Primary immunodeficiency Contents Signs and symptoms Diagnosis Conditions Causes Treatment Research Epidemiology History See also References External links Navigation menu[update]"The Molecular Pathology of Primary Immunodeficiencies"10.1016/S1525-1578(10)60493-X18674741509656110.1006/clim.1999.479910600329"Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency"10.3389/fimmu.2014.00162400107224795713"Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005"10.1016/j.jaci.2005.12.134716680902"Primary Immunodeficiency Disease""Primary Immunodeficiencies""Primary immunodeficiency"10.1186/1710-1492-7-S1-S1132454342216591310.1038/bmt.2008.6118545252"Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes"10.1016/j.jaci.2015.12.1311486005026920464"Population prevalence of diagnosed primary immunodeficiency diseases in the United States"10.1007/s10875-007-9103-117577648"International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity"10.1007/s10875-017-0464-90271-9142574260129226302Immune Deficiency FoundationEuropean Society for ImmunodeficienciesInternational Union of Immunological societiesPrimary Immunodeficiency Resource CenterInternational Patient Organisation for Primary ImmunodeficienciesResource for Asian Primary Immunodeficiency DiseasesUK Primary Immunodeficiency Patient Support AssociationPrimary Immunodeficiency UKee

X-linked agammaglobulinemiaTransient hypogammaglobulinemia of infancyIgA deficiencyIgG deficiencyIgM deficiencyHyper IgM syndrome12345Wiskott–Aldrich syndromeHyper-IgE syndromeCommon variable immunodeficiencyICF syndromethymic hypoplasiaDi George's syndromeNezelof syndromeAtaxia-telangiectasiaHyper IgM syndrome1X-SCIDAdenosine deaminase deficiencyOmenn syndromeZAP70 deficiencyBare lymphocyte syndromeIdiopathic CD4+ lymphocytopeniaHistiocytosisChronic granulomatous diseaseMonocytosisMonocytopeniagranulocytosisNeutrophiliaEosinophiliaHypereosinophilic syndromeBasophiliaBandemiaGranulocytopenia/agranulocytosisNeutropeniaKostmann syndromeEosinopeniaBasopeniaLeukocyte adhesion deficiencyLAD1LAD2Chédiak–Higashi syndromeNeutrophil-specific granule deficiencyChronic granulomatous diseaseNeutrophil immunodeficiency syndromeMyeloperoxidase deficiency


Immunodeficiency


immune systemimmunodeficiencygenetic disorderschildreninfectionsdevelopmental delayskinheartautoimmune diseasecancerlymphomafull blood countlymphocytegranulocyteimmunoglobulinIgGIgAIgMInternational Union of Immunological Societieshumoral immunityT-cellB-cellphagocyticcomplementIgA deficiencycommon variable immunodeficiencysevere combined immunodeficiencyX-linked agammaglobulinemiaWiskott-Aldrich syndromeDiGeorge syndromeataxia telangiectasiaantibioticsantiviralshumoral immune deficiencyintravenous immunoglobulinimmunosuppressionBone marrow transplantgraft-versus-host diseaseselective immunoglobulin A deficiencyWorld Health OrganizationPurine nucleoside phosphorylase deficiency




Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a primary immunodeficiency (PID), the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 300 recognized PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency.[1] Immune deficiencies can result in persistent or recurring infections, autoinflammatory disorders, tumors, and disorders of various organs. There are currently limited treatments available for these conditions; most are specific to a particular type of PID. Research is currently evaluating the use of stem cell transplants (HSCT) and experimental gene therapies as avenues for treatment in limited subsets of PIDs.




Contents





  • 1 Signs and symptoms


  • 2 Diagnosis


  • 3 Conditions


  • 4 Causes


  • 5 Treatment


  • 6 Research


  • 7 Epidemiology


  • 8 History


  • 9 See also


  • 10 References


  • 11 External links




Signs and symptoms


The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body's own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.[1]



Diagnosis


The basic tests performed when an immunodeficiency is suspected should include a full blood count (including accurate lymphocyte and granulocyte counts) and immunoglobulin levels (the three most important types of antibodies: IgG, IgA and IgM).[1]


Other tests are performed depending on the suspected disorder:[1]


  • Quantification of the different types of mononuclear cells in the blood (i.e. lymphocytes and monocytes): different groups of T lymphocytes (dependent on their cell surface markers, e.g. CD4+, CD8+, CD3+, TCRαβ and TCRγδ), groups of B lymphocytes (CD19, CD20, CD21 and immunoglobulin), natural killer cells and monocytes (CD15+), as well as activation markers (HLA-DR, CD25, CD80 (B cells).

  • Tests for T cell function: skin tests for delayed-type hypersensitivity, cell responses to mitogens and allogeneic cells, cytokine production by cells

  • Tests for B cell function: antibodies to routine immunisations and commonly acquired infections, quantification of IgG subclasses

  • Tests for phagocyte function: reduction of nitro blue tetrazolium chloride, assays of chemotaxis, bactericidal activity.

Due to the rarity of many primary immunodeficiencies, many of the above tests are highly specialised and tend to be performed in research laboratories.[1]


Criteria for diagnosis were agreed in 1999. For instance, an antibody deficiency can be diagnosed in the presence of low immunoglobulins, recurrent infections and failure of the development of antibodies on exposure to antigens. The 1999 criteria also distinguish between "definitive", "probable" and "possible" in the diagnosis of primary immunodeficiency. "Definitive" diagnosis is made when it is likely that in 20 years, the patient has a >98% chance of the same diagnosis being made; this level of diagnosis is achievable with the detection of a genetic mutation or very specific circumstantial abnormalities. "Probable" diagnosis is made when no genetic diagnosis can be made, but the patient has all other characteristics of a particular disease; the chance of the same diagnosis being made 20 years later is estimated to be 85-97%. Finally, a "possible" diagnosis is made when the patient has only some of the characteristics of a disease which are present, but not all.[2]



Conditions



There are many forms of PID. The International Union of Immunological Societies recognizes nine classes of primary immunodeficiencies, totaling over 120 conditions. A 2014 update of the classification guide added a 9th category and added 30 new gene defects from the prior 2009 version.[3][4] As of 2018[update], there are approximately 300 forms of PID that have been identified.[5]


Different forms of PID have different mechanisms. Rough categorizations of conditions divide them into humoral immunity disorders, T-cell and B-cell disorders, phagocytic disorders, and complement disorders.[6]


Most forms of PID are very rare. IgA deficiency is an exception, and is present in 1 in 500 people. Some of the more frequently seen forms of PID include common variable immunodeficiency, severe combined immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, DiGeorge syndrome, ataxia telangiectasia, [7]



Causes


By definition, primary immune deficiencies are due to genetic causes. They may result from a single genetic defect, but most are multifactorial. They may be caused by recessive or dominant inheritance. Some are latent, and require a certain environmental trigger to become manifest, like the presence in the environment of a reactive allergen. Other problems become apparent due to aging of bodily and cellular maintenance processes.



Treatment


The treatment of primary immunodeficiencies depends foremost on the nature of the abnormality. Somatic treatment of primarily genetic defects is in its infancy. Most treatment is therefore passive and palliative, and falls into two modalities: managing infections and boosting the immune system.


Reduction of exposure to pathogens may be recommended, and in many situations prophylactic antibiotics or antivirals may be advised.


In the case of humoral immune deficiency, immunoglobulin replacement therapy in the form of intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) may be available.


In cases of autoimmune disorders, immunosuppression therapies like corticosteroids may be prescribed.



Research


Bone marrow transplant may be possible for Severe Combined Immune Deficiency and other severe immunodeficiences.[8]


Virus-specific T-lymphocytes (VST) therapy is used for patients who have received hematopoietic stem cell transplantation that has proven to be unsuccessful. It is a treatment that has been effective in preventing and treating viral infections after HSCT. VST therapy uses active donor T-cells that are isolated from alloreactive T-cells which have proven immunity against one or more viruses. Such donor T-cells often cause acute graft-versus-host disease (GVHD), a subject of ongoing investigation. VSTs have been produced primarily by ex-vivo cultures and by the expansion of T-lymphocytes after stimulation with viral antigens. This is carried out by using donor-derived antigen-presenting cells. These new methods have reduced culture time to 10–12 days by using specific cytokines from adult donors or virus-naive cord blood. This treatment is far quicker and with a substantially higher success rate than the 3–6 months it takes to carry out HSCT on a patient diagnosed with a primary immunodeficiency.[9] T-lymphocyte therapies are still in the experimental stage; few are even in clinical trials, none have been FDA approved, and availability in clinical practice may be years or even a decade or more away.



Epidemiology


A survey of 10,000 American households revealed that the prevalence of diagnosed primary immunodeficiency approaches 1 in 1200. This figure does not take into account people with mild immune system defects who have not received a formal diagnosis.[10]


Milder forms of primary immunodeficiency, such as selective immunoglobulin A deficiency, are fairly common, with random groups of people (such as otherwise healthy blood donors) having a rate of 1:600. Other disorders are distinctly more uncommon, with incidences between 1:100,000 and 1:2,000,000 being reported.[1]



History


Primary immunodeficiencies were initially classified in 1970 by a committee of the World Health Organization. At the time, they identified 16 immunodeficiencies. By 1998, the number had reached 50. As of 2018, more than 330 have been categorized.[11]



See also


  • Immunodeficiency


References




  1. ^ abcdef Lim MS, Elenitoba-Johnson KS (2004). "The Molecular Pathology of Primary Immunodeficiencies". The Journal of Molecular Diagnostics : JMD. 6 (2): 59–83. doi:10.1016/S1525-1578(10)60493-X. PMC 1867474. PMID 15096561..mw-parser-output cite.citationfont-style:inherit.mw-parser-output .citation qquotes:"""""""'""'".mw-parser-output .citation .cs1-lock-free abackground:url("//upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center.mw-parser-output .citation .cs1-lock-limited a,.mw-parser-output .citation .cs1-lock-registration abackground:url("//upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center.mw-parser-output .citation .cs1-lock-subscription abackground:url("//upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registrationcolor:#555.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration spanborder-bottom:1px dotted;cursor:help.mw-parser-output .cs1-ws-icon abackground:url("//upload.wikimedia.org/wikipedia/commons/thumb/4/4c/Wikisource-logo.svg/12px-Wikisource-logo.svg.png")no-repeat;background-position:right .1em center.mw-parser-output code.cs1-codecolor:inherit;background:inherit;border:inherit;padding:inherit.mw-parser-output .cs1-hidden-errordisplay:none;font-size:100%.mw-parser-output .cs1-visible-errorfont-size:100%.mw-parser-output .cs1-maintdisplay:none;color:#33aa33;margin-left:0.3em.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-formatfont-size:95%.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-leftpadding-left:0.2em.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-rightpadding-right:0.2em


  2. ^ Conley ME, Notarangelo LD, Etzioni A (1999). "Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)". Clin. Immunol. 93 (3): 190–7. doi:10.1006/clim.1999.4799. PMID 10600329.


  3. ^ Waleed Al-Herz; Aziz Bousfiha; Jean-Laurent Casanova; et al. (2014). "Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency" (PDF). Frontiers in Immunology. 5 (162): 1–33. doi:10.3389/fimmu.2014.00162. PMC 4001072. PMID 24795713.


  4. ^ Notarangelo L, Casanova JL, Conley ME, et al. (2006). "Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005". J. Allergy Clin. Immunol. 117 (4): 883–96. doi:10.1016/j.jaci.2005.12.1347. PMID 16680902.


  5. ^ "Primary Immunodeficiency Disease". Retrieved 30 July 2018.


  6. ^ Cooper, Megan A.; Pommering, Thomas; Koranyi, Katalin (15 November 2003). "Primary Immunodeficiencies". American Family Physician. 68 (10): 2001–2008.


  7. ^ McCusker, Christine; Warrington, Richard (10 November 2011). "Primary immunodeficiency". Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology. 7 (Suppl 1): S11. doi:10.1186/1710-1492-7-S1-S11. PMC 3245434. PMID 22165913.


  8. ^ Porta F, Forino C, De Martiis D, et al. (June 2008). "Stem cell transplantation for primary immunodeficiencies". Bone Marrow Transplant. 41 Suppl 2: S83–6. doi:10.1038/bmt.2008.61. PMID 18545252.


  9. ^ Naik, S; Nicholas, S; Martinez, C; Leen, A; Hanley, P; Gottschalk, S; Rooney, C; Hanson, I; Krance, R; Shpall, E; Cruz, C; Amrolia, P; Lucchini, G; Bunin, N; Heimall, J; Klein, O; Gennery, A; Slatter, M; Vickers, M; Orange, J; Heslop, H; Bollard, C; Keller, M (24 February 2016). "Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes". Journal of Allergy and Clinical Immunology. 137 (5): 1498–1505.e1. doi:10.1016/j.jaci.2015.12.1311. PMC 4860050. PMID 26920464. Retrieved 12 April 2016.


  10. ^ Boyle JM, Buckley RH (2007). "Population prevalence of diagnosed primary immunodeficiency diseases in the United States". J. Clin. Immunol. 27 (5): 497–502. doi:10.1007/s10875-007-9103-1. PMID 17577648.


  11. ^ Picard, Capucine; Bobby Gaspar, H.; Al-Herz, Waleed; Bousfiha, Aziz (2018). "International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity". Journal of Clinical Immunology. 38 (1): 96–128. doi:10.1007/s10875-017-0464-9. ISSN 0271-9142. PMC 5742601. PMID 29226302.




External links


  • Immune Deficiency Foundation


  • European Society for Immunodeficiencies (ESID)


  • International Union of Immunological societies (IUIS)


  • Primary Immunodeficiency Resource Center (Jeffrey Modell Foundation)


  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)


  • Resource for Asian Primary Immunodeficiency Diseases (RAPID)


  • UK Primary Immunodeficiency Patient Support Association (UKPIPS - UK Primary Immunodeficiency Patient Support Association)


  • Primary Immunodeficiency UK (UK representative member of IPOPI - PID UK - Primary Immunodeficiency UK)









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