X-linked lymphoproliferative disease

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X-linked lymphoproliferative disease
Other namesDuncan disease, Purtilo syndrome
SpecialtyHematology Edit this on Wikidata
SymptomsReduced resistance to the Epstein-Barr virus (EBV), leading to infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), dysgammaglobulinemia, non-Hodgkin lymphoma, aplastic anemia, vasculitis, chronic gastritis, skin lesions
DurationLife long
CausesGenetic (X-linked recessive)
TreatmentChemotherapy, stem cell transplants
Frequency1 in 1,000,000 males (XLP1); 1 in 5,000,000 males (XLP2)

X-linked lymphoproliferative disease (also known as Duncan disease

lymphoproliferative disorder,[4] usually caused by SH2DIA gene mutations in males. XLP-positive individuals experience immune system deficiencies that render them unable to effectively respond to the Epstein-Barr virus (EBV),[3] a common virus in humans that typically induces mild symptoms or infectious mononucleosis (IM) in patients.[5] There are two currently known variations of the disorder, known as XLP1 (XLP Type 1) and XLP2. XLP1 is estimated to occur in approximately one in every million males, while XLP2 is rarer, estimated to occur in one of every five million males.[6] Due to therapies such as chemotherapy and stem cell transplants, the survival rate of XLP1 has increased dramatically since its discovery in the 1970s.[3][7]

Presentation

In boys with X-linked lymphoproliferative disorder, the inability to mount an immune response to EBV may lead to death via

skin lesions, as well as IM.[3][8]

Nearly half of XLP patients express humoral immune anomalies, which can include diminished responses to vaccines and low levels of immunoglobulin G (IgG).[3][9]

Patients produce insufficient numbers of CD27 memory B cells.[10]

Cause

XLP1

XLP1 is caused by mutations in the

SLAM)-associated protein, or SAP. A variety of mutations have been implicated in XLP1 expression, including deletions, single nucleotide changes, and incorrect splicing, although a correlation between the type of mutation and the severity of the disorder has not been established.[8]

These defects in SAP fundamentally change the function of two SLAM receptors, 2B4 (CD244) and NTB-A (SLAMF6). Typically, after the receptors bind to their associated ligands, the immunoreceptor tyrosine-based switch motifs (ITSMs) in their cytoplasms are phosphorylated, which activates cell-activating signaling pathways. In an XLP patient, the defects in SAP cause these receptors to induce an inhibitory, rather than activating effect. Ligand binding thus fails to activate natural killer (NK) and cytotoxic T cells that typically eliminate EBV infection, leading to cytokine overproduction and tissue damage.[8]

The term "SH2" domain stands for src-homology 2 domain, which is a three-dimensional domain structure of about 100 amino acid residues. These domains are present in many signalling proteins because they permit specific, non-covalent bonding to proteins that contain phosphotyrosines. The amino acid residues adjacent to the phosphotyrosine on the target protein are what determine the unique binding specificity.[11]

XLP2

Any instance of XLP caused by a mutation not in SHD21A is categorized as XLP2, although the variation is typically caused by mutations in the XIAP (X-linked inhibitor of apoptosis, also known as BIRC4) gene.[3][6] XLP2 patients express different features from those typically found in XLP1 patients, such as splenomegaly and colitis. This variation is closely associated with HLH, so much so that some sources recommend classifying this condition as "X-linked familial hemophagocytic lymphohistiocytosis" instead of X-linked lymphoproliferative disease.[3][12]

Mutations in XIAP inhibit the expression of the gene, which usually regulates the rate of lymphocyte apoptosis during an immune response. Nonfunctional XIAP is unable to prevent lymphocytes from undergoing apoptosis in response to stimuli, which include the formation of the T-cell receptor (TCR)-CD3 complex, the binding the CD95 death receptor, and the activation TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). This leads to higher rates of lymphocyte apoptosis during a normal immune response.[13]

XIAP-deficient individuals also produce low numbers of natural killer cells, a feature shared with XLP1 patients, which leads to a similarly inefficient response to EBV infection.[8][13]

Treatment

Chemotherapy and hematopoietic stem-cell transplantation (HSCT) therapies have shown great success in treating XLP. The development of the two therapies, alongside more efficient monitoring techniques and supportive care, has reduced the overall mortality of the disease from 75% to 29%. Care differs depending on the phenotype of XLP expressed, with treatments varying between those experiencing HLH or lymphoma, and whether or not they have been infected with EBV.[3]

Still, a bone marrow transplant that includes CD34+ hematopoietic stem cells is the only known treatment for the disorder as a whole. Patients who cannot find a bone marrow donor have a survival rate of less than 20%. In addition to the typical restrictions imposed on donor-recipient matches, XLP1 patients who have been infected with EBV typically receive transplants from EBV-positive donors.[3]

Eponym

XLP is also known as Duncan disease, after 6 of 18 males in the Duncan family died of lymphoproliferative disease, including fulminant

Omaha, Nebraska and died on September 28, 1992, in Florida, following a stroke before he could deliver a speech to a forum.[15]

References

  1. ISBN 0-7216-2921-0
    .
  2. ^ "X-linked lymphoproliferative disease". MedlinePlus. U.S. National Library of Medicine.
  3. ^
    PMID 29670631
    .
  4. ISBN 978-1-4160-2999-1
    .
  5. ^ "About Epstein-Barr Virus (EBV)". U.S. Centers for Disease Control and Prevention. 2021-03-17. Retrieved 2022-03-09.
  6. ^ a b "X-linked lymphoproliferative disease: MedlinePlus Genetics". MedlinePlus Genetics. U.S. National Library of Medicine. Retrieved 2022-03-09.
  7. S2CID 44576367
    .
  8. ^
    S2CID 53220284
    .
  9. PMID 29670631
    .
  10. PMID 16424938
    .
  11. ISBN 978-0-7216-0008-6
    .
  12. PMID 20489057
    .
  13. ^
    S2CID 4416976
    .
  14. PMID 4852784
    .
  15. ^ Saxon W (3 October 1992). "David T. Purtilo, 53, a Specialist In Disorders of the Immune System". The New York Times.

External links

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