CD40 receptor expression in hyper IgM syndrome
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- CD40 receptor expression in hyper IgM syndrome
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CD40 receptor expression in hyper IgM syndrome
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[ID] => 554598
[post_author] => 12815
[post_date] => 2024-12-23 18:06:46
[post_date_gmt] => 2024-12-23 23:06:46
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Hyper-IgM (HIGM) syndrome represents a heterogeneous group of immune disorders that arise from a failure of B cells’ somatic hypermutation and/or class-switch recombination. Patients typically present with recurrent infections and have low serum levels of immunoglobulins G and A, with normal-to-elevated levels of immunoglobulin M. To date, five different genetic defects leading to HIGM have been characterized.
The most common subtype is CD40 ligand (CD40L) deficiency. This is an X-linked recessive condition (XHIGM) that arises from a mutation in the CD40LG gene, which encodes CD40L (primarily expressed on activated T cells). The rarer autosomal-recessive HIGM (ARHIGM), on the other hand, results from a mutation in the TNFRSF5 gene. This gene encodes transmembrane cell-surface receptor CD40, which is present on both hematopoietic and non-hematopoietic cells. The binding of this receptor by its T-cell ligand (CD40L) is essential for B cells’ terminal maturation and proliferation.
Researchers performed an experiment to figure out why the CD40 receptor might not be expressed on the cell surface in ARHIGM. B cells were taken from patients with a genetic diagnosis of ARHIGM. The researchers fluorescently labeled CD40 and also added fluorescent co-labels for different intracellular structures: the endoplasmic reticulum (co-label: calnexin), Golgi apparatus (giantin), trans-Golgi network (TGN46), and the endosomal compartment (transferrin). Under confocal microscopy, the researchers tracked the signal for each co-label/receptor pair and found that wild-type CD40 exhibited colocalization with calnexin, giantin, and transferrin, and was also detected on the cell surface (Figure 1). Partial results for two patients with ARHIGM are shown in Figure 2.
Figure 1 Colocalization of wild-type CD40 with fluorescent labels for intracellular structures; colocalization is visible as signal in the merged micrographs
Figure 2 Colocalization of CD40 in ARHIGM patient 1 and patient 5
Image adapted from Lanzi, Gaetana, et al. Different molecular behavior of CD40 mutants causing hyper-IgM syndrome. Blood 116.26 (2010): 5867-5874. C, control patient; P2, Patient 2; P5, Patient 5.
[post_title] => CD40 receptor expression in hyper IgM syndrome
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[post_name] => cd40-receptor-expression-hyper-igm-syndrome
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[quiz_unique_key] => 602779517
[question] => CD40 colocalization with different co-labels indicates that, in ARHIGM, CD40 was:
[value] => Array
(
[answer] => 3
[description] => Reason for Correct Answer:
In the ARHIGM patients, mutant CD40 shows colocalization with calnexin but not giantin.
Giantin is the co-label for the Golgi apparatus.
Calnexin is the co-label for the endoplasmic reticulum.
These results indicate that CD40 is only colocalized with the endoplasmic reticulum and has not progressed to the Golgi apparatus. Therefore, CD40 has been retained in the endoplasmic reticulum.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. degraded in the Golgi apparatus.
)
[1] => Array
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[each_answer] => B. degraded in the recycling endosomal compartment.
)
[2] => Array
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[each_answer] => C. retained in the endoplasmic reticulum.
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[3] => Array
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[each_answer] => D. retained in the trans-Golgi network.
)
)
)
[1] => Array
(
[quiz_unique_key] => 1403770772
[question] => Failure of CD40 to appear on the cell surface in ARHIGM patients is most likely due to:
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
The last column of Figure 2 shows whether CD40 in these patients colocalized with markers for different cellular structures: the endoplasmic reticulum (co-label: calnexin) or Golgi apparatus (giantin).
Figure 2 shows that CD40 is present in cells. We therefore know that CD40 protein is produced, and that there is not a failure of protein production. We also know that the fluorescence tags are able to detect the protein.
As stated in the last question/explanation, Figure 2 shows that CD40 is present colocalized in the endoplasmic reticulum (co-label: calnexin) but not the Golgi apparatus (giantin).
A missense mutation that results in protein misfolding is most likely to cause the abnormal colocalization pattern; this is because misfolded proteins can get trapped in the ER. There is no data to indicate the CD40 protein is being degraded nor that it makes it to the endosomal compartment.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. a frameshift mutation in the TNFRSF5 gene resulting in failure of protein production.
)
[1] => Array
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[each_answer] => B. rapid degradation of the protein in the endosomal compartment.
)
[2] => Array
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[each_answer] => C. a missense mutation causing production of a misfolded protein.
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[3] => Array
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[each_answer] => D. a significant deletion in the TNFRSF5 gene that results in loss of the binding site for tagged antibodies.
)
)
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => X-linked HIGM could manifest clinically in a female patient by what mechanism?
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
According to the passage, X-linked Hyper-IgM syndrome (XHIGM) is caused by mutations in the CD40LG gene, which encodes the CD40L ligand protein.
Mosaicism refers to the presence of genetically distinct populations of cells within an individual, often originating from mutations occurring after fertilization. This can lead to the coexistence of cells with different genetic compositions, which may result in various phenotypic expressions within the same individual. This more often would lead to disease caused by a dominant mutation being expressed in some cells; it would not likely lead to disease caused by a recessive trait.
Lyonization, also known as X-inactivation, is the process by which one of the two X chromosomes in mammalian females becomes transcriptionally inactive in each cell, ensuring that males and females have an equal dosage of X-linked genes.
Females who are carriers (heterozygous for the mutation) can manifest a recessive X-linked disease if there is skewed inactivation of X-chromosome in certain cells, leading to the expression of the mutated gene in a higher proportion of cells than expected in a typical X-linked recessive disorder.
Skewed inactivation is also called atypical lyonization.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Presence of mutated CD40LG and atypical lyonization
)
[1] => Array
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[each_answer] => B. Presence of mutated TNFRSF5 and atypical lyonization
)
[2] => Array
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[each_answer] => C. Clonal expansion of cells expressing mutated CD40
)
[3] => Array
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[each_answer] => D. Mosaicism of the CD40LG gene
)
)
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[3] => Array
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[quiz_unique_key] => 1403770772
[question] => Flow cytometry can be used to identify cells lacking CD40 receptors and can be useful for HIGM diagnosis. In which situation might flow cytometry fail to identify an abnormality in a patient bearing an HIGM-associated TNFRSF5 mutation?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
Flow cytometry can be used to identify receptors on the cell surface by labeling cells with fluorescently tagged antibodies that specifically bind to the target receptor. A cell-antibody mixture is incubated to allow the antibodies to bind to their respective receptors, and then the cell suspension is introduced into the flow cytometer. As cells pass through the laser beam, the fluorescently labeled antibodies bound to the cell surface receptors emit fluorescence.
In this case, we are looking for a scenario in which the protein is present on the cell surface such that it could still be recognized by flow cytometry.
However, we are looking for a scenario where the patient’s mutation does result in HIGM.
Ubiquitination would cause intracellular degradation; therefore, the protein would not be recognized on the surface by flow cytometry.
A missing sorting signal sequence plus/minus transmembrane domain would interfere with the transport of the protein to the cell surface and integration into the membrane, so again the protein would not be recognized by flow cytometry.
A full-sized protein that is correctly folded would likely be detected by flow cytometry, assuming that a mutation is not within the particular epitope that is used by the detection antibodies.
However, this protein would only be HIGM-related if it were caused by a mutation that interfered with the function of the CD40 receptor. On the other hand, a silent mutation would not be an HIGM-related mutation and therefore is not the correct answer.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. The receptor is missing a sorting signal sequence that directs it to its appropriate cellular location.
)
[1] => Array
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[each_answer] => B. The receptor is full-sized and correctly folded, but a mutation in its extracellular region renders it non-functional.
)
[2] => Array
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[each_answer] => C. The receptor is full-sized and correctly folded due to a silent mutation in its noncoding region.
)
[3] => Array
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[each_answer] => D. The receptor is full-sized and correctly folded but is immediately ubiquitinated for degradation.
)
)
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[4] => Array
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[quiz_unique_key] => 1403770772
[question] => In Figure 1, the colocalization of CD40 with transferrin shows CD40 in the process of:
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
Figure 1 shows that CD40 is colocalized with transferrin in normal cells. The function of this marker is stated in the preceding paragraph, Paragraph 3.
Paragraph 3 states that transferrin is a marker of endosomal compartments.
It is reasonable to conclude that the CD40 that is colocalized with transferrin (in endosomal compartments) is on its way to the cell surface from the ER/Golgi.
By definition, movement from these organelles to the cell surface is anterograde trafficking.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. undergoing protein folding and modifications.
)
[1] => Array
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[each_answer] => B. undergoing sorting and packaging into vesicles.
)
[2] => Array
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[each_answer] => C. retrograde trafficking to the cell surface.
)
[3] => Array
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[each_answer] => D. anterograde trafficking to the cell surface.
)
)
)
[5] => Array
(
[quiz_unique_key] => 1325138223
[question] => Which of the following could be used as a curative intervention for XHIGM?
[value] => Array
(
[answer] => 1
[description] => Reason for Correct Answer:
As stated in the passage, XHIGM is caused by a mutation in the CD40LG gene. This gene encodes the CD40 ligand, which is primarily expressed on activated T cells.
Because XHIGM is not caused by a dysfunctional CD40 receptor, the restoration of CD40 function would not be an effective treatment.
For a similar reason, the inhibition of CD40 would also not be an effective treatment.
Because XHIGM is a CD40 ligand deficiency, CD40 ligand inhibitors would not be effective.
Because CD40 ligand is expressed primarily on T cells, hematopoietic stem cell transplantation is a potential curative treatment for XHIGM. This procedure involves replacing the defective bone marrow cells, which carry the mutated CD40LG gene, with healthy hematopoietic stem cells from a compatible donor. By doing so, the patient receives functional T cells with a properly functioning CD40 ligand, addressing the root cause of XHIGM and providing a potential cure for the condition.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Hematopoietic stem cell (bone marrow) transplantation
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[1] => Array
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[each_answer] => B. Gene therapy to restore CD40 function
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[2] => Array
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[each_answer] => C. Treatment with a CD40 inhibitor
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[each_answer] => D. Treatment with an inhibitor of the CD40 ligand
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[554598|6] => A
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Figure 1
Figure 2