Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a disease that is based on birth defects of Fas-mediated apoptosis. It was described in 1995, but since the 1960s, a disease with a similar phenotype was known as the 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 the physiological death of a cell, is one of the integral mechanisms of maintaining the body's homeostasis. Apoptosis develops due to the activation of various signaling mechanisms. A special role in the regulation of the hematopoietic system and the immune system is played by apoptosis, mediated by the activation of Fas receptors (CD95) when they interact with the corresponding ligand (Fas ligand, FasL). Fas is represented on various hematopoietic cells, high expression of the Fas receptor is characteristic for activated lymphocytes. Fasl-is expressed mainly by CD8 + T-lymphocytes.

Activation of the Fas receptor entails a number of sequential intracellular processes, which result in disorganization of the cell nucleus, DNA denaturation, changes in the cell membrane, leading to its disintegration into a number of fragments without ejection into the extracellular environment of lysosomal enzymes and without inflammation induction. In the transfer of the apoptotic signal, a number of enzymes called caspases, including caspase 8 and caspase 10, participate in the nucleus.

Fas-mediated apoptosis plays an important role in eliminating cells with somatic mutations, autoream- mal lymphocytes, as well as lymphocytes that have fulfilled their role in the process of normal immune response. Violation of apoptosis of T-lymphocytes leads to the expansion of activated T-cells, and also the so-called double negative T-lymphocytes, which express the T-cell receptor with a / b chains (TCRa / b), but have neither CD4 nor CD8 molecules. The defect of programmed B cell death in conjunction with the increase in the level of interleukin 10 (IL-10) results in hypergammaglobulinemia and an increase in the 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, leading to apoptosis disorder and ALLS development. These are mutations in the genes Fas, FasL, Caspase 8 and Caspaea 10.

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Symptoms of the 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 the clinical manifestation may also fluctuate depending on the severity of the symptomatology. There are cases of 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), enlargement of the spleen, and often also of the liver. The size of the lymphoid organs can vary throughout life, sometimes their growth is noted in intercurrent infections. Lymph nodes have a usual consistency, sometimes dense; painless. There are cases of pronounced 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 the syndrome of compression and respiratory failure. Lymphoid infiltrates in the lungs are 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 severity of splenomegaly is also very variable.

The severity of the course of the disease is mainly determined by autoimmune manifestations, which can develop at any age. Most often there are various immune hemopathies - neutropenia, thrombocytopenia, hemolytic anemia, which can be combined in the form of two- and three-stage cytopenia. There may be a single episode of immune cytopenia, but often they are chronic or recurrent.

Of the other, more rare autoimmune manifestations, autoimmune hepatitis, arthritis, sialadenitis, inflammatory bowel disease, erythema nodosum, panniculitis, uveitis, Guiltain-Barre syndrome can be observed. In addition, there may be  various skin  rashes, mainly urticaria, subfebrile or fever without being associated with the infectious process.

In patients with autoimmune lymphoproliferative syndrome, the incidence of malignant tumors was increased in comparison with the population. The cases of hemoblastosis, lymphomas and solid tumors (carcinoma of the liver, stomach) are described.

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Forms

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

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

Inheritance type

ALPS 0 type  - complete deficiency of CD95 - described in only a few patients. Because heterozygous members of families do not have the ALPS phenotype, a hypothesis was proposed about the autosomal recessive type of inheritance. However, unpublished data on family monitoring in which a patient with ALPS 0 was identified does not fully agree with this statement. The scientists found that many, if not all, mutations are dominant, and that if they are homozygous, this leads to a more pronounced phenotype of the disease.

With  type I ALPS, the  type of inheritance is autosomal dominant, with incomplete penetrance and variable expressivity. In particular, with ALPS1a, cases of homozygosity or combined heterozygosity are described, in which various mutations of the Fas gene are determined in both alleles. These cases were characterized by severe course with prenatal or neonatal manifestation (fetal edema, hepatosplenomegaly, anemia, thrombocytopenia). In addition, a correlation was found between the severity of the clinical symptomatology and the type of mutation in the Fas gene; for a mutation in the intracellular domain, a more severe course is characteristic. In total, more than 70 patients with ALPS la are described in the world. 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 of the classic autoimmune lymphoproliferative syndrome (double negative T cells and splenomegaly were absent). The first homozygous A247E mutation in the FasL gene (extracellular domain) was recently described, in 2006, by Del-Rey M et al. In a patient with non-lethal ALPS, which indicates the important role of the terminal domain of FasL C0OH in the interaction of Fas / FasL. The authors propose to subgroup ALPS Ic to the current classification of autoimmune lymphoproliferative syndrome.

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

In more than 30 patients, the clinical picture of ALPS of moderate severity, including hypergammaglobulinemia and an elevated level of double negative T-cells in the blood, was detected, and activated lymphocytes of patients with ALPS III type (this was the name of this syndrome) showed normal activation of Fas- mediated pathway in vitro, and no molecular defects were found. Perhaps, the cause of the disease is disorders of other apoptotic pathways, mediated, for example, by Trail-R, DR3 or DR6. Of interest is the observation of R. Qementi on the detection of mutation N252S in the perforin gene (PRF1) in a patient with ALPS III type, in which there was a significant decrease in NK activity. The author notes that a significant difference between the frequency of detection of N252S in patients with ALPS (2 of 25) and the frequency of detection in the control group (1 of 330) suggests that it is associated with the development of ALPS in the Italian population. On the other hand, F. Rieux-Laucat notes that this variant of PRF1 mutation was detected by him in 18% of healthy and 10% of ALPS patients (unpublished data). And, besides 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, speaks of the non-pathogenicity of the heterozygous mutation N252S in the perforin gene described earlier in R. Qementi in a patient with ALPS (Fas mutation) and large-cell B-lymphoma. Thus, the question of the causes of the appearance of ALPS III type is still open today.

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Diagnostics of the autoimmune lymphoproliferative syndrome

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

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

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

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

There are isolated cases of autoimmune lymphoproliferative syndrome with hypoimmunoglobulinemia, a nature that has not been clarified. Immunodeficiency is more typical for patients with ALPS IIb, although it is also described with ALPS 1a type.

In patients, various autoantibodies can be detected: antibodies to blood cells, ANF, antibodies to native DNA, anti-RNP, anti-SM, anti-SSB, RF, antibodies to factor VIII coagulation.

Reported increased serum triglyceride levels in patients with autoimmune lymphoproliferative syndrome; The secondary nature of hypertriglyceridemia is expected due to increased production of cytokines affecting lipid metabolism, in particular, tumor necrosis factor (TNF). A significant increase in TNF levels is found in most patients with autoimmune lymphoproliferative syndrome. In some patients, the level of hypertriglyceridemia correlates with the course of the disease, increasing with exacerbations.

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

In patients who underwent splenectomy for chronic immune hemopathies, mixed lymphoid infiltration was detected, including by cells of a double negative population.

A specific method for diagnosing autoimmune lymphoproliferative syndrome is the study of apoptosis of peripheral mononuclear cells (PMN) in vitro, when induction with monoclonal antibodies to the Fas receptor. With 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. In cases of normal PMN apoptosis and the presence of a phenotypic pattern of ALPS, a study of the FasL gene

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Differential diagnosis

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

• Infectious diseases (viral infections, tuberculosis, leishmaniasis, etc.)
• Malignant lymphomas.
• Hemophagocytic lymphohistiocytosis.
• Diseases of accumulation (Gaucher disease).
• Sarcoidosis.
• Lymphadenopathy with systemic conquest of connective tissue.
• Other immunodeficiency states (general variable immune deficiency, Wiskott-Aldrich syndrome).

Treatment of the autoimmune lymphoproliferative syndrome

With isolated lymphoproliferative syndrome, therapy is usually not required, except in cases of severe hyperplasia with mediastinum compression syndrome, development of lymphoid infiltrates in organs. At the same time, immunosuppressive therapy is used (glucocorticoids, cyclosporin A, cyclophosphamide),

Treatment of autoimmune complications is carried out according to the general principles of therapy of the corresponding diseases - with hemopathies prescribe (methyl) prednisolone in a dose of 1-2 mg / kg, or in the pulse-therapy regime with the subsequent transition to maintenance doses; with an insufficient or unstable effect, a combination of corticosteroids with other immunosuppressors is used, for example: mycophenolate mofetil, cyclosporin 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. In connection with the propensity to a chronic or recurrent course, long-term therapy with maintenance doses is required, which are selected individually. With insufficient effect of drug therapy, the need for high doses of drugs, splenectomy may prove effective.

In the case of a severe course or a predictable progression of the disease, transplantation of hematopoietic stem cells is indicated, but the experience of transplantation in the autoimmune lymphoproliferative syndrome is limited worldwide.

Forecast

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

With age, the lymphoproliferative syndrome can 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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