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52-604: The charity is named after Anthony Nolan (born 1971–died 1979), who did not suffer from leukaemia but from Wiskott–Aldrich syndrome , a rare inherited blood disorder. It was founded by Anthony's mother Shirley Nolan (1942–2001) in 1974 as the Anthony Nolan Register . Initially based at the Westminster Children's Hospital , it moved to St Mary Abbots Hospital in 1978 and to its present offices, laboratory and research institute in north London, in

104-553: A gene on the short arm of the X chromosome (Xp11.23) that was originally termed the Wiskott–Aldrich syndrome protein gene and is officially known as WAS (Gene ID: 7454). X-linked thrombocytopenia (XLT) is also linked to pathogenic variants in the WAS gene, although some variants tend to be more strongly associated with XLT versus others that are more associated with WAS. The rare disorder X-linked neutropenia has also been linked to

156-407: A protease that destroys IgA . Additionally, Blastocystis species have been shown to have several subtypes that generate cysteine and aspartic protease enzymes which degrade human IgA. IgA nephropathy is caused by IgA deposits in the kidneys. The pathogenesis involves the production of hypoglycosylated IgA1, which accumulates and subsequently leads to the formation of immune complexes and

208-420: A genetically modified lentivirus. In April 2015 results from a follow-up British and French trial six out of seven individuals showed improvement of immune function and clinical symptoms an average of 27 months after treatment with gene therapy. Importantly, neither study showed evidence of leukemic proliferation following treatment, a complication of early attempts at gene therapy using a retroviral vector. It

260-656: A leukaemia patient, inspired his mother Beverley and her partner, Orin Lewis, to set up the African-Caribbean Leukaemia Trust in June 1996. ACLT worked "in partnership with the ... Nolan Trust" to build the number of bone marrow donors, specifically of African, African Caribbean, and mixed parentage on the UK register. The organisation organizes several novel campaigns to increase the number of donors joining

312-457: A novel frameshift mutation of the first exon of the WASp gene. peripheral: Purine nucleoside phosphorylase deficiency Ankyrin : Long QT syndrome 4 IgA Immunoglobulin A ( Ig A , also referred to as sIgA in its secretory form) is an antibody that plays a role in the immune function of mucous membranes . The amount of IgA produced in association with mucosal membranes

364-739: A numerical grading of severity: This score, which ranges from 0 to 5, may have clinical utility for predicting disease severity. Those with higher WAS scores (e.g., 5) at younger ages (e.g., age less than 5 years old), are thought to be at highest risk for increased morbidity and mortality related to their condition. As individuals can develop more WAS-related symptoms (e.g. autoimmune disease, malignancy) with age, one's WAS score can increase over time. A lower WAS score may be more compatible with conservative management versus higher WAS scores that may favor intervention with treatments such as hematopoietic stem cell transplant . Hematopoietic stem cell transplant Treatment of Wiskott–Aldrich syndrome depends on

416-425: A positive family history of the disorder; new mutations do occur. Often, leukemia may be suspected on the basis of low platelets and infections, and bone marrow biopsy may be performed. Decreased levels of WASp are typically observed. The current gold standard for diagnosis is DNA sequence analysis , which can detect WAS and the related disorders XLT and XLN in 95% of patients and carriers. Jin et al. (2004) employ

468-484: A rare disease, this makes it more common than many genetic immunodeficiency syndromes such as hyper-IgM syndrome or SCID , which have an estimated incidence of about one in 1,000,000 live births, and Wiskott–Aldrich syndrome is thought to account for 1.2% of all inherited immunodeficiencies in the United States. WAS occurs worldwide and is not known to be more common in any particular ethnic group. The syndrome

520-592: A specific subset of WAS mutations. The protein product of WAS is known as WASp. It contains 502 amino acids and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by serving as a nucleation-promoting factor (NPF) for the Arp2/3 complex , which generates branched actin filaments. Several proteins can serve as NPFs, and it has been observed that in WAS platelets

572-461: A third of patients. Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to thrombocytopenia, WAS patients have abnormally small platelets (i.e. microthrombocytes) and ~30% also have elevated eosinophil counts (i.e. eosinophilia ). The microthrombocytes seen in WAS patients have only been observed in one other condition, ARPC1B deficiency. In both conditions

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624-530: A thrombopoietic agent used to increase platelets in immune thrombocytopenic purpura (ITP), in WAS concluded that although it increased platelet numbers it failed to increase platelet activation in most patients. It has since been proposed the eltrombopag may be used to bridge to HCT in patients with severe thrombocytopenia to normalize platelet numbers without transfusions and decrease bleeding events. Anemia from bleeding may require iron supplementation or blood transfusion . Regular surveillance of blood counts

676-506: Is a condition with variable expressivity , meaning that even within the same family some may exhibit only chronic thrombocytopenia while others experience severe, life-threatening complications of Wiskott–Aldrich syndrome in infancy or childhood. Given symptoms often progress with age, it is challenging to predict how affected a newly diagnosed infant will eventually be. There is some genotype-phenotype correlation, with most individuals with X-linked thrombocytopenia having missense variants in

728-514: Is a rare X-linked recessive disease characterized by eczema , thrombocytopenia (low platelet count), immune deficiency , and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present with similar but less severe symptoms and are caused by mutations of

780-537: Is affected (the WAS score may be used to assess disease severity). The milder end of the disease spectrum associated with the WAS gene is referred to as X-linked neutropenia or X-linked thrombocytopenia , and the latter is thought to have a normal life expectancy with reports of minimally affected males surviving into their seventh decade without treatment. Traditionally however Wiskott–Aldrich syndrome has been associated with premature death from causes including bleeding, infections, or malignancy. Wiskott–Aldrich syndrome

832-444: Is expressed on immune effector cells, to initiate inflammatory reactions. Ligation of FcαRI by IgA containing immune complexes causes antibody-dependent cell-mediated cytotoxicity (ADCC), degranulation of eosinophils and basophils , phagocytosis by monocytes , macrophages , and neutrophils , and triggering of respiratory burst activity by polymorphonuclear leukocytes . Unlike IgM and IgG , which activate complement through

884-420: Is extreme bloodloss (such as during surgery) or for very low platelets splenectomy (removal of the spleen) may also be lifesaving. However, splenectomy is generally considered palliative and is not universally recommended in WAS because it can increase the risk of life-threatening infections. Post-splenectomy patients will require lifelong antibiotic prophyllaxis to prevent infections. Study of eltrombopag ,

936-419: Is free to diffuse throughout the lumen , with dimeric IgA and SC together forming the so-called secretory IgA (sIgA) In the gut, IgA can bind to the mucus layer covering the epithelial cells. In this way, a barrier capable of neutralizing threats before they reach the epithelial cells is formed. Secretory IgA levels fluctuate diurnally, with the highest levels found in the small intestine and feces around ZT6,

988-409: Is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body. IgA has two subclasses ( IgA1 and IgA2 ) and can be produced as a monomeric as well as a dimeric form. The IgA dimeric form is the most prevalent and, when it has bound

1040-434: Is important including blood cultures to guide therapy (often IV antibiotics). Live vaccines (such as MMR or rotavirus ) should be avoided during routine childhood vaccination. Inactivated vaccines may be given safely but may not provide protective levels of immunity. Eczema is generally treated with topical steroids , and if chronic skin infections exacerbate eczema an antibiotic may also be given. Autoimmune disease

1092-761: Is managed with judicious use of appropriate immunosuppressants. Gene therapy For severely affected males without an HLA-matched donor, studies of correcting Wiskott–Aldrich syndrome with gene therapy using a lentivirus are underway. Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome. In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that three children with Wiskott–Aldrich syndrome showed significant improvement (improved platelet counts, immune functiona, and clinical symptoms) 20–30 months after being treated with

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1144-451: Is named after Dr. Alfred Wiskott (1898–1978), a German pediatrician who first noticed the syndrome in 1937, and Dr. Robert Anderson Aldrich (1917–1998), an American pediatrician who described the disease in a family of Dutch-Americans in 1954. Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006, a German research group analyzed family members of Wiskott's three cases, and surmised they probably shared

1196-696: Is recommended. Infections and autoimmune disease For patients with frequent infections, intravenous immunoglobulins (IVIG) or subcutaneous immunoglobulins can be regularly scheduled to boost the immune system. Adequacy of IVIG replacement can be assessed via periodic lab draws. WAS patients with immune system compromise may benefit from antibiotic prophylaxis , for example by taking trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii -related pneumonia . Similarly, prophylactic antibiotic use may also be considered in patients with recurrent bacterial sinus or lung infections. When there are signs or symptoms of an infection, prompt and thorough evaluation

1248-674: Is termed selective IgA deficiency and can produce a clinically significant immunodeficiency . Anti-IgA antibodies, sometimes present in individuals with low or absent IgA, can result in serious anaphylactic reactions when transfused with blood products that incidentally contain IgA. However, most persons with suspected IgA anaphylactic reactions had experienced acute generalized reactions that were from causes other than anti-IgA transfusion. Neisseria species including Neisseria gonorrhoeae (which causes gonorrhea ), Streptococcus pneumoniae , and Haemophilus influenzae type B all release

1300-403: Is thought to allow IgA1 to adapt more effectively to varying epitope spacings on multivalent antigens, while also presenting less resistance to bacterial proteases. It is also possible to distinguish forms of IgA based upon their location – serum IgA vs. secretory IgA. In secretory IgA, the form found in secretions, polymers of 2–4 IgA monomers are linked by two additional chains; as such,

1352-464: Is unknown why these gene therapies did not restore normal platelet numbers, but gene therapy treatment was still associated with transfusion-independence and a significant reduction in bleeding events. A version of this treatment, OTL-103 , is being developed by Orchard Therapeutics and (as of 28 June 2021 ) is undergoing Phase I/II clinical trials . Outcomes from Wiskott–Aldrich syndrome are variable and depend on how severely an individual

1404-571: The CD43 molecule has also been found in WAS patients. CD43, a transmembrane sialoglycoprotein also known as a leukosialin, is part of a greater complex involved in T-cell activation and acts as a sensitive indicator of abnormal, malignant B cell populations. Defects in this molecule may be detrimental to WAS patients, who are at a much higher risk of autoimmune diseases that may be exacerbated in later-detected B-cell lymphomas. The diagnosis can be made on

1456-633: The WAS gene generally correlates with their effects on WASp. Missense variants generally are associated with less severe disease than truncating variants that produce no protein due to nonsense-mediated decay . However, this correlation is not perfect, and sometimes the same variant can be seen both in XLT and in WAS (sometimes within two different members of the same family), a concept in genetics referred to as variable expressivity . Although autoimmune disease and malignancy may occur in both conditions, patients with loss of WASp are at higher risk. A defect in

1508-416: The WAS gene versus 86.5% of those that make no WAS protein having the classic Wiskott–Aldrich syndrome phenotype. Overall the prognosis for individuals with Wiskott–Aldrich syndrome has improved considerably over the past decades due to earlier diagnoses and more access to treatments. The estimated incidence of Wiskott–Aldrich syndrome in the United States is one in 250,000 live male births. While still

1560-483: The molecular weight of slgA is 385kD. One of these is the J chain (joining chain), which is a polypeptide of molecular mass 15kD, rich with cysteine and structurally completely different from other immunoglobulin chains. This chain is formed in the IgA-secreting cells. The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kD) called

1612-404: The secretory component that is produced by epithelial cells . This molecule originates from the poly-Ig receptor (130 kD) that is responsible for the uptake and transcellular transport of oligomeric (but not monomeric) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid. In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89 ), which

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1664-454: The Arp2/3 complex functions normally, indicating that WASp is not required for its activation in platelets. In T-cells, WASp is important because it is known to be activated via T-cell receptor signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse . The severity of the symptoms produced by pathogenic variants in

1716-523: The Secretory component, is also called secretory IgA (sIgA). sIgA is the main immunoglobulin found in mucous secretions , including tears , saliva , sweat , colostrum and secretions from the genitourinary tract , gastrointestinal tract , prostate and respiratory epithelium . It is also found in small amounts in blood. The secretory component of sIgA protects the immunoglobulin from being degraded by proteolytic enzymes; thus, sIgA can survive in

1768-415: The basis of clinical findings, the peripheral blood smear , and low immunoglobulin levels. Typically, IgM levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed. Skin immunologic testing (allergy testing) may reveal hyposensitivity. Individuals with Wiskott–Aldrich syndrome however are at higher risk for severe food allergies. Not all patients have

1820-485: The bone marrow and circulate systemically. The best outcomes are with HLA -identical or similar donors (often siblings). In cases of milder disease the potential benefits of HCT (>90% probability of cure if transplant occurs before age two) must be considered in the context of non-trivial risks presented by the procedure itself and the potential need for lifelong immunosuppression to prevent graft-versus-host disease . Generally outcomes are better if HCT occurs prior to

1872-455: The classical pathway, IgA can activate complement via the alternative and lectin pathways . The high prevalence of IgA in mucosal areas is a result of a cooperation between plasma cells that produce polymeric IgA (pIgA), and mucosal epithelial cells that express polymeric immunoglobulin receptor (pIgR). Polymeric IgA (mainly the secretory dimer) is produced by plasma cells in the lamina propria adjacent to mucosal surfaces. It binds to

1924-514: The component of IgA can associate with the mucus layer that sits atop epithelial cells. Since sIgA is a poor opsonin and activator of complement, simply binding a pathogen isn't necessarily enough to contain it—specific epitopes may have to be bound to sterically hinder access to the epithelium. Clearance of IgA is mediated at least in part by asialoglycoprotein receptors , which recognizes galactose -terminating IgA N- glycans . Decreased or absent IgA due to an inherited inability to produce IgA

1976-412: The defective platelets are thought to be removed from circulation by the spleen and/or liver, leading to low platelet counts. WAS patients have increased susceptibility to infections, particularly of the ears and sinuses, and this immune deficiency has been linked to decreased antibody production and the inability of immune T cells to effectively combat infection. WAS is associated with mutations in

2028-904: The development of autoimmune disease or malignancy , however there are risks associated with chemotherapy (needed to make room for the new stem cells) especially in young infants (risk of a second cancer, or infertility ). Bleeding complications Otherwise WAS treatment is focused on managing symptoms and preventing complications. The greatest mortality risk in WAS before age 30 is from bleeding so aspirin and other nonsteroidal anti-inflammatory drugs that may interfere with already compromised platelet function should generally be avoided. Circumcision , as well as elective surgeries, should generally be deferred in males with thrombocytopenia until after HCT if possible. Protective helmets can help protect children from life-threatening intracranial hemorrhage (brain bleed) which could result from head injuries. Patients may require platelet transfusions when there

2080-445: The first stem cell register in the world to start recruiting 16-year-olds. Today the register has over 720,000 potential donors on it. One of the charity's main aims is to recruit more male donors, as they are the most likely to be chosen by doctors to donate, and are selected for 54% of donations. A student organisation operating in universities throughout the UK known as 'Marrow' works with Anthony Nolan to recruit potential donors to

2132-552: The grounds of the Royal Free Hospital. The charity was renamed in 2001 as the Anthony Nolan Trust . and again in 2010 to Anthony Nolan . In 2008 Anthony Nolan set up the UK's first dedicated cord blood bank, allowing mothers to safely donate the blood from their umbilical cord and placenta after they give birth, the charity then use this blood in their stem cell transplants. In 2012 Anthony Nolan became

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2184-490: The harsh gastrointestinal tract environment and provide protection against microbes that multiply in body secretions. sIgA can also inhibit inflammatory effects of other immunoglobulins. IgA is a poor activator of the complement system , and opsonizes only weakly. IgA exists in two isotypes , IgA1 and IgA2. They are both heavily glycosylated proteins. While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions);

2236-623: The middle of the light period. The regulation of IgA secretion is related to the microbiota, and IgA is known to control specific members of oscillating microbes through direct interactions. However, the underlying cause of the rhythmic secretion of IgA is not completely understood and may differ from one region of the body to another. Production of sIgA against specific antigens depends on sampling of M cells and underlying dendritic cells , T cell activation, and B cell class switching in GALT, mesenteric lymph nodes , and isolated lymphoid follicles in

2288-423: The pIgR on the basolateral surface of epithelial cells, and is taken up into the cell via endocytosis . The receptor-IgA complex passes through the cellular compartments before being secreted on the luminal surface of the epithelial cells, still attached to the receptor. Proteolysis of the receptor occurs, and the dimeric IgA molecule, along with a portion of the receptor known as the secretory component (SC),

2340-542: The production of IgA-specific IgG, further leading to tissue inflammation. Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies. Additional testing has been conducted using IgA trans-glutaminase autoantibodies which has been identified as a specific and sensitive for the detection of celiac disease. Henoch–Schönlein purpura (HSP) is a systemic vasculitis caused by deposits of IgA and complement component 3 (C3) in small blood vessels. HSP occurs usually in small children and involves

2392-507: The ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body: Both IgA1 and IgA2 have been found in external secretions like colostrum , maternal milk, tears and saliva , where IgA2 is more prominent than in the blood. Polysaccharide antigens tend to induce more IgA2 than protein antigens. Both IgA1 and IgA2 can be in membrane-bound form. ( see B-cell receptor ) The heavy chain of IgA1, in contrast to IgA2, features an extended hinge region. This

2444-545: The register and raise awareness of the charity and blood cancers within universities and their local communities. It was set up in 1998 at the University of Nottingham and now operates in more than 50 universities in the UK and worldwide. In 2014, Anthony Nolan was the official charity partner for the London Marathon . Midland Metro named an AnsaldoBreda T-69 tram in his honour. Daniel De Gale (1987–2008),

2496-479: The registry. For example, it organised the Spit and Save a life campaign in 2010 which featured Devaanshi Mehta (1996–2012), an aplastic anemia patient. During the campaign donors could join the registry and find out if they could save a life by simply giving a sample of their saliva. Olivia Colman became Patron of Anthony Nolan in 2018. Wiskott%E2%80%93Aldrich syndrome Wiskott–Aldrich syndrome ( WAS )

2548-610: The same gene. WAS occurs most often in males due to its X-linked recessive pattern of inheritance, affecting between 1 and 10 males per million. The first signs are usually petechiae and bruising, resulting from a low platelet count (i.e. thrombocytopenia ). Spontaneous nose bleeds and bloody diarrhea are also common and eczema typically develops within the first month of life. Recurrent bacterial infections typically develop by three months of age. The majority of children with WAS develop at least one autoimmune disorder , and cancers (mainly lymphoma and leukemia ) develop in up to

2600-423: The severity of the disease. WAS is primarily a disorder of the blood-forming tissues, so in cases of severe disease (WAS score 3–5) the only widely available curative treatment currently available is a hematopoietic stem cell transplant (HCT). In this procedure stem cells are harvested from umbilical cord blood , bone marrow , or peripheral blood following treatment with medications that cause stem cells to leave

2652-477: The skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys. It usually follows an upper respiratory infection and resolves within a couple weeks as the liver clears out the IgA aggregates. Linear IgA bullous dermatosis and IgA pemphigus are two examples of IgA-mediated immunobullous diseases. IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab. Vancomycin can induce

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2704-430: The small intestine. sIgA primarily acts by blockading epithelial receptors (e.g. by binding their ligands on pathogens), by sterically hindering attachment to epithelial cells, and by immune exclusion. Immune exclusion is a process of agglutinating polyvalent antigens or pathogens by crosslinking them with antibody, trapping them in the mucus layer, and/or clearing them peristaltically . The oligosaccharide chains of

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