I understand the first question but not the rest, please help. 1. Billy continue
ID: 260660 • Letter: I
Question
I understand the first question but not the rest, please help.
1. Billy continued to remain asymptomatic even though he eventually only had around 30% engrafment of his sister's bone marrow stem cells (as judged from the proportions of the T cells). Why is full engraftment is not necessary in patients with IPEX?
Answer > 1) Immune dysregulation , polyendocrinopathy enteropathy X linked syndrome (IPEX) is an inherited syndrome of early onset systemic autoimmunity and the prototype of immune disregulatory disorder. It caused by mutation in FOXP3 gene encoding a key transcription factor for natural regulatory T cell ( nTreg). Complete donor engraftment in all hematopoietic lineage may not be necessary because the preferential engraftment of donor Treg cell seems to be sufficient to control the disease.
2. Why did Billy's diarrhea improve when he was being prepared for transplantation?
3. Intravenous immunoglobulin has been used to treat IPEX . How might that be an effective therapy?
4. The occurrence of colitis in IPEX suggests that Treg cells may be implicated in it's parthenogenesis and that might be used therapeutically in more common forms of colitis. Is there experimental data to support this claim?
5. What other gene mutations can be give rise to a clinical picture similar to IPEX?
Explanation / Answer
2. Why did Billy's diarrhea improve when he was being prepared for transplantation?
Ans: To control diarrhea Billy might be given many possible treatments starting from low carbohydrate and elemental formula or TPN diets, to suppress T cell-directed immune responses given with intravenous antibiotics lik cyclosporine and steroids like methylprednisolone. As per literature sirolimus (rapamycin) can be given to suppress effector T cell function while allowing Treg cells to function ameliorates the diarrhea. Or as per the question 3 intravenous immunoglobulins (may be monoclonal anti effector T cell antibodies) given to Billy to prevent diarrhea.
3. Intravenous immunoglobulin has been used to treat IPEX . How might that be an effective therapy?
Ans: Intravenous genetically engineered immunoglobulin drug like Rituximab antibody can be given to eliminate circulating CD20 antigen present on the surface of B lymphocytes and prevent B lymphocytesmediated immune response , which results in reduction in auto antibody productions through B lymphocytes which act as antibody presenting cells.
4. The occurrence of colitis in IPEX suggests that Treg cells may be implicated in it's parthenogenesis and that might be used therapeutically in more common forms of colitis. Is there experimental data to support this claim?
Ans: Many experimental evidences are presented recently for the role played by CD4+CD25+Foxp3+ regulatory T cells (Tregs) its found that Tregs actively inhibit inflammation when activated by their cognate antigen, thus raising hope that these cells could be engineered into a highly targeted, antigen-specific, immunosuppressant therapy. Although Tregs represent less than 10% of circulating CD4+T cells, they have been shown to play an essential role in preventing or limiting inflammation in a variety of animal models and human diseases. In particular, spontaneous intestinal inflammation has been shown to occur in the absence of Tregs, suggesting that there may be a Treg defect central to the pathogenesis of human inflammatory bowel disease (IBD). However, over the past decade, multiple groups have reported no qualitative or quantitative deficits in Tregs from the intestines and blood of IBD patients to explain why these cells fail to regulate inflammation in Crohn’s disease and ulcerative colitis. You may read the following reference works for experimental data
.James D Lord, Promises and paradoxes of regulatory T cells in inflammatory bowel disease World J Gastroenterology. 2015 Oct 28; 21(40): 11236–11245. doi: 10.3748/wjg.v21.i40.11236
5. What other gene mutations can be give rise to a clinical picture similar to IPEX?
Ans: IPEX is due to FOXP3 (Xp11.23) gene mutations. IL2R? (10p15.1) and STAT5b (17q11.2) are two genes involved in FOXP3 pathway whose mutations have been associated with IPEX-like phenotype. IL2R? mutations leading to the absence of CD25 expression, Variations and deficiencies in STAT5b, STAT1 associated with mutations in FOXP3-related genes which manifest clinical features very similar to IPEX.