Syndrome of immune dysregulation, polyendocrinopathy, enteropathy (IPEX)

X-linked immune dysregulation syndrome, polyendocrinopathy and enteropathy (Immunodysregiilation, Polyendocrinopathy, and Enteropathy, X-Linked - IPEX) is a rare serious disease. For the first time it was described more than 20 years ago in a large family, where sex-linked inheritance was revealed.

Pathogenesis of X-linked syndrome of immune dysregulation, polyendocrinopathy and enteropathy

It has been shown that IPEX develops as a result of impaired regulation of CD4 + cell functions in the form of increased T cell activity and hyperproduction of cytokinone. The IPEX model is the "Scurfy" mouse (sf). The disease in them is X-linked and is characterized by skin damage, developmental delay, progressive anemia, thrombocytopenia, leukocytosis, lymphadenopathy, hypogonadism, infections, diarrhea, intestinal bleeding, cachexia and early death. Immunological studies showed an increase in CD4 + cell activity, hyperproduction of cytokines (IL-2, IL-4, IL-5, IL-6, IL-10, INF-Y, and TNF-a). In 2001, the mice of the gene f0хр3 were detected in mice. This gene encodes a protein - scurfin, involved in the regulation of gene transcription.

The f0xp3 gene responsible for the development of IPEX is mapped to Xp11.23-Xq13.3 near the WASP gene. It is specifically expressed by CD4 + CD25 + regulatory T cells. In patients with IPEX, mutations of this gene have been identified.

Normally, autoreactive T and B cells undergo ripple elimination during maturation. Along with passive mechanisms of autotolerance, regulatory CD4 + T cells (Tia cells), which support peripheral autotolerance, suppress activation and expansion of autoreactive T-lymphocytes in this process. Most, CD4 + Tr cells formally express CD25.

The f0xp3 gene encoding a scurfin protein that inhibits transcription is specifically expressed on CD25 + CD4 + r cells in the thymus and periphery. CD25 + CD4 + Tr cells are a population of functionally mature lymphocytes that recognize a wide range of "own" and "foreign" antigens. The absence of Tr in the thymus leads to the development of autoimmune diseases. It is shown that CD25 + CD4 + peripheral blood T cells express f0xp3 and are able to suppress the activation and expansion of other T cells. Activation of CD25-CD4 + T cells by stimulation of TCR induces f0xp3 expression, and f0xp3 + CD25-CD4 + T cells have the same suppressor activity as CD25 + CD4 + TrCD25-Tr cells can become CD25 + after stimulation with antigen.

Symptoms of X-linked syndrome of immune dysregulation, polyendocrinopathy and enteropathy

The main symptoms of the X-linked syndrome of immune dysregulation, polyendocrinopathy and enteropathy are ectocrinopathies, celiac-negative enteropathy, eczema, autoimmune hemolytic anemia. Clinical manifestations develop, as a rule, in the perinatal period or the first months of life. Single cases of the "late onset" of IPEX (after the first year of life and even in adults) are described.

Typically, the first symptoms of the X-linked syndrome of immune dysregulation, polyendocrinopathy and enteropathy are type 1 diabetes and enteropathy, represented by secretory diarrhea or ileus. In patients with diabetes, despite the use of insulin, it is difficult to achieve euglycemia. The cause of diabetes in IPEX is the destruction of islet cells due to inflammation, and not their agenesis, as previously thought. Diarrhea sometimes develops before the beginning of feeding, and always increases against the background of feeding, often leading to the inability to use enteral nutrition. The use of the aglyadine diet is in most cases ineffective. Often diarrhea is accompanied by intestinal bleeding.

Other clinical symptoms of X-linked syndrome of immune dysregulation, polyendocrinopathy and enteropathy are manifested primarily in patients older than three years. As mentioned above, they include eczema (exfoliative or atonic dermatitis), thrombocytopenia, Coombs-positive hemolytic anemia, autoimmune neutropenia, lymphadenopathy, hypothyroidism. Patients who do not suffer from diabetes mellitus often develop polyarthritis, asthma, ulcerative colitis, membranous glomerulonephropathy and interstitial nephritis, sarcoidosis, peripheral polyneuropathy.

Infectious manifestations (sepsis, including catheter-associated, peritonitis, pneumonia, septic arthritis) are not always a complication of immunosuppressive therapy. The main pathogens of infections are Enterococcus and Staphylococcus aureus. The causes of increased propensity to infections may be immune dysregulation and / or neutropenia. The presence of enteropathy and skin lesions contribute to infection.

Growth retardation can begin antenatally, and cachexia is a common symptom of IPEX syndrome. Oka develops due to several reasons: enteropathy, poorly controlled diabetes, increased release of cytokines.

The most common causes of death of patients are bleeding, sepsis, uncontrolled diarrhea and complications of diabetes. Fatal outcomes are often associated with vaccination, viral infections and other exogenous immunostimulating effects.

Laboratory indices of X-linked syndrome of immune dysregulation, polyendocrinopathy and enteropathy

The ratio of CD4 + / CD8 + subpopulations of peripheral blood T-lymphocytes is normal in most patients. The amount of HLA-DR + and CD25 + T cells is increased. Proliferative response of lymphocytes to mitogens is slightly reduced or normal. Stimulation of lymphocytes by mitogens in vitro results in increased expression of IL-2, IL-4, IL-5, IL-10, IL-13 and reduced expression of INF-y. In most patients, IgA, IgG and IgM serum immunoglobulin concentrations are normal, only hypogammaglobulinemia, reduced production of specific antibodies after vaccination, and a decrease in proliferative activity of T cells were detected only in single cases. The concentration of IgE is increased. Eoeinophilia is often detected. Autoantibodies have been detected in most patients, these are antibodies to pancreatic islet cells, insulin, glutamic acid decarboxylase (GAD), smooth muscle, red blood cells, intestinal epithelium, gliadin, renal antigens, thyroid hormones, keratinocytes.

Histological examination reveals atrophy of the intestinal mucosa, infiltration of its own plate and submucosal layer with inflammatory cells. Inflammatory infiltration is present in many organs. In the pancreas - foci of inflammation and a decrease in the number or absence of islet cells; in the liver - cholestasis and fatty degeneration; in the skin - infiltration by immune cells and changes characteristic of psoriatic dysplasia; in the kidneys - tubulointerstitial nephritis, focal tubular aplasia, membranous glomerulopathy and granular immune deposits in the basal membranes of the glomeruli and tubules.

Treatment of X-linked syndrome of immune dysregulation, polyendocrinopathy and enteropathy

Constant immunosuppressive therapy, including cyclosporin A, tacrolimus, corticosteroids, infliximab and rituximab, has a positive effect in some patients. Long-term use of tacrolimus is limited due to toxicity. In most cases, despite treatment, the disease continues to progress steadily.

Stem cell transplantation has been performed in only a few patients, and the available results do not allow to judge its effectiveness in the IREH syndrome.