Autoimmune lymphoproliferative syndrome is a group of genetically determined diseases that occur due to hereditary or somatic mutations in the genes responsible for various stages of FAS-induced apoptosis. Symptoms can be variable and most often include lymphadenopathy, splenomegaly and various autoimmune lesions of the blood system, liver, thyroid gland. Diagnosis of autoimmune lymphoproliferative syndrome is based on the results of general and biochemical blood tests, lymph node biopsy, genetic studies. There is currently no specific treatment for the disease, a combination of immunosuppressive and cytotoxic therapy is used.
Autoimmune lymphoproliferative syndrome (ALS, ALPS, Canale-Smith syndrome) is a group of immunodeficiency conditions characterized by autoimmune cytopenia, lymphadenopathy, splenomegaly. The first data on the disease began to arrive in 1968, after which a rapid study of pathology soon began. Initially, ALS was attributed to primary immunodeficiency, but over time, forms of the syndrome were discovered due to somatic mutations in the child and adolescent body.
Data on the occurrence of different researchers vary quite a lot, to date, more than 500 cases of various forms of autoimmune lymphoproliferative syndrome have been described. Hereditary forms of the disease are transmitted by autosomal dominant type, while spontaneous mutations also play a rather large role in the development of congenital forms. Both boys and girls are found among patients with the same frequency.
It was found that the cause of any type of ALS is a violation of FAS-mediated apoptosis of lymphocytes. During the formation of T-lymphocytes, those lines that are capable of attacking their own tissues are destroyed by activating CD-95 receptors (Fas receptors) on the surface of their membrane. Activation of CD-95, belonging to the group of tumor necrosis factor receptors, triggers a multi-stage reaction involving caspases, which ends in cell apoptosis.
In autoimmune lymphoproliferative syndrome, genetic mutations lead to a block of this process at a certain stage, which is why the elimination of potentially dangerous T-lymphocyte clones does not occur, and they begin to accumulate in the lymph nodes. In addition, conditions are created for autoimmune damage to organs and tissues.
Hereditary and spontaneous mutations are most common in the TNFRSF6 gene, which encodes the Fas receptor itself. In this case, a violation of the structure of the protein (especially the domain responsible for interacting with the FADD molecule) leads to the fact that it becomes unable to perform its receptor functions and activate apoptosis. Somatic mutations in the FAS gene are also possible, which fully manifest themselves in late childhood or adolescence, and therefore they are referred to a separate group of ALS.
The second most common variant of autoimmune lymphoproliferative syndrome is caused by a mutation in the CASP10 gene encoding cystine-asparagine acid protease (caspase-10). This protein plays a key role in transmitting the signal of apoptosis from the cell membrane to the cell nucleus. The same variant includes mutations of the CASP8 gene.
The third most common is autoimmune lymphoproliferative syndrome, which is caused by a mutation in the FASLG gene encoding the Fas ligand or CD-178 receptor. It plays an auxiliary role in the recognition of factors that stimulate apoptosis, and participates in the transmission of a signal to the cell.
Some forms of ALS are caused by a mutation of the NRAS gene, which encodes a “small G protein” that participates as a secondary messenger in the transmission of signals from the membrane to the cell, including the nucleus. In about a third of cases of autoimmune lymphoproliferative syndrome, immunologists are unable to determine the immediate cause of the disease.
Using the methods of modern genetics , it was possible to identify six main forms of ALS:
ALPS 1A is caused by a mutation of the TNFRSF6 gene located on the 10th chromosome, most often has an innate character, inherited by an autosomal dominant type. According to statistics, more than 40% of ALS belong to this particular variety.
ALPS 1B is caused by a mutation of the FASLG gene, which also quite often leads to congenital autoimmune lymphoproliferative syndrome. About 10% of all clinical cases of ALS belong to this type.
ALPS 1m – its cause is somatic mutations in the FAS gene that occur in childhood or adolescence and therefore lead to late forms of ALS. In this case, damage to the gene must occur in a polypotent progenitor cell, which is capable of giving rise to many lines of lymphocytes. In this form, sudden spontaneous remission of the disease most often occurs.
ALPS 2 is caused by a mutation in the CASP10 and, according to some data, CASP8 genes, which encode caspase proteins that transmit a signal about apoptosis from the receptor to the cell nucleus. This form of autoimmune lifoproliferative syndrome accounts for approximately 25% of all cases of the disease, can be both congenital and manifest at an older age.
ALPS 3 – mutation of which gene and the nature of its inheritance in this form are unknown. The peculiarity of this variant of ALS is the violation of not only FAS-, but also IL2-mediated apoptosis, as well as the more severe nature of the course.
ALPS 4 is caused by a mutation of the NRAS gene, which also encodes intracellular signal transmitter proteins. This type of autoimmune lymphoproliferative syndrome is characterized by a more benign course and moderate severity of symptoms.
ALS symptoms are quite variable due to the large number of mutations that can lead to such a condition. The onset of the disease can be noticed already on the 15th day after birth (with congenital forms), in childhood or adolescence in the case of somatic mutations in the FAS, CASP10 or NRAS genes. Usually, the first manifestation of the disease is lymphadenopathy – axillary, inguinal or cervical lymph nodes increase in size, but they are painless and not soldered to the surrounding tissues. Splenomegaly is registered, in some cases it is accompanied by an increase in the liver (hepatosplenomegaly).
Autoimmune manifestations of ALS are usually registered some time after lymphadenopathy and enlargement of the spleen. These are mainly lesions of blood sprouts – thrombocytopenia, hemolytic anemia leading to jaundice, occasionally neutropenia. In addition to blood, the gastrointestinal tract can be affected by autoimmune damage (gastritis, pancreatitis, colitis, autoimmune hepatitis occur). Signs of vasculitis may appear on the skin, making the clinic of autoimmune lymphoproliferative syndrome similar to that of systemic lupus erythematosus. In addition, autoimmune forms of thyroiditis, glomerulonephritis may occur, joints, eye tissues (iridocyclitis, uveitis) may be affected. Lesions of the central nervous system are not uncommon – epileptic seizures, myelitis, cerebellar ataxia.
The severity of symptoms and their number can vary significantly in each individual patient. In addition, with autoimmune lymphoproliferative syndrome, the risk of developing malignant tumors increases tenfold, since tumor clones of lymphocytes are also eliminated through apoptosis.
In about 20% of cases ALS leads to non-Hodgkin’s lymphomas (Burkitt’s lymphoma, follicular lymphoma), and other oncological diseases have been described. Because of this, ALS manifestations may be mistakenly identified as a consequence of tumor infiltration of lymphoid tissue. Among other complications of autoimmune lymphoproliferative syndrome, traumatic rupture of the spleen, sepsis and other infectious lesions are most common.
ALS is diagnosed on the basis of examination, as well as laboratory, immunological and genetic studies. On examination, an increase in more than three groups of lymph nodes, splenomegaly, and liver enlargement are detected. A blood test may show a decrease in the number of certain cells (anemia, thrombocytopenia), some patients have high (up to 30%) eosinophilia. The Coombs test is positive, pronounced hypergammaglobulinemia is determined in the biochemical blood test.
One of the highly sensitive methods of immunological diagnosis of autoimmune lymphoproliferative syndrome is flow immunocytofluorometry, performed to detect the number of lymphocytes with an atypical set of receptors (CD3+CD4-CD8-). In ALS, the number of such cells exceeds 1% of all lymphocytes. In a biopsy of lymph nodes, follicular hyperplasia is determined, the result of a histological examination of the spleen is lymphoid hyperplasia.
A geneticist can sequence the FAS gene in order to identify mutations that have caused autoimmune lymphoproliferative syndrome. Taking into account the significant size of this gene, in order to speed up and reduce the cost of the procedure, the search can be performed only in individual exons of the FAS gene, in which violations are most often detected – these areas are called “hot spots”. Thus, with the help of genetic diagnostics, it is possible to determine ALS of only 1A, 1B and 1m types. Methods for determining the remaining forms of ALS by genetic methods have not been developed to date. The study of hereditary anamnesis in some cases will be ineffective due to a significant proportion of forms of the disease caused by somatic mutations.
Etiotropic treatment of autoimmune lymphoproliferative syndrome has not been developed, pathogenetic therapy is reduced to the use of immunosuppressive and cytotoxic agents. Corticosteroids (prednisone, dexamethasone) are most often used as means that suppress autoimmune activity. Specific drugs that limit the rate of lymphocyte proliferation include mycophenolate mofetil, sirolimus. Also, in autoimmune lymphoproliferative syndrome, traditional cytotoxic agents are actively used – methotrexate, cyclosporine A and others.
With a significant increase in the spleen or no effect from conservative treatment, splenectomy is resorted to. Bone marrow transplantation and the use of stem cells in the long term gave only a temporary effect. With significantly pronounced hematological disorders, hemotransfusion, the introduction of erythrocyte or platelet mass is used. The patient should avoid physical exertion, use a high-vitamin diet.
The prognosis of the disease, due to the high variability and severity of symptoms, is uncertain or unfavorable. In most patients, the manifestations of the disease gradually increase, eventually leading to lethal anemia, thrombocytopenia, biliary cirrhosis of the liver. Immune disorders also play an important role in the prognosis, since sepsis and other infectious lesions are often the cause of death. The prognosis of autoimmune lymphoproliferative syndrome should also take into account the increased risk of cancer, about a fifth of patients die from various types of lymphomas. In some cases, spontaneous and prolonged remission of pathology occurs.