Immunology Case 2: CD40 Ligand Deficiency

Question 1

after exposure to an antigen, which antibody is the first to appear?

Answer 1

IgM

later, antibodies of other classes appear due to class switching

Question 2

where is IgG mostly found?

Answer 2

serum

extravascular space

Question 3

where is IgA mostly found?

Answer 3

gut

respiratory tract

Question 4

which antibodies are most involved in neutralization?

Answer 4

IgG1-4

IgA

Question 5

which antibodies are most involved in opsonization?

Answer 5

IgG1 > IgG3

Question 6

which antibodies are most involved in sensitization for killing by NK cells?

Answer 6

IgG1

IgG3

Question 7

which antibodies are most involved in sensitization of mast cells?

Answer 7

IgE

Question 8

which antibodies are most involved in activation of the complement system?

Answer 8

IgM, IgG3 > IgG1 > IgG2, IgA

Question 9

which antibodies can be transported across the epithelium?

Answer 9

IgA dimer&raquo_space; IgM

Question 10

which antibodies can be transported across the placenta?

Answer 10

IgG1 > IgG3 > IgG2

Question 11

which antibodies can diffuse into extravascular sites?

Answer 11

IgG1-4 > IgA monomer > IgE

Question 12

how does isotype switching occur?

Answer 12

repetitive DNA sequences that guide idotype switching are found upstream of each of the immunoglobulin C-region genes

switching occurs by recombination between these repetitive sequences or switch signals as a result of the repair of double strand breaks with deletion of the intervening DNA

Question 13

what induces class switching?

Answer 13

T cells

it can also be induced by T-cell independent toll-like receptor (TLR)-mediated signaling

T cells are required to initiate B-cell responses to many antigens

Question 14

how are B cells activated by T cells?

Answer 14

B cells are activated by helper T cells that recognize antigenic peptide bound to class II molecules on their surface

an epitope on a viral protein is recognized by the surface immunoglobulin on a B cell and the virus is internalized and degraded

peptides derived from viral proteins are returned to the B-cell surface bound to MHC class II molecules where they are recognized by previously activated helper T cells that activate the B cells to produce antibody against the virus

Question 15

what is CD40 and CD40L?

Answer 15

when a B cell binds a virus epitope, the virus particle is internalized and degraded

then the T cell expresses cell-surface protein CD40L which in turn delivers an activating signal to the B cell by binding CD40 on the B cell surface

the activated T cell then secretes cytokines which are required intimate the humoral immune response to drive the proliferation and differentiation of naive B cells to produce antibodies

T cell cytokines are also needed later for class switching!

CD40L is on T cells
CD40 receptor is on B cells

Question 16

what do follicular helper T cells do?

Answer 16

TFH produce IL-21 which promotes the germinal center reaction and differentiation of B lymphocytes into plasma blasts

Question 17

which cytokines induce class switching to IgE?

Answer 17

IL-4 or IL-13 as well as stimulation of the b cell through CD40

Question 18

what is hyper IgM syndrome?

Answer 18

CD40L gene is located on the X chromosome at Xq26

in males with a defect in this gene, isotype switching fails to occur and individuals only make IgM and IgD

they have severely impaired class switching and can’t make IgG, IgA or IgE

Question 19

on what cells is CD40 expressed?

Answer 19

B cells

also on the surfaces of macrophages, dendritic cells, follicular dendritic cells, mast cells and some endothelial cells

Question 20

on what cells is CD40L expressed?

Answer 20

T cells

Question 21

what’s the surface marker for NK cells?

Answer 21

CD56

Question 22

what parts of the immune system are effected when there’s CD40L deficiency?

Answer 22

they exhibit consequences of a defect in both humoral and cell-mediated immunity

Question 23

what kinds of infections are you more susceptible to if you have a CD40L deficiency?

Answer 23

pyogenic infections = pus forming

they’re caused by bacteria that are resistant to destruction by phagocytic cells unless they are coated (opsonized) with antibody and complement

ex. haemophilus influenzae, steptococcus pneumoniae, stephylococcus aureus

also, defects in cellular immunity from CD40L deficiency result in susceptibility to opportunistic infections

Question 24

which types of antibodies can CD40L deficient patients make?

Answer 24

they can make IgM in response to T-cell independent
antigens but they are unable to make antibodies of any other isotype

also, they cannot
make antibodies against T-cell dependent antigens, which leaves the patient
largely unprotected from many bacteria

they also have a defect in cell-mediated
immunity that strongly suggests a role for CD40L in the T cell-mediated activation
of macrophages

Question 25

which type of WBC is decreased in CD40L deficiency?

Answer 25

neutrophils; they have neutropenia

it’s due to a block at the promyelocyte/
myelocyte stage of differentiation in the bone marrow

the lack
of neutrophils accounts for the presence of severe sores and blisters in the mouth

Question 26

what can a cryptosporidium infection cause?

Answer 26

persistent inflammation in the liver which ultimately leads to liver failure

Question 27

how do you treat CD40L deficiency?

Answer 27

immunoglobulin replacement therapy,
prophylaxis with trimethoprim-sulfamethoxazole to prevent Pneumocystis
jirovecii infection, and protective measures to reduce the risk of Cryptosporidium
infection

despite treatment, many patients with CD40L
deficiency die in late childhood or adulthood of infections, liver disease, or tumors

Question 28

how do you cure CD40L deficiency?

Answer 28

hematopoietic cell transplantation

Question 29

Dennis’s B cells expressed IgD as well as IgM on their surface. Why did he not
have any difficulty in isotype switching from IgM to IgD?

Answer 29

there is no DNA switch region 5´ to the Cδ gene.

a single transcript of VDJCμCδ is
alternatively spliced to yield either the μ or the δ heavy chain

in contrast,
there are DNA switch regions 5´ to all the other heavy-chain C genes, and isotype
switching must occur before functional transcripts of these genes are made

isotype
switching requires the enzyme activation-induced cytidine deaminase, which is
expressed in B lymphocytes in response to signals from T cells.

Question 30

Normal mice are resistant to Pneumocystis jirovecii. SCID mice, which have
no T or B cells but have normal macrophages and monocytes, are susceptible to
this microorganism. In normal mice, Pneumocystis jirovecii organisms are taken
up and destroyed by macrophages. Macrophages express CD40. When SCID mice
are reconstituted with normal T cells they acquire resistance to Pneumocystis
infection. This can be abrogated by antibodies against the CD40 ligand. What do
these experiments tell us about this infection in Dennis?

Answer 30

these experiments tell us that the activation of macrophages against this opportunistic
microorganism requires binding of CD40 on the macrophage surface to the
CD40L on the surface of activated T cells

Question 31

Why did Dennis make antibodies against blood group A and B antigens but not
against tetanus toxoid, typhoid O and H, and streptolysin antigens? Would he have
made any antibodies in response to his Streptococcus pyogenes infection?

Answer 31

patients with CD40L deficiency have impaired antibody responses to T-cell dependent
antigens, but can make IgM antibodies to antigens that can stimulate a B-cell
response without T-cell help

the blood group antigens are sugars that are also found
on bacteria in the gut and can activate B cells in the absence of T-cell help

tetanus
toxoid, typhoid O and H antigens, and streptolysin, in contrast, are proteins, which
cannot elicit a B-cell response in the absence of T cells

without CD40L, Dennis’s
T cells cannot activate his B cells to respond to these protein antigens. He would also
have been unable to make antibodies against Streptococcus pyogenes, because the
antigenic component of the bacterial capsule is a protein

Question 32

Most IgM is circulating in the blood, and less than 30% of IgM molecules get
into the extravascular fluid. On the other hand, more than 50% of IgG molecules
are in the extravascular space. Furthermore, we have 30–50 times more IgG than
IgM in our body. Why are IgG antibodies more important in protection against
pyogenic bacteria?

Answer 32

the polysaccharide capsules of these pyogenic bacteria are resistant to destruction
by phagocytes unless they are opsonized

IgM largely promotes the phagocytosis of
bacteria by activating complement, leading to the deposition of C3 fragments on the
bacterial surface

the C3 is recognized by complement receptors on the phagocytic
cells

IgG, however, is more efficient than IgM in promoting the phagocytosis of most
bacteria

in addition, there is a range of Fc receptors for IgG isotypes on phagocytes,
and IgG1, IgG2, and IgG3 antibodies all promote complement activation on bacterial
surfaces

this means that bacteria coated with IgG stimulate phagocytosis through
two different classes of receptor, Fc and C3

this results in much more efficient
phagocytosis than stimulation through a single class of receptor

Question 33

Newborns have difficulty in transcribing the gene for CD40L. Does this help to
explain the susceptibility of newborns to pyogenic infections? Cyclosporin A, a drug
widely used for immunosuppression in graft recipients, also inhibits transcription
of the gene for CD40L. What does this imply for patients taking this drug?

Answer 33

both neonates and people taking immunosuppressive drugs such as cyclosporin A
exhibit increased susceptibility to both pyogenic and opportunistic infections

a second reason for the increased susceptibility of neonates to some pyogenic infections
is the immaturity of many of their B cells. Neonates are normally protected by
preexisting maternal IgG until their lymphocytes mature.

Cyclosporin A also inhibits transcription of the IL2 gene, thereby preventing the expansion
of T-cell clones activated by antigen. This means that all T cell-mediated immune
responses, including cytotoxic T-cell responses, are suppressed by cyclosporin A