X-linked lymphoproliferative syndrome: symptoms, diagnosis, treatment

X-Linked Lymphoproliferative Syndrome (XLP) is a rare hereditary disease characterized by a violation of the immune response to the Epstein-Barr virus-EBV virus. 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" - by the family name. After a while, this immunodeficiency became known in the literature as an X-linked lymphoproliferative syndrome, and in 1998 a gene was identified whose damage leads to Duncan's disease - SH2D1A (SAP, DSHP).

Pathogenesis of X-linked lymphoproliferative syndrome

EBV is related 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 supercapsid shell carrying capsid genes (viral capsid antigen - VCA and early antigen - EA) and surface glycoproteins that facilitate the introduction of the virus into the cell; a tag containing the proteins necessary for replication of the virus; nucleus containing viral DNA encased in nucleocapsid. One part of these proteins is responsible for insertion into the target cells and replication of the virus. The action of other viral proteins is aimed at reducing the level of EBV's being lost by the host's immune system during latent persistence. The viral genome is a double-stranded DNA consisting of approximately 172,000 nucleotide pairs encoding about 100 proteins.

Infected EBV among the population is on average 90%. In 70% of cases, infection occurs up to 3 years. By the age of 50, EBV infection reaches 100%. Most people suffer infection subclinically or in the form of mild catarrhal syndrome in childhood and adolescence. Clinically expressed primary infection occurs mainly in the nid of infectious mononucleosis at the age of 5-15 years. After the primary primary EBV infection, the persistence of the virus remains in the memory B-cells throughout life.

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

Normally, an immune response to a productive (acute or reactive latent) infection of EBV occurs by eliminating the virus-infected B-cells with cytotaxic T-lymphocytes (predominantly CD8 +) and NK cells and the action of neutralizing antibodies that 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 superfamily of immunoglobulins homologous to CD2: Signal Lymphocytic activation molecule (SLAM (CD150), 2B4 (CD244), Ly-9 (CD229), CD84 As a result of the SLAM-SLAM-associated protein (SAP) compound, the lymphocyte activation signal is transmitted in the T cell's cytoplasm, and SAP is also required for the transmission of the activation signal to 2B4 on NK cells.

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

Symptoms of X-linked lymphoproliferative syndrome

As a result of the violation of the immune response leading to uncontrolled proliferation of transformed EBV B lymphocytes and virus infection of new target cells, a debut of clinical and immunological manifestations of XLP occurs. Four most common XLP phenotypes are described: severe and more often fatal, infectious mononucleosis, malignant lymphoproliferative conditions (lymphomas, leukemia predominantly, B-cell), anemia or pancytopenia, including due to virus-induced hemophagocyte syndrome, dysgammaglobulinemia. The development of systemic necrotizing lymphoid vasculitis with chorioretinitis is also described. The reasons for the development of a particular XLP phenotype are not well understood. It is most likely that the combination of genetic factors with external factors predetermines various clinical manifestations.

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

The most severe manifestation of XLP is fulminant infectious mononucleo, which in 58% of patients leads to death. Patients have fever episodes with leukocytosis and the appearance of atypical mononuclears, lymphadenopathy and hepatosplenomegaly as a result of lymphocytic infiltration. It can be observed maculopapular rash, catarrhal phenomena, severe current tonsillitis. The severity of the course is determined by progressive damage to hepatocytes with the formation of extensive necrosis. Damage to cells and vessels of the liver occurs under the influence of cytokines produced by circulating cytotoxic T-lymphocytes. Acute fast-progressive liver failure is the most common cause of death of XLP patients who developed infectious mononucleosis.

Cytopenia as acute conditions in patients with XLP develop more rarely. It can be isolated red cell anemia, aplastic or autoimmune anemia. The most severe cytopenias are due to the development of virus-associated hemophagocytic lymphogystyocytosis (HLG), which is the result of B cell marrow expansion, T-cell cytotoxicity and cytokinemia. The clinic of virus-associated HLG can develop both against a background of severe infectious mononucleosis, and independently. Its main manifestations are progressive cytopenia with the defeat of one or several germs of hematopoiesis, the phenomenon of lymphogistocytic hyperplasia and phagocytosis of blood cells in the bone marrow, and less often in other organs. In the absence of treatment, lymphohystocyte activation leads to a fatal outcome as a result of complications (severe infections, bleeding, cardiopulmonary insufficiency) in almost 100% of cases.

As mentioned above, dysgamaglobulinemia can develop both in EBV-positive and in EBV-negative patients with XLP. The most common types of hypogammaglobulinemia are: a decrease in the levels of all immunoglobulins, a selective IgA deficiency, a deficiency of IgA and IgG at a normal or elevated level IgM. Less often are hypergammaglobulinemia. Immunodeficiency in patients with XLP is combined, which leads to the development of not only severe bacterial, on and fungal, viral and opportunistic infections.

Uncontrolled poly- and oligoclonal lymphoproliferation in 30% of patients with XLP leads to the development of lymphomas. More often, these are B-cell non-Hodgkin's or Hodgkin's lymphomas, including immunoblastic sarcomas, less common T- and NK-cell lymphomas, nasopharyngeal and gastrointestinal carcinomas, smooth muscle tumors. Localization of them in most cases 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 the disease. However, sometimes, from an early and correct diagnosis depends the prognosis of the disease.

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

Diagnosis of XLP makes it difficult to atypical course of the disease, which can hide under the guise of other primary immunodeficiencies, primary HLG, hemoblastosis and other malignant tumors. Most often, with a decrease in the levels of one or more immunoglobulin fractions associated with infectious complications, autoimmune diseases (immune cytopenia, hemophagocytic syndrome, autoimmune-inflammatory diseases of the gastrointestinal tract), malignant processes, and excluding other immunodeficiencies with antibody defects, a general variable immunodeficiency (OBID). In a genetic study, several patients with CVID and a family history were diagnosed with XLP. Thus, the analysis of the 5H2D1A gene should be carried out for all male patients with a picture of OBID, especially if the aquatic family meets more than one case of OBID in males.

Treatment of X-linked lymphoproliferative syndrome

Single approaches to the therapy of patients with XLP have not been developed. Various preventive regimens can be used in case of detection of a defect in the preclinical stages of the course of XLP. First of all, it is possible to suggest the disease in boys with a characteristic family history and sero- or PCR-negative for EBV. As a preventive agent, acyclovir can be used. It was shown that his early administration inhibits viral replication in the oropharynx. With the preventive goal, some authors recommend the use of IVIG therapy. However, neither acyclovir nor intravenous immunoglobulin prevent infection of EBV.

With the development of a clinical picture of one of XLP phenotypes, specific therapy is needed. When hypogammaglobulinemia is recommended to use intravenous immunoglobulin monthly in a maintenance dose, as well as antibiotic therapy.

A combination of high doses of acyclovir 500 mg / m ² and methylprednisolone (up to 5-6 mg / kg / day), high-dose IVIG with a high titre of anti-EBV antibodies and a combination of high-dose IVIG therapy with interferon-alpha were used to treat fulminant infectious mononucleosis , however, when using both regimens, only a short-term positive effect was obtained.

With the development of hemophagocytic syndrome, treatment with 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 to control lymphocyte-macrophage activation in the framework of XLP and, subsequently, to conduct TSCS.

For the treatment of malignant diseases that occur in the background of XLP, the corresponding standard protocols of antineoplastic therapy are applied.

Forecast

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