Autoimmune lymphoproliferative

The clinical spectrum in a large kindred with autoimmune lymphoprolif-erative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis. J Pediatr 1998 133 629-633. 

Shenoy S, Arnold S, Chatila T Response to steroid therapy in autoimmune lymphoproliferative syndrome secondary to ALPS. J Pediatr 2000 3 101-109. 

ALPS = autoimmune lymphoproliferative syndrome CSS = Canale-Smith syndrome. 

Straus, S. E., and Lenardo, M. J., 1999, Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98 47-58. 

Abnormalities in cell death regulation can be a significant component of diseases such as cancer, autoimmune lymphoproliferative syndrome, AIDS, ischemia, and neurodegenerative diseases such as Parkinson s disease, Alzheimer s disease, Huntington s disease, and amyotrophic lateral sclerosis. Some conditions feature insufficient apoptosis, whereas others feature excessive apoptosis. 

In addition to cancer, too little apoptosis can also result in diseases such as autoimmune lymphoproliferative syndrome (ALPS). This occurs when there is insufficient apoptosis of auto-aggressive T cells, resulting in multiple autoimmune diseases. An overproliferation of B cells occurs as well, resulting in excess immunoglobulin production, leading to autoimmunity. Some of the common diseases of ALPS include hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. The different types of this condition are caused by different mutations. Type 1A results from a mutation in the death domain of the Fas receptor, Type IB results from a mutation in Fas ligand, and Type 2 results from a mutation in caspase 10, reducing its activity. 

Probably mutations hitting the FAS signalling pathway downstream from FAS ALPS-III, Dianzani autoimmune lymphoproliferative disease (DALD)... 

Although in most cases the described syndromes are inherited, it cannot be excluded that environmental as well as additional genetic factors may interact, which may explain the wide spectrum of disease signs and symptoms, the possibility of manifestations in adulthood, and the healthy state of parents carrying mutations (Rieux-Laucat et al., 1999 Deutsch et al., 2004). In this sense, these syndromes are not truly monogenic. The development of autoimmune lymphoproliferative syndromes seems to require accumulations of several genetic defects involved in apoptosis (Ramenghi et al., 2000). 

Compared with the autoimmune polyglandular and autoimmune lymphoproliferative syndromes described above, all other known autoimmune diseases and syndromes may not be inherited nonetheless, genes are responsible for differences in the susceptibility for disease development. Multiple genes, acting in concert with various environmental factors, seem to be involved in the autoimmune pathogenesis of most autoimmune diseases (see chapter 9). 

Autoimmune lymphoproliferative syndrome (ALPS). Also known as Canale-Smith syndrome. Characterized by lymphadenop-athy, hepatosplenomegaly, autoimmune cytopenias, and hyper-gammaglobulinaemia. Associated with defects in the Fas-FasL apoptosis signalling pathway due to mutations in the Fas gene, the FasL gene, or other genes coding for factors of this pathway. 

Deutsch M, Tsopanou E, Dourakis SP (2004) The autoimmune lymphoproliferative syndrome (Canale-Smith) in adulthood. Clin Rheumatol, 23 43-44. 

Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Leonardo MJ, Puck JM (1995) Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell, 81 935-946. 

Pensati L, Costanzo A, lanni A, Accapezzato D, lorio R, Natoli G, Nisini R, Almerighi C, Balsano C, Vajro P, Vegnente A, Levrero M (1997) Fas/Apol mutations and autoimmune lymphoproliferative syndrome in a patient with type 2 autoimmune hepatitis. Gastroenterology 113 1384-1389... 

A fuller understanding of the Fas-FasL interaction is necessary to comprehend better the signaling pathway involved in death receptor-induced apoptosis. Inappropriate expression of Fas and FasL on lymphocytes and other immune cells has previously been documented in patients with HIV infection it has also been implicated in the loss of lymphocytes that characterizes this immunodeficiency syndrome [32]. Conversely, hereditary mutations in the death domain of the Fas gene are known to cause an autoimmune lymphoproliferative syndrome in humans [33]. 

AITD, autoimmune thyroid disease ALPS, autoimmune lymphoproliferative syndrome AS, ankylosing spondylitis CD, celiac disease HSP, Henoch-Schonlein purpura MG, myasthenia gravis RA, rheumatoid arthritis TID, type 1 diabetes. 

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