X-linked hyper-IgM syndrome type 1 (HIGM1)

X-linked hyper-IgM type 1 syndrome (NIGM1) is the most common form of the disease: this variant accounts for about 70% of cases of hyper-IgM syndromes.

More than 10 years ago, a gene was discovered whose mutations lead to the development of the HIGM1 form of the disease. In 1993, the results of five independent research groups were published showing that mutations in the CD40 ligand gene (CD40L) are a molecular defect underlying the X-linked form of the hyper-IgM syndrome. The gene encoding the gp39 (CD154) - CD40L protein is located on the long arm of the X chromosome (Xq26-27). The ligand CD40 is expressed on the surface of activated T lymphocytes.

To date, more than 100 unique mutations of the gene CD40L have been discovered. Mutations occur throughout the entire gene. With some mutations, small amounts of CD40L can be expressed, which causes a milder clinical phenotype of the disease. A wide range of infectious manifestations in patients with XHIGM is due to combined immunodeficiency. The defect of antibody formation is a direct consequence of the disruption of the interaction of the receptor pair CD40-CD40L, leading to disruption of the signal through CD40 B-lymphocytes and the synthesis of IgG. The cell defect, due to which the anti-infective resistance against intracellular pathogens is violated and opportunistic infections develop, as well as the maturation of T-lymphocytes is disturbed, is caused by a violation of the interaction of T-lymphocytes with antigen-presenting cells (APCs). Probably, the level of IgM in patients increases with age, especially in cases with late onset of replacement therapy, which reflects a greater degree of chronic antigenic stimulation than the direct consequence of a molecular defect.

Symptoms of X-linked hyper-IgM syndrome type 1 (NIGM1)

The first clinical manifestations of HIGM1 can be attributed to infections of different locations.

As with other antibody product defects, the clinical picture of HIGMI is dominated by repeated bacterial infections. With the greatest frequency, involvement of various departments of the broncho-pulmonary system, ENT organs is noted. Repeated pneumonia is characterized by a tendency to prolonged flow, an inadequate response to standard antibiotic therapy.

In addition, the infectious spectrum contains Toxoplasma gondii P.carinii, Cryptosporidia, Mycobacterias, i.e. Opportunistic infections peculiar to cellular defects. Viral and fungal infections are also noted. Approximately one-third of patients with hyper-IgM diagnosed with an immunodeficiency state are placed when the patient develops pneumocystis pneumonia at 1 year of age.

Characteristic for XHIGM syndrome is the involvement of the gastrointestinal tract in the infectious process, with ulcerative lesions of its various departments. Diarrhea that develops in 50% of patients can be both acute and chronic, and often it is caused by cryptosporidiosis. This infection is also associated with a high incidence of sclerosing cholangitis - a severe and often fatal complication of X linked gynep-IgM syndrome. The high incidence of liver tumors and biliary tract is also characteristic of patients with XHIGM. Normally, CD40 is not expressed by biliary epithelium, and its expression occurs when inflammation, infection occurs. The lack of binding of CD40 cells of biliary epithelium with CD40 ligand leads to their uncontrolled proliferation. Liver damage in this group of patients can be identified as one of the most serious complications that determine the course and prognosis of the disease.

Among the infections of the central nervous system in patients with hyper-IgM syndrome, meningoencephalitis due to enteroviruses and toxoplasma is noted.

The most common non-infectious manifestation of the disease is neutropenia. Neurotropenia, with recurrent stomatitis, occurs in 50% of cases of X-linked hyper-IgM syndrome. In some patients, the course of neutropenia is severe, with frequent relapses, in others it is intermittent. Genesis of neutropenia with XH1GM is not entirely clear, autoantibodies to neutrophils are not detected , there is no clear correlation between the mutation variant in the CD40 ligand gene and the development of neutropenia. Neutropenia is also found in patients infected with B19 parvovirus infection. B-lymphocytes, thymic epithelial cells, and possibly others (bone marrow microenvironment cells) secrete a granulocyte colony-stimulating factor in response to stimulation of the CD40 receptor, but this does not explain the absence of neutropenia in the remaining part of CD40 ligand deficient patients.

Autoimmune disorders are a characteristic manifestation of hyper-IgM syndrome. Among autoimmune complications, the frequency of nonspecific ulcerative colitis, sclerosing cholangitis is high. Developed also immune cytopenia, seronegative arthritis, nephritis,

For the X-linked form of the giper-IgM syndrome, lymphadenopathy is characteristic, in some cases significant, hepatosplenomegaly. Lymph nodes of patients with CD40L deficiency are characterized by structural breakdown, underdevelopment or absence of germinal centers, which is explained by ineffective interaction of CD40-CD40L in the ex-follicular zones, and as a result, disruption of recruitment of precursor cells of terminal centers.

Diagnosis of X-linked hyper-IgM syndrome type 1 (NIGM1)

Immunologically, patients with CD40L mutations are characterized by a sharp decrease in serum IgG, IgA, IgE at normal or high IgM levels.

The number of circulating B-lymphocytes and major subpopulations of lymphocytes is normal, although the population of IgDCD27 + B-lymphocytes in these patients is significantly reduced. In most cases, the proliferative response to anti-CD3 antibodies and PHA is not compromised, positive skin tests with bacterial and fungal antigens are positive. The CD40 receptor function of B-lymphocytes in the X-linked form of hyper-IgM is conserved, as demonstrated in vitro by the ability of IgG and IgE production of peripheral blood lymphocytes when incubated with anti-CD40 antibodies or soluble CD40L in the presence of cytokines. In patients with X-linked form, CD40L expression by activated CD4 + lymphocytes is absent or sharply reduced (rarely), which is the diagnostic criterion of the X-linked form of hyper-IgM,

Treatment of X-linked hyper-IgM syndrome type 1 (NIGM1)

If the patient's age is less than 8 years, in the absence of serious infectious manifestations, and also in the presence of an optimal donor, the transplantation of bone marrow stem cells is a therapy of choice. Conservative therapy XHIGM consists in prophylactic replacement with intravenous immunoglobulin preparations (DIGI) in doses of 400-600 mg / kg per month.

The pre-transfusion level of IgG in patients should be maintained at a concentration of 500 mg / dL. Control of infections is achieved by maintaining a normal level of serum IgG, antibiotic therapy. Young children are particularly susceptible to pneumocyst infection and pneumonia, and therefore should receive prophylaxis with trimethoprim / sulfamethoxazole (biseptol). Patients with neutropenia are prescribed granule preparations for a cytotoxic colony-stimulating factor (granitocyte, neurogen). With the development of severe autoimmune complications, glucocorticosteroids, immunosuppressive drugs, intravenous immunoglobulin in high-dose (1-5 g / kg) regimen are included in the therapy. To prevent the development of lesions of the liver and the biliary tract, careful monitoring of their condition is necessary, including regular ultrasound, if necessary, liver biopsy. Since the development of chronic cholangitis in these patients is associated with cryptosporidiosis, it is necessary to exclude possible sources of infection, i.e. Use boiled or filtered water.

The prognosis of X-linked hyper-IgM syndrome type 1 (NIGM1)

The long-term forecast of XHIGM remains unfavorable. A multicentre European study showed that only 20% of patients survive to 25 years of age. The causes of death are infections at an early age, liver disease and tumor processes. In this regard, the best method for treating these patients is bone marrow transplantation from HLA identical sibling, an identical unrelated donor or a partially compatible cord blood. Although the first reports of bone marrow transplantation in these patients were very encouraging, the results of a recent study in a group of patients with XHIM transplanted in European centers showed only a 68% survival rate.