial

Question 28

Deficiencies of components C5-C9 result in susceptibility only to one bacterial genus:

Answer 28

Neisseria.

Question 29

Deficiencies of C1, C2, or C4 all result in _____. Why?

Answer 29

immune complex disease. The reason for this is that small immune complexes created by antibody binding to its antigen are usually further opsonized by activation of the classical complement cascade, promoting uptake and destruction of these small immune complexes.

Question 30

C3 deficiency results in what?

Answer 30

no ability to activate any of the complement cascades, and it leaves a patient susceptible to bacterial infections, especially encapsulated bacteria.Factor I deficiency is similar in phenotype to a C3 deficiency because the final result is depletion of C3b. In this condition, there is reduced cleavage of C3b or C4b, allowing for abnormally high amounts of C3 convertase to form, resulting in an accelerating reaction that uses up all of the C3.

Question 31

C5-C9 deficiencies result in no MAC formation and susceptibility to one genus of bacteria (Neisseria). C5 deficiency is more severe than C6-C9.

Answer 31

C5-C9 deficiencies result in no MAC formation and susceptibility to one genus of bacteria (Neisseria). C5 deficiency is more severe than C6-C9.

Question 32

Factor D is a critical component of the alternative pathway. Deficiency of Factor D (or properdin, aka Factor P) leads to susceptibility to what?

Answer 32

susceptibility to encapsulated bacteria and Neisseria results from this deficiency but no immune complex disease

Question 33

MBL is the initiator protein of the lectin pathway. Deficiency of this secreted pattern recognition receptor results in increased susceptibility to severe bacterial infection. I suspect that the reason for this is that the acute phase response is impaired in these patients.

Answer 33

MBL is the initiator protein of the lectin pathway. Deficiency of this secreted pattern recognition receptor results in increased susceptibility to severe bacterial infection. I suspect that the reason for this is that the acute phase response is impaired in these patients.

Question 34

C1INH deficiency results in what?

Answer 34

HANE (edema caused by overproduction of C2 kinin)

Question 35

What is paraoxymal nocturnal hemoglobinuria caused by?

Answer 35

a rare, acquired and potentially life-threatening disease characterized by complement induced intravascular hemolytic anemia, red urine, and thrombosis results from eugenic deficiency of glycophosphatidylinositol, which required for surface expression of CD59 and DAF

Question 36

What is there treatment for paraoxymal nocturnal hemoglobinuria?

Answer 36

Allogeneic bone marrow transplant is the only curative therapy, although the complement component C5-specific monoclonal antibody (Eculizumab or Soliris) is effective at reducing the need for blood transfusions, improving quality of life, and reducing risk of thrombosis

Question 37

What is glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Answer 37

an X-linked recessive hereditary disease that results in reduced respiratory burst (production an release of superoxide radicals and H2O2) and impaired killing of phagocytosed microorganisms).Patients suffer from chronic bacterial and fungal infections (milder than CGD)will also have low C3 and factor B levelsG6PD is also involved in RBC metabolism, therefore, many patients suffer from anemia

Question 38

In myeloperoxidase deficiency, patient’s macrophages are unable to efficiently kill phagocytosed microbes because they have impaired ability to produce hypochlorous acid and toxic oxygen species, and therefore have a defective respiratory burst; many patients with this condition are asymptomatic, so the condition is not clinically relevant in those patients.

Answer 38

In myeloperoxidase deficiency, patient’s macrophages are unable to efficiently kill phagocytosed microbes because they have impaired ability to produce hypochlorous acid and toxic oxygen species, and therefore have a defective respiratory burst; many patients with this condition are asymptomatic, so the condition is not clinically relevant in those patients.

Question 39

A 6 y/o has a history of infections with encapsulated bacterial pathogens. What genetic defect is likely?

Answer 39

asplenia

Question 40

Your 6 y/o patient has been mostly healthy is being evaluated because he recently suffered a near fatal septic infection with a gram - encapsulated diplococcal bacterium. Deficiency?

Answer 40

This is Neisseria so any C5-C9 deficiency would cause this

Question 41

Your 3 y/o patient has a history of bacterial and fungal infections that resolve slowly. He has normal B and T cells in peripheral blood and his serum contains a normal array of antibody types. What is his immunodeficiency?

Answer 41

Neutropenia

Question 42

A 12 yo female presents with a two-day history of fever and sore throat. A culture from a throat swab grows out Strep. pyro. This bacterial pathogen is known to produce and secrete a DNase enzyme. This is a virulence factor that gives the bacterium a survival advantage by interfering with an immune response mediated by:

Answer 42

neutrophils because they prevent NET formation