Primary immunodeficiency

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.

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).

Other tests are performed depending on the suspected disorder:

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

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.

Conditions

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.

Table I: Combined T and B–cell immunodeficiencies

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).

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
20. Activated PI3K Delta Syndrome
21. MALT1 deficiency
22. BCL10 deficiency
23. CARD11 deficiency

Table II: Predominantly antibody deficiencies

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.

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 subclass 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

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

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

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

1. Immunodeficiency with hypopigmentation or albinism: Chédiak–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

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.

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

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.

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

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).

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

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.

1. C1q deficiency (lupus-like syndrome, rheumatoid disease, infections)
2. C1r deficiency (idem)
3. C1s deficiency
4. C4 deficiency (lupus-like syndrome)
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

Table IX. Phenocopies of primary immune deficiencies

These are a few specialized autoimmune disorders resulting from environmental rather than genetic causes, which mimic the genotypic disorders.

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.

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. 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.

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.