Immunology Case 32: Deficiency of the C8 Complement Component

Question 1

what is the complement system of plasma proteins?

Answer 1

it’s an effector mechanism of both
innate and adaptive immunity that tags pathogens for destruction

the assembly of the so-called terminal components of the complement system (C5-C9) on the surface of a bacterial cell or a human cell results in the
formation of protein complexes that make pores in the cell membrane, leading to
cell lysis and death

Question 2

how is the terminal complex assembled?

Answer 2

1. assembly is initiated when C5 binds to the cell surface and is cleaved by C5 convertase
2. this reaction
   releases C5a, a peptide with potent chemotactic activity, from the α, or heavy
   chain, of C5
3. the rest of the molecule, C5b, binds to C6 to initiate formation of the membrane-attack complex of terminal complement components
4. C5b6 complex binds one C7 molecule; the complex sinks partway into the lipid bilayer of the cell membrane
5. C8 is composed of three chains; the C8γ chain binds to the
   C5a67 complex and enables the hydrophobic portion of C8 to embed itself in the
   cell membrane
6. C9 molecules bind to the complex and polymerizes
7. this last event induces the polymerization of 10–16 molecules
   of C9 to make a cylindrical structure, the membrane-attack complex, which
   forms a pore in the cell membrane

Question 3

what happens after the terminal complex is formed?

Answer 3

the complex forms a pore in the cell membrane

through this channel sodium and water enter the cell, which swells until it
bursts

Question 4

what inhibits the terminal complex?

Answer 4

the cell-surface protein CD59, which is found in most mammalian
cell membranes, inhibits the action of C8 on C9, thereby preventing formation of
the membrane-attack complex on the cells of the body but not on those of bacteria

Question 5

what causes an increased susceptibility to Neisseria bacteria?

Answer 5

humans with a genetic deficiency in C5, C6, C7, C8, or C9 have an
increased susceptibility to systemically invasive infection with bacteria of the
genus Neisseria

N. meningitides = meningitis

N. gonorrhoeae = gonorrhea

Question 6

what is the clinical presentation of meningitis?

Answer 6

Dolly Oblonsky was doing well in her first year at university when she developed a
cough and diarrhea. She felt very tired and achy and went to bed early in her dormitory
room

The next morning she woke early with a severe headache. She felt sick
and her neck seemed to be stiff. Her roommate took her to the university infirmary
emergency room.

She seemed ill and somewhat confused to the nurse on duty, who
found that Dolly had a blood pressure of 70/40 (low), a pulse of 124 (fast), a respiratory
rate of 24 (increased), and a temperature of 39.2ºC (elevated). The nurse noticed
a petechial rash (small areas of reddish-purple discoloration) on Dolly’s chest and
urgently summoned the physician on call, Dr Tolstoy.

He found that Dolly had a red
throat with moderate enlargement of the tonsils. No other physical symptoms were
apparent except for the neck stiffness and the petechial rash on her palate, trunk,
and extremities.

Dr Tolstoy immediately obtained blood for blood counts and bacterial
cultures, and started intravenous administration of the antibiotic Cephtriaxone
because he suspected meningococcal meningitis. He then performed a lumbar
puncture to obtain cerebrospinal fluid (CSF)

Question 7

what would the CBC of someone with meningitis show?

Answer 7

CSF would have elevated WBC

low Hct

90% of the WBCs would be neutrophils

Question 8

how do you treat meningitis?

Answer 8

antibiotics

Cephtriax-one

Question 9

what lab measurement would tell you about someones complement activity?

Answer 9

CH50

Question 10

deficiencies of what result in immune-complex disease?

Answer 10

deficiencies of C1q, C1r, C1s, C4, or C2 of the

classical pathway result in immune-complex disease

Question 11

defects in what result in increased susceptibility to neisserial infections?

Answer 11

factor D, or properdin of the alternative pathway

defects n components of the membrane-attack complex, C5, C6, C7, C8, or C9,
on which both pathways converge

Question 12

what does C3 deficiency cause?

Answer 12

increased susceptibility

to all pyogenic infections

Question 13

what does a MBL deficiency cause?

Answer 13

mannose-binding lectin (MBL) is part of the lectin pathway of complement

MBL deficiency is associated with recurrent infections

deficiency of the MBL-associated
serine protease-2 (MASP2) is rare and may cause increased risk of infections or
autoimmunity.

Question 14

which population has high C9 deficiency?

Answer 14

Japan

1 in 40

Question 15

which population has a high C2 deficiency?

Answer 15

caucasians

1 in 100 are heterozygous for C2 deficiency

the gene encoding C2 is in the MCH locus - the genes encoding C4 are also in the MHC complex

Question 16

what mutation causes C8 deficiency?

Answer 16

caucasians: mutations
in the gene encoding the C8β chain

due to C–>T transition

african americans: mutations in the gene encoding the C8α
chain

Question 17

hemolytic complement levels were determined by measuring the CH50. what is that and how is the test performed?

Answer 17

CH50 is the quantity of complement required for 50% lysis of 5 × 108 optimally
sensitized sheep red blood cells in 1 hour at 37°C

this assay measures the functional integrity of all
the complement components comprising the classical pathway

it is the single best
screening test when a general diagnosis of complete complement deficiency is being
considered.

Question 18

Bacteria of the genus Neisseria are encapsulated in a thick carbohydrate
capsule. Clinical evidence shows that the membrane-attack complex is vital in host
defense against these bacteria. It is obvious that the hydrophobic components
of the membrane-attack complex cannot penetrate the polysaccharides of the
bacterial capsule. How, then, is complement involved in bacterial killing?

Answer 18

the bacteria are temporarily vulnerable to killing by complement when they divide

at this time the bacterial membrane is exposed and is vulnerable to attack by the
membrane-attack complex

the association between genetic deficiencies of membrane-
attack complex proteins and neisserial infections illustrates that an important
aspect of host defense against these infections is the killing of extracellular bacteria
by complement-mediated lysis

Neisseria that escape killing enter a variety of cell
types and establish an intracellular infection

Question 19

Patients who are completely deficient in C1q, C1r, C1s, or C4 sustain
persistent and severe immune-complex disease such as glomerulonephritis, which
can ultimately be fatal. In contrast, patients who are C2-deficient usually sustain
only minor forms of immune-complex disease. How do you explain this difference?

Answer 19

in humans, clearance of immune complexes from the blood is largely effected by their
attachment to complement receptor 1 (CR1) on the surface of RBCs

one of
the ligands for CR1 is C4b (the other is C3b)

all the C1 components are required for
the formation of C4b, and if C4b is part of an immune complex, the binding of the
complex by CR1 is facilitated

immune complexes bound to the surface
of the RBC are transported to the liver and spleen, where C4b (or C3b) is converted
by factor I to iC4b (or iC3b); this facilitates uptake of the immune complexes
by phagocytes via complement receptor CR3 and others, and their destruction

in the
absence of C4b, immune complexes are less efficiently attached to red cells and are
therefore less efficiently cleared from the blood