Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoimmune manifestations have long been perceived as paradoxical in patients with primary immune deficiencies (PID). However, a defect in the mechanisms of control of self-reactive B and T cells may favour these manifestations. Three PID are defined by the occurrence of autoimmune manifestations: APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy), autoimmune lymphoproliferative syndrome (ALPS) and IPEX syndrome (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). In these conditions, organ specific autoimmune diseases such as type 1 diabetes mellitus or Hashimoto's thyroiditis are prominently encountered. Several other PID such as common variable immunodeficiency (CVID), Good syndrome and hyper-IgM syndrome are associated with a wide variety of autoimmune manifestations, mainly autoimmune cytopenias. Thus, autoimmune manifestations have been reported in 22% of patients with CVID, increasing to 50% in the subgroup of patients with systemic granulomatosis. Complement deficiencies involving components of the classical pathway are associated with systemic lupus erythematosus (SLE). Homozygous C2 deficiency, which is the most frequent hereditary deficiency in complement classical pathway components, is associated with SLE in 10% of the cases. Complete C1q and C4 deficiencies are less frequent but associated with a higher prevalence of SLE.
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PMID:Autoimmune manifestations in primary immune deficiencies. 1902 7

We report a case series of four infants with severe autoimmune haemolytic anaemia (AIHA) who responded to treatment with rituximab and cyclosporine after having failed first line therapy with high-dose steroid (prednisolone 4-8 mg/kg/d). Rituximab was started at 11-90 d from onset due to continued haemolysis; three infants also received cyclosporine A. Three of four infants reached complete response, defined as normal haemoglobin, reticulocytes and negative indices of haemolysis, at 7-21 months from diagnosis. In long-term follow-up two infants remained disease-free with normal immunology, one had undefined immunodeficiency and one had autoimmune lymphoproliferative syndrome.
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PMID:Rituximab-based immunosuppression for autoimmune haemolytic anaemia in infants. 1920 98

Autoimmune manifestations are increasingly being recognized as a component of several forms of primary immunodeficiencies (PID). Defects in purging of self-reactive T and B cells, impaired Fas-mediated apoptosis, abnormalities in development and/or function of regulatory T cells, and persistence of immune activation as a result of inability to clear infections have been shown to account for this association. Among autoimmune manifestations in patients with PID, cytopenias are particularly common. Up to 80% of patients with autoimmune lymphoproliferative syndrome (ALPS) have autoantibodies, and autoimmune hemolytic anemia and immune thrombocytopenia have been reported in 23% and 51% of ALPS patients, and may even mark the onset of the disease. ALPS-associated cytopenias are often refractory to conventional treatment and represent a therapeutic challenge. Autoimmune manifestations occur in 22% to 48% of patients with common variable immunodeficiencies (CVIDs), and are more frequent among CVID patients with splenomegaly and granulomatous disease. Finally, autoimmune cytopenias have been reported also in patients with combined immunodeficiency. In particular, autoimmune hemolytic anemia is very common among infants with nucleoside phosphorylase deficiency. While immune suppression may be beneficial in these cases, full resolution of the autoimmune manifestations ultimately depends on immune reconstitution, which is typically provided by hematopoietic cell transplantation.
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PMID:Primary immunodeficiencies (PIDs) presenting with cytopenias. 2000 92

The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise multidomain proteins with diverse roles in cell activation, proliferation and cell death. These proteins play pivotal roles in the initiation, maintenance and termination of immune responses and have vital roles outside the immune system. The discovery and analysis of diseases associated with mutations in these families has revealed crucial mechanistic details of their normal functions. This review focuses on mutations causing four different diseases, which represent distinct pathological mechanisms that can exist within these superfamilies: autoimmune lymphoproliferative syndrome (ALPS; FAS mutations), common variable immunodeficiency (CVID; TACI mutations), tumor necrosis factor receptor associated periodic syndrome (TRAPS; TNFR1 mutations) and hypohidrotic ectodermal dysplasia (HED; EDA1/EDAR mutations). In particular, we highlight how mutations have revealed information about normal receptor-ligand function and how such studies might direct new therapeutic approaches.
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PMID:Disease causing mutations in the TNF and TNFR superfamilies: Focus on molecular mechanisms driving disease. 2172 65

Childhood immune thrombocytopenia (ITP) is generally a benign self-limiting disorder of young children with <10% of cases requiring regular platelet enhancing therapy at 1 year following diagnosis. Increasingly, children with newly diagnosed ITP, who have isolated thrombocytopenia and no atypical features in the history or physical examination, are managed with minimal investigation and observation alone. The role of up-front, short-course corticosteroid therapy without bone marrow aspiration in this subgroup of cases merits further investigation. For children with clinically significant chronic ITP, the timing of elective splenectomy and the role of splenectomy-sparing strategies such as rituximab continues to be debated. Management of children with combined autoimmune cytopenias secondary to systemic lupus erythematosus, common variable immunodeficiency, and the autoimmune lymphoproliferative syndrome is often a challenge. Splenectomy should be avoided in cases with documented immunodeficiencies because of the increased risk of overwhelming sepsis postsplenectomy. For these cases, as well as for children with resistant primary chronic ITP who have failed splenectomy, the role of therapies such as mycophenolate mofetil, sirolimus, and the thrombopoietins remains to be determined.
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PMID:Childhood immune thrombocytopenia: a changing therapeutic landscape. 2218 97

Although primary immunodeficiencies (PID) are typically marked by increased susceptibility to infections, autoimmune manifestations have increasingly been recognized as an important component of several forms of PID. Here, we discuss two forms of PID in which autoimmune cytopenias are particularly common and may be the first manifestation of the disease in adults: autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency (CVID). Approximately one fifth of patients with CVID develop autoimmune diseases, and immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AHA) are the most common. Since autoimmune cytopenias frequently precede the diagnosis of CVID, testing for immunoglobulin levels should be performed in patients diagnosed with AITP and AHA. Patients with CVID in association with autoimmune cytopenias have a "particular phenotype" with lower susceptibility to infection and higher susceptibility to autoimmune manifestations and, for patients with AHA, a more frequent development of splenomegaly and lymphoma. Corticosteroids and high doses of intravenous immunoglobulins (IVIg) seem to have the same efficacy as in idiopathic AITP and AHA. Splenectomy and rituximab are as effective as in idiopathic autoimmune cytopenias but are associated with an increased risk of severe infection and should, in our opinion, be considered only for those rare patients with "refractory diseases". The course and outcome of autoimmune cytopenias is not affected by supportive IVIg therapy. Autoimmune destruction of blood cells affects over 70% of ALPS patients. The median age of first presentation is 24 months of age, but with increasing awareness of this condition, adults with autoimmune cytopenias are now being diagnosed more frequently. Testing for ALPS should therefore be considered in young adults with unexplained Evan's syndrome. Patients usually respond to immunosuppressive medications, including corticosteroids. Unlike many patients with idiopathic autoimmune cytopenias, the cytopenias in patients with ALPS typically do not respond to IVIg. After corticosteroids, the immunosuppressive drug that is the most studied in ALPS patients is mycophenolate mofetyl. Rituximab and splenectomy are relatively contraindicated in ALPS because of an increase risk of severe infection and should be reserved for patients who fail all other therapies.
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PMID:[Primary immunodeficiencies presenting with autoimmune cytopenias in adults]. 2270 29

The World Health Organization recognizes four categories of immunodeficiency-associated lymphoproliferative disorders (ID-LPDs): (1) lymphoproliferative diseases associated with primary immune disorders, (2) lymphomas associated with HIV infection, (3) post-transplant LPDs, and (4) other iatrogenic immunodeficiency-associated LPDs. Although these lesions are heterogeneous, due to their various underlying causes, they share several features, including frequent involvement of extranodal sites, diffuse aggressive histology, B-cell lineage, associated herpesvirus infection, and rapid clinical progression. The accurate diagnosis and treatment of the patients who develop immunodeficiency-associated LPDs often require careful evaluation of the morphology, immunophenotype, genotype, viral status, and clinical history. In this article, two of these four categories of ID-LPD are examined: lymphomas associated with HIV infections and lymphoproliferative diseases associated with primary immune disorders (PIDs), focusing on autoimmune lymphoproliferative syndrome (ALPS), as a representative disorder from this latter category.
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PMID:Immunodeficiency-associated lymphoid proliferations (ALPS, HIV, and KSHV/HHV8). 2353 12

The diagnosis and management of children with autoimmune cytopenias can be challenging. Children can present with immune-mediated destruction of a single-cell lineage or multiple cell lineages, including platelets (immune thrombocytopenia [ITP]), erythrocytes (autoimmune hemolytic anemia), and neutrophils (autoimmune neutropenia). Immune-mediated destruction can be primary or secondary to a comorbid immunodeficiency, malignancy, rheumatologic condition, or lymphoproliferative disorder. Treatment options generally consist of nonspecific immune suppression or modulation. This nonspecific approach is changing as recent insights into disease biology have led to targeted therapies, including the use of thrombopoietin mimetics in ITP and sirolimus for cytopenias associated with autoimmune lymphoproliferative syndrome.
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PMID:Diagnosis and management of autoimmune cytopenias in childhood. 2423 84

We describe a girl, now 9 years of age, with chronic idiopathic thrombocytopenic purpura, persistent nonmalignant lymphadenopathy, splenomegaly, recurrent infections, and autoimmune hemolytic anemia. Her symptoms partly fit the definitions of both autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency disorders (CVIDs). Genetic analysis showed no abnormalities in the ALPS-genes FAS, FASLG, and CASP10. The CVID-associated TACI gene showed a homozygous polymorphism (Pro251Leu), which is found also in healthy controls.
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PMID:A girl with autoimmune cytopenias, nonmalignant lymphadenopathy, and recurrent infections. 2537 3

Caspase-8 deficiency (CED) was originally described in 2002 in two pediatric patients presenting with clinical manifestations resembling autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects. Since then, no new CED patients were published. Here we report two adult siblings (Pt1 and Pt2) presenting in their late thirties with pulmonary hypertension leading to lung transplant (Pt1), and a complex neurological disease leading to multiple cranial nerves palsies (Pt2) as their main manifestations. A thorough clinical and immunological evaluation was performed at the Primary Immunodeficiency Clinic at NIH, followed by whole exome sequencing. The patients had multiorgan lymphocytic infiltration and granulomas, as well as clinical signs of immune deficiency/ immune dysregulation. Both siblings carried homozygous mutations in CASP8, c.1096C > T, p.248R > W. This was the same mutation described on the previously published CED patients, to whom these new patients were likely distantly related. We report two new CED patients presenting during adulthood with life-threatening end-organ lymphocyte infiltrates affecting the lungs, liver, spleen, bone marrow and central nervous system. This phenotype broadens the clinical spectrum of manifestations associated with this disease and warrants the search of CASP8 mutations in other cohorts of patients.
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PMID:Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings. 2581 41


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