Primary immunodeficiency

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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, 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. About 1 in 500 people are born with a primary immunodeficiency.[1]

Signs and symptoms[edit]

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[edit]

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]

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 are present, but not all.[2]

Conditions[edit]

The International Union of Immunological Societies recognises eight classes of primary immunodeficiencies, totaling over 120 conditions.[3] Their most recent update retained the classification into eight groups, while adding several new conditions into these groups (such as coronin-1A deficiency, immunodeficiency with centromeric instability and facial anomalies, and defects of Ficolin 3).[4]

Table I: Combined T and B–cell immunodeficiencies[edit]

Genetic immunodeficiencies. (In general, those on the left are in Table I, while those on the right are in Table II, but there are exceptions.)

In these disorders both T lymphocytes and often B lymphocytes, regulators of adaptive immunity, are dysfunctional or decreased in number. The main members are various types of severe combined immunodeficiency (SCID).[4]

  1. T-/B+ SCID (T cells predominantly absent): γc deficiency, JAK3 deficiency, interleukin 7 receptor chain α deficiency, CD45 deficiency, CD3δ/CD3ε deficiency.
  2. T-/B- SCID (both T and B cells absent): RAG 1/2 deficiency, DCLRE1C deficiency, adenosine deaminase (ADA) deficiency, reticular dysgenesis
  3. Omenn syndrome
  4. DNA ligase type IV deficiency
  5. Cernunnos deficiency
  6. CD40 ligand deficiency
  7. CD40 deficiency
  8. Purine nucleoside phosphorylase (PNP) deficiency
  9. CD3γ deficiency
  10. CD8 deficiency
  11. ZAP-70 deficiency
  12. Ca++ channel deficiency
  13. MHC class I deficiency
  14. MHC class II deficiency
  15. Winged helix deficiency
  16. CD25 deficiency
  17. STAT5b deficiency
  18. Itk deficiency
  19. DOCK8 deficiency

Table II: Predominantly antibody deficiencies[edit]

In primary antibody deficiencies, one or more isotypes of immunoglobulin are decreased or don't function properly. These proteins, generated by plasma cells, normally bind to pathogens, targeting them for destruction.[4]

  1. Absent B cells with a resultant severe reduction of all types of antibody: X-linked agammaglobulinemia (btk deficiency, or Bruton's agammaglobulinemia), μ-Heavy chain deficiency, l 5 deficiency, Igα deficiency, BLNK deficiency, thymoma with immunodeficiency
  2. B cells low but present or normal, but with reduction in 2 or more isotypes (usually IgG & IgA, sometimes IgM): common variable immunodeficiency (CVID), ICOS deficiency, CD19 deficiency, TACI (TNFRSF13B) deficiency, BAFF receptor deficiency.
  3. Normal numbers of B cells with decreased IgG and IgA and increased IgM: Hyper-IgM syndromes
  4. Normal numbers of B cells with isotype or light chain deficiencies: heavy chain deletions, kappa chain deficiency, isolated IgG subclass deficiency, IgA with IgG subsclass deficiency, selective immunoglobulin A deficiency
  5. Specific antibody deficiency to specific antigens with normal B cell and normal Ig concentrations
  6. Transient hypogammaglobulinemia of infancy (THI)

Table III: Other well defined immunodeficiency syndrome[edit]

A number of syndromes escape formal classification but are otherwise recognisable by particular clinical or immunological features.[4]

  1. Wiskott-Aldrich syndrome
  2. DNA repair defects not causing isolated SCID: ataxia telangiectasia, ataxia-like syndrome, Nijmegen breakage syndrome, Bloom syndrome
  3. DiGeorge syndrome (when associated with thymic defects)
  4. Various immuno-osseous dysplasias (abnormal development of the skeleton with immune problems): cartilage-hair hypoplasia, Schimke syndrome
  5. Hermansky-Pudlak syndrome type 2
  6. Hyper-IgE syndrome
  7. Chronic mucocutaneous candidiasis
  8. Hepatic venoocclusive disease with immunodeficiency (VODI)
  9. XL-dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome)

Table IV: Diseases of immune dysregulation[edit]

In certain conditions, the regulation rather than the intrinsic activity of parts of the immune system is the predominant problem.[4]

  1. Immunodeficiency with hypopigmentation or albinism: Chediak-Higashi syndrome, Griscelli syndrome type 2
  2. Familial hemophagocytic lymphohistiocytosis: perforin deficiency, MUNC13D deficiency, syntaxin 11 deficiency
  3. X-linked lymphoproliferative syndrome
  4. Syndromes with autoimmunity:
    1. (a) Autoimmune lymphoproliferative syndrome: type 1a (CD95 defects), type 1b (Fas ligand defects), type 2a (CASP10 defects), type 2b (CASP8 defects)
    2. (b) APECED (autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy)
    3. (c) IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome)
    4. (d) CD25 deficiency

Table V: Congenital defects of phagocyte number, function, or both[edit]

Phagocytes are the cells that engulf and ingest pathogens (phagocytosis), and destroy them with chemicals. Monocytes/macrophages as well as granulocytes are capable of this process. In certain conditions, either the number of phagocytes is reduced or their functional capacity is impaired.[4]

  1. Severe congenital neutropenia: due to ELA2 deficiency (with myelodysplasia)
  2. Severe congenital neutropenia: due to GFI1 deficiency (with T/B lymphopenia)
  3. Kostmann syndrome
  4. Neutropenia with cardiac and urogenital malformations
  5. Glycogen storage disease type 1b
  6. Cyclic neutropenia
  7. X-linked neutropenia/myelodysplasia
  8. P14 deficiency
  9. Leukocyte adhesion deficiency type 1
  10. Leukocyte adhesion deficiency type 2
  11. Leukocyte adhesion deficiency type 3
  12. RAC2 deficiency (Neutrophil immunodeficiency syndrome)
  13. Beta-actin deficiency
  14. Localized juvenile periodontitis
  15. Papillon-Lefèvre syndrome
  16. Specific granule deficiency
  17. Shwachman-Diamond syndrome
  18. Chronic granulomatous disease: X-linked
  19. Chronic granulomatous disease: autosomal (CYBA)
  20. Chronic granulomatous disease: autosomal (NCF1)
  21. Chronic granulomatous disease: autosomal (NCF2)
  22. IL-12 and IL-23 β1 chain deficiency
  23. IL-12p40 deficiency
  24. Interferon γ receptor 1 deficiency
  25. Interferon γ receptor 2 deficiency
  26. STAT1 deficiency (2 forms)
  27. AD hyper-IgE
  28. AR hyper-IgE
  29. Pulmonary alveolar proteinosis

Table VI: Defects in innate immunity[edit]

Several rare conditions are due to defects in the innate immune system, which is a basic line of defence that is independent of the more advanced lymphocyte-related systems. Many of these conditions are associated with skin problems.[4]

  1. Hypohidrotic ectodermal dysplasia
    1. NEMO deficiency
    2. IKBA deficiency
  2. EDA-ID
  3. IRAK-4 deficiency
  4. MyD88 deficiency
  5. WHIM syndrome (warts, hypogammaglobulinaemia, infections, myleokathexis)
  6. Epidermodysplasia verruciformis
  7. Herpes simplex encephalitis
  8. Chronic mucocutaneous candidiasis
  9. Trypanosomiasis

Table VII: Autoinflammatory disorder[edit]

Rather than predisposing for infections, most of the autoinflammatory disorders lead to excessive inflammation. Many manifest themselves as periodic fever syndromes. They may involve various organs directly, as well as predisposing for long-term damage (e.g. by leading to amyloid deposition).[4]

  1. Familial Mediterranean fever
  2. TNF receptor associated periodic syndrome (TRAPS)
  3. Hyper-IgD syndrome (HIDS)
  4. CIAS1-related diseases:
    1. Muckle-Wells syndrome
    2. Familial cold autoinflammatory syndrome
    3. Neonatal onset multisystem inflammatory disease
  5. PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, acne)
  6. Blau syndrome
  7. Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)
  8. DIRA (deficiency of the IL-1 receptor antagonist)

Table VIII. Complement deficiencies[edit]

The complement system is part of the innate as well as the adaptive immune system; it is a group of circulating proteins that can bind pathogens and form a membrane attack complex. Complement deficiencies are the result of a lack of any of these proteins. They may predispose to infections but also to autoimmune conditions.[4]

  1. C1q deficiency (lupus-like syndrome, rheumatoid disease, infections)
  2. C1r deficiency (idem)
  3. C1s deficiency
  4. C4 deficiency (idem)
  5. C2 deficiency (lupus-like syndrome, vasculitis, polymyositis, pyogenic infections)
  6. C3 deficiency (recurrent pyogenic infections)
  7. C5 deficiency (Neisserial infections, SLE)
  8. C6 deficiency (idem)
  9. C7 deficiency (idem, vasculitis)
  10. C8a deficiency
  11. C8b deficiency
  12. C9 deficiency (Neisserial infections)
  13. C1-inhibitor deficiency (hereditary angioedema)
  14. Factor I deficiency (pyogenic infections)
  15. Factor H deficiency (haemolytic-uraemic syndrome, membranoproliferative glomerulonephritis)
  16. Factor D deficiency (Neisserial infections)
  17. Properdin deficiency (Neisserial infections)
  18. MBP deficiency (pyogenic infections)
  19. MASP2 deficiency
  20. Complement receptor 3 (CR3) deficiency
  21. Membrane cofactor protein (CD46) deficiency
  22. Membrane attack complex inhibitor (CD59) deficiency
  23. Paroxysmal nocturnal hemoglobinuria
  24. Immunodeficiency associated with ficolin 3 deficiency

Treatment[edit]

The treatment of primary immunodeficiencies depends foremost on the nature of the abnormality. This may range from immunoglobulin replacement therapy in antibody deficiencies—in the form of intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG)—to hematopoietic stem cell transplantation for SCID and other severe immunodeficiences.[5] Reduction of exposure to pathogens may be recommended, and in many situations prophylactic antibiotics may be advised.

Epidemiology[edit]

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.[6]

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]

References[edit]

  1. ^ a b c d e f 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. 
  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. ^ 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. 
  4. ^ a b c d e f g h i Notarangelo LD, Fischer A, Geha RS, et al. (December 2009). "Primary immunodeficiencies: 2009 update: The International Union of Immunological Societies (IUIS) Primary Immunodeficiencies (PID) Expert Committee". J. Allergy Clin. Immunol. 124 (6): 1161–78. doi:10.1016/j.jaci.2009.10.013. PMC 2797319. PMID 20004777. 
  5. ^ 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. 
  6. ^ 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. 

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