Lecture 22: Congenital Immunodeficiencies

Question 1

What are the 5 phagocytic deficiencies?

Answer 1

Leukocyte adhesion deficiency (LAD)

Chronic granulomatous dz (CGD)

G6P dehydrogenase deficiency (G6PD)

Myeloperoxidase deficiency

Chediak-Higashi syndrome

Question 2

1. LAD is what type of deficiency?
2. What cell type is typically 2x the normal level?
3. What is defective in this mechanism resulting in LAD?
4. What occurs as a result of numer 3?
5. What type of bacteria is involved?

Answer 2

1. Macrophage deficiency
2. Neutrophils (neutrophilia) however they are unable to aggregate
3. Defective CD18 (cell adhesion mlcl present on phagocytes)
4. Neutrophils are unable to bind intercellular adhesion mlcls (ie. selectins) which normally enable passage thru endothelium
   * so they are unable to leave the vasculature and reach the site of inflammation
5. Capsulated (moreso just bacteria in general –> have severe bacterial infections)

Question 3

1. LAD pt’s present with hx of ______ ______ of oral/genital mucosa, skin, GI tract, and respiratory tract.
2. What are the clinical manifestations of LAD?
3. LAD workup includes flow cytometric assessment which is assesing for what?

Answer 3

1. Reccurrent infections
2. Slow wound healing, severe bacterial infections, failure to form pus, and delayed detachment of umbilical cord
3. CD18 and CD11 neutrophil adhesion mlcls (neutrophils unable to aggregate)

LAD = ** defective migration of leukocytes (NEUTROPHILS) –> inability to move to site of infection/injury

Question 4

What are granulomas?

Answer 4

masses of immune cells that form at sites of infection or inflammation

Question 5

1. CGD is what type of disorder, resuling in tendency to form what?
2. What is enzymatic deficiency? What does that result in?
3. What is the immune defect? (hint does it involve extracellular or intracellular pathogens)?
4. Pt’s are susceptible to recurrent infections with what type of organisms?
5. More common in males or females?

Answer 5

1. Phagocytic disorder; granulomas
2. NADPH oxidase; failure of phagocytes to generate superoxide anions and ROS (causes #3)
3. Defective elimination of extracellular pathogens (bacteria and fungi)
4. Catalase-positive orgs –> Staphylococci
5. Males

Chronic granulatomas dz

Question 6

1. G6PD is what type of disorder?
2. What is the inheritance?
3. Caused by lack of substrate for what?
4. What is the clinical manifestation? (althought most ppl are asymptomatic)

Answer 6

1. Phagocyte cell deficiency
2. X-linked
3. NADPH (i.e. lack of G6P = the substrate for NADPH)
4. Tendency to form granulomas

Question 7

What does myeloperoxidase (MPO) usually do?

Answer 7

Catlyzes conversion of H202 –> hypohalous acid (bleach)

Gives pus its green color

Question 8

1. What is the most common primary phagocyte disorder?
2. How is it inherited?
3. When staining neutrophils/eosinophils for this type of deficiency would there be abundunt amount of staining or no staining? (if the pt had the deficiency)
4. This deficiency has a PROFOUND effect on neutrophils ability to kill what?

Answer 8

1. MPO (myeloperoxidase) deficiency
2. Autosomal recessive, w/ variable clinical PT
3. No staining (or very little)
   * normally neutrophils would be abundantly stained
4. Candida (fungal)

Question 9

1. What is a very rare, autosomal recessive disorder, in which patients become wheelchair-bound and usually die of infection in their early 30s?
2. In this syndrome, there is a molecular defect in the stx of neutrophils making them appear like what?
   * these granules are laking what 2 important mlcls?
3. There are abnormalities in chemotaxis and what?

Answer 9

1. Chediak-Higashi Syndrome
2. abnormal giant granules
   * lacking cathepsin G and elastase
3. Degranulation

Question 10

1. In Chediak-Higashi Syndrome, pt’s are prone to ____ granulomas caused by _____ infections.
2. What cell type would have NO activity in this syndrome? (this is part of diagnostic criteria)

Answer 10

1. pyogenic granulomas; bacterial infections –> staphylococci and streptococi
   * response to infection is a blunted neutrophillia due to delayed diapedesis
2. NK cells

• diagnostic criteria also includes giant cytoplasmic inclusions in RBCs
• partial albinism (due to growth defect in melanocytes)

This is a biphasic immunodeficiency:

• first phase is succesptibility to infections
• second phase is accelerated lymphoproliferative syndrome with hepatosplenomegaly and lymphadenopathy

Question 11

1. MyD88 deficiency is an ____ immunity deficiency resulting in impaired signaling for all _____ (except for one).

• leads to very frequent and SEVERE infections to what type of bacteria?
  2. In this type of deficiency your patient would lack what clinical manifestations?
  3. What pro-inflammatory cytokines would have low levels?

Answer 11

1. innate; TLR —> EXCEPT FOR TLR3
   * pyogenic bacteria –> cocci/spherical bacteria that cause pus-like infections
2. Fever and elevated levels of CRP despite active infection
3. TNF-α, IL-1, and IL-6 –> explains why there is no fever and no elevated levels of CRP

Pts w/ MyD88 deficiency still have normal resistance other common bacteria, viruses, fungi and parasites

Question 12

TLR3 deficiency is an autosomal recessive disorder resulting in increased susceptibility to what?

Is TLR3 MyD88 dependent or independent?

Answer 12

HSV encephalitis (herpes simplex virus)

• this is bc TLR3 responds to dsDNA viruses (INTRACELLULAR PATHOGEN)

Independent –> why its the only TLR not effected by MyD88 deficiency

Question 13

1. Defects in IL-12/IFN-γ pathways result in inability to eliminate ____ infections and cause increase susceptibility to ____ infections.
2. What produces IL-12?

• what is IL-12 effect on?
• what type of type of immunity does this involve?

3. How is this pathway involved in adaptive immunity?

Answer 13

1. mycobaterium (an intracellular path) infections; viral infections
2. Macrophages

• IL-12 causes NK cells (which has an IL-12R) to increase their production of IFN-γ which acts on the MΦ to increase production of IL-12
• creating an amplificaiton loop
• innate

3. IL-12 sitmulates Th1 cells to produce INF-γ –> stimulating MΦ to increase production of IL-12
   * creates another FB Loop

Question 14

1. Deficiency of what complement prtn causes the loss of major complement opsonin and failure to activvate MAC pathway, ultimately leading to severe immunodeficiency?
2. Deficiency of what complement prtns causes failure to form MAC?
3. Deficiency of what complement prtn causes loss of regulation of C1 and failure to activate kallikrein, causing an overactive IR?
4. Deficiency of what complement prtns cause failure to activate the Classical pathway (CP)?
5. Deficiency of what complement prtns result in the failure to regute C3 activation, causing severe secondary C3 deficiency?

Answer 14

1. C3

• pyogenic bacterial infections w/ or w/o rash
• membranoproliferative glomerulonephritis

2. C3, properdin, and MAC complex prtns (C6, 7, 8, and 9)

Neisserial infection –> ie meningitis

3. C1 inhibitor
   * Angioedema
4. C1q, C1r, C1s, C4, C2
   * SLE –> no elimination of immune complexes
5. Factor H and Factor I

• Hemolytic-uremic syndrome
• membranoproliferative glomerulonephritis

Question 15

1. Abnormalities in which complement deficiencies are manifested as SLE-like AUTOIMMUNITY?
2. Defect in which complement proteins result in clinical PT that is indistinguishable from Ab deficiencies?
3. Defects in late components result in defects in the generation of what?
   * leading to increased susceptibility to infections w/ Neisseria species

Answer 15

1. C1, C2, C4
   * assoc. w/ recurrent sinopulmonary infections (esp. C2 deficiency)
2. C3
3. MAC complex

Question 16

1. CP is responsible for clearing _____ _____, apoptotic cells, and cell debris from damaged tissues.
2. C1 and C4 deficiencies are liked to what two disorders?
3. What is the most common complement deficiency in Caucasion popln?
4. Which are more common.. acquired or inherited complement disorders?

Answer 16

1. Immune complexes
2. SLE and RA

• small complexes are normally cleared from circ when bind to C3b compelement receptors
• w/o complement these complexes grow too large –> large complexes are no longer soluble –> form deposits in tissues –> site of inflammation

3. C2
   * seen in kids who have recurrent infections w/ streptococcus pneumoniae
4. Acquired

Question 17

1. C8 deficiency is inherited in what type of pattern?
2. Most pt’s w/ C8 deficiency have what type of infections?
3. Diagnosis:

• Absent C8 but normal C3 and C4 consistent w/ ___ deficiency.
• Absent C8 in presence of low C3 and C4 suggesst complement ______

Answer 17

1. Autosomal recessive
2. Invasive neisserial infections (includes C5, C6, C7, C8, & C9)
3. C8; consumption (due to chronic infections/inflammatory conditions)

Question 18

Alternative pathway immunodeficiencies all involve what regulatory proteins.

1. Patients w/ Factor D deficiency are unable to activate ____ by the AP.
2. Factor H deficiency causes deposition of substantial quantities of ___ w/in the glomerula basement causing membranoproliferative glomerulonephritis.

Answer 18

1. C3
   * ppl usually have systemic meningococcal infections
2. C3
   * also found to be underlying basis for some pt’s w/ hemolytic uremic syndrome

Question 19

Factor H primary fxn = control of the fluid-phase tickover of the AP, thru what 3 key activities:

• binding of ____
• displacement of Bb from _____
• cofactor for Factor _____ mediated cleavage of C3b

2. What is the clinical manifestation?
3. These two factors play a role in _______ ____ syndrome.

Answer 19

• C3b
• C3bBb (C3 convertase of AP)
• Factor I

2. So get uncontrolled activaiton of AP, causing too much C3 consumption. Assoc. w/ damage to kidney BM
3. Hemolytic uremic syndrome
   * Factor H abnormalities also assoc. w/ age-related macular degeneration

Question 20

What kind of condition would be seen with moderate to low levels of C3 and C4 (ie complement consumption)?

Answer 20

Chronic inflammatory condition –> constantly consume C3 and C4

Question 21

1. Deficiency in what causes herediatry angioedema (HAE)?
2. What other inflammatory mediator is involved in HAE
3. Where is the edema commonly seen?
4. Why can this be dangerous or life threatening?

Answer 21

1. C1-inhibitor (C1-INH) (a CP control protein)

• which normally controlls swelling caused by trauma, H changes, stressors
• when non-fxnioning abnormal swelling occurs

2. Bradykinin = peptide that causes vasodilation and BP to fall
   * low C1-inh –> inc. bradykinin –> Inc BV permeability –> swelling
3. Hands, feet, face, abdominal wall (causes extreme pain, N/V), airways
4. Swelling of airway or throat can cause death by asphyxiation

**very rare, genetic condition –> defect in the gene that controls C1 inhibitor, so get C1-inh deficiency***

Question 22

Pathophysiology of Bradykinin-Induced Angioedema

C1-INH normally prevents formation of _______ an enz that produces bradykinin.

What are the side effects of this mechanism?

Answer 22

1. Kallikrein (which cleaves Kininogen forming bradykinin)
2. low C1-INH –> High bradykinin
3. Vasodilation

increased capillary permeability

fluid extravasion and edema

Question 23

1. Paroxysmal nocturnal hemoglobinuria (PNH) is a big example of what happens when there is failure to regulate the formation of what?
2. PNH cells lack what two important GPI anchor proteins on their cell membranes?
3. These two complement regulatory prtns are responsible for protecting _____.
   * this results in intravascular hemolysis (hemoglobinuria)

Answer 23

1. the MAC complex
2. CD55 (DAF) and CD59
3. RBCs from susceptibility to complement

Question 24

1. DAF (CD55) normally inhibits what?
2. CD59 normally inhibits what?

Answer 24

1. C3 convertase

• includes C4b2a (CP C3convertase) and C3bBb (AP C3 convertase)
• DAF also inhibits C4b2a3b (CP - C5 convertase) and C3bBb3b (AP - C5 convertase) by inducing rapid disassociation of C2a or Bb

2. MAC complex formation
   * by binding to C8 and C9 blocking polymerization of C9