X-linked lymphoproliferative syndrome: symptoms, diagnosis, treatment

X-linked lymphoproliferative syndrome (XLP) is a rare hereditary disease characterized by a disorder of the immune response to the Epstein-Barr virus (EBV). XLP was first identified in 1969 by David T. Purtilo et al., who observed a family in which boys died from infectious mononucleosis. The disease was called "Duncan syndrome" - after the family's surname. After some time, this immunodeficiency began to be referred to in the literature as X-linked lymphoproliferative syndrome, and in 1998 the gene, the damage to which leads to Duncan disease - SH2D1A (SAP, DSHP) was identified.

Pathogenesis of X-linked lymphoproliferative syndrome

EBV belongs to the family of human herpes viruses, it persists in the host cells throughout life. The introduction of EBV into the body leads to the development of various conditions, from asymptomatic carriage to the development of severe EBV infections, lymphoproliferative and oncological diseases.

The viral particle consists of a membrane - supercapsid, carrying capsid genes (viral capsid antigen - VCA and early antigen - EA) and surface glycoproteins that facilitate the introduction of the virus into the cell; tag-ment, including proteins necessary for viral replication; core containing viral DNA, enclosed in a membrane - nucleocapsid. One part of these proteins is responsible for the introduction into target cells and replication of the virus. The action of other viral proteins is aimed at reducing the detection of EBV by the host immune system during latent persistence. The viral genome is a double-stranded DNA consisting of approximately 172 thousand nucleotide pairs encoding about 100 proteins.

The EBV infection rate among the population averages 90%. In 70% of cases, infection occurs before the age of 3. By the age of 50, EBV infection reaches 100%. Most people carry the infection subclinically or as a mild catarrhal syndrome in childhood and adolescence. Clinically expressed primary infection occurs mainly in the form of infectious mononucleosis at the age of 5-15 years. After primary EBV infection, the virus persists in memory B cells throughout life.

The introduction of E8V into immune system cells leads to the implementation of a chain of complex interactions of viral proteins with cellular proteins, the result of which is the polyclonal activation of lymphocytes transformed by the virus.

Normally, the immune response to productive (acute or reactivation of latent) EBV infection is carried out through the elimination of virus-infected B cells by cytotactic T lymphocytes (mainly CD8+) and NK cells and the action of neutralizing antibodies, which inhibit the spread of the virus between target cells.

Activation of T and NK cells is initiated by the interaction of ligands of the infected B lymphocyte with surface molecules belonging to the immunoglobulin superfamily homologous to CD2: signaling lymphocytic activation molecule - SLAM (CD150), 2B4 (CD244), Ly-9 (CD229), CD84. As a result of the connection of SLAM with SLAM-associated protein (SAP) in the cytoplasm of the T cell, the signal for lymphocyte activation is transmitted. SAP is also necessary for the transmission of the activation signal from 2B4 on NK cells.

When individuals with defects in the SAP gene are infected with EBV, the phenotype of X-linked lymphoproliferative syndrome is realized. Such patients are characterized by impaired activation and decreased cytotoxicity of CD8+ and NK cells, and decreased synthesis of proinflammatory and regulatory cytokines.

Symptoms of X-linked lymphoproliferative syndrome

As a result of the immune response disorder leading to the uncontrolled proliferation of EBV-transformed B-lymphocytes and infection of new target cells with the virus, the clinical and immunological manifestations of XLP debut. Four most common phenotypes of XLP have been described: severe and often fatal infectious mononucleosis, malignant lymphoproliferative conditions (lymphomas, leukemias - mainly B-cell), anemia or pancytopenia, including due to virus-induced hemophagocytic syndrome, dysgammaglobulinemia. The development of systemic necrotizing lymphoid vasculitis with chorioretinitis has also been described. The causes of the development of one or another XLP phenotype are insufficiently studied. Most likely, a combination of genetic and external factors predetermines various clinical manifestations.

Among external factors, the most significant for the development of certain clinical manifestations is the contact of an XLP patient with EBV. Infection with the virus is a trigger mechanism for the formation of the most severe, rapidly progressing and fatal diseases, such as fulminant infectious mononucleosis, hemophagocytic syndrome. In 10% of cases, the XLP phenotype appears before EBV infection. As a rule, in this case, dysgammaglobulinemia and lymphomas develop.

The most severe manifestation of XLP is fulminant infectious mononucleosis, which is fatal in 58% of patients. Patients have episodes of fever with leukocytosis and the appearance of atypical mononuclear cells, lymphadenopathy and hepatosplenomegaly as a result of lymphocytic infiltration. Maculopapular rash, catarrhal symptoms, and severe tonsillitis may be observed. The severity of the course is determined by progressive damage to hepatocytes with the formation of extensive necrosis. Damage to liver cells and vessels occurs under the influence of cytokines produced by cytotoxic T-lymphocytes migrating from the circulation. Acute rapidly progressive liver failure is the most common cause of death in XLP patients who have developed infectious mononucleosis.

Cytopenias as acute conditions in patients with XLP develop less frequently. This may be isolated red-cell anemia, aplastic or autoimmune anemia. The most severe cytopenias are observed due to the development of virus-associated hemophagocytic lymphohistiocytosis (HLH), which is a result of B-cell expansion of the bone marrow, T-cell cytotoxicity and cytokinemia. The clinic of virus-associated HLH can develop both against the background of severe infectious mononucleosis and independently. Its main manifestations are progressive cytopenia with damage to one or more hematopoietic germs, lymphohistiocytic hyperplasia and phagocytosis of blood cells in the bone marrow, less often - in other organs. Without treatment, lymphohistiocytic activation leads to a fatal outcome due to complications (severe infections, bleeding, cardiopulmonary failure) in almost 100% of cases.

Dysgammaglobulinemia, as mentioned above, can develop in both EBV-positive and EBV-negative patients with XLP. The most common types of hypogammaglobulinemia are: decreased levels of all immunoglobulins, selective IgA deficiency, IgA and IgG deficiency with normal or elevated IgM levels. Hypergammaglobulinemia is less common. Immunodeficiency in patients with XLP is combined, which leads to the development of not only severe bacterial, but also fungal, viral and opportunistic infections.

Uncontrolled poly- and oligoclonal lymphoproliferation in 30% of patients with XLP leads to the development of lymphomas. Most often, these are B-cell non-Hodgkin's or Hodgkin's lymphomas, including immunoblastic sarcomas, less common are T- and NK-cell lymphomas, nasopharyngeal and gastrointestinal carcinomas, smooth muscle tumors. Their localization in most cases is extranodal, about 80% of them develop in the ileocecal angle.

Diagnosis of XLP is often difficult due to the polymorphism of the clinical picture and the rarity of this disease. However, sometimes the prognosis of the disease depends on early and correct diagnosis.

The final confirmation of the XLP diagnosis is the detection of the SH2D1A gene mutation by molecular genetic analysis. However, SAP gene mutations are detected only in 60-70% of patients with typical XLP clinical features and a positive family history. The absence of mutation during genetic analysis should not exclude the diagnosis of XLP. When studying the SAP expression in patients with the XLP phenotype without an identified mutation and in patients with a genetically confirmed diagnosis, it was low or absent in both cases. Thus, a combination of SH2D1A genetic analysis and SAP expression assessment is recommended for diagnosing the disease in patients with typical and atypical XLP phenotypes.

The diagnosis of XLP is complicated by the atypical course of the disease, which can be hidden under the mask of other primary immunodeficiencies, primary HLH, hemoblastoses and other malignant neoplasms. Most often, with a decrease in the levels of one or more immunoglobulin fractions associated with infectious complications, autoimmune diseases (immune cytopenias, hemophagocytic syndrome, autoimmune-inflammatory diseases of the gastrointestinal tract), malignant processes, and with the exclusion of other immunodeficiencies with defects in antibody production, common variable immunodeficiency (CVID) is diagnosed. Genetic testing has diagnosed XLP in several patients with CVID and a family history. Thus, 5H2D1A gene analysis should be performed in all male patients with a picture of CVID, especially if there is more than one case of CVID in males in a family.

Treatment of X-linked lymphoproliferative syndrome

There are no uniform approaches to the treatment of patients with XLP. Various prophylactic regimens can be used if the defect is detected at the preclinical stages of XLP. First of all, the disease can be assumed in boys with a characteristic family history and sero- or PCR-negative for EBV. Acyclovir can be used as a prophylactic agent. Its early administration has been shown to inhibit viral replication in the oropharynx. For prophylactic purposes, some authors recommend IVIG therapy. However, neither acyclovir nor intravenous immunoglobulin prevent EBV infection.

In the case of developed clinical picture of one of the XLP phenotypes, specific therapy is necessary. In case of hypogammaglobulinemia, it is recommended to use intravenous immunoglobulin monthly in a maintenance dose, as well as antibacterial therapy.

For the treatment of fulminant infectious mononucleosis, a combination of high doses of acyclovir - 500 mg/m2 ^and methylprednisolone (up to 5-6 mg/kg/day), high-dose IVIG therapy with a high titer of anti-EBV antibodies and a combination of high-dose IVIG therapy with interferon-alpha were used, however, when using both therapy regimens, only a short-term positive effect was achieved.

In the case of development of hemophagocytic syndrome, treatment according to the HLH-94 protocol is recommended - a combination of high doses of dexamethasone with etoposide (VP-16) for 15 months, or according to the immunosuppression protocol proposed by N. Jabado. Both protocols allow monitoring lymphocyte-macrophage activation within the framework of XLP and, subsequently, performing HSCT.

For the treatment of malignancies arising in the context of XLP, appropriate standard antineoplastic therapy protocols are used.

Forecast

Given the poor prognosis of the disease, the radical method of treating XLP is HSCT before EBV infection, but experience with transplantation is very limited.