Autoimmune limfoproliferativny syndrome
Autoimmune limfoproliferativny syndrome – group of genetically caused diseases which arise because of hereditary or somatic mutations in the genes which are responsible for various stages of the FAS caused apoptosis. The symptomatology can be variable and most often includes a limfadenopatiya, a splenomegaliya and various autoimmune defeats of system of blood, a liver, thyroid gland. Diagnostics of an autoimmune limfoproliferativny syndrome is made on the basis of results of the general and biochemical blood tests, a biopsy of lymph nodes, genetic researches. There is no specific treatment of a disease at the moment, apply combinations of immunnosupressivny and cytotoxic therapy.
Autoimmune limfoproliferativny syndrome
Autoimmune limfoproliferativny syndrome (ALS, ALPS, a syndrome to Canala-Smith) – group of the immunodeficiency which are characterized by autoimmune cytosinging, a limfadenopatiya, splenomegaliy. The first data on a disease began to arrive in the 1968th year then rough studying of pathology soon began. Initially ALS was carried to primary immunodeficiencies, however the syndrome forms caused by somatic mutations in a children's and teenage organism were found over time. Data on occurrence at different researchers quite strongly differ, more than 500 cases of various forms of an autoimmune limfoproliferativny syndrome are described for today. Hereditary forms of a disease are transferred on autosomno-prepotent type, at the same time in development of congenital forms the role of spontaneous mutations is also quite big. With an identical frequency occur among patients both boys, and girls.
Reasons of an autoimmune limfoproliferativny syndrome
It is found out that violation of the FAS mediated apoptosis of lymphocytes is the reason of any ALS type. At formation of T-lymphocytes those lines which are capable to attack own fabrics are destroyed due to activization of receptors of CD-95 (Fas-receptors) on a surface of their membrane. Activation of CD-95 relating to group of receptors of a factor of a necrosis of tumors starts multistage reaction with participation which terminates in cage apoptosis. At an autoimmune limfoproliferativny syndrome genetic mutations lead to the block of this process at a certain stage because of what elimination of potentially dangerous clones of T-lymphocytes does not happen, and they begin to collect in lymph nodes. Besides, conditions for autoimmune defeat of bodies and fabrics are created.
Most often hereditary and spontaneous mutations in a gene of TNFRSF6 which codes actually a Fas-receptor meet. At the same time violation of structure of protein (especially the domain which is responsible for interaction with a FADD molecule) leads to the fact that it becomes incapable to perform the receptor functions and to make active apoptosis. Also somatic mutations in a gene of FAS which fully prove in the late children's or teenage period and therefore they are carried to the ALS separate group are possible. The option of an autoimmune limfoproliferativny syndrome, the second for prevalence, is caused by a mutation in CASP10 gene coding cystine-asparagin acid protease (kaspaza-10). This protein plays a key role in signal transmission about apoptosis from a cellular membrane in a cage kernel. Carry to the same option also CASP8 gene mutations.
The third on prevalence is the autoimmune limfoproliferativny syndrome which is caused by a mutation in FASLG gene coding a Fas-ligand or a receptor of CD-178. He plays a supporting role in recognition of the factors stimulating apoptosis and participates in signal transmission in a cage. The ALS some forms are caused by a mutation of a gene of NRAS which codes the "small G-protein" which is taking part as a secondary messenger in signaling from a membrane in a cage including a kernel. Approximately in a third of cases of an autoimmune limfoproliferativny syndrome immunologists do not manage to establish an immediate cause of a disease.
Classification of an autoimmune limfoproliferativny syndrome
By means of methods of modern genetics it was succeeded to reveal six ALS main forms:
ALPS 1A – is caused by a mutation of a gene of TNFRSF6 located on the 10th chromosome, most often has congenital character, is inherited on autosomno-prepotent type. Statistically, more than 40% of ALS belong to this version.
ALPS 1B – is caused by FASLG gene mutation, also quite often leads to a congenital autoimmune limfoproliferativny syndrome. Carry about 10% of all clinical cases of ALS to this type.
ALPS 1m – are its reason the somatic mutations in FAS gene arising at children's or teenage age and therefore leading to the ALS late forms. At the same time damage of a gene has to happen in a polipotentny cage predecessor which is capable to give rise to many lines of lymphocytes. At this form most often there is a sudden spontaneous remission of a disease.
ALPS 2 – is caused by a mutation in genes of CASP10 and, according to some information, CASP8 which code the proteins-kaspazy transmitting a signal of apoptosis from a receptor to a cage kernel. This form of an autoimmune lifoproliferativny syndrome makes about 25% of all cases, can be as congenital, and to be shown at more advanced age.
ALPS 3 – what mutation of a gene and the nature of its inheritance at this form are unknown. Feature of such option of ALS is violation not only FAS-, but also the IL2 mediated apoptosis, and also more difficult character of a current.
ALPS 4 – is caused by a mutation of a gene of NRAS which is also coding proteins transmitters of an intracellular signal. This type of an autoimmune limfoproliferativny syndrome is characterized by more good-quality current and moderate expressiveness of symptoms.
Symptoms of an autoimmune limfoproliferativny syndrome
Symptoms of ALS are quite variable because of a large number of mutations which can lead to such state. The beginning of a disease can be noticed for the 15th day after the birth (at congenital forms), at children's or teenage age in case of somatic mutations in genes of FAS, CASP10 or NRAS. Usually the first display of a disease is the limfadenopatiya – axillary, inguinal or cervical lymph nodes increase in sizes, but at the same time are painless and are not soldered to surrounding fabrics. The splenomegaliya is registered, in certain cases it is followed by increase in a liver (gepatosplenomegaliya).
Autoimmune manifestations of ALS are registered usually after a while after a limfadenopatiya and increase in a spleen. Generally it defeats of blood sprouts – thrombocytopenia, the hemolytic anemia leading to jaundice, occasionally neytropeniye. Besides blood, bodies of a GIT can be exposed to autoimmune defeat (there are gastritis, pancreatitis, colitis, autoimmune hepatitis). On skin signs of a vaskulit can be shown, doing clinic of an autoimmune limfoproliferativny syndrome similar to that at system red a wolf cub. Besides, there can be autoimmune forms of a tireoidit, a glomerulonefrit, to be surprised joints, eye tissues (iridotsiklit, uveit). Damages of the central nervous system – epileptic seizures, miyelita, a cerebellar ataxy are frequent.
Expressiveness of symptoms and their quantity can vary considerably at each specific patient. Besides, at an autoimmune limfoproliferativny syndrome in tens of times the risk of development of malignant tumors as tumoral clones of lymphocytes are also eliminated by means of apoptosis increases. Approximately in 20% of cases of ALS leads to nekhodzhkinsky lymphoma (Berkitt's lymphoma, a follicular lymphoma), also other oncological diseases are described. Because of this manifestation of ALS can be mistakenly defined as a result of tumoral infiltration of lymphoid fabric. The traumatic rupture of a spleen, sepsis and other infectious defeats most often occurs among other complications of an autoimmune limfoproliferativny syndrome.
Diagnostics of an autoimmune limfoproliferativny syndrome
Diagnostics of ALS is made on the basis of survey, and also laboratory, immunological and genetic researches. At survey reveal increase more than three groups of lymph nodes, a splenomegaliya, increase in a liver. Blood test can show reduction of quantity of some cages (anemia, thrombocytopenia), at a part of patients the eozinofiliya is defined high (to 30%). Koombs's test positive, in biochemical blood test is defined the expressed gipergammaglobulinemiya. One of highly sensitive methods of immunological diagnostics of an autoimmune limfoproliferativny syndrome is the flowing immunotsitoflyuorimetriya which is carried out for the purpose of identification of quantity of lymphocytes with an atypical set of receptors (CD3+CD4-CD8-). At ALS the quantity of such cages exceeds 1% of all lymphocytes. In a bioptata of lymph nodes the follicular giperplaziya is defined, as result of a histologic research of a spleen serves the lymphoid giperplaziya.
By the doctor geneticist FAS gene sekvenirovaniye for the purpose of identification of the mutations which became the reason of an autoimmune limfoproliferativny syndrome can be made. Taking into account the considerable size of this gene for acceleration and reduction in cost of the procedure search can be run only in separate ekzona of a gene of FAS in which violations most often are found – these sites are called "hot spots". Thus, by means of genetic diagnostics it is possible to define ALS only 1A, 1B and 1m types. Techniques of definition of the ALS other forms are not developed by genetic methods today. Studying of the hereditary anamnesis in some cases will be inefficient because of a considerable share of the forms of a disease caused by somatic mutations.
Treatment and forecast of an autoimmune limfoproliferativny syndrome
Etiotropny treatment of an autoimmune limfoproliferativny syndrome is not developed, pathogenetic therapy comes down to application of immunosupressivny and cytotoxic means. As the means suppressing autoimmune activity most often use corticosteroids (Prednisolonum, dexamethasone). Carry a mikofenolat to the specific medicines limiting the speed of proliferation of lymphocytes mofetit, . Also at an autoimmune limfoproliferativny syndrome traditional cytotoxic means – a methotrexate, And yes others are actively applied. At significant increase in a spleen or lack of effect of conservative treatment resort to a splenektomiya. Bone marrow transplantation and use of stem cells in the long term gave only temporary effect. At much the expressed hematologic violations apply hemotransfusions, introduction of eritrotsitarny or trombotsitarny weight. The patient should avoid physical activities, to use a high-vitamin diet.
The forecast of a disease, in view of high variability and expressiveness of symptoms, uncertain or adverse. At the most part of patients of display of a disease gradually accrue, over time leading to lethal anemia, thrombocytopenia, biliarny cirrhosis. Also important role in the forecast is played by immunity violations as quite often sepsis and other infectious defeats act as a cause of death. In the forecast of an autoimmune limfoproliferativny syndrome it is necessary to consider and the increased risk of oncological diseases, approximately the fifth part of patients dies of various types of lymphoma. In certain cases there is a spontaneous and long remission of pathology.