Inborn errors of immunity

Last updated
Inborn errors of immunity
Specialty Clinical immunologist
Usual onsetNewborns, children, and, uncommonly, adults
CausesDefects in specific genes
Diagnostic method Genetic testing
Prognosis Variable
FrequencyRare but becoming much more common

Inborn errors of immunity (IEI) are a heterogenous group of disorders in which a mutation in any one of various genes that regulate the immune system causes increases in the susceptibility of individuals to develop a dysfunction in their immune system. [1] [2] (As used here, mutations include deletions or other changes in any part of a gene that causes it to be dysfunctional.) Depending on the gene involved, this dysfunction may induce the development of an: a) autoinflammatory disease by causing a malfunction in the innate immune system; b) autoimmune disease by causing a malfunction in the adaptive immune system; [3] c) viral, bacterial, fungal, or mycobacterial infection by causing a malfunction in one of the various components of the immune system that combat these pathogens; [3] [4] d) allergic disease by causing a hypersensitive immune system that overreacts to otherwise harmless substances; e) lose of one or more types of circulating blood cells by causing a failure of the bone marrow to produce the circulating blood cell type(s); f) hematological cancers by causing a mutation in any one of various oncogenes (i.e., genes with the potential to cause a cancer); g) non-hematological cancers as well as hematological cancers by causing a mutation in the ATM serine/threonine kinase gene (these cancers are mainly pancreatic cancer, prostate cancer, stomach cancer and invasive ductal carcinoma of the breast; [5] see cancers in ATM serine/threonine kinase gene defects); [3] [6] [7] and h) non-malignant lymphoproliferative disorders by causing the excessive proliferation of T-cell or B-cell lymphocytes in the lymph nodes, gastrointestinal tract, liver, skin, or more than one of these organs. [8]

Contents

A human immune disease that would later be classified as an IEI was first defined by Ogden Bruton. In the early 1950s, he examined an 8-year-old boy who had 19 episodes of pneumonia over a period of 4 years. Expecting that individuals with such a history of repeated infections would have high levels of infection-fighting antibodies in their serum, Dr. Bruton was surprised to find that the boy had hypogammaglobulinemia, i.e., his serum lacked detectible levels of circulating antibodies which attack infection-causing microorganisms and virus. [9] [10] That same year, Dr. Bruton and colleagues published on two other infection-prone patients who also lacked detectable levels of these serum antibodies [10] [11] This particular from of hypogammaglobulinemia, now termed X-linked agammaglobulinemia and characterized as an IEI, occurs in about 1 per 379,000 live births. [12] [13] It is also termed Bruton's agammaglobulinemia and the gene that when mutated causes this disease is termed the Bruton's tyrosine kinase , i.e., BKT, gene. The product of this gene, the BTK protein, contributes indirectly to promoting the production of all the antibody subtypes, i.e., IgG, IgA, IgM, and IgE. [14]

Impairments in the immune system's protective actions have been referred to as primary immunodeficiencies (PID), i.e., immune deficiencies that are present at birth and not caused by secondary factors such as other diseases or exposure to genotoxic agents. [15] The PID disorders (see List of primary immunodeficiencies) and its subgroup, the primary immune regulatory disorders (PIRDs; i.e., disorders of immunity characterized as excessive proliferations of lymphocytes and the development of immune responses against one's own normal tissues [16] ), are immune disorders similar to those in IEI. [2] [17] Finally, inborn errors of metabolism (i.e., IEM) are a group of about 1700 disorders caused by a mutation in any one of about 1500 genes that causes a defect in a pathway that metabolizes proteins, fats, or carbohydrates or that impairs the function of a subcellular organelle. This mutation usually causes a complicated medical condition involving several human organ systems. [18] [19] When any one of the disorders in the PID, PIRDs, or IEM classifications is caused by a single gene mutation that disrupts the immune system, it is termed an IEI. Consequently, many IEIs are also termed a PID, PIRDs, and/or IEM. [2] [17] [18] [19]

In 1973, the World Health Organization (WHO) established the Inborn Errors of Immunity Committee for the purpose of classifying and identifying immune defects in humans. The committee focused on rare immune diseases. In the 1990s, the WHO decided to focus on more common diseases, and the committee was taken on by the International Union of Immunological Societies (i.e., IUIS). This relationship was made official in 2008. [20] The number of genes that when mutated to cause specific IEI disorders has steadily rose from less than 10 in the 1980s [21] to the IUIS expert committee's 2022 classification of 485 mutated genes causing these disorders. [22] These numbers are expected to increase further as DNA sequencing using automated methods (e.g., massive parallel sequencing), further studies of less severe immune disorders, and analyses of multiple tissues in individuals that may have carry the dysfunctional gene in some but not their tissues (see mosaicism). Thus, the prevalence of IEIs in 2023 was estimated to be between 1 in 1,000 and 1 in 5,000 individuals but this may be an underestimate: its true prevalence may turn out to be as high as 1 in 500 individuals. [2] [23] [24]

Expression of IEI genes

As with other human genes, an IEI gene may be defective because it is not expressed (see gene expression), is under expressed, is overexpressed, or directs the formation of a product with reduced, increased, or no activity. Furthermore, the defective IEI gene in parents may not be expressed in their offspring depending on the IEI gene's dominant or recessive activity or may not be present in offspring depending on its location in the X chromosome, Y chromosome, or one of 46 remaining non-sex chromosomes (termed autosomes; see sex linkage). [1] [25] Individuals who do inherit an IEI gene may still not exhibit symptoms because: a) the gene is under expressed (termed reduced penetrrance) or not expressed (termed non-penetrance) in males or females (these different expression patterns are also termed gender-related penetrance), b) the presence of other genes which modify the activity of the inherited IEI gene (termed genetic modifiers), c) exposure to environmental factors with modify the activity of the inherited IEI gene (termed environmental modifiers), and/or d) epigenetic, i.e., caused by factors which regulate the expression of the IEI gene without changing this gene's nucleic acid sequence (termed epigenetic regulation). Mosaicism, i.e., an IEI mutation arising after fertilization of an egg, has been shown to lead to offsspring with two different cell populations, one with and one without the IEI gene. Individuals with this mosaicism may develop a mild IEI disorder, an IEI disorder much later in life, or no IEI disorder. [23]

International Union of Immunological Societies classification of IEI

The International Union of Immunological Societies (2022) has classified IEI disorders into the following 10 categories: [22] [24]

1). Cellular and hormonal immunodeficiencies consisting of 66 defective genes causing 58 different diseases. These diseases include severe combined immunodeficiency diseases that are associated with low levels of CD3 protein-expressing T cells plus low levels of T-cell receptor excision circles (low levels of the circles indicate that the T cells have not matured); less severe forms of the combined immunodeficiencies are also included in this category.
2). Combined immunodeficiencies with associated or syndromic features consisting of 69 defective genes causing 68 diseases. These diseases are a set of signs and symptoms characteristic of a particular immune disorder and tend to occur together in people with the same disorder. These disorders include combined immunodeficiencies of T cells and B cells (i.e., gene defects that alter the development and function of the immune system).
3). Predominantly antibody disorders consisting of 45 defective genes causing 51 diseases. These antibody disorders include hypogammaglobulinemia, i.e., reductions in one or more of the four antibody classes, and other types of antibody deficiencies.
4). Diseases of immune dysregulation consisting of 52 defective genes causing 51 diseases. These diseases include hemophagocytic lymphohistiocytosis and defects that cause an increases in the susceptibility of individuals to develop Epstein–Barr virus-induced immunity disorders. (About 50% of all five-year-old children and 90% of adults have evidence of previous infection with this virus; [26] see Epstein–Barr virus–associated lymphoproliferative diseases).
5). Congenital defects of phagocyte number or function consisting of 42 gene defects causing 35 diseases. These diseases include neutropenia not caused by antibodies directed against neutrophils and functional defects in phagocyte function.
6). Defects in intrinsic and innate immunity consisting of 74 gene defects causing 63 diseases. These diseases include a predisposition to develop bacterial, fungal, parasite and/or viral infections.
7). Autoinflammatory disorders consisting of 56 defective genes causing 59 diseases. These diseases include various types of autoinflammatory diseases, e.g., familial Mediterranean fever and Blau syndrome.
8). Complement deficiencies consisting of 36 defective genes causing 30 diseases. These diseases involve decreases in the levels of a component protein in the complement system (i.e., a system of proteins the increases the ability of antibodies and phagocytic cells to clear infecting microbes) and thereby increases an individual susceptibility to acquire Neisseria and pus-forming bacterial infections.
9). Bone marrow failure disorders consisting of 44 defective genes that cause 43 cases of Bone marrow failure. These disorders are losses in the levels of circulating red blood cells, white blood cells, and/or platelets due to the failure of the bone marrow to produce sufficient level of one or more of these cells.
10). Phenocopies of inborn errors of immunity consisting of 15 genes that cause 15 cases of various primary immunodeficiency diseases (i.e., PID) such as the chronic mucocutaneous candidiasis and the VEXAS syndrome. These phenocopy cases are due to somatic mutations that occur after fertilization of an ovum, i.e., they are mosaicism in which individuals developing from these post-fertilized ova have cells that do and do not have the altered gene that is responsible for a immune disorder. Depending on the amount and type of cells that express the dysfunctional gene, individuals may not develop the disorder or develop it in varying degrees of severity and/or develop it at a later age than individuals that have the dysfunctional gene in all cells. Usually, individuals with this mosaicism do not pass the defective gene to their offspring.

See also

Related Research Articles

<span class="mw-page-title-main">Severe combined immunodeficiency</span> Genetic disorder leading to severe impairment of the immune system

Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in differing clinical presentations. SCID involves defective antibody response due to either direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells. Consequently, both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is the most severe form of primary immunodeficiencies, and there are now at least nine different known genes in which mutations lead to a form of SCID. It is also known as the bubble boy disease and bubble baby disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, have become famous for living in a sterile environment. SCID is the result of an immune system so highly compromised that it is considered almost absent.

<span class="mw-page-title-main">Eosinophilia</span> Excess number of eosinophil cells in the blood

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.

<span class="mw-page-title-main">Wiskott–Aldrich syndrome</span> Medical condition

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. 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 the same gene.

<span class="mw-page-title-main">X-linked agammaglobulinemia</span> Medical condition

X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies, which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.

Hypogammaglobulinemia is an immune system disorder in which not enough gamma globulins are produced in the blood. This results in a lower antibody count, which impairs the immune system, increasing risk of infection. Hypogammaglobulinemia may result from a variety of primary genetic immune system defects, such as common variable immunodeficiency, or it may be caused by secondary effects such as medication, blood cancer, or poor nutrition, or loss of gamma globulins in urine, as in nonselective glomerular proteinuria. Patients with hypogammaglobulinemia have reduced immune function; important considerations include avoiding use of live vaccines, and take precautionary measures when traveling to regions with endemic disease or poor sanitation such as receiving immunizations, taking antibiotics abroad, drinking only safe or boiled water, arranging appropriate medical cover in advance of travel, and ensuring continuation of any immunoglobulin infusions needed.

Common variable immunodeficiency (CVID) is an inborn immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM, and IgA. Symptoms generally include high susceptibility to pathogens, chronic lung disease, as well as inflammation and infection of the gastrointestinal tract.

<span class="mw-page-title-main">Nijmegen breakage syndrome</span> Medical condition

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA.

<span class="mw-page-title-main">X-linked severe combined immunodeficiency</span> Medical condition

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

<span class="mw-page-title-main">Bruton's tyrosine kinase</span> Kinase that plays a role in B cell development

Bruton's tyrosine kinase, also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.

<span class="mw-page-title-main">Hyper IgM syndrome</span> Primary immune deficiency disorders

Hyper IgM syndrome is a rare primary immune deficiency disorders characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM.

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 immune deficiency must be inborn, not caused by secondary factors such as 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 430 recognized inborn errors of immunity (IEIs) as of 2019, the vast majority of which are PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, auto-inflammatory 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.

An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:

<span class="mw-page-title-main">Deoxyribonuclease gamma</span> Protein-coding gene in the species Homo sapiens

Deoxyribonuclease gamma is an enzyme that in humans is encoded by the DNASE1L3 gene. This gene's is located on chromosome 3's "p arm", i.e., short arm, between region 1, band 4, sub-band 3 and region 2, band 1, sub-band 1

<span class="mw-page-title-main">Humoral immune deficiency</span> Medical condition

Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. The most common such immunodeficiency is inherited selective IgA deficiency, occurring between 1 in 100 and 1 in 1000 persons, depending on population. They are associated with increased vulnerability to infection, but can be difficult to detect in the absence of infection.

<span class="mw-page-title-main">Hyper-IgM syndrome type 3</span> Primary immune deficiency disorder

Hyper-IgM syndrome type 3 is a form of hyper IgM syndrome characterized by mutations of the CD40 gene. In this type, Immature B cells cannot receive signal 2 from helper T cells which is necessary to mature into mature B cells.

<span class="mw-page-title-main">Hyper-IgM syndrome type 4</span> Medical condition

Hyper-IgM syndrome type 4 is a form of Hyper IgM syndrome which is a defect in class switch recombination downstream of the AICDA gene that does not impair somatic hypermutation.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disease. It is a primary immunodeficiency featured by molecular defects in IL12/IFNγ dependent signalling pathway, leading to increased susceptibility to local or disseminated infections by environmental mycobacteria, Mycobacterium bovis Bacille Calmette-Guerin strain, nontyphoidal and typhoidal Salmonella serotypes.

An innate immune defect is a defect in the innate immune response that blunts the response to infection. These defects may occur in monocytes, neutrophils, natural killer cells, basophils, mast cells or complement proteins.

References

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