Immune dysregulation syndrome, polyendocrinopathy, enteropathy (IPEX)

Immunodysregiilation, Polyendocrinopathy, and Enteropathy (X-Linked - IPEX) is a rare, severe disorder. It was first described over 20 years ago in a large family where sex-linked inheritance was identified.

Pathogenesis of X-linked immune dysregulation syndrome, 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 cytokine hyperproduction. The IPEX model is "Scurfy" mice (sf). The disease in them is X-linked and is characterized by skin lesions, developmental delay, progressive anemia, thrombocytopenia, leukocytosis, lymphadenopathy, hypogonadism, infections, diarrhea, intestinal bleeding, cachexia and early death. Immunological studies have revealed increased CD4+ cell activity, hyperproduction of cytokines (IL-2, IL-4, IL-5, IL-6, IL-10, INF-Y, and TNF-a). In 2001, a mutation in the f0xp3 gene was detected in mice. This gene encodes the scurfin protein, which is involved in the regulation of gene transcription.

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

Normally, autoreactive T and B cells undergo rapid elimination during maturation. Along with passive mechanisms of self-tolerance, regulatory CD4+ T cells (T cells) participate in this process, maintaining peripheral self-tolerance by suppressing the activation and expansion of autoreactive T lymphocytes. Most CD4+ T cells constitutionally express CD25.

The F0xp3 gene encoding the scurfin protein, which inhibits transcription, is specifically expressed on CD25+ CD4+ T cells in the thymus and periphery. CD25+ CD4+ T cells are a population of functionally mature lymphocytes that recognize a wide range of "self" and "foreign" antigens. The absence of T cells in the thymus leads to the development of autoimmune diseases. It has been shown that CD25+ CD4+ T cells in peripheral blood express f0xp3 and are able to suppress the activation and expansion of other T cells. Activation of CD25- CD4+ T cells through TCR stimulation induces f0xp3 expression, and f0xp3+ CD25- CD4+ T cells have the same suppressive activity as CD25+ CD4+ T cells.CD25- Tr cells can become CD25+ upon antigen stimulation.

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

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

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

Other clinical symptoms of X-linked immune dysregulation syndrome, polyendocrinopathy and enteropathy occur mainly in patients over three years of age. As mentioned above, they include eczema (exfoliative or atopic dermatitis), thrombocytopenia, Coombs-positive hemolytic anemia, autoimmune neutropenia, lymphadenopathy, hypothyroidism. In patients without diabetes mellitus, polyarthritis, asthma, ulcerative colitis, membranous glomerulonephropathy and interstitial nephritis, sarcoidosis, peripheral polyneuropathy often develop.

Infectious manifestations (sepsis, including catheter-associated sepsis, 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 susceptibility to infections may be immune dysregulation and/or neutropenia. The presence of enteropathy and skin lesions contribute to infection.

Growth failure may begin antenatally, and cachexia is a common feature of IPEX syndrome. OCA develops due to several causes: enteropathy, poorly controlled diabetes mellitus, increased cytokine release.

The most common causes of death in 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 findings of X-linked immune dysregulation syndrome, polyendocrinopathy and enteropathy

The CD4+/CD8+ ratio of peripheral blood T-lymphocyte subsets is normal in most patients. The number of HLA-DR+ and CD 25+ T cells is increased. The proliferative response of lymphocytes to mitogens is slightly reduced or normal. Stimulation of lymphocytes with mitogens in vitro leads to increased expression of IL-2, IL-4, IL-5, IL-10, IL-13 and decreased expression of INF-y. In most patients, serum immunoglobulin concentrations IgA, IgG and IgM are normal, only in isolated cases hypogammaglobulinemia, decreased production of specific antibodies after vaccination, and decreased proliferative activity of T cells were detected. IgE concentration is increased. Eoinophilia is often detected. Autoantibodies are found in most patients; these are antibodies to pancreatic islet cells, insulin, glutamic acid decarboxylase (GAD), smooth muscle, erythrocytes, intestinal epithelium, gliadin, kidney antigens, thyroid hormones, and keratinocytes.

Histological examination reveals atrophy of the intestinal mucosa, infiltration of the lamina propria and submucosal layer by 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 basement membranes of the glomeruli and tubules.

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

Chronic immunosuppressive therapy, including cyclosporine 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 us to judge its effectiveness in IPEX syndrome.