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

X-linked hyper-IgM syndrome type 1 (HIGM1) is the most common form of the disease, accounting for approximately 70% of hyper-IgM syndrome cases.

More than 10 years ago, a gene was discovered, mutations in which lead to the development of the HIGM1 form of the disease. In 1993, the results of the work 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 hyper-IgM syndrome. The gene encoding the protein gp39 (CD154) - CD40L, is localized on the long arm of the X chromosome (Xq26-27). CD40 ligand is expressed on the surface of activated T-lymphocytes.

To date, more than 100 unique mutations in the CD40L gene have been discovered. Mutations occur throughout the gene. Some mutations may express small amounts of CD40L, which causes a milder clinical phenotype of the disease. A wide range of infectious manifestations in patients with XHIGM is explained by combined immunodeficiency. The defect in antibody formation is a direct consequence of impaired interaction of the CD40-CD40L receptor pair, leading to impaired signal transmission through CD40 B-lymphocytes and IgG synthesis. The cellular defect, due to which anti-infective resistance to intracellular pathogens is impaired, opportunistic infections develop, and maturation of T-lymphocytes is impaired, is caused by impaired interaction of T-lymphocytes with antigen-presenting cells (APCs). It is likely that IgM levels in patients increase with age, especially in cases with late initiation of replacement therapy, reflecting chronic antigenic stimulation rather than a direct consequence of a molecular defect.

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

The first clinical manifestations of HIGM1 may include infections of various localizations.

As with other defects of antibody production, the clinical picture of HIGMI is dominated by repeated bacterial infections. The involvement of various parts of the bronchopulmonary system and ENT organs is noted with the greatest frequency. Repeated pneumonias are characterized by a tendency to a protracted course, an insufficient response to standard antibacterial therapy.

In addition, the infectious spectrum includes Toxoplasma gondii P.carinii, Cryptosporidia, Mycobacterias, i.e. opportunistic infections characteristic of cellular defects. Viral and fungal infections are also noted. Approximately one third of hyper-IgM patients are diagnosed with immunodeficiency 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 sections. Diarrhea, developing in 50% of patients, can be both acute and chronic, and is often caused by cryptosporidiosis infection. A high incidence of sclerosing cholangitis, a severe and often fatal complication of X-linked ginep-IgM syndrome, is also associated with this infection. A high incidence of liver and biliary tract tumors is also characteristic of patients with XHIGM. Normally, CD40 is not expressed by the biliary epithelium, and its expression occurs during inflammation and infection. The absence of CD40 binding of biliary epithelial cells to the CD40 ligand leads to their uncontrolled proliferation. Liver damage in this group of patients can be identified as one of the most severe complications determining the course and prognosis of the disease.

Among the CNS infections in patients with hyper-IgM syndrome, meningoencephalitis caused by enteroviruses and toxoplasma is observed.

The most common non-infectious manifestation of the disease is neutropenia. Neutropenia, 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, while in others it is intermittent. The genesis of neutropenia in XH1GM is not entirely clear, autoantibodies to neutrophils are not detected, and there is no clear correlation between the mutation variant in the CD40 ligand gene and the development of neutropenia. Neutropenia is also detected in patients infected with B19 parvovirus infection. B lymphocytes, thymic epithelial cells, and possibly others (bone marrow microenvironment cells) secrete granulocyte colony-stimulating factor in response to stimulation of the CD40 receptor, but this does not explain the absence of neutropenia in the remaining patients with CD40 ligand deficiency.

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

The X-linked form of HI-IgM syndrome is characterized by lymphadenopathy, in some cases significant, hepatosplenomegaly. The lymph nodes of patients with CD40L deficiency are characterized by structural disorders, underdevelopment or absence of germinal centers, which is explained by ineffective CD40-CD40L interaction in exgrafollicular zones, and, as a result, by impaired recruitment of terminal center progenitor cells.

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

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

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

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

If the patient is under 8 years old, in the absence of serious infectious manifestations, and in the presence of an optimal donor, bone marrow stem cell transplantation is the treatment of choice. Conservative therapy for XHIGM consists of prophylactic replacement with intravenous immunoglobulin (DIGI) preparations at doses of 400-600 mg/kg per month.

Pretransfusion IgG level in patients should be maintained at 500 mg/dl. Infection control is achieved by maintaining normal serum IgG levels and antibacterial therapy. Young children are particularly susceptible to Pneumocystis pneumonia and the development of pneumonia, and therefore should receive prophylaxis with trimetprim/sulfamethoxazole (Biseptol). Patients with neutropenia are prescribed granule-containing colony-stimulating factor preparations (Granocyte, Neurogen). In the case of severe autoimmune complications, glucocorticosteroids, immunosuppressive drugs, and high-dose intravenous immunoglobulin (1-5 g/kg) are included in the therapy. To prevent the development of liver and biliary tract damage, careful monitoring of their condition is necessary, including regular ultrasound examination and, 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. drink boiled or filtered water.

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

The long-term prognosis of XHIGM remains poor. A multicenter European study showed that only 20% of patients survive to age 25. Causes of death include early-onset infections, liver disease, and tumor processes. Therefore, the optimal treatment for these patients is bone marrow transplantation from an HLA-matched sibling, an identical unrelated donor, or a partially matched cord blood. Although early reports of bone marrow transplantation in these patients were very encouraging, the results of a recent study in a group of XHIM patients transplanted in European centers showed only a 68% survival rate.