T cell primary immunodeficiencies

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What genetic event(s) result(s) in severe combined immunodeficiency (SCID)?	50-60% of cases are X-linked and result from a defect in the IL-2/IL-17 receptor. ~15% of cases result from adenosine deaminase (ADA) deficiency. The remainder are deficiencies in: purine nucleoside phosphorylase (PNP), CD3, MHC.
What do the genetic events causing severe combined immunodeficiency do to T cells (or any other cells)?	Depends on the genetic aetiology: X-linked IL-2/IL-17 defect means that T cells do not respond to growth/proliferation signals and none are present; ADA/PNP deficiency means that lymphocyte populations die as toxic purine metabolites cannot be removed. CD3/MHC deficiency means that T cells do not make it through selection, or cannot mature and proliferate once activated.
How does severe combined immunodeficiency present clinically?	There are severe and recurrent infections from birth. Pneumocystis carnii pneumonia (unusual, but seen here), chronic diarrhoea from rotaviruses or enteroviruses, Candida albicans colonisation, Epstein-Barr virus and cytomegalovirus infections, and many other infections - patterns may depend on B cell elimination as well as T cells, but antibodies are hugely depleted in either case. Further, individuals do not have recognisable tonsils, lymphocytes, or thymuses as there are so few lymphocytes.
How is severe combined immunodeficiency diagnosed?	Clinical anatomical features, age of onset of infections, type of infections, failure to thrive, alongside low B/T/NK cell numbers by flow cytometry, and sometimes hypersensitivity tests to tetanus/diptheria.
What is the treatment for severe combined immunodeficiency?	Sterile isolation ('bubble children'), then bone marrow transplant ideally from an allogeneic histocompatible donor e.g. sibling or parent, or gene therapy using a non-virulent vector directly or indirectly (removal and replacement of treated stem cells).
Who is David Vetter? How did he die?	David Vetter was the first 'bubble boy' whose sterile isolation environment was at home. He died of Burkitt's lymphoma developed as a result of contracting Epstein-Barr Virus from his sister's bone marrow when it was transplanted in an attempt to cure him. EBV was not looked for until this point, as not much was known about it, and David's case helped clarify the direct relationship between EBV and lymphoma as he had never had any other illness so it couldn't possibly be anything else.
What genetic event results in DiGeorge anomaly?	Deletion in chromosome 22 from a meiotic recombination error during embryogenesis.
What does the genetic event causing DiGeorge anomaly result in?	A congenital defect in the thymic epithelium leading to T cell deficiency, as well as distinctive facial features and potentially cardiac malformations.
How does DiGeorge anomaly present clinically?	Protozoal, virus, and function infections (but not bacterial as this is primarily mediated by opsonophagocytosis), as well as the distinctive facial features and potentially cardiac malformations.
How is DiGeorge anomaly diagnosed?	Infection types (those usually mediated by T cells), facial features, and potentially chromosome analysis by Giemsa stain to see the abnormality in chromosome 22.
Why is DiGeorge anomaly variable in its phenotype?	The variability in the phenotype results from variability in the amount of genetic material deleted from chromosome 22 during the error in meiotic recombination.
How is DiGeorge anomaly treated?	Thymic transplant with foetal tissue, and a bone marrow transplant from an allogeneic histocompatible donor e.g. a sibling or parent.
What genetic event results in Wiscott-Aldrich syndrome?	X-linked mutation in sialophorin, a cytoskeletal protein.
What does the genetic event in Wiscott-Aldrich syndrome do to B/T cells? And other cells?	Their cytoskeletal abnormalities mean that they are unable to communication with one another, and gradually their function declines. It also results in thrombocytopenia, and potentially haemorrhage due to low numbers of small, abnormal platelets.
How does Wiscott-Aldrich syndrome present clinically?	Gradual loss of B/T cell function with age (more so than the decline expected, in a much shorter time frame), eczema, increased susceptibility to pyogenic and opportunistic infections.
How is Wiscott-Aldrich syndrome diagnosed?	The lack of communication between B and T cells resulting from their cytoskeletal abnormalities in turn results in an unusual immunoglobulin profile: low IgM, high IgA/IgE, and normal IgG. There is also gradual decline in B/T cell numbers and function, as well as the thrombocytopenia, resulting in easy and potentially fatal haemorrhage.
How is Wiscott-Aldrich syndrome treated?	With a bone marrow transplant and antibiotics to treat the infections.
What genetic event results in ataxia telangiectasia?	An autosomal recessive mutation in the ataxia telangiectasis mutated (ATM) gene, a cell cycle regulatory protein.
What does the genetic event causing ataxia telangiectasia do to T cells? And other immune components?	There is a lack of cell cycle regulation and DNA double strand breaks are not fixed. This results in IgA deficiency, as well as T cell function depression.
How does ataxia telangiectasia present clinically?	Ataxia = wobbly gait by 18 months of age. Telangiectasia = dilated blood vessels in the eyes and skin by 6 years of age. Sinopulmonary infections result from IgA and T cell deficiencies.
How is ataxia telangiectasia diagnosed?	By its namesake signs, as well as IgA deficiency, and in vitro T cell function depression.
How is ataxia telangiectasia treated?	With long term antibiotics, or intravenous immunoglobulins, or potentially by bone marrow transplant depending on the severity.

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T cell primary immunodeficiencies

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