Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr−/− mice or in patients with autoimmune lymphoproliferative syndrome

@article{Rao2007PyrimethamineTD,
  title={Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr−/− mice or in patients with autoimmune lymphoproliferative syndrome},
  author={V. Koneti Rao and Kennichi C. Dowdell and Janet K. Dale and Faith Dugan and Lesley Pesnicak and Lilia Bi and Victoria Hoffmann and Scott R. Penzak and Nilo A. Avila and Thomas A. Fleisher and Jennifer M. Puck and Stephen E. Straus},
  journal={American Journal of Hematology},
  year={2007},
  volume={82}
}
Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte apoptosis leading to childhood onset of marked lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, and increased risk of lymphoma. Most cases are associated with heterozygous mutations in the gene encoding Fas protein. Prolonged use of immunosuppressive drugs that do ameliorate its autoimmune complications fail to consistently lessen lymphoproliferation in ALPS. A case series had described children… 

How I treat How I treat autoimmune lymphoproliferative syndrome

TLDR
Some patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma, and the best approaches to diagnosis, followup, and management of ALPS, its associated cytopenias, and other complications resulting from infiltrative lymphoproliferation and autoimmunity are presented.

Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations.

TLDR
Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma.

Rapid regression of lymphadenopathy upon rapamycin treatment in a child with autoimmune lymphoproliferative syndrome

TLDR
A case of a child with ALPS whose greatly enlarged lymph nodes rapidly regressed upon initiation of rapamycin, a novel potential therapeutic agent in the treatment of ALPS is presented.

Optimal Management of Autoimmune Lymphoproliferative Syndrome in Children

TLDR
Though ALPS is a rare disorder, it should be suspected and ruled out in children presenting with chronic and refractory multilineage cytopenias associated with nonmalignant lymphoproliferation, and sirolimus and mycophenolate mofetil should be considered first-line therapy for patients who need chronic treatment.

Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)

TLDR
The clinical and laboratory manifestations found in ALPS patients are described, as well as the molecular basis for the disease and new advances in treatment are described.

Targeting Notch signaling in autoimmune and lymphoproliferative disease.

TLDR
Inhibiting the Notch signaling pathway may present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases.

FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta+ T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function.

TLDR
It is shown that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.

Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS)

TLDR
The experience of rituximab use during the last 8 years in 12 patients, 9 children, and 3 adults with ALPS, belonging to 166 families currently enrolled in studies at the National Institutes of Health are summarized.

Novel molecular and cellular therapeutic targets in acute lymphoblastic leukemia and lymphoproliferative disease

TLDR
Potential molecular and cellular therapeutic strategies that target key signaling networks which regulate lymphocyte growth, survival, and function and block the interaction of ALL cells with stromal cells or lymphoid growth factors secreted by the bone marrow microenvironment are reviewed.

References

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TLDR
It is found that the drug induced apoptosis in activated lymphocytes through activation of the mitochondrial apoptotic pathway in ALPS patients treated with the antimalarial drug Fansidar.

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS).

TLDR
It is concluded that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.

Autoimmune lymphoproliferative syndrome presenting with glomerulonephritis

TLDR
It is suggested that glomerulonephritis is one of the characteristic features of ALPS, which is characterized clinically by chronic non-malignant lymphoproliferation and autoimmunity.

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TLDR
It is determined that patients with germline mutations of the intracellular domain of Fas protein have a significantly increased risk of developing Hodgkin and non-Hodgkin lymphoma (NHL), underscoring the critical role played by cell surface receptor-mediated apoptosis in eliminating redundant proliferating lymphocytes with autoreactive and oncogenic potential.

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TLDR
Evidence is provided that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans and in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity.

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TLDR
The autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms that help maintain normal lymphocyte homeostasis, with a consequent accumulation of lymphoid mass and persistence of autoreactive cells.

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TLDR
It is shown that arsenic trioxide (As2O3) is able to achieve quasi-total regression of antibody- and cell-mediated manifestations in MRL/lpr mice, demonstrating that it is a novel promising therapeutic agent for autoimmune diseases.

Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression.

TLDR
It is shown that the circulating levels of interleukin 10 (IL-10) were significantly higher in 21 patients with ALPS than in healthy controls, and overexpression of IL-10 in patients with inherited apoptotic defects is strongly associated with the overt manifestations of ALPS.

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TLDR
ALPS type III could be more common than believed until now, and evidence is provided for this hypothesis.

Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome

TLDR
Mycophenolate mofetil was used to treat cytopenias in patients with ALPS and preliminary experience suggests that MMF may spare steroid usage in patientswith ALPS‐associated cy topenias.