Common variable immunodeficiency

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Common variable immunodeficiency
Specialty Immunology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Hypogammaglobulinemia, recurrent opportunistic infections, fatigue
Complications Autoimmune manifestations; increased risk of malignancies such as gastric carcinomas, non-Hodgkin lymphoma; lymphocytic infiltration of tissues; nodular regenerative hyperplasia; enteropathy
Usual onsetVaries; median age for symptoms is early 20s for males and mid-20s for females
Duration Lifelong
TypesCVID1, CVID2, CVID3, CVID4, CVID5, CVID6
CausesUncertain; at least 30% have an identified heterogeneous gene mutation and/or inheritance of mutations
Diagnostic method Exclusion of other possible causes of hypogammaglobulinemia
Differential diagnosis Varies by age group
Age <4: leaky SCID, transient hypogammaglobulinemia of infancy, XLP, XLA, hyper-IgM syndromes, myelodysplastic syndromes, Wiskott-Aldrich syndrome, rare combined immune deficiencies, cystic fibrosis, HIV
Age 5-55: loss of immunoglobulin due to renal/gut disease; side effects of medications (particularly anticonvulsants and anti-rheumatics)
Age >56: thymoma, lymphoid malignancies, side effects of medications (particularly anticonvulsants and anti-rheumatics), loss of immunoglobulin due to renal/gut disease [1]
Treatment Immunoglobulin replacement therapy, symptom management
Prognosis Varies by type; recent studies suggest those with only recurrent infections have little or no reduced life expectancy post-diagnosis, while those with disease-related complications have around 50% survival rate 33 years post-diagnosis
FrequencyLess than 1 in 30,000

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. [2] Symptoms generally include high susceptibility to pathogens, chronic lung disease, as well as inflammation and infection of the gastrointestinal tract. [2]

Contents

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. [3] CVID is a lifelong disease.

Signs and complications

The symptoms of CVID vary between those affected. Its main features are hypogammaglobulinemia and recurrent infections. Hypogammaglobulinemia manifests as a significant decrease in the levels of IgG antibodies, usually alongside IgA antibodies; IgM antibody levels are also decreased in about half of those affected. [4]

Infectious complications

People with common variable immunodeficiency have trouble fighting off infections due to the lack of antibodies produced, which normally resist invading microbes. [5] Infections are also the leading cause of morbidity and mortality in CVID patients. Due to impaired antibody development, vaccination is not effective for CVID patients.

The prevalence of bacterial complications (42%) is higher in comparison to viral (25%), parasitic (19%) or fungal (3%). Recurring bacterial infections are generally found in the upper and lower areas of the respiratory tract and in gastrointestinal tract. Many who have a recurring lung infection report developing chronic lung diseases and potentially life-threatening complications later in life. [6]

Common infections include:

The microorganisms that most frequently cause infections in CVID are Haemophilus influenzae , Streptococcus pneumoniae , and Staphylococcus aureus . Pathogens less often isolated from those affected include Neisseria meningitidis , Pseudomonas aeruginosa , respectively Giardia lamblia, Salmonella sp., Campylobacter jejuni for gastrointestinal tract. [7]

Infections mostly affect the respiratory tract (nose, sinuses, bronchi, lungs) and the gastrointestinal tract; they can also occur at other sites, such as the eyes, skin, and ears. These infections respond to antibiotics but can recur upon discontinuation of antibiotics. Bronchiectasis can develop when severe, recurrent pulmonary infections are left untreated.

Gastrovascular infections or inflammation are very common for those with CVID. Signs of a gastrovascular infection include abdominal pain, nausea, bloating, vomiting, diarrhea, and weight loss. Many individuals with CVID have an impaired ability to absorb nutrients, including vitamins, proteins, minerals, fats, and sugar, within the digestive tract. [5]

Autoimmune disorders

CVID is frequently associated with a variety of autoimmune diseases. They could present as the first or the only clinical manifestation of the disease. The reported prevalence of autoimmunity ranged from 14% to 54% in CVID patients and is higher for females. The most common autoimmune disorders observed in CVID are autoimmune cytopenia, idiopathic thrombocytopenic purpura (ITP), AIHA and neutropenia. Furthermore, autoimmune endocrinological (insulin-dependent diabetes, autoimmune thyroiditis), gastrointestinal (anemia, autoimmune enteropathy), dermatological (psoriasis, vitiligo) and rheumatological disorders were described in CVID too. [8]

The reason for such a high prevalence of autoimmunity in CVID individuals is not fully understood. CVID patients with autoimmunity show decreased number of immunosuppressive regulatory T cells (Treg) and impaired selection process of self-reactive antibodies, suggesting the possible mechanism. [8]

Malignancy and CVID

The patients with CVID have a risk 5 to 12 times higher than the general population. The most frequent malignancies are Non-Hodgkin lymphoma (NHL), gastric carcinoma and leukemia. [9]

Enteropathy

There is a wide spectrum of noninfectious gastrointestinal pathology and inflammation in CVID that is a part of the general immune dysregulation affecting patients with CVID.

The most common upper gastrointestinal inflammation is chronic gastritis, which may in rare cases develop to gastric cancer, and duodenal inflammation resembling celiac disease. The inflammation affecting the lower GI tract is heterogenous and often characterized as an unspecific colitis.

Recent studies have suggested a role of gut microbiota in the etiology of CVID, and the reduction of mucosal IgA in CVID enteropathy. The heterogenous group of patients makes it difficult to find common grounds for treatment for the GI inflammation in CVID. [7]

Other complications

Due to changes in B cell development, some individuals with CVID have accumulations of lymphocytes in lymphoid tissues. [10] This can cause mild to severely swollen lymph nodes or inflammation of the spleen.

Lymphocytic infiltration to tissues may cause enlargement of lymph nodes (lymphadenopathy), of the spleen (splenomegaly), and of the liver (hepatomegaly), as well as the formation of granulomas. In the lung, this is known as granulomatous–lymphocytic interstitial lung disease.

Anxiety and depression can occur as a result of dealing with the other symptoms. [11]

CVID patients generally complain of severe fatigue. [12]

Pathogenesis of CVID

Genetic defects

The causative factors of CVID are not fully known. Genetic mutations can be identified as the cause of disease in about 10% of people, while familial inheritance accounts for 10–25% of cases. [13] Rather than arising from a single genetic mutation, CVID seems to result from a variety of mutations that all contribute to a failure in antibody production.

Mutations in the genes encoding ICOS, TACI, CD19, CD20, CD21, CD80, and BAFFR have been identified as causative of CVID. [13] [14] [15] Susceptibility to CVID may also be linked to the major histocompatibility complex (MHC) of the genome, particularly to DR-DQ haplotypes. [16] A mutation in the NFKB2 gene has recently been shown to cause CVID-like symptoms in a murine model. The frequency of this NFKB2 mutation in the CVID population is, however, yet to be established. [17] [18]

The examples of molecular defects in CVID [19] [18]
MoleculeRole in CVID
Surface molecules
TACI B-cell activation defect and autoimmunity
BAFF-R Low peripherial B-cell numbers, decreased antibody responses
CD27 Hypogammaglobulinemia, absent memory B cells
CD19 complex

(CD19,CD81, CD21)

Impaired BCR signaling
IL-21R and IL-21 Impaired germinal center formation, impaired class-switch process and plazma cell differentiation
CTLA-4 Impaired function of Treg cells
ICOSReduced B cell counts and low levels of antibodies
Cytosolic molecules
PKC-deltaDecreased number of memory B cells
PLC-gamma-2Defective BCR signaling
PI3K Impaired B and T cell homeostasis
ZAP70 Impaired T cell function
TLR7 and TLR9 Defects in B cells activation in response to TLRs ligands
Nuclear defects
STAT1 Hypogammaglobulinemia, reduced number of memory and plasma cells
NFKB Impaired B cell maturation, differentiation and class switching

Epigenetic factors

Several recent studies have described a potential role of epigenetics factor (including DNA methylation, chromatin and histone modulation and also non-coding RNAs) in pathogenesis of CVID. [19] [20]

Immune cell abnormalities

There are several abnormalities described in CVID patients connected to the count of particular cell (sub)populations.

The majority of CVID patients have normal B cell counts, suggesting the impaired antibody production is mainly a defect in the differentiation process of B cells into memory and plasma cells.

There are also T cell abnormalities in CVID including counts, percentages, surface markers and function differences. [19]

The examples of possibleimmune cell population changesin CVID [19]
PopulationChange
B cells
Memory B (CD19+CD27+)decreased
Plasma cellsdecreased
Transitional B cellsincreased
CD21low B cellsincreased
T cells
Naive CD4+decreased
Memory CD4+increased
Naive CD8+decreased
Memory CD8+increased

Diagnosis

According to a European registry study, the mean age at onset of symptoms was 26.3 years old. [21] As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if: [22]

Diagnosis is chiefly by exclusion, i.e., alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.

Diagnosis is difficult because of the diversity of phenotypes seen in people with CVID. For example, serum immunoglobulin levels in people with CVID vary greatly. Generally, people can be grouped as follows: no immunoglobulin production, immunoglobulin (Ig) M production only, or both normal IgM and IgG production. [23] Additionally, B cell numbers are also highly variable. 12% of people have no detectable B cells, 12% have reduced B cells, and 54% are within the normal range. [22] In general, people with CVID display higher frequencies of naive B cells and lower frequencies of class-switched memory B cells. Frequencies of other B cell populations, such as IgD memory B cells, transitional B cells, and CD21 B cells, are also affected and are associated with specific disease features. Although CVID is often thought of as a serum immunoglobulin- and B cell-mediated disease, T cells can display abnormal behavior. Affected individuals typically present with low frequencies of CD4+, a T-cell marker, and decreased circulation of regulatory T cells and iNKT cells. Notably, approximately 10% of people display CD4+ T cell counts lower than 200 cells/mm3; this particular phenotype of CVID has been named LOCID (Late Onset Combined Immunodeficiency) and has a poorer prognosis than classical CVID.

Types

The following types of CVID have been identified, and correspond to mutations in different gene segments:

Type OMIM Gene
CVID1 607594 ICOS
CVID2 240500 TACI
CVID3 613493 CD19
CVID4 613494 TNFRSF13C
CVID5 613495 CD20
CVID6 613496 CD81

Treatment

Treatment options are limited and usually include lifelong immunoglobulin replacement therapy. [24] This therapy is thought to help reduce bacterial infections. This treatment alone is not wholly effective, and many people still experience other symptoms such as lung disease and noninfectious inflammatory symptoms. This treatment replenishes Ig subtypes that the person lacks, is given at frequent intervals for life, and is thought to help reduce bacterial infections and boost immune function. [25] Before therapy begins, plasma donations are tested for known blood-borne pathogens, then pooled and processed to obtain concentrated IgG samples. Infusions can be administered in three different forms: intravenously (IVIg), [26] subcutaneously (SCIg), and intramuscularly (IMIg).

The administration of intravenous immunoglobulins requires the insertion of a cannula or needle in a vein, usually in the arms or hands. Because a highly concentrated product is used, IVIg infusions take place every three to four weeks. Subcutaneous infusions slowly release the Ig serum underneath the skin, again through a needle, and take place every week. [27] Intramuscular infusions are no longer widely used, as they can be painful and are more likely to cause reactions.

People often experience adverse side effects from immunoglobulin infusions, including:

In addition to Ig replacement therapy, treatment may also involve immune suppressants to control autoimmune symptoms of the disease and high-dose steroids like corticosteroids. [22] In some cases, antibiotics are used to fight chronic lung disease resulting from CVID. [28] The outlook for people varies greatly depending on their level of lung and other organ damage prior to diagnosis and treatment.

Epidemiology

CVID has an estimated prevalence of about 1:50,000 in Caucasians. [29] The disease seems to be less prevalent among Asians and African Americans. Males and females are equally affected; however, among children, boys predominate. [23] A recent study of people in Europe with primary immunodeficiencies found that 30% had CVID as opposed to a different immunodeficiency. [13] 10–25% of people inherit the disease, typically through autosomal-dominant inheritance. Given the rarity of the disease, it is not yet possible to generalize about its prevalence among ethnic and racial groups. CVID shortens the lifespan, but no study currently has a median age recorded. One study suggests the median age of death for men and women is 42 and 44 years old, respectively, but most patients involved in the study are still alive. [24] Those people with accompanying disorders had the worst prognosis (50% survival 33 years after diagnosis), and those with only CVID-caused frequent infections had the longest survival rates, with another study stating a life expectancy almost equaling that of the general UK population. [1] Additionally, people with CVID with one or more noninfectious complications have an 11 times higher risk of death as compared to people with only infections.

History

Immunodeficiencies comprise many diseases and are genetic defects affecting the immune system. There are roughly 150 immunodeficiencies spanning over 120 genetic defects. [22] Charles Janeway Sr. is generally credited with the first description of a case of CVID in 1953. [30] The case involved a 39-year-old who had recurrent infections, bronchiectasis, and meningitis. [13] CVID has since emerged as the predominant class of primary antibody deficiencies. It is thought to affect between 1 in 25,000 to 1 in 50,000 people worldwide. Though described in 1953, there was no standard definition for CVID until the 1990s, which caused widespread confusion during diagnosis. During the 1990s, the European Society for Immunodeficiency (ESID) and Pan-American Group for Immunodeficiency (PAGID) developed diagnostic criteria for the disease, including the minimum age of diagnosis and the need to exclude other conditions. Since publication in 1999, some criteria have been changed, such as increasing the minimum age of diagnosis.

Research

Current research is aimed at studying large cohorts of people with CVID in an attempt to better understand the age of onset as well as the mechanism, genetic factors, and progression of the disease. [23]

Funding for research in the US is provided by the National Institutes of Health. Key research in the UK was previously funded by the Primary Immunodeficiency Association (PiA) until its closure in January 2012, [31] and funding is raised through the annual Jeans for Genes campaign. Current efforts are aimed at studying the following: [22]

Related Research Articles

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

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.

<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">Selective immunoglobulin A deficiency</span> Medical condition

Selective immunoglobulin A (IgA) deficiency (SIgAD) is a kind of immunodeficiency, a type of hypogammaglobulinemia. People with this deficiency lack immunoglobulin A (IgA), a type of antibody that protects against infections of the mucous membranes lining the mouth, airways, and digestive tract. It is defined as an undetectable serum IgA level in the presence of normal serum levels of IgG and IgM, in persons older than 4 years. It is the most common of the primary antibody deficiencies. Most such persons remain healthy throughout their lives and are never diagnosed.

<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.

<span class="mw-page-title-main">Hyper-IgM syndrome type 5</span> Primary immune deficiency disorder

The fifth type of hyper-IgM syndrome has been characterized in three patients from France and Japan. The symptoms are similar to hyper IgM syndrome type 2, but the AICDA gene is intact.

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">IgG deficiency</span> Form of immune disorder

IgG deficiency is a form of dysgammaglobulinemia where the proportional levels of the IgG isotype are reduced relative to other immunoglobulin isotypes.

<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.

<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">Autoimmune enteropathy</span> Medical condition

Autoimmune enteropathy is a rare autoimmune disorder characterized by weight loss from malabsorption, severe and protracted diarrhea, and autoimmune damage to the intestinal mucosa. Autoimmune enteropathy typically occurs in infants and younger children however, adult cases have been reported in literature. Autoimmune enteropathy was first described by Walker-Smith et al. in 1982.

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

LRBA deficiency is a rare genetic disorder of the immune system. This disorder is caused by a mutation in the gene LRBA. LRBA stands for “lipopolysaccharide (LPS)-responsive and beige-like anchor protein”. This condition is characterized by autoimmunity, lymphoproliferation, and immune deficiency. It was first described by Gabriela Lopez-Herrera from University College London in 2012. Investigators in the laboratory of Dr. Michael Lenardo at National Institute of Allergy and Infectious Diseases, the National Institutes of Health and Dr. Michael Jordan at Cincinnati Children’s Hospital Medical Center later described this condition and therapy in 2015.

Immunoglobulin therapy is the use of a mixture of antibodies to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy, Kawasaki disease, certain cases of HIV/AIDS and measles, Guillain–Barré syndrome, and certain other infections when a more specific immunoglobulin is not available. Depending on the formulation it can be given by injection into muscle, a vein, or under the skin. The effects last a few weeks.

Granulomatous–lymphocytic interstitial lung disease (GLILD) is a lung complication of common variable immunodeficiency disorders (CVID). It is seen in approximately 15% of patients with CVID. It has been defined histologically as the presence of (non-caseating) granuloma and lymphoproliferation in the lung. However, as GLILD is often associated with other auto-immune features such as splenomegaly, adenopathy and cytopenias, a definition based on abnormalities on lung imaging together with evidence of granulomatous inflammation elsewhere has also been employed.

Nuclear factor-kappa B Essential Modulator (NEMO) deficiency syndrome is a rare type of primary immunodeficiency disease that has a highly variable set of symptoms and prognoses. It mainly affects the skin and immune system but has the potential to affect all parts of the body, including the lungs, urinary tract and gastrointestinal tract. It is a monogenetic disease caused by mutation in the IKBKG gene. NEMO is the modulator protein in the IKK inhibitor complex that, when activated, phosphorylates the inhibitor of the NF-κB transcription factors allowing for the translocation of transcription factors into the nucleus.

References

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  19. 1 2 3 4 Yazdani R, Habibi S, Sharifi L, Azizi G, Abolhassani H, Olbrich P, Aghamohammadi A (February 20, 2020). "Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management". Journal of Investigational Allergology and Clinical Immunology. 30 (1): 14–34. doi: 10.18176/jiaci.0388 . PMID   30741636.
  20. ↑ Amato G, Vita F, Quattrocchi P, Minciullo PL, Pioggia G, Gangemi S (October 16, 2020). "Involvement of miR-142 and miR-155 in Non-Infectious Complications of CVID". Molecules. 25 (20): 4760. doi: 10.3390/molecules25204760 . ISSN   1420-3049. PMC   7587593 . PMID   33081305.
  21. ↑ Bonilla FA, Geha RS (2009). "Common Variable Immunodeficiency". Pediatric Research. 65 (5): 13R–19R. doi: 10.1203/pdr.0b013e31819dbf88 . PMID   19190529. S2CID   9361175.
  22. 1 2 3 4 5 Chapel H, Cunningham-Rundles C (2009). "Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions". British Journal of Haematology. 145 (6): 709–727. doi:10.1111/j.1365-2141.2009.07669.x. PMC   2718064 . PMID   19344423.
  23. 1 2 3 Abbott JK, Gelfand EW (2015). "Common Variable Immunodeficiency: Diagnosis, Management, and Treatment". Immunol Allergy Clin N Am. 35 (4): 637–658. doi:10.1016/j.iac.2015.07.009. PMID   26454311.
  24. 1 2 Resnick ES, Cunningham-Rundles C (2012). "The many faces of the clinical picture of common variable immune deficiency". Current Opinion in Allergy and Clinical Immunology. 12 (6): 595–601. doi:10.1097/aci.0b013e32835914b9. PMID   23026770. S2CID   205435779.
  25. ↑ "Primary immunodeficiency". Mayo Clinic. Retrieved February 17, 2016.
  26. ↑ Pourpak Z, Aghamohammadi A, Sedighipour L, et al. (2006). "Effect of regular intravenous immunoglobulin therapy on prevention of pneumonia in patients with common variable immunodeficiency". J Microbiol Immunol Infect. 39 (2): 114–20. PMID   16604243. Archived from the original (abstract) on September 29, 2008. Retrieved March 1, 2008.
  27. ↑ Schwartz RA, Modak R, Modak P. "Common Variable Immunodeficiency Treatment and Management". Medscape. Retrieved February 17, 2016.
  28. ↑ "Common Variable Immune Deficiency". Immune Deficiency Foundation. Retrieved February 16, 2016.
  29. ↑ Common Variable Immunodeficiency : Article by Robert A Schwartz at eMedicine
  30. ↑ Janeway CA, Apt L, Gitlin D (1953). "Agammaglobulinemia". Trans Assoc Am Physicians. 66: 200–2. PMID   13136263.
  31. ↑ "Archived copy". Archived from the original on September 13, 2012. Retrieved October 26, 2012.{{cite web}}: CS1 maint: archived copy as title (link)
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