Autoimmune lymphoproliferative disease

Author: Fabio Pescarmona
Date: 11/11/2013


autoimmune lymphoproliferative disease

fabio pescarmona
liloia silvia


The autoimmune lymphoproliferative disease is a genetic disease in which a defect in the activation of apoptosis leads to the failure of deletion clones of T lymphocytes , which derive from a lymphocyte proliferation with excessive accumulation in secondary lymphoid organs and the appearance of autoimmune manifestations , especially hematologic .

Programmed cell death (apoptosis)

Programmed cell death ( PCD ) is a natural phenomenon through which the tissues eliminate senescent cells . The term defines the apoptotic morphological changes (reduction of cell volume , condensation and fragmentation of the nucleus and chromatin ) that are associated with programmed cell death, apoptosis , but today the term is commonly used as a synonym for PCD . Death by cell apoptosis prevents the release of substances into the surrounding tissue with pro-inflammatory and toxic action . The PCD has a key role in immune function . The maturation of B and T lymphocytes in the bone marrow and thymus , the control of the activation and deactivation of the immune response and the development of effector activity , such as activity citototossica , are regulated through the PCD . Are thus eliminated autologous T lymphocytes that recognize peptides and that are harmful because autoreactive and potentially able to determine autoimmune diseases.
Apoptosis is triggered by the interaction of specific receptors on the cell membrane ( death receptors ), with their soluble ligands . These receptors belong to the family of TNF -R ( tumor necrosis factor receptor) / R - NGF ( nerve growth factor receptor) and are characterized by a rich part of cysteine ​​residues in the extracellular region and a functional domain called death domain in the intracytoplasmic region . In lymphocytes, the apoptotic pathway is more efficient and better characterized the Fas / FasL . The activation of the death receptor Fas ( CD95 , TNFRSF6 or Apo 1 ) triggers the formation of a protein complex called the DISC ( death inducing signaling complex) which allows the interaction between the FADD ( Fas Associated Death Domain) and procaspase 8:10 , leading to their activation . The activation of caspases ( cysteine ​​protease ) 8, 10, also called caspase activators , induces the activation cascade of other caspases such as 3 and 7 , resulting in the activation of a proteolytic complex which has as final effect apoptosis of the cell

The lack of apoptosis and autoimmune disease

The association between genetic defects of Fas and the development of autoimmune diseases has initially been identified in the mouse. It has been shown by Nagata that mutations in the gene coding for Fas lpr were present in mice , a strain of mice that presented a clinical picture similar to lupus ( hypergammaglobulinemia , lymphadenopathy and nephritis ) . In the peripheral blood of mice lpr were characteristically present numerous T lymphocytes that do not express either the CD4 antigen or the CD8 antigen ( defined for this double negative ) . The corresponding human disease was described in 1995 in parallel by Fisher and Rieux- Laucat , which demonstrated the presence of mutations in the gene coding for Fas in children with autoimmune manifestations associated with adenopathy . Even in this case was presents an associated adenopathy . Also in this case this was an increase of T lymphocytes circulating double negative . This disease was designated by the acronym ALPS ( autoimmune lymphoproliferative syndrome) . The mutations of Fas identified in subjects with ALPS are numerous and different type of rule are found in the heterozygous and for most affect their ability to transmit the signal of PCD with dominant - negative mechanism (the molecule mutated Fas interferes with the function of the receptor Fas non-mutated ) . There are also of Fas mutations that reduce the expression of membrane receptor , causing the disease to haploinsufficiency . Although the disease is genetically transmitted in an autosomal dominant mechanism , the parent carries the mutation often have no symptoms . It is believed , therefore , that the only mutation in the Fas gene is not always sufficient to produce the syndrome , in particular , while mutations in the death domain , the most serious , are per se always associated with the manifestation of pathology, other mutations milder ( es.quelle of the extracellular portion ) seem to determine the phenotype only in the presence of other factors. Experimental evidence suggests that some patients may ALPS inherit two genetic alterations distinct from the two healthy parents : one in charge of Fas , the other in a gene involved in signal transduction downstream of Fas or other apoptotic pathways . Not all patients with ALPS have mutations in the gene coding for Fas , therefore, the syndrome is genetically heterogeneous . In 1999, two families have been described with ALPS associated with mutations in another gene pathway of apoptosis of Fas , Caspase 10. The homozygous mutation of Caspase 8 has been described in a family with clinical partly overlap via the Alps ( lymphoproliferation , immune deficiency, absence of autoimmune manifestations ) . Numerous patients with ALPS phenotype not have mutations in either Fas or in Caspasi.Tra patients whose molecular defect is not known, we identified a subgroup characterized by framework autoimmune / lymphoproliferative and reduced functionality of the Fas , but with normal levels of T lymphocytes double negative circulating . We have shown how this disease ALD ( autoimmune lymphoproliferative disease) , Mk Cusik proposed to call it D- ALD ( Dianzani - ALD) to avoid confusion with the more frequent adrenoleukodystrophy . In families ALD both parents of patients manifest a reduced function of the Fas , suggesting that even in this case at least two mutations should be concentrated in the same individual to manifest the disease. The current classification of ALPS syndrome , identified as:
ALPS - 1 - forms in which it is documented unamutazione in the Fas gene ;
ALPS - 2 forms with mutations in caspase 10;
ALPS - 3 - autoimmune lymphoproliferative syndromes with functional defect of the system without Fas mutations identified , including the subgroup D- ALD .
By some authors ALPS1 the group is further divided into ALPS -1a mutations in Fas , ALPS - 1b, mutations in FasL ( only 1 case in the literature ) and ALPS -0 the rare interesting shapes both alleles or mutations in the gene incompatible with protein synthesis ; ALPS2 the group is also divided into ALPS -2a by mutation of Caspase 10 and ALPS 2b by mutation of Caspase 8 .

Diagnostic criteria

The ' ALPS is diagnosed based on the simultaneous presence of the following 4 criteria:
1 . presence of chronic non-neoplastic lymphoproliferation ( hepato- splenomegaly and/or lymphadenopathy )
2 . presence of autoimmune manifestations and / or laboratory markers of autoimmunity ;
3 . Fas mediated apoptosis deficiency lymphocyte ( T cell survival relative ≥ 82 in two independent tests )

4.espansione of T lymphocytes double negative (CD4 - CD8- > 1
of circulating lymphocytes TCRαβ ) . The sequence analysis of the genes Fas and Caspase 10 allows the classification of patients in ALPS1 , 2 and 3, if they are present lymphoproliferation , autoimmunity and functional defect of route of Fas in the absence of mutation of the Fas / caspase and in the absence of an increase in double negative , is diagnosed ALPS - 3 (or D- ALD) .

Table 1 shows the main events

ALPS tipo 1ALPS tipo 3
Anemia emolitica autoimmune 40 %Piastrinopenia 63 %
Piastrinopenia 34 %Neutropenia 33 %
Neutropenia 18 %Anemia emolitica autoimmune 33 %
Rash cutaneo, vasculiti 14 %Febbre ricorrente 18 %
Glomerulonefrite 7 %Artrite 11%
Guillain Barrè 6 %Epatite autoimmune 7 %
Artrite 4 %Rash cutaneo, vasculiti 4 %
Epatite autoimmune 2 %Tiroidite
Vitiligo 2%Diabete

Clinical and laboratory

The clinical picture of the syndrome has been described for the first time by Smith and Channel . The disease begins in childhood , often the first symptoms appear in pre-school age , but the full clinical picture may be evident at a later time . L ' excessive lymphocyte survival is the basis of the invasion of secondary lymphoid organs characteristic of these patients, which is manifested by a framework of hepatosplenomegaly and / or lymphadenopathy, persistent , engaging more frequently stations lateral cervical and inguinal . Sometimes the massive lymphadenopathy necessary excision , histological examination demonstrated in these cases reactive follicular hyperplasia , sometimes with expansion parafollicular cells double - negative . As for the autoimmune manifestations , it is mostly of cytopenias ( hemolytic anemia and / or thrombocytopenia and / or neutropenia) , frequent skin rash, sometimes vasculitis , glomerulonephritis , autoimmune hepatitis type 2 . There may be recurrent febrile episodes , which do not regress if not with steroid therapy. Many patients have stretched PTT for the presence of anti-cardiolipin antibodies and antiphospholipid antibodies .
Table 1 shows the main autoimmune manifestations and the frequency with which they were observed nell'ALPS 1 and nell'ALPS -3 . There is no clear genotype-phenotype correlation , but the mutations related to intra cytoplasmic portion , which modify the death domain , are associated with particularly severe clinical manifestations and are transmitted with dominant mechanism . The majority of patients present with alterations in the levels of immunoglobulins. It is mostly increases in IgG and / or IgA , sometimes associated with low levels of IgM . We observed that patients over time develop immunoglobulin deficiency so severe as to require replacement therapy . The picture of these patients is similar to that of patients with common variable immunodeficiency ( CVID ) . Over one quarter of patients with CVID has autoimmune manifestations and many have lymphadenopathy . As the ALPS III , CVID is very heterogeneous clinical manifestations and multiple genes are involved in its pathogenesis . In families with CVID , as well as in those with ALPS there is an increase in the incidence of autoimmune diseases and neoplasms . Has been found a Fas -mediated apoptosis resistance in 2 /3 of patients CVID examined. It is likely there is an overlap between some forms of CVID and ALPS 3 , that only the identification of the genes responsible will clarify .

Therapy and prognosis

The autoimmune manifestations respond mostly well to steroid therapy , whereas thrombocytopenia appear to be less responsive to treatment with IGIV . In the treatment of autoimmune manifestations have been employed with success also other immunosuppressive agents such as mycophenolate , rituximab , and a certain number of patients has been subjected to splenectomy. In some cases , given the severity of the clinical picture , has been made ​​a successful bone marrow transplantation from unrelated donor family . The evolution of the disease is varied : generally observed a clinical improvement with age , especially dell'adenomegalia and splenomegaly , but the prognosis is strongly influenced by the risk of developing cancer.

Neoplasia and ALPS

The ALPS patients have a higher susceptibility to develop malignancies, mostly in the hematopoietic system : about 10% of patients developed lymphoma , but are described in various types of tumors. A higher incidence of tumors than the normal population has been demonstrated also in the families of patients. It is likely that the cause resides in the deficit of induction of PCD by cytotoxic T lymphocytes . We believe that alterations of the Fas pathway may be one of the genetic factors that favor the development of autoimmune diseases different from ALPS . In families of patients ALPS3 we observed a high frequency of autoimmune diseases , we have also observed the absence of Fas -mediated apoptosis in pediatric patients with polyendocrinopathies ( insulin-dependent diabetes thyroiditis + + rheumatoid arthritis and / or celiac disease ) .

In conclusion, the ALPS may be suspected if we consider the association between autoimmune manifestations and linfomegalia or splenomegaly , especially if the subject there are high levels of immunoglobulins. In these patients should seek the possible expansion of double- negative T cells ( αβ + , CD4- , CD8- ) and evaluate the activation of Fas -induced apoptosis by specific test cell survival . Later molecular studies will be conducted . The correct diagnosis allows to better managing the disease , not only from a pathogenetic point of view , but also prognostic and therapeutic .

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