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. [1] 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. [2] [3] [4] About 1 in 500 people in the United States are born with a primary immunodeficiency. [5] 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.

Contents

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. [5]

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.

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). [6] [5]

Other tests are performed depending on the suspected disorder: [5] [6]

Due to the rarity of many primary immunodeficiencies, many of the above tests are highly specialised and tend to be performed in research laboratories. [5]

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. [7]

Classifications

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. [8] [9] As of 2019, there are approximately 430 forms of PID that have been identified. [4]

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. [10]

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, [11]

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. Antibiotic prophylaxis is also commonly used to prevent respiratory tract infections in these patients. [12]

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

For primary immunodeficiencies that are caused by genetic mutation does not exist a causal therapy that would "repair" the mutation. Although there is a therapeutic option, gene therapy which has been in a trial for few immune deficiencies affecting the hematopoietic system. Over the past two decades there were some successful treatments of patients with specific primary immunodeficiencies (PID), including X-linked severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome and metabolic conditions such as leukodystrophy. [13]

Gene therapy evolved in the 90s from using of gammaretroviral vectors to more specific self-inactivating vector platforms around 2006. [14] The viral vectors randomly insert their sequences into the genomes. However, it is rarely used because of a risk of developing post-treatment T-cell leukemia as a result of interfering tumor-suppressor genes [14] and because of ethical issues. [15] But the progress in gene therapy is promising for the future of treating primary immunodeficiencies. [11]

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. [16]

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. [5]

Research

Bone marrow transplant may be possible for Severe Combined Immune Deficiency and other severe immunodeficiences. [17]

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. [18] 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.

Induced pluripotent stem cells obtained reprogramming patients' cells, for example leukocytes, are a promising tool to study these pathologies and develop personalized therapies. [19]

History

X-linked agammaglobulinemia was one of the first described primary immunodeficiencies, discovered by Ogden Bruton in 1952. [4] [20] 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. [21]

Discovery of novel genetic causes of innate immunodeficiencies accelerated greatly in the 2010s due to high-throughput DNA sequencing technologies. [22] As of 2019, more than 430 have been categorized. [4]

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.

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 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 foreign invaders, chronic lung disease, and inflammation and infection of the gastrointestinal tract. CVID affects males and females equally. The condition can be found in children or teens but is generally not diagnosed or recognized until adulthood. The average age of diagnosis is between 20 and 50. However, symptoms vary greatly between people. "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent bacterial infections, increased risk for autoimmune disease and lymphoma, as well as gastrointestinal disease. CVID is a lifelong disease.

<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">Combined immunodeficiencies</span> Medical condition

Combined immune deficiencies (CIDs) are a diverse group of inherited immune disorders characterized by impaired T lymphocyte development, function, or both, with variable B cell defects. The primary clinical manifestation of CID is infection susceptibility. Clinical manifestations of combined immunodeficiencies vary greatly, ranging from diarrhea and sinus infections to opportunistic infections caused by mycobacteria, fungi, and vaccination reactions resulting in localized to systemic symptoms.

Bare lymphocyte syndrome is a condition caused by mutations in certain genes of the major histocompatibility complex or involved with the processing and presentation of MHC molecules. It is a form of severe combined immunodeficiency.

<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.

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">Isolated primary immunoglobulin M deficiency</span> Medical condition

Isolated primary immunoglobulin M deficiency is a poorly defined dysgammaglobulinemia characterized by decreased levels of IgM while levels of other immunoglobulins are normal. The immunodeficiency has been associated with some clinical disorders including recurrent infections, atopy, Bloom's syndrome, celiac disease, systemic lupus erythematosus and malignancy, but, surprisingly, SIgMD seems to also occur in asymptomatic individuals. High incidences of recurrent upper respiratory tract infections (77%), asthma (47%) and allergic rhinitis (36%) have also been reported. SIgMD seems to be a particularly rare antibody deficiency with a reported prevalence between 0.03% and 0.1%.

<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.

Thymoma with immunodeficiency is a rare disorder that occurs in adults in whom hypogammaglobulinemia, deficient cell-mediated immunity, and thymoma may develop almost simultaneously. Most reported cases are in Europe, though it occurs globally.

<span class="mw-page-title-main">T cell deficiency</span> Medical condition

T cell deficiency is a deficiency of T cells, caused by decreased function of individual T cells, it causes an immunodeficiency of cell-mediated immunity. T cells normal function is to help with the human body's immunity, they are one of the two primary types of lymphocytes(the other being B cells).

<span class="mw-page-title-main">Reticular dysgenesis</span> Medical condition

Reticular dysgenesis (RD) is a rare, inherited autosomal recessive disease that results in immunodeficiency. Individuals with RD have mutations in both copies of the AK2 gene. Mutations in this gene lead to absence of AK2 protein. AK2 protein allows hematopoietic stem cells to differentiate and proliferate. Hematopoietic stem cells give rise to blood cells.

<span class="mw-page-title-main">XMEN disease</span> Medical condition

XMEN disease is a rare genetic disorder of the immune system that illustrates the role of glycosylation in the function of the immune system. XMEN stands for “X-linked MAGT1 deficiency with increased susceptibility to Epstein–Barr virus (EBV) infection and N-linked glycosylation defect.” The disease is characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Investigators in the laboratory of Dr. Michael Lenardo, National Institute of Allergy and Infectious Diseases at the National Institutes of Health first described this condition in 2011.

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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  2. ↑ Casanova JL, Abel L (January 2021). "Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories". Annual Review of Pathology. 16: 23–50. doi:10.1146/annurev-pathol-031920-101429. PMC   7923385 . PMID   32289233.
  3. ↑ Notarangelo LD, Bacchetta R, Casanova JL, Su HC (July 2020). "Human inborn errors of immunity: An expanding universe". Science Immunology. 5 (49): eabb1662. doi:10.1126/sciimmunol.abb1662. PMC   7647049 . PMID   32651211.
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  5. 1 2 3 4 5 6 Lim MS, Elenitoba-Johnson KS (May 2004). "The molecular pathology of primary immunodeficiencies". The Journal of Molecular Diagnostics. 6 (2): 59–83. doi:10.1016/S1525-1578(10)60493-X. PMC   1867474 . PMID   15096561.
  6. 1 2 Grammatikos A, Bright P, Bhatnagar R, Johnston S (September 2020). "How to investigate a suspected immune deficiency in adults". Respiratory Medicine. 171: 106100. doi: 10.1016/j.rmed.2020.106100 . PMID   32799060. S2CID   221143773.
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  12. ↑ Grammatikos A, Albur M, Gompels M, Barnaby CL, Allan S, Johnston S (October 2020). "Antibiotic prophylaxis for the prevention of respiratory tract infections in antibody deficient patients: A retrospective cohort study". Clinical Infection in Practice. 7–8: 100048. doi: 10.1016/j.clinpr.2020.100048 . S2CID   228965989.
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  14. 1 2 Cavazzana M, Six E, Lagresle-Peyrou C, André-Schmutz I, Hacein-Bey-Abina S (February 2016). "Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?". Human Gene Therapy. 27 (2): 108–116. doi:10.1089/hum.2015.137. PMC   4779287 . PMID   26790362.
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  20. ↑ Bruton OC (June 1952). "Agammaglobulinemia". Pediatrics. 9 (6): 722–728. doi:10.1542/peds.9.6.722. PMID   14929630. S2CID   245180200.
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  22. ↑ Bucciol G, Moens L, Bosch B, Bossuyt X, Casanova JL, Puel A, Meyts I (February 2019). "Lessons learned from the study of human inborn errors of innate immunity". The Journal of Allergy and Clinical Immunology. 143 (2): 507–527. doi:10.1016/j.jaci.2018.07.013. PMC   6358521 . PMID   30075154.
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