Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a disease that is caused by congenital defects in Fas-mediated apoptosis. It was described in 1995, but since the 1960s a disease with a similar phenotype has been known as CanaLe-Smith syndrome.

The disease is characterized by chronic non-malignant lymphoproliferation and hypergammaglobulinemia, which can be combined with various autoimmune disorders.

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Pathogenesis

Apoptosis, or physiological cell death, is one of the integral mechanisms for maintaining the body's homeostasis. Apoptosis develops as a result of activation of various signaling mechanisms. Apoptosis mediated by activation of Fas receptors (CD95) during their interaction with the corresponding ligand (Fas ligand, FasL) plays a special role in the regulation of the hematopoiesis system and the immune system. Fas is present on various hematopoietic cells; high expression of the Fas receptor is characteristic of activated lymphocytes. Fasl is expressed mainly by CD8+ T lymphocytes.

Activation of the Fas receptor entails a series of sequential intracellular processes that result in disorganization of the cell nucleus, denaturation of DNA, and changes in the cell membrane that lead to its disintegration into a number of fragments without the release of lysosomal enzymes into the extracellular environment and without inducing inflammation. A number of enzymes called caspases, including caspase 8 and caspase 10, participate in the transmission of the apoptotic signal to the nucleus.

Fas-mediated apoptosis plays an important role in the elimination of cells with somatic mutations, autoreactive lymphocytes, and lymphocytes that have fulfilled their role in the normal immune response. Impaired T-lymphocyte apoptosis leads to the expansion of activated T cells, as well as so-called double-negative T lymphocytes that express the T-cell receptor with a/b chains (TCRa/b), but have neither CD4 nor CD8 molecules. Defective programmed B-cell death in combination with increased interleukin 10 (IL-10) levels lead to hypergammaglobulinemia and increased survival of autoreactive B lymphocytes. Clinical consequences include excessive accumulation of lymphocytes in the blood and lymphoid organs, an increased risk of autoimmune reactions and tumor growth.

To date, several molecular defects have been identified that lead to apoptosis failure and the development of ALL. These are mutations in the Fas, FasL, caspase 8, and caspase 10 genes.

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Symptoms autoimmune lymphoproliferative syndrome.

ALPS is characterized by a large variability in the spectrum of clinical manifestations and severity of the course, and the age of clinical manifestation can also fluctuate depending on the severity of symptoms. There are known cases of the debut of autoimmune manifestations in adulthood, when ALPS was diagnosed. Manifestations of lymphoproliferative syndrome are present from birth in the form of an increase in all groups of lymph nodes (peripheral, intrathoracic, intra-abdominal), an increase in the size of the spleen, and often the liver. The size of the lymphoid organs can change during life, sometimes their increase is noted with intercurrent infections. The lymph nodes have a normal consistency, sometimes dense; painless. There are known cases of severe manifestations of hyperplastic syndrome, imitating lymphoma, with an increase in peripheral lymph nodes, leading to deformation of the neck, hyperplasia of the intrathoracic lymph nodes up to the development of compression syndrome and respiratory failure. Lymphoid infiltrates in the lungs have been described. However, in many cases the manifestations of hyperplastic syndrome are not so dramatic and they remain unnoticed by doctors and parents. The degree of splenomegaly is also quite variable.

The severity of the disease is determined mainly by autoimmune manifestations that can develop at any age. Most often, various immune hemopathy are encountered - neutropenia, thrombocytopenia, hemolytic anemia, which can be combined in the form of two- and three-line cytopenia. A single episode of immune cytopenia may occur, but they are often chronic or recurrent.

Other, rarer autoimmune manifestations may include autoimmune hepatitis, arthritis, sialadenitis, inflammatory bowel disease, erythema nodosum, panniculitis, uveitis, and Guiltain-Barre syndrome. In addition, various skin rashes, mainly urticarial, subfebrile or fever without connection with an infectious process may be observed.

Patients with autoimmune lymphoproliferative syndrome have an increased incidence of malignant tumors compared to the general population. Cases of hemoblastoses, lymphomas, and solid tumors (liver and stomach carcinoma) have been described.

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Forms

In 1999, a working classification of autoimmune lymphoproliferative syndrome was proposed based on the type of apoptosis defect:

• ALP5 0 - complete deficiency of CD95, resulting from a homozygous null mutation (homozygous nuLl mutation) in the Fas/CD95 gene;
• ALPS I - defect in signal transduction through the Fas receptor.
  • In this case, ALPS la is a consequence of a defect in the Fas receptor (heterozygous mutation in the Fas gene);
  • ALPS lb is a consequence of a defect in the Fas ligand (FasL) associated with a mutation in the corresponding gene - FASLG/CD178;
  • ALPS Ic is the result of a newly identified homozygous mutation in the FA5LG/CD178 gene;
• ALPS II - a defect in intracellular signal transmission (mutation in the caspase 10 gene - ALPS IIa, in the caspase 8 gene - ALPS IIb);
• ALPS III - molecular defect not identified.

Type of inheritance

ALPS type 0, a complete deficiency of CD95, has been described in only a few patients. Since heterozygous family members do not have the ALPS phenotype, an autosomal recessive inheritance pattern has been proposed. However, unpublished data from a family with ALPS type 0 are not entirely consistent with this assumption. Scientists have found that many, if not all, mutations are dominant, and that when homozygous, they result in a more severe disease phenotype.

In ALPS type I, the inheritance pattern is autosomal dominant, with incomplete penetrance and variable expressivity. In particular, in ALPS1a, cases of homozygosity or combined heterozygosity have been described, in which various mutations of the Fas gene are determined in both alleles. These cases were characterized by a severe course with prenatal or neonatal manifestation (fetal hydrops, hepatosplenomegaly, anemia, thrombocytopenia). In addition, a correlation was found between the severity of clinical symptoms and the type of mutation in the Fas gene; a more severe course is characteristic of a mutation in the intracellular domain. In total, more than 70 patients with ALPS la have been described worldwide. The FasL mutation was first described in a patient with clinical manifestations of systemic lupus erythematosus and chronic lymphoproliferation. It was categorized as ALPS lb, although the phenotype did not fully meet the criteria for classical autoimmune lymphoproliferative syndrome (double negative T cells and splenomegaly were absent). The first homozygous mutation A247E in the FasL gene (extracellular domain) was described recently, in 2006, by Del-Rey M et al. in a patient with non-lethal ALPS, which indicates an important role of the terminal domain of FasL C0OH in the Fas/FasL interaction. The authors propose to include the ALPS Ic subgroup in the current classification of autoimmune lymphoproliferative syndrome.

ALPS type II is inherited in an autosomal recessive manner, and many patients with this type of disease have typical clinical and immunological ALPS, including impaired Fas-mediated apoptosis, in the implementation of which both caspase 8 (involved in the early stages of intercellular signaling at the level of TCR and BCR interactions) and caspase 10 (involved in the apoptotic cascade at the level of all known receptors that induce lymphocyte apoptosis) are involved.

More than 30 patients had a moderate clinical picture of ALPS, including hypergammaglobulinemia and elevated levels of double negative T cells in the blood, and activated lymphocytes from patients with ALPS type III (as this syndrome was named) showed normal activation of the Fas-mediated pathway in vitro, and no molecular defects were found. It is possible that the disease is caused by disturbances in other apoptotic pathways, such as those mediated by Trail-R, DR3, or DR6. Of interest is the observation by R. Qementi of the N252S mutation in the perforin gene (PRF1) in a patient with ALPS type III, who had a significant decrease in NK activity. The author notes that the significant difference between the frequency of N252S detection in patients with ALPS (2 of 25) and the frequency of its detection in the control group (1 of 330) suggests its connection with the development of ALPS in the Italian population. On the other hand, F. Rieux-Laucat notes that he detected this variant of PRF1 mutation in 18% of healthy individuals and in 10% of patients with ALPS (unpublished data). And, in addition, along with the N252S polymorphism, he found a mutation of the Fas gene in a patient with ALPS and his healthy father, which, according to F. Rieux-Laucat, indicates the non-pathogenicity of the heterozygous mutation N252S in the perforin gene, described somewhat earlier by R. Qementi in a patient with ALPS (Fas mutation) and large cell B-lymphoma. Thus, the question of the causes of ALPS type III remains open today.

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Diagnostics autoimmune lymphoproliferative syndrome.

One of the signs of lymphoproliferative syndrome may be absolute lymphocytoes in the peripheral blood and bone marrow. The lymphocyte content increases due to B- and T-lymphocytes, in some cases - only due to one of the subpopulations,

An increase in the content of double negative lymphocytes with the CD3+CD4-CD8-TCRa/b phenotype in the peripheral blood is characteristic. These same cells are found in the bone marrow, lymph nodes, and lymphocytic infiltrates in organs.

Decreased expression of CD95 (Fas receptor) on lymphocytes is not a diagnostic criterion for autoimmune lymphoproliferative syndrome, since its level may remain within the normal range in some Fas defects with mutation in the intracellular domain, as well as in ALPS types II and III.

A typical sign of autoimmune lymphoproliferative syndrome is hyperimmunoglobulinemia, due to an increase in the level of both all and individual classes of immunoglobulins. The degree of increase may vary.

There are isolated cases of autoimmune lymphoproliferative syndrome with hypoimmunoglobulinemia, the nature of which is unclear. Immunodeficiency is more typical for patients with ALPS IIb, although it has also been described in ALPS type 1a.

Patients may have various autoantibodies: antibodies to blood cells, ANF, antibodies to native DNA, anti-RNP, anti-SM, anti-SSB, RF, antibodies to coagulation factor VIII.

Elevated serum triglyceride levels have been reported in patients with autoimmune lymphoproliferative syndrome; hypertriglyceridemia is thought to be secondary to increased production of cytokines that affect lipid metabolism, particularly tumor necrosis factor (TNF). Significant increases in TNF levels are found in most patients with autoimmune lymphoproliferative syndrome. In some patients, hypertriglyceridemia levels correlate with the course of the disease, increasing during exacerbations.

The need for differential diagnostics with malignant lymphomas determines the indications for open biopsy of the lymph node. Morphological and immunohistochemical examination of the lymph node reveals hyperplasia of the paracortical zones and, in some cases, follicles, infiltration by T- and B-lymphocytes, immunoblasts, plasma cells. In some cases, histiocytes are found. The structure of the lymph node is usually preserved, in some cases it can be somewhat erased due to pronounced mixed cellular infiltration.

In patients who have undergone splenectomy for chronic immune hematopathies, mixed lymphoid infiltration is detected, including cells of the double-negative population.

A specific method for diagnosing autoimmune lymphoproliferative syndrome is the study of apoptosis of peripheral mononuclear cells (PMN) of the patient in vitro, with induction by monoclonal antibodies to the Fas receptor. In ALPS, there is no increase in the number of apoptotic cells when PMN is incubated with anti-FasR antibodies.

Molecular diagnostic methods are aimed at identifying mutations in the Fas, caspase 8 and caspase 10 genes. In the case of normal results of PMN apoptosis and the presence of a phenotypic picture of ALPS, a study of the FasL gene is indicated.

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Differential diagnosis

Differential diagnosis of autoimmune lymphoproliferative syndrome is carried out with the following diseases:

• Infectious diseases (viral infections, tuberculosis, leishmaniasis, etc.)
• Malignant lymphomas.
• Hemophagocytic lymphohistiocytosis.
• Storage diseases (Gaucher disease).
• Sarcoidosis.
• Lymphadenopathy in systemic connective tissue invasions.
• Other immunodeficiency states (common variable immunodeficiency, Wiskott-Aldrich syndrome).

Treatment autoimmune lymphoproliferative syndrome.

In isolated lymphoproliferative syndrome, therapy is usually not required, except in cases of severe hyperplasia with mediastinal compression syndrome, development of lymphoid infiltrates in organs. In this case, immunosuppressive therapy is used (glucocorticoids, cyclosporine A, cyclophosphamide),

Treatment of autoimmune complications is carried out according to the general principles of therapy of the corresponding diseases - in case of hemopathies, (methyl)prednisolone is prescribed at a dose of 1-2 mg/kg, or in pulse therapy mode with subsequent transition to maintenance doses; in case of insufficient or unstable effect, a combination of corticosteroids with other immunosuppressants is used, for example: mycophenolate mofetil, cyclosporine A, azathioprine, monoclonal antibodies to anti-CD20 (rituximab). Therapy with high doses of intravenous immunoglobulin (IVIG), as a rule, gives an unsatisfactory or unstable effect. Due to the tendency to chronic or recurrent course, long-term therapy with maintenance doses is necessary, which are selected individually. In case of insufficient effect of drug therapy, the need for high doses of drugs, splenectomy may be effective.

In case of severe course or predicted progression of the disease, hematopoietic stem cell transplantation is indicated, however, experience with transplantation in autoimmune lymphoproliferative syndrome is limited worldwide.

Forecast

The prognosis depends on the severity of the disease, which is most often determined by the severity of autoimmune manifestations. In severe, therapy-resistant hemopathies, an unfavorable outcome is likely.

With age, the severity of lymphoproliferative syndrome may decrease, but this does not exclude the risk of manifestation of severe autoimmune complications. In any case, an adequate prognosis helps to develop an optimal therapeutic approach to each patient.

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