IPEX is immunodysregulation, polyendocrinopathy, enteropathy, X linked syndrome. It is a rare inborn error of the immune regulation characterised by early onset of one or more autoimmune diseases in boys. IPEX occurs due to mutations in Foxp3. Prior to this IPEX had many alternative names including X linked polyendocrinopathy, immune dysfunction and diarrhoea and X linked autoimmunity and allergic dysregulation. This fatal infection was seen in young males and the presence of this phenotype in multiple generations followed an X linked pattern of inheritance. The presence of auto antibodies and infiltrates in pancreas suggested that it was immunologically mediated. The syndrome was mapped to chromosome Xp.11.23-Xq 13.3. The syndrome was seen in mice too but it was called as 'Scurfy.' This is characterised by lymphocytic infiltration of lymphnodes, spleen liver and skin causing splenomegaly, hepatomagaly and enlarged lymph node. The patients who have IPEX were studied and it was found that approximately 50% of them had mutations in Foxp3.
There are missense, nonsense mutations and deletions seen. Most of the missense mutations cluster in three specific functional domains the proline rich, leucine zipper and forkhead domain. Most patients with IPEX lack Tregs characterised as CD4+CD25+Foxp3+ lymphocytes. Primary immunodeficiency is not present in IPEX; local and systemic infections are seen here mainly due to loss of skin and gut barriers, central lines and poor nutrition. Foxp3 located on chromosome Xp11.23 gene has 11 exons plus one upstream non coding exon. IPEX mutations all appear to disrupt the gene function. They cause disease in hemizygous males but not in carrier females. Animal model used: The scurfy mouse which is naturally mutant and resembling IPEX. Scurfy mice show X linked recessive inheritance of scaly skin, runting, progressive anaemia, bleeding and death really early.
Main defect in IPEX is the lack of CD4+CD25+ T regulatory cells, these help in activity of antigen stimulated T cells. However the most striking features which are also consistent are the absence of normal small bowel mucosa and the presence of inflammatory cells in the lamina propria. There are inflammatory infiltrates seen in multiple organs. Pathology in lymphoid organ is variable and evidence of bleeding or hemorrhage is not unusual. Histology of skin shows immune cell infiltration with other changes characterized as psoriaform hyperplasia or eczematoid. In blood there are antibodies which can be detected.
CLINICAL FEATURES OF IPEX:
Most common clinical features were TIDM which is Type 1 diabetes mellitus and enteropathy manifesting as secretory diarrhea or ileus. TIDM is because of inflammatory destruction of islet cells. Other clinical features included are eczema, thrombocytopenia, coombs positive anemia and lymphadenopathy. Artheritis and ulcerative colitis also occurred in some cases. Hypotonia and muscle atrophy was noted too. Growth retardation was also seen as a result of TIDM.
Symptoms associated with IPEX are described to develop shortly after birth or during the first three months of life. However the three most common clinical findings are:
Endocrinology: Common type 1 diabetes mellitus with onset in the first months or years of life. Autoimmune thyroid disease leading to hypothyroidism or hyperthyroidism observed.
Enteropathy: There is manifestation of chronic watery diarrhea. Onset is in the 1st few months of life; villous atrophy with a mononuclear cell infiltrate in lamina propria is the most common biopsy finding.
Dermatitis: Most commonly eczematous, erythroderma, psoriasis like lesions and pemphigous nodularis has been observed.
Therapies associated with IPEX:
Early diagnosis of IPEX is essential. Many new treatment methods are being studied but the two most important ones are:
(2)Bone marrow transplantation (BMT)
a.Chronic immunosuppression has proven to be partially effective in some patients but ineffective in others.
b.Cyclosporine A, methotrexate corticosteroids and rituximab are some of the therapies. However these cause severe hypertension, renal insufficiency, cardiac hypertrophy and sepsis.
c.Stirolimus is a recent intervention. This is a better tolerated and less nephrotoxic. This allows Treg expansion while growth of T effector cells is inhibited.
BMT is effective provided it is done in the earlier stages. BMT however has mixed opinions. However the genetic defect in IPEX permits one to perform molecular diagnosis in newborns at risk to contemplate presymptomatic BMT.
Th2 cells produce IL-4, IL-5, IL-9 and IL-10 which control and amplify the allergic inflammatory responses. Th1 cells cross regulate Th2 cells.Th1 down modulate effects of Th2 cells and play a role in allergic disease and asthma. IFN-γ is also present at the sites of allergic inflammation and contributes to the disease.
Allergies are inflammatory disorders which cause an aberrant immune response to harmless environmental antigens and occur in susceptible individuals. Immune responses to allergens are characterized by presence of allergen specific IgE antibodies that bind to IgE receptors namely FcεRI.
Exposure to allergen leads to the activation of allergen-specific CD4+ T cells that differentiate to Th2 cells, which secrete Th2 cytokines (e.g., IL-4, -5, -9, -13). These (IL-4, IL-13) promote B lymphocytes to switch to the synthesis of allergen-specific IgE antibodies. IgE binds to high-affinity receptors (FcεRI) expressed on the surface of recruited inflammatory cells. Allergen binding of bound IgE molecules induces cells to release both preformed and newly synthesised inflammatory mediators (e.g., histamine, leukotrienes, MBP, cytokines, chemokines) responsible for the histological effects occurring in the infiltrated tissue. These contribute variously to the recruitment and activation of inflammatory cells (e.g., Th2 cells, dendritic cells, mast cells, eosinophils). In the case of the airways, smooth muscle cell contraction together with mucus hyperproduction results in the clinical symptoms of asthma. The inhibitory effects of Tregs occur via the production of suppressive cytokines (IL-10, TGF-β) and via cell-cell contact dependent mechanisms. Together these have the capacity to block the initiation of the immune response, through their effects on antigen-presenting cells and inhibition of allergen-specific Th2 cells. In addition, Tregs are thought to interfere in the later stages of the allergic disease. They induce B cell effectors to produce non-inflammatory IgG4 or IgA isotypes, instead of IgE, and they suppress the effector cells (e.g., mast cells, eosinophils) of allergic inflammation.
Regulatory T cells are studied in context to tolerance of self antigens. Respiratory administration of whole allergens induces development of T cell hyporesponsiveness and there is development of Tr cells seen. Production of OVA (Ovalbumin) specific IgG and IgG2A was increased indicating immune deviation. Tolerance and regulatory T cells are involved in controlling development of asthma and allergic diseases but it is not clear as to what role the Tregs play here. In some studies there was lack of Tr1 cells seen and in some others depletion of CD4+CD25+ T cells from peripheral blood of these individuals revealed greater invitro proliferative and Th2 cytokine production responses to allergens. Elevated frequencies of Tr1 cells prevent asthma and blocks Tr1 cell function and they enhance allergen induced Th2 cell activation in vitro. Both ex vivo or in vivo methods for generating and/or expanding allergen specific Treg cells hold a promise for the treatment of allergens. Tregs are very essential for the suppression of the immune system however they remain to be learned and understood especially the mechanisms associated with Tregs. Clinical trial and therapies involving Tregs are still in process of development.
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